A PHASE 3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLINDED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF A CLOSTRIDIUM DIFFICILE VACCINE IN ADULTS 50 YEARS OF AGE AND OLDER
Phase: PHASE3
Conditions: Clostridium Difficile Infection
Sponsor: Pfizer

PF-06425090 (Clostridium difficile Vaccine)
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Final Protocol Amendment 4, 28 Sept. 2020
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A PHASE 3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLINDED 
STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF A 
CLOSTRIDIUM DIFFICILE VACCINE IN ADULTS 50 YEARS OF AGE AND 
OLDER
Investigational Product Number:
PF-06425090
Investigational Product Name:
Clostridium difficile Vaccine
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2016-003866-14
Protocol Number:
B5091007
Phase:
3
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information 
in confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version Date
Summary of Changes
Original protocol
28 October 2016
Not applicable (N/A)
Protocol amendment 1
26 January 2017
Following regulatory 
consultation:
•
Rationalized objectives and 
endpoints.
•
Clarified case definitions.
•
Revised permissible timing 
for administration of 
nonadjuvanted seasonal or 
pandemic influenza vaccine.
•
Added a Month 12 
telephone contact for 
collection of serious adverse 
events.
•
Changed description of 
diagnostic methodology for 
detection of toxin.
•
Added safety reporting 
requirements for studies 
employing medical devices.
•
Updated statistical 
methodology to reflect 
changes in objectives and 
endpoints.
•
Made minor editorial 
updates.
Protocol amendment 2
03 January 2019
In order to control overall Type 
I error and Type I error for the 
evaluation of the secondary 
objectives:
•
Revised secondary
 
 objectives and 
endpoints.
Following blinded case count 
review:
•
Revised sample size.
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Additionally:

Refined the parameters
collected for and included in
the healthcare resource 
utilization score.

Defined the mITT-1 
population.

Included analyses of the 
primary endpoints for the 
m-ITT populations for cases 
occurring 14 days after the 
second and third doses.

Made editorial updates to 
the Data Analysis/Statistical 
Methods section.

Incorporated a protocol 
administrative change to the 
medical device complaint 
reporting procedure.

Incorporated a protocol 
administrative change to 
clarify that Visit 6 can be 
conducted in person.

Incorporated France- and 
Japan-specific appendices.
Protocol Amendment 3
06 January 2020

Added the annual retention 
visit.

Added the requirement to 
reconsent subjects at the
additional visit.

Extended the study duration.
Protocol Amendment 4
28 Sept. 2020

Added the definition of an 
outpatient visit to inclusion 
criterion 4.

Clarified systemic antibiotic 
use for the purposes of 
inclusion criterion 4.

Added a reminder every 2 
weeks for all subjects to 
collect a stool sample should 
a diarrheal episode occur.

Clarified the requirement to
capture major protocol 
deviations.

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
Clarified that if an SAE is 
reported after subject Visit 
6, all the requirements will 
apply, including the respect 
of the reporting timelines as 
if the SAE occurred within 
the reporting period.

Adjusted the assumption for 
vaccine efficacy and the 
total cases required for the 
study, introduced 
2 additional interim 
analyses, and updated the 
statistical design operating 
characteristics accordingly.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).  

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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
LIST OF FIGURES ...................................................................................................................9
APPENDICES ...........................................................................................................................9
PROTOCOL SUMMARY.......................................................................................................11
SCHEDULE OF ACTIVITIES................................................................................................14
1. INTRODUCTION ...............................................................................................................17
1.1. Mechanism of Action/Indication.............................................................................17
1.2. Background and Rationale ......................................................................................17
1.2.1. Clostridium difficile Disease Background..................................................17
1.2.2. Clostridium difficile Vaccine Development Rationale...............................18
1.2.3. Clostridium difficile Vaccine Candidate.....................................................19
1.2.3.1. Nonclinical Development..........................................................19
1.2.3.2. Clinical Development................................................................19
1.2.3.3. Summary of Benefit-Risk Assessment......................................21
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................22
2.1. CDI Case Definitions ..............................................................................................26
2.1.1. Definition 1 – Primary Episode..................................................................26
2.1.2. Definition 2 – Recurrent Episode ...............................................................26
2.1.3. Definition 3 – Primary Episode Diagnosed Locally...................................26
2.1.4. Definition 4 – Recurrent Episode Diagnosed Locally................................27
3. STUDY DESIGN.................................................................................................................27
3.1. Approximate Number of Subjects...........................................................................27
3.2. Approximate Duration of the Study........................................................................28
3.3. Approximate Duration of Subject Participation......................................................28
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................28
4.1. Inclusion Criteria.....................................................................................................29
4.2. Exclusion Criteria....................................................................................................30
4.3. Criteria for Temporarily Delaying Vaccine Administration...................................31
4.4. Lifestyle Requirements ...........................................................................................32
4.4.1. Contraception..............................................................................................32

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4.5. Sponsor’s Qualified Medical Personnel..................................................................33
5. INVESTIGATIONAL PRODUCTS ...................................................................................33
5.1. Allocation to Investigational Product......................................................................33
5.2. Blinding of Site Personnel.......................................................................................34
5.3. Blinding of the Sponsor...........................................................................................34
5.4. Breaking the Blind ..................................................................................................34
5.5. Subject Compliance.................................................................................................34
5.6. Vaccine Supplies.....................................................................................................35
5.6.1. Formulation and Packaging........................................................................35
5.6.1.1. Clostridium difficile Vaccine ....................................................35
5.6.1.2. Placebo ......................................................................................35
5.6.2. Preparation and Dispensing ........................................................................35
5.6.3. Administration............................................................................................35
5.7. Investigational Product Storage ..............................................................................36
5.8. Investigational Product Accountability...................................................................37
5.8.1. Destruction of Investigational Product Supplies ........................................37
5.9. Concomitant Medication(s).....................................................................................37
5.9.1. Recording Concomitant Vaccinations and Medications.............................37
5.9.2. Prohibited Concomitant Vaccinations and Medications.............................38
5.9.3. Permitted Concomitant Medications ..........................................................38
6. STUDY PROCEDURES .....................................................................................................38
6.1. Study Period ............................................................................................................38
6.1.1. Visit 1: Month 0 – Vaccination 1 ...............................................................39
6.1.2. Visit 2: Month 1 – Vaccination 2 (28 to 42 Days After Visit 1) ................41
6.1.3. Visit 3: Month 2 (28 to 42 Days After Visit 2)...........................................42
6.1.4. Visit 4: Month 6 – Vaccination 3 (140 to 168 Days After Visit 2) ............43
6.1.5. Visit 5: Month 7 (28 to 42 Days After Visit 4)...........................................45
6.1.6. Visit 6: Month 12 (165 to 195 Days After Visit 4).....................................46
6.1.7. Annual Retention Visits (Every 280 to 392 Days After Visit 5)................46
6.1.8. Visit 7: End of Study ..................................................................................47
6.1.9. At the Time of a Potential CDI Case (Follow-up Related to Each 
Diarrheal Episode) ...........................................................................................47

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6.1.10. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction............48
6.2. Subject Withdrawal.................................................................................................49
6.2.1. Major Protocol Violations ..........................................................................49
6.3. Stool Sample Collection..........................................................................................50
6.4. Subject Communication and Use of Technology....................................................50
7. ASSESSMENTS..................................................................................................................51
7.1. Efficacy Assessments..............................................................................................51
7.1.1. Central Laboratory Testing for Clostridium difficile..................................51
7.1.1.1. Detection of Toxigenic Clostridium difficile by PCR...............52
7.1.1.2. Detection of Free Toxins in the Stool Sample ..........................52
7.1.2. Diagnosis of Pseudomembranous Colitis...................................................52
7.2. Safety Assessments .................................................................................................52
7.2.1. Electronic Diary..........................................................................................53
7.2.1.1. Grading Scales...........................................................................53
7.2.1.2. Local Reactions.........................................................................53
7.2.1.3. Systemic Events ........................................................................54
7.2.1.4. Fever..........................................................................................55
7.4. Other Assessments ..................................................................................................56
7.5. Pregnancy Testing...................................................................................................56
8. ADVERSE EVENT REPORTING......................................................................................57
8.1. Requirements...........................................................................................................57
8.1.1. Additional Details on Recording Adverse Events on the CRF...................58
8.1.2. Eliciting Adverse Event Information..........................................................58
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................58
8.1.4. Time Period for Collecting AE/SAE Information......................................59
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................59
8.1.4.2. Recording Nonserious AEs and SAEs on the CRF...................59
8.1.5. Causality Assessment .................................................................................59
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................60
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8.2. Definitions...............................................................................................................60
8.2.1. Adverse Events...........................................................................................60
8.2.2. Abnormal Test Findings .............................................................................61
8.2.3. Serious Adverse Events ..............................................................................61
8.2.4. Hospitalization............................................................................................62
8.3. Severity Assessment................................................................................................64
8.4. Special Situations ....................................................................................................64
8.4.1. Protocol-Specified Serious Adverse Events...............................................64
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................64
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................66
8.4.3.1. Exposure During Pregnancy......................................................66
8.4.3.2. Exposure During Breastfeeding ................................................67
8.4.3.3. Occupational Exposure .............................................................67
8.4.4. Medication Errors .......................................................................................68
8.4.4.1. Medication Errors......................................................................68
8.5. Medical Device Complaint Reporting Requirements .............................................69
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................69
9.1. Sample Size Determination.....................................................................................69
9.2. Efficacy Analysis ....................................................................................................71
9.2.1. Analysis of the Primary Endpoints.............................................................71
9.2.1.1. Multiplicity Control for the Primary Endpoints........................73
9.2.2. Analysis of the Secondary Endpoints.........................................................73
9.2.2.1. Analysis of the Secondary Efficacy Endpoints.........................73
9.4. Safety Analysis........................................................................................................74
9.4.1. Reactogenicity ............................................................................................75
9.5. Interim Analysis ......................................................................................................75
9.6. Data Monitoring Committee ...................................................................................78
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................78
11. DATA HANDLING AND RECORD KEEPING .............................................................79
11.1. Case Report Forms/Electronic Data Record .........................................................79
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11.2. Record Retention...................................................................................................80
12. ETHICS..............................................................................................................................80
12.1. Institutional Review Board/Ethics Committee......................................................80
12.2. Ethical Conduct of the Study ................................................................................80
12.3. Subject Information and Consent..........................................................................80
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................81
13. DEFINITION OF END OF TRIAL...................................................................................81
13.1. End of Trial in a Member State.............................................................................81
13.2. End of Trial in All Other Participating Countries.................................................81
14. SPONSOR DISCONTINUATION CRITERIA ................................................................82
15. PUBLICATION OF STUDY RESULTS..........................................................................82
15.1. Communication of Results by Pfizer ....................................................................82
15.2. Publications by Investigators ................................................................................83
16. REFERENCES ..................................................................................................................84
LIST OF TABLES
Table 1.
Intended Numbers of Subjects Included in the Study, by Age.................27
Table 2.
Cepheid Xpert C. difficile/Epi Results......................................................52
Table 3.
Local Reaction Grading Scale ..................................................................54
Table 4.
Systemic Event Grading Scale..................................................................54
Table 5.
Scale for Fever..........................................................................................55
Table 6.
Statistical Analysis Specifications for the Primary Endpoints .................72
Table 7.
Statistical Design Operating Characteristics ............................................77
LIST OF FIGURES
Figure 1.
Two-Step Testing Algorithm for Determination of Clostridium 
difficile Infection Case Definition ............................................................51
APPENDICES
Appendix 1. Abbreviations......................................................................................................90
Appendix 2. Bristol Stool Chart...............................................................................................92

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Appendix 3. France Appendix.................................................................................................93
Appendix 4. Japan Appendix...................................................................................................94

PF-06425090 (Clostridium difficile Vaccine)
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Final Protocol Amendment 4, 28 Sept. 2020
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PROTOCOL SUMMARY
Indication
Pfizer’s investigational Clostridium difficile vaccine (PF-06425090) is a prophylactic vaccine 
that is currently being investigated for the prevention of primary C difficile infection (CDI) in 
adults 50 years of age and older.
Objectives and Endpoints
Primary Efficacy Objective(s):
Primary Efficacy Endpoint(s):

To demonstrate that Pfizer’s C difficile vaccine is 
effective in reducing the incidence of a first primary 
episode of CDI (see case definition 1).a

CDI incidence per 1000 person-years of follow-up, 
assessed during up to 2 time periods (each analysis 
will be performed only if the preceding one was 
successful):

After receipt of the third dose of investigational 
product onwards.

After receipt of the second dose of 
investigational product onwards.
Primary Safety Objective(s):
Primary Safety Endpoint(s):

To evaluate the safety profile of Pfizer’s C difficile
vaccine as measured by the percentage of subjects 
reporting local reactions and systemic events, adverse 
events (AEs), and serious adverse events (SAEs).

Local reactions (pain, erythema, and induration), as 
self-reported on electronic diaries (e-diaries) for up to 
7 days following each dose of investigational product.

Systemic events (fever, vomiting, headache, fatigue, 
new or worsening muscle pain, and new or worsening 
joint pain), as self-reported on e-diaries for up to 7 
days following each dose of investigational product.

Nonserious AEs from signing of the informed consent 
document (ICD) to 1 month after receipt of the third 
dose of investigational product.

SAEs from signing of the ICD to 6 months after 
receipt of the third dose of investigational product.
a.
Each subject may contribute only once to the primary endpoint.
Study Design
This is a Phase 3, placebo-controlled, randomized, observer-blinded study to evaluate the 
efficacy, safety, and tolerability of aluminum hydroxide (AlOH)-containing C difficile
vaccine (200 µg total toxoid) administered as a 3-dose regimen at Months 0, 1, and 6 in 
adults 50 years of age and older.
Subjects will be randomly assigned in parallel in a 1:1 ratio to receive C difficile vaccine 
(200 µg total toxoid) or placebo (saline).

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This is an event-driven study with a total target of 66 first primary CDI cases (meeting case 
definition 1 in the per-protocol-3 population); the total enrollment number may vary 
depending on the incidence rate of the primary endpoint, true underlying vaccine efficacy 
(VE), and potential early stop for efficacy or futility.
Investigational Products
Clostridium difficile Vaccine
The investigational C difficile vaccine is toxoid based. C difficile toxin A and toxin B are 
inactivated by a combination of genetic mutations and chemical treatments. The vaccine is 
provided as a sterile lyophilized powder in a dosage strength of 200 µg/dose (total for 
toxoids A and B). The vaccine will be reconstituted with AlOH diluent immediately before 
use as instructed in the investigational product (IP) manual. The AlOH diluent is supplied as 
a 1-mg aluminum/mL (as AlOH) liquid suspension.
Placebo
The placebo will consist of a sterile normal saline solution for injection (0.9% sodium 
chloride injection, in a 0.5-mL dose) and will be provided by the sponsor to each study site.
Statistical Methods
The VE is defined as VE = 100 × (1 – IRR), where IRR is the infection rate ratio, the 
calculated ratio of first primary CDI incidence between the C difficile vaccine group and the
placebo group.  
Three (3) formal interim analyses are planned to check both efficacy and futility after 30, 40
and 50 cases of first primary CDI have occurred from 14 days after receipt of the third dose 
of investigational product. Only the primary efficacy endpoints will be examined during 
these interim analyses. 
With 30 cases of first primary CDI at the first planned interim analysis, if there are 6 or fewer 
cases observed in the C difficile vaccine group, the null hypothesis (H03) will be rejected, the 
C difficile vaccine will be deemed efficacious, and a full analysis of the data will be 
conducted. If there are 11 or more cases observed in the C difficile vaccine group, futility 
may be declared, and the study may be terminated.
With 40 cases of first primary CDI at the second planned interim analysis, if there are 9 or 
fewer cases observed in the C difficile vaccine group, the null hypothesis (H03) will be 
rejected, the C difficile vaccine will be deemed efficacious, and a full analysis of the data 
may be conducted. If there are 13 or more cases observed in the C difficile vaccine group, 
futility may be declared, and the study may be terminated.
With 50 cases of first primary CDI at the third planned interim analysis, if there are 13 or 
fewer cases observed in the C difficile vaccine group, the null hypothesis (H03) will be 
rejected, the C difficile vaccine will be deemed efficacious, and a full analysis of the data 
may be conducted. If there are 16 or more cases observed in the C difficile vaccine group, 
futility may be declared, and the study may be terminated.

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If the study continues after 3 interim analyses, for the final analysis, the primary objective 
will have been met if there are 20 or fewer cases observed in the C difficile vaccine group out 
of a total of 66 first primary cases from 14 days after receipt of the third dose of 
investigational product onwards.
AEs will be summarized using 3-tier methodology. Local reactions and systemic events will 
be summarized.

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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the Study Procedures and 
Assessments sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Visit ID
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Annual 
Retention 
Visit
Visit 7
At Time of 
Potential 
CDI Case
Visit Description
Month 0
(Vax 1)
Month 1
(Vax 2)
Month 2
Month 6
(Vax 3)
Month 7
Month 12
End of 
Study
Visit Window (Days)
1
28-42 Days 
After Visit 
1
28-42 Days 
After Visit 
2
140-168 
Days After 
Visit 2
28-42 Days 
After Visit 
4
165-195
Days After 
Visit 4
Every 280-
392 Days 
After 
Visit 5a
Not 
Applicable
Informed consentb
X
Xc
Demographyb
X
Clinical assessment, including 
medical historyb
X
Record nonstudy vaccinationsd
X
X
X
X
X
Record specified concomitant 
medications
X
Measure and record height and 
weightb
X
Oral temperatureb
X
X
X
Urine pregnancy test (females of 
childbearing potential)b
X
X
X
Discuss contraceptive used
X
X
X
X
Confirm eligibilityd
X
X
X
X
Review temporary delay criteriab
X
X
X
Randomizationb
X
Blood draw for immunogenicity 
assessmentd
X
X
X
Xe

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Visit ID
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Annual 
Retention 
Visit
Visit 7
At Time of 
Potential 
CDI Case
Visit Description
Month 0
(Vax 1)
Month 1
(Vax 2)
Month 2
Month 6
(Vax 3)
Month 7
Month 12
End of 
Study
Visit Window (Days)
1
28-42 Days 
After Visit 
1
28-42 Days 
After Visit 
2
140-168 
Days After 
Visit 2
28-42 Days 
After Visit 
4
165-195
Days After 
Visit 4
Every 280-
392 Days 
After 
Visit 5a
Not 
Applicable
Vaccination
X
X
X
Postvaccination observation (at least 
30 minutes) and AE assessment
X
X
X
Review stool sample collection and 
shipping instructions with the subject 
and ensure understanding
X
X
X
X
X
X
X
Issue or send a stool collection kit 
and shipping box, and provide 
instructions on their use, as required
X
X
X
X
X
X
X
Issue measuring device, and 
thermometer and provide instructions 
on their use, as required
X
X
X
Review subject communication 
methods (including for e-diary 
completion), assist the subject with 
downloading the app, or issue 
provisioned device, if required
X
X
X
X
X
X
X
Record AEs
X
X
X
X
Xf
Xf
Record SAEs 
X
X
X
X
X
X
Capture major protocol violations
X
X
X
X
X
X
X
X
Telephone contact visit
Xg
X
X
Electronic reminders
Telephone contact for subjects 
unresponsive to electronic reminders
Provision of stool sample
X
Completion of diarrheal episode 
questionnaire
X

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Visit ID
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Annual 
Retention 
Visit
Visit 7
At Time of 
Potential 
CDI Case
Visit Description
Month 0
(Vax 1)
Month 1
(Vax 2)
Month 2
Month 6
(Vax 3)
Month 7
Month 12
End of 
Study
Visit Window (Days)
1
28-42 Days 
After Visit 
1
28-42 Days 
After Visit 
2
140-168 
Days After 
Visit 2
28-42 Days 
After Visit 
4
165-195
Days After 
Visit 4
Every 280-
392 Days 
After 
Visit 5a
Not 
Applicable
Subject completes e-diary 
X
X
X
Review e-diary data 
Abbreviations: CDI = Clostridium difficile infection; e-diary = electronic diary; Vax = vaccination; = ongoing/continuous event.
a.
Following approval of Amendment 3, subjects already enrolled in the study should have an annual retention visit arranged at the earliest opportunity, and 
then every 280 to 392 days thereafter.
b.
Prior to vaccination.
c.
At the first annual retention visit or potential CDI visit, whichever occurs first.
d.
Prior to vaccination, if at a vaccination visit.
e.
Optimally within 48 hours of the third unformed stool (Bristol stool chart types 5-7).
f.
Any AEs occurring up to 48 hours after each blood draw must be recorded.
g.
Visit is intended to be conducted by telephone but, if desired, may be conducted in person.

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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Pfizer’s investigational Clostridium difficile vaccine (PF-06425090) is a prophylactic vaccine
that is currently being investigated for the prevention of primary C difficile infection (CDI) in 
adults 50 years of age and older.
1.2. Background and Rationale
1.2.1. Clostridium difficile Disease Background
C difficile, a gram-positive anaerobic, spore-forming bacillus, is the main cause of 
nosocomial infectious diarrhea in industrialized countries.1,2,3,4,5  It accounts for 20% to 30% 
of cases of antibiotic-associated diarrhea and is the most commonly recognized cause of 
infectious diarrhea in healthcare settings.6  C difficile is carried in approximately 3% of 
healthy adults and approximately 16% to 35% of hospital inpatients; among the latter the rate 
increases with exposure to antibiotics.7  As many as 50% or more of hospital patients 
colonized by C difficile are asymptomatic carriers.6
C difficile can produce 3 toxins, toxin A (TcdA), toxin B (TcdB), and binary toxin.8  TcdA 
and TcdB are the principal virulence factors for CDI,9 causing severe inflammation in the 
bowel.10,11  The spectrum of CDI ranges from asymptomatic colonization and mild 
self-limiting diarrhea, to more serious complications such as severe diarrhea, 
pseudomembranous colitis, toxic megacolon, intestinal perforation, and death.2,12
Individuals with mild to moderate CDI may experience diarrhea 3 or more times a day for 2 
or more days, along with mild abdominal cramping and tenderness.  However, individuals 
with a severe infection may experience watery diarrhea 10 to 15 times a day, abdominal 
cramping and pain that may be severe, fever, blood or pus in the stool, nausea, dehydration, 
loss of appetite, weight loss, swollen abdomen, kidney failure, and increased white blood cell 
count.13
The main risk factors for an initial episode of CDI are antibiotic therapy, prolonged 
hospitalization, and severe comorbidities.  Older adults (>65 years of age) are at an increased 
risk for CDI, particularly when exposed to healthcare settings.11,14,15,16,17  Although most 
patients experiencing a first episode of CDI respond well to standard antibiotic treatment, 
approximately 15% to 35% of patients suffer from at least 1 recurrence.11,18,19   Additional 
risk factors for recurrence include failure to mount an immune response to TcdA and/or 
TcdB and infection with a hypervirulent strain.20,21
Increased incidence and severity of the disease with associated complications, colectomy 
rates, and mortality have been observed over the last 10 to 20 years.22,23,24  In Europe, 
increased mortality, prolonged length of hospital stay, and incremental cost of hospitalization 
in association with CDI have been reported.25,26  A systematic review published in 2012 
reported 30-day mortality estimates in Europe ranging from 6.8% to 42%.26  In a surveillance 
study conducted in the United States, approximately 453,000 cases of CDI and
approximately 29,000 deaths were reported in 2011.27

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Based on data reported from acute care facilities, the cost of caring for patients experiencing 
CDI in the United States ranges from $1.1 to $4.8 billion annually.28,29
In the last decade, the numbers and severity of C difficile iatrogenic outbreaks in hospitals 
and nursing homes have increased.27,28,30  Key factors in this escalation include emergence of 
hypervirulent pathogenic strains such as BI/NAP1/027,31,32,33 increased use of antibiotics,34
improved detection methods, and increased exposure to spores in healthcare facilities.35
Metronidazole has been recommended as initial therapy since the late 1990s and continues to 
be the first choice for all but seriously ill patients and those with complicated or fulminant 
infections or multiple recurrences of CDI, for whom vancomycin is recommended.6,21,36  
Fidaxomicin has been developed more recently and has been shown to be noninferior to 
vancomycin for treatment of CDI.  In addition, treatment with fidaxomicin was associated 
with a significantly lower rate of recurrence than was treatment with vancomycin.19
European guidelines for treatment of CDI include fidaxomicin as an option for treatment of 
recurrence.21  Fecal transplantation has also been shown to be effective in some patients for 
the treatment of multiple recurrences of CDI.37,38  However, regulatory oversight of this 
method remains in development,39 and, therefore, a highly effective noninvasive treatment 
for complicated CDI does not exist.
To date, the only measures available to help prevent CDI are behavioral ones such as 
encouraging appropriate use of antimicrobials, use of contact precautions, and cleaning and 
disinfection of equipment and the environment.40
1.2.2. Clostridium difficile Vaccine Development Rationale
It is well established that humoral immune responses to C difficile toxins play a significant 
role in preventing a more severe outcome or a recurrence of the disease in humans.  Several 
clinical studies suggest a correlation between high serum concentrations of antitoxin A and B 
immunoglobulin G (IgG) (as measured by enzyme-linked immunosorbent assay [ELISA])
and protection from CDI or recurrence after primary CDI.20,41,42,43 Preclinical studies have 
shown that active immunization with inactivated toxins (“toxoids”) and passive 
immunization with antitoxin antibodies protect animals from lethal challenge.44,45,46   
Furthermore, a Phase 2 trial with monoclonal antibodies (mAbs) designed to neutralize TcdA
and TcdB provides clinical evidence supporting a role for antitoxin antibodies in the 
prevention of CDI recurrences.47 Systemic administration of a combination of 2 neutralizing 
human mAbs against TcdA and TcdB was associated with fewer recurrences than placebo 
(7% versus 25% recurrences, respectively; p<0.001).  These results were confirmed in 2 
Phase 3 studies.  In both studies, results showed that the rate of recurrence of CDI was 
significantly lower when the mAb against TcdB (bezlotoxumab) was administered, whether 
on its own or in combination with the mAb against TcdA (actoxumab), compared with 
placebo.48  Finally, another group demonstrated that a combination of 2 mAbs directed 
against different epitopes from the binding domain of TcdA was significantly more potent in 
neutralizing the toxin in vitro than a single mAb.49  Furthermore, while the TcdA and TcdB 
amino acid sequences are generally well conserved within the same sequence types, there is 
high variation between sequence types,50 indicating that a polyclonal antibody approach, 
such as elicited by active immunization with C difficile toxoids, may be more efficacious to 

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prevent primary and recurrent CDI.  Taken together, these findings provide the rationale for 
the development of a C difficile toxoid-based vaccine to prevent CDI that includes both TcdA 
and TcdB.  Pfizer therefore is developing a bivalent vaccine composed of both toxoids to 
elicit broad antitoxin immunity against TcdA and TcdB.
To date, there is no approved vaccine to prevent primary or recurrent CDI.  There are at least 
2 other vaccines in development that target C difficile toxins.  A toxoid-based vaccine 
adjuvanted with aluminum hydroxide (AlOH) has been evaluated in Phase 1 and 2 
studies,51,52,53,54 and efficacy is currently being evaluated in a Phase 3 study.55  The other is a 
recombinant fusion protein comprising fragments of the receptor-binding domains of TcdA
and TcdB separated by a 4–amino acid linker;56 this vaccine has been evaluated in a
completed Phase 2 study.57
The increasing burden of CDI on patients and on the healthcare system demonstrates that 
prevention of CDI constitutes a significant unmet medical need.
1.2.3. Clostridium difficile Vaccine Candidate
Pfizer’s C difficile vaccine candidate consists of a 1:1 mixture of C difficile toxoids A and B.  
The toxoids were derived from native toxins by genetic modification to decrease toxin 
activity, and chemical inactivation prior to final purification and formulation of the drug 
substance.
1.2.3.1. Nonclinical Development
In nonclinical experiments, Pfizer’s C difficile candidate vaccine was studied either alone or 
in combination with AlOH.  Using the standard hamster C difficile disease model, vaccine 
formulations with and without AlOH demonstrated a survival benefit, providing at least 90% 
protection from a lethal challenge with C difficile spores in the immunized hamsters.  In 
addition, pooled sera obtained from hamsters immunized with the C difficile vaccine 
formulated with AlOH neutralized secreted toxins from C difficile isolates representing 
diverse ribotypes/pulsed-field gel electrophoresis (PFGE) types, including hypervirulent 
strains, and covering >67% and >70% of the circulating strains in the United States and 
Europe, respectively. Furthermore, in nonhuman primates, Pfizer’s toxoid vaccine 
formulations with and without AlOH induced robust neutralizing antitoxin antibody 
responses to both TcdA and TcdB.  The nonclinical data generated by Pfizer in rhesus 
macaques support the use of a 3-dose regimen of the C difficile vaccine, with or without 
AlOH.
1.2.3.2. Clinical Development
The B5091001 first-in-human study was a placebo-controlled, randomized, observer-blinded 
Phase 1 study that evaluated the safety, tolerability, and immunogenicity of Pfizer’s 
C difficile vaccine.  Three (3) antigen dose levels (50, 100, and 200 g) were assessed and 
administered either alone or in combination with AlOH at Months 0, 1, and 6 to healthy 
adults 50 to 85 years of age.58 Overall, the C difficile vaccine formulations and dose levels 
administered were generally well tolerated.  Local reactions and systemic events were 
predominantly mild to moderate, were more common in the 50- to 64-year age cohort, and 

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comprised mostly injection site pain, headache, and fatigue.  Adverse events (AEs) were 
reported in all vaccine groups, with little difference in the number of subjects between the 
dose groups and the placebo group or between vaccine formulations.  In subjects who 
received the vaccine formulations, both the toxin A– and toxin B–specific neutralizing 
antibody geometric mean concentrations increased substantially at 1 month after Dose 2 and 
after Dose 3 compared to baseline.  In the 50- to 64-year age cohort, geometric mean fold 
rises (GMFRs) in toxin A–specific neutralizing antibodies from baseline at Month 7 ranged 
from 59.19 to 149.23 in the dose groups compared to 2.47 in the control group.  For 
toxin B–specific neutralizing antibodies, the GMFRs from baseline at Month 7 ranged from 
116.67 to 2503.75 in the dose groups compared to 2.48 in the control group.  In the 65- to 
85-year age cohort, the GMFRs in toxin A–specific neutralizing antibodies from baseline at 
Month 7 ranged from 42.73 to 254.77 in the dose groups compared to 2.03 in the control 
group.  For toxin B–specific neutralizing antibodies, the GMFRs from baseline at Month 7 
ranged from 136.12 to 4922.80 in the dose groups compared to 1.58 in the control group.  
Potent antitoxin neutralizing responses were still evident in immunized subjects in both age 
groups at Month 12.  Although there was no clear dose-level response pattern, the data 
suggest that both the antitoxin A– and antitoxin B–specific neutralizing responses were 
trending higher in the toxoid-only groups compared to the toxoid + AlOH groups.  
Furthermore, the magnitude of the immune response was similar in the 2 age cohorts.
Based on these data, a Phase 2 study (B5091003) was initiated using a 3-dose regimen 
(Days 1, 8, and 30) and 2 antigen dose levels (100 and 200 g) of the toxoids alone 
reconstituted with sodium chloride diluent.  However, recruitment and vaccinations were 
halted because of the occurrence of 7 cases of Grade 3 injection site redness after Dose 2.  In 
light of this observed tolerability profile, the decision was made to progress development of 
the AlOH-containing formulation into a second Phase 2 study. This Phase 2 study 
(B5091009) of the AlOH-containing formulation is ongoing to assess the safety, tolerability, 
and immunogenicity of 2 antigen dose levels (100 and 200 g) and two 3-dose regimens 
(Days 1, 8, and 30 and Months 0, 1, and 6).  A prespecified interim analysis of data up to 
Month 7 from this study demonstrated that the immunogenicity profile following 3 doses 
administered at Months 0, 1, and 6 was superior to that when the doses were administered at 
Days 1, 8, and 30. In addition, the 200-g dose level was more immunogenic than the 
100-g dose level. On this basis, it was decided to progress into Phase 3 development with 
the 200-g dose level administered at Months 0, 1, and 6.
The present study (B5091007) is therefore a placebo-controlled, randomized (1:1, 
vaccine:placebo), observer-blinded, parallel-group study in up to approximately 17,476
subjects 50 years of age or older who have an increased risk of CDI. In the absence of an 
accepted immunological correlate of protection for CDI, vaccine efficacy (VE) will be 
determined by comparing the CDI incidence in recipients of the investigational vaccine with 
those receiving placebo. Any time during the study period that a subject experiences passage 
of 3 or more unformed stools (Bristol stool chart types 5-7; see Appendix 2)59 within 24 
hours, the subject will be asked to collect the third or subsequent stool for provision to the 
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Stool specimens will be tested at a central laboratory for presence of the C difficile organism 
and TcdA/TcdB. The study is designed to accrue 66 first primary CDI cases, meeting case 
definition 1 (Section 2.1.1), occurring from 14 days after the third dose of vaccine.
1.2.3.3. Summary of Benefit-Risk Assessment
C difficile is the main cause of nosocomial infectious diarrhea in industrialized 
countries.1,2,3,4,5  It accounts for 20% to 30% of cases of antibiotic-associated diarrhea and is 
the most commonly recognized cause of infectious diarrhea in healthcare settings.6  To date, 
there is no approved vaccine to prevent primary or recurrent CDI.  The increasing burden of 
CDI on patients and on the healthcare system demonstrates that prevention of CDI 
constitutes a significant unmet medical need.
The B5091001 first-in-human study, which assessed 3 antigen dose levels (50, 100, and 
200 g) administered either alone or in combination with AlOH at Months 0, 1, and 6 to 
healthy adults 50 to 85 years of age, demonstrated that the C difficile vaccine formulations 
and dose levels administered were generally well tolerated.  Local reactions and systemic 
events were predominantly mild to moderate, and comprised mostly injection site pain, 
headache, and fatigue. There was little difference in the number of subjects reporting AEs 
between the dose groups and the placebo group or between vaccine formulations.
The B5091009 Phase 2 study, which assessed 2 antigen dose levels (100 and 200 g) 
administered in combination with AlOH at Months 0, 1, and 6 or Days 1, 8, and 30 to healthy 
adults 65 to 85 years of age, demonstrated that both regimens and both dose levels 
administered were generally well tolerated. Local reactions were predominantly mild to 
moderate, with injection site pain being the most frequent manifestation. After Dose 2, local 
reactogenicity was greater when the vaccine was administered at Day 8 compared to 
Month 1, particularly for the 200-g dose level. Systemic events were also predominantly 
mild to moderate and the incidences of individual events were similar between the placebo
group, the 100-g dose group, and the 200-g dose group. Within each regimen, the overall 
AE incidence rates were also similar between the placebo, 100-g, and 200-g dose groups. 
For both regimens, serious adverse events (SAEs) were numerically higher in the 100-g and 
200-g dose groups than in the placebo group. However, there was no pattern to these 
events and no safety concern was identified. Both studied dose levels resulted in substantial 
neutralizing antitoxin A and B titers, with the immunogenicity profile following 3 doses 
administered at Months 0, 1, and 6 being preferred.  In addition, the 200-g dose level was 
more immunogenic than the 100 g dose level.
Pfizer considers the available information from Studies B5091001 and B5091009 with 
PF-06425090 to support a favorable benefit-risk profile for studies administering 3 doses of 
the C difficile vaccine at dose levels up to 200 µg formulated with AlOH, as a potential 
prevention against CDI.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the investigator’s brochure (IB).

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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Efficacy Objective(s):
Primary Efficacy Endpoint(s):

To demonstrate that Pfizer’s C difficile vaccine is 
effective in reducing the incidence of a first primary 
episode of CDI (see case definition 1).a

CDI incidence per 1000 person-years of follow-up, 
assessed during up to 2 time periods (each analysis 
will be performed only if the preceding one was 
successful):

After receipt of the third dose of investigational 
product onwards.

After receipt of the second dose of 
investigational product onwards.
Primary Safety Objective(s):
Primary Safety Endpoint(s):

To evaluate the safety profile of Pfizer’s C difficile
vaccine as measured by the percentage of subjects 
reporting local reactions and systemic events, AEs, and 
SAEs.

Local reactions (pain, erythema, and induration), as 
self-reported on electronic diaries (e-diaries) for up to 
7 days following each dose of investigational product.

Systemic events (fever, vomiting, headache, fatigue, 
new or worsening muscle pain, and new or worsening 
joint pain), as self-reported on e-diaries for up to 7 
days following each dose of investigational product.

Nonserious AEs from the signing of the informed 
consent document (ICD) to 1 month after receipt of 
the third dose of investigational product.

SAEs from the signing of the ICD to 6 months after 
receipt of third dose of investigational product.
Evaluation 
Order
Secondary Objective(s):
Secondary Endpoint(s):
3-Dose Family
1.

To evaluate the efficacy of Pfizer’s 
C difficile vaccine in reducing:

The incidence of all CDI cases
(see case definition 1 and case 
definition 2).

CDI incidence per 1000 person-years of follow-up, 
assessed after receipt of the third dose of 
investigational product onwards.
2.

To evaluate the efficacy of Pfizer’s 
C difficile vaccine in reducing the 
severity of CDI, defined by:

The duration of CDI episodes.

The requirement to seek medical 
attention.

Mean time to resolution of diarrhea in first primary 
episodes of CDI (case definition 1).

Proportion of subjects experiencing a first primary 
episode of CDI (case definition 1) who have a non–
protocol-related medically attended visit during the 
CDI episode.
(Each analysis will be performed only if the 
preceding one was successful).

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3.
•
To evaluate the efficacy of Pfizer’s 
C difficile vaccine in reducing the 
incidence of recurrent CDI (see case 
definition 2).
•
CDI incidence per 1000 person-years of follow-up, 
assessed after receipt of the third dose of 
investigational product onwards.
At-Least-2-Dose/Only-2-Dose Family
1.b
•
To evaluate the efficacy of Pfizer’s 
C difficile vaccine in reducing: 
•
The incidence of all CDI cases 
(see case definition 1 and case 
definition 2).
•
CDI incidence per 1000 person-years of follow-up, 
assessed after receipt of the second dose of 
investigational product onwards.
2.b
•
To evaluate the efficacy of Pfizer’s 
C difficile vaccine in reducing the 
incidence of recurrent CDI 
(see case definition 2).
•
CDI incidence per 1000 person-years of follow-up, 
assessed after receipt of the second dose of 
investigational product onwards.
3.c
•
In subjects who receive only 2 doses of 
vaccine, to evaluate the efficacy of 
Pfizer’s C difficile vaccine in reducing:
•
The incidence of a first primary 
episode of CDI 
(see case definition 1).
•
The incidence of recurrent CDI 
(see case definition 2).
•
CDI incidence per 1000 person-years of follow-up.
(Each analysis will be performed only if the 
preceding one was successful).
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI

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CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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a.
Each subject may contribute only once to the primary endpoint.
b.
At-least-2-dose family.
c.
Only-2-dose family.
Immunogenicity samples will also be collected during the study. All subjects with a first 
primary episode of CDI (meeting case definition 1, Section 2.1.1) will be matched with 1 or 
more control subjects; a separate analysis may be conducted on these case-control data to 
ascertain if it is possible to determine an immunological correlate of protection.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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2.1. CDI Case Definitions
For all definitions, an episode will be considered to have resolved once there have been at 
least 2 days without passage of 3 or more unformed stools (Bristol stool chart types 5-7) and 
there is no further need for antibiotic treatment for CDI.
2.1.1. Definition 1 – Primary Episode
A primary episode of CDI (ie, no previous CDI onset in the prior 8 weeks) is defined as 
either:
•
Presence of diarrhea, defined as passage of 3 or more unformed stools (Bristol stool chart 
types 5-7) in 24 or fewer consecutive hours; and
•
Stool sample that is positive for the toxin B gene (by PCR) and positive for toxin A 
and/or toxin B, as measured in the central laboratory.
or:
•
Pseudomembranous colitis diagnosed at colonoscopy, at surgery, or histopathologically; 
and corresponding stool sample that is positive for the toxin B gene (via PCR) as 
measured in the central laboratory.
2.1.2. Definition 2 – Recurrent Episode
An episode of CDI that occurs 8 weeks or less after the onset of a previous CDI episode 
(provided the symptoms of the previous episode had resolved), defined as either:
•
Presence of diarrhea, defined as passage of 3 or more unformed stools (Bristol stool chart 
types 5-7) in 24 or fewer consecutive hours; and
•
Stool sample that is positive for the toxin B gene (by PCR) and positive for toxin A 
and/or toxin B, as measured in the central laboratory.
or:
•
Pseudomembranous colitis diagnosed at colonoscopy, at surgery, or histopathologically; 
and corresponding stool sample that is positive for the toxin B gene (by PCR) as 
measured in the central laboratory.
 
CCI

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3. STUDY DESIGN
This is a Phase 3, placebo-controlled, randomized, observer-blinded study to evaluate the 
efficacy, safety, and tolerability of AlOH-containing C difficile vaccine (200 μg total toxoid) 
administered as a 3-dose regimen at Months 0, 1, and 6 in adults 50 years of age and above.
Subjects will be randomly assigned in parallel in a 1:1 ratio to receive C difficile vaccine 
(200 μg total toxoid) or placebo (saline).
This is an event-driven study with a total target of 66 first primary CDI cases (meeting case 
definition 1 in the per-protocol-3 population, Section 2.1.1 and Section 9.2.1) to be accrued 
for the study; the total enrollment number may vary depending on the incidence rate of the 
primary endpoint, true underlying VE, and potential early stop for efficacy or futility 
(see Section 9.2).
3.1. Approximate Number of Subjects
It is anticipated that up to approximately 17,476 adults, 50 years of age and above, may be 
enrolled globally to accumulate 66 first primary CDI cases (meeting case definition 1, 
Section 2.1.1).  As this is an event-driven and group-sequential (GS) study, the final 
enrollment number may vary depending on the incidence rate of the primary endpoint, true 
underlying VE, and potential early stop for efficacy or futility. The number of subjects 
enrolled in each country and at each site will vary based on enrollment capabilities.
Update as Part of Amendment 2 (January 2019):
Based on the ongoing blinded review of pooled primary CDI events, it is planned to 
enroll approximately 1700 additional subjects, giving a total of approximately 17,476
subjects (see Section 9.1).
To achieve a broad representation of age groups among those 50 years and older, and achieve 
an adequate rate of CDI, the numbers of subjects intended to be enrolled in each of 4 age 
categories is shown in Table 1.
Table 1.
Intended Numbers of Subjects Included in the Study, by Age
Age Category
Minimum Number for Inclusion
Maximum Number for Inclusion
50-59 years
800 subjects
1600 subjects
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Table 1.
Intended Numbers of Subjects Included in the Study, by Age
Age Category
Minimum Number for Inclusion
Maximum Number for Inclusion
60-69 years
1600 subjects
Not limited
70-79 years
1600 subjects
Not limited
80 years
400 subjects
Not limited
On monitoring the pooled primary CDI event rates in different age groups, inclusion criteria 
subgroups, Charlson Comorbidity Index61 (CCI) subgroups, and other baseline factors, once 
the specified minimum numbers in each age group have been achieved, if a substantially 
higher pooled CDI event rate is observed in some subgroups, the intention may be to stop 
enrollment in lower-risk subgroups and complete enrollment with the higher-risk subgroups 
thereafter. This is mainly to help to achieve the targeted total number of first primary cases
in a timely manner.
Subjects withdrawn from the study after randomization will not be replaced, regardless of the 
reason for withdrawal.
3.2. Approximate Duration of the Study
As this study is event-driven, the study duration will be dependent on CDI event rate. The 
study may be terminated earlier for efficacy or futility as described in Section 9.5.
Given that this is an event-driven study, the end of trial is defined as database lock as 
described in Section 13.
3.3. Approximate Duration of Subject Participation
Subjects will be followed from the time they sign the ICD until sufficient cases have been 
accrued to declare efficacy or futility. 
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.

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4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated ICD indicating that the subject has been 
informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, vaccination plan, and other study 
procedures.
3. 50 Years or older at enrollment.
4. Subjects with an increased risk of future contact with healthcare systems by virtue of:
At least 1 inpatient hospitalization 2 nights’ duration in the previous 12 months; 
or
At least 2 emergency room visits in the previous 12 months; or
At least 10 outpatient visits (primary and/or secondary care visits; defined as an 
in-person visit to the office/clinic of a prescribing healthcare provider for the 
purposes of the diagnosis, treatment, or ongoing management of a medical 
condition, excluding pharmacy and mental health visits) in the previous 
12 months; or
Residence in a skilled nursing facility (a residential institution that provides 
professional nursing care and rehabilitation services, usually following discharge 
from the hospital); or
Residence in a nursing home (a residential institution that provides assistance with 
activities of daily living); or
Inpatient hospitalization 2 nights’ duration scheduled 37 days after 
randomization.
Or subjects who have received systemic (ie, oral or injected) antibiotics for a 
minimum of 48 hours at any time in the previous 12 weeks.
5. Ability to be contacted by telephone during study participation.
6. Negative urine pregnancy test for female subjects of childbearing potential.

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Female subjects of nonchildbearing potential must meet at least 1 of the following 
criteria:
a. Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or physiological 
cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) 
level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c. Have medically confirmed ovarian failure. 
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential. 
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
2. Participation in other studies involving investigational drug(s)/vaccine(s) within
28 days prior to study entry until Visit 5 (1 month after the third vaccination).
3. Previous administration of an investigational C difficile vaccine or C difficile mAb 
therapy.
4. Prior episode of CDI, confirmed by either laboratory test or diagnosis of 
pseudomembranous colitis at colonoscopy, at surgery, or histopathologically. 
5. Receipt of blood products or immunoglobulins within 6 months before enrollment.
6. Subjects who may be unable to respond to vaccination because of: 
Metastatic malignancy; or
End-stage renal disease (glomerular filtration rate <15 mL/min/1.73 m2 or on 
dialysis); or
Any serious medical disorder that in the investigator’s opinion is likely to be fatal 
within the next 12 months; or
Congenital or acquired immunodeficiency; or

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Receipt of systemic corticosteroids (20 mg/day of prednisone or equivalent) for 
14 days within 28 days of enrollment; or
Receipt of chronic systemic treatment with other known immunosuppressant 
medications, or radiotherapy, within 6 months of enrollment. 
7. Known infection with human immunodeficiency virus (HIV).
8. Any bleeding disorder or anticoagulant therapy that would contraindicate 
intramuscular injection.
9. Any contraindication to vaccination or vaccine components, including previous 
anaphylactic reaction to any vaccine or vaccine-related components.
10. Prior small- or large-bowel resection (does not include appendectomy).
11. Any condition or treatment resulting in frequent diarrhea (3 loose stools per day 
more than once per month), as reported by the subject.
12. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavioral 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.
13. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and 
female subjects of childbearing potential who are, in the opinion of the investigator, 
sexually active and at risk for pregnancy with their partner(s) and are unwilling or 
unable to use 2 highly effective methods of contraception as outlined in this protocol 
from the signing of the informed consent until at least 28 days after the last dose of 
investigational product.
4.3. Criteria for Temporarily Delaying Vaccine Administration
The following conditions are temporary or self-limiting and a subject may be vaccinated 
once the condition(s) has/have resolved and no other exclusion criteria are met:
1. Current febrile illness (oral temperature of 100.4°F [38.0°C]) or other acute illness
(including diarrhea of 3 unformed stools within 24 hours) within 48 hours prior to 
investigational product administration.
2. Subject has received nonadjuvanted seasonal or pandemic influenza vaccine within 
the previous 14 days or adjuvanted seasonal influenza vaccine or any noninfluenza 
nonstudy vaccine within the previous 28 days before investigational product 
administration.

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3. If systemic corticosteroids have been administered short term (<14 days) for 
treatment of an acute illness, investigational product administration should be delayed 
until systemic corticosteroid use has been discontinued for at least 28 days. Inhaled, 
intra-articular/intrabursal, or topical corticosteroids are permitted.
If a subject meets any delay criteria for vaccination, all study procedures, including blood 
sample collection relating to that visit, should be delayed until the day of vaccination.
4.4. Lifestyle Requirements
4.4.1. Contraception
All fertile male subjects and female subjects who are of childbearing potential who are, in the 
opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) 
must agree to use 2 highly effective methods of contraception consistently and correctly for 
the duration of the vaccination 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 2 appropriate methods of contraception for 
the individual subject and his or her partner from the permitted list of contraception methods 
(see below) and will confirm that the subject has been instructed in its consistent and correct 
use.  At time points indicated in the schedule of activities, the investigator or designee will 
inform the subject of the need to use 2 highly effective methods of contraception consistently 
and correctly and document the conversation and the subject’s affirmation in the subject’s 
chart (subjects need to affirm their consistent and correct use of at least 2 of the selected 
methods of contraception).  In addition, the investigator or designee will instruct the subject 
to call immediately if 1 or both of the selected contraception methods is discontinued or if 
pregnancy is known or suspected in the subject or the partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the entire 
study and has been using that hormonal contraceptive for an adequate period of time to 
ensure effectiveness.  
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, gel, 
film, cream, or suppository). For countries where spermicide is not available or condom 
plus spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.

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5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
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 study reference manual (SRM).
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. INVESTIGATIONAL PRODUCTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational products are C difficile vaccine and placebo (saline). Since 
the appearance of these investigational products is not identical, the study is 
observer-blinded.
5.1. Allocation to Investigational Product
Allocation of subjects to vaccine groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR]). Study personnel 
(either blinded or unblinded) will be required to enter or select information including but not 
limited to the user’s identification (ID) and password, the protocol number, and the subject 
number. They will then be provided with a randomization number, vaccine assignment, and 

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dispensable unit (DU) or container number.  The IRT system will provide a confirmation 
report containing the subject number, randomization number, and DU or container number 
assigned. The confirmation report must be retained by the unblinded dispenser in the 
unblinded site files.
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system.
5.2. Blinding of Site Personnel
In this observer-blinded study, the study staff dispensing and administering the vaccine will 
be unblinded, but all other site study personnel, including the principal investigator and the 
subject, will be blinded.
The principal investigator will assign the responsibility of the unblinded 
dispenser/administrator to persons who will not participate in the evaluation of any study 
subject.  More than 1 unblinded dispenser/administrator will be assigned per site. A member 
of the study site staff or clinic pharmacy should fulfill this role.  Contact between the 
unblinded dispenser and study subjects should be kept to a minimum.  The investigator, study 
coordinator, and any site staff other than the unblinded dispenser/administrator must not be 
allowed to know the investigational product assigned to any study subject and must not be 
allowed to see the investigational product container contents.
5.3. Blinding of the Sponsor
Those study team members who are involved in ensuring that protocol requirements for 
investigational product handling, allocation, and administration are fulfilled at the site 
(eg, study manager; clinical research associates [CRAs]) will be unblinded for the duration of 
the study. All other study team members and all laboratory personnel performing the stool 
and serology assays will remain blinded to vaccine assigned/received throughout the study.  
5.4. Breaking the Blind 
The study will be subject and investigator blinded.
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process.  Blinding codes should be 
broken only in exceptional circumstances when knowledge of the actual vaccine assignment
is absolutely essential for further management of the subject. Investigators are encouraged to 
discuss with a member of the study team if they believe that unblinding is necessary. When 
the blinding code is broken, the reason must be fully documented and entered on the case 
report form (CRF).
5.5. Subject Compliance
All doses of investigational product will be administered by the appropriately designated 
study staff at the investigator site.

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5.6. Vaccine Supplies
5.6.1. Formulation and Packaging
5.6.1.1. Clostridium difficile Vaccine
The investigational C difficile vaccine is toxoid based. C difficile toxin A and toxin B are 
inactivated by a combination of genetic mutations and chemical treatments.  The vaccine is 
provided as a sterile lyophilized powder in a dosage strength of 200 µg/dose (total for 
toxoids A and B).  The vaccine will be reconstituted with AlOH diluent immediately before 
use as instructed in the investigational product (IP) manual.  The AlOH diluent is supplied as 
a 1-mg aluminum/mL (as AlOH) liquid suspension.
Blinded, sealed cartons will contain 1 single-use vial of C difficile vaccine lyophilized 
powder for reconstitution and 1 single-dose syringe of AlOH diluent.  The total volume of 
resuspended vaccine to be injected is 0.5 mL per dose.
The investigational products will be provided by the sponsor to each study site.  
Investigational product and diluent will be packed and labeled by Pfizer or its designee as 
investigational product in accordance with current guidelines and applicable local and legal 
regulatory requirements.  For detailed information on the antigenic components of the 
investigational product, please refer to the IB.
5.6.1.2. Placebo
The placebo will consist of a sterile normal saline solution for injection (0.9% sodium 
chloride injection, in a 0.5-mL dose) and will be provided by the sponsor to each study site.
The placebo will be packaged within cartons labeled by Pfizer or its designee in accordance 
with current guidelines and applicable local and legal regulatory requirements.  Blinded, 
sealed cartons will contain 1 single-dose syringe of placebo.  Refer to the IP manual for 
details regarding the preparation and dispensing of placebo.
5.6.2. Preparation and Dispensing
See the IP manual for instructions on how to prepare the investigational product for 
administration.  Investigational product should be prepared and dispensed by an 
appropriately qualified and experienced unblinded member of the study staff.
5.6.3. Administration
All injections will be administered in the upper deltoid muscle, preferably of the 
nondominant arm, by the unblinded administrator.  
Subjects will receive 1 dose of C difficile vaccine/placebo at Visits 1 (Month 0), 2 (Month 1), 
and 4 (Month 6). 
Standard vaccination practices must be observed and vaccine must not be injected into blood 
vessels.  Appropriate medication and other supportive measures for management of an acute 
hypersensitivity reaction should be available in accordance with local guidelines for standard 
immunization practices.

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Administration of investigational products should be performed by an appropriately 
qualified, Good Clinical Practice (GCP)-trained, and vaccine-experienced member of the 
study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacist, or 
medical assistant) as allowed by local, state, and institutional guidance. 
Investigational product administration details will be recorded on the CRF.
5.7. Investigational Product Storage
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.
See the IP manual for storage conditions of the product once reconstituted.
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
The investigational vaccine, AlOH diluent, and placebo will be shipped at +2C to +8C to 
each study site after required regulatory and legal documents have been received by the 
sponsor. Upon receipt at the study site, the products should be immediately transferred to a 
+2C to +8C temperature-monitored refrigerator for storage.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all nonworking days upon return to normal operations.  The operation of the 
temperature-monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 

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considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
5.8. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
5.8.1. 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 investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.9. Concomitant Medication(s)
5.9.1. Recording Concomitant Vaccinations and Medications
The following concomitant medications and vaccinations will be recorded in the CRF:

All vaccinations received from 28 days prior to study enrollment until Visit 5 (Month 7 
[1 month after the third vaccination]).

At the time of a suspected CDI case, start date, name of medication, dose, unit, route, and 
frequency will be recorded for the following:

Antibiotic use within the 12 weeks prior to the onset of the suspected CDI case.

Antibiotic use for the treatment of the suspected CDI case.

Known immunosuppressant medication, or radiotherapy use, within the 6 months 
prior to the onset of the suspected CDI case.

Systemic corticosteroid use within the 28 days prior to the onset of the suspected CDI 
case.

Proton-pump inhibitor use within the 12 weeks prior to the onset of the suspected 
CDI case.

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5.9.2. Prohibited Concomitant Vaccinations and Medications
Receipt of the following prohibited vaccines and medications during the time periods listed 
below may exclude a subject from the per-protocol analysis, and may require vaccinations to 
be discontinued in that subject; however, it is anticipated that the subject would not be 
withdrawn from the study (see Section 6.2).
Unless considered medically necessary, no vaccines other than investigational product should 
be administered within 28 days before and 28 days after each study vaccination 
(administered at Visits 1, 2, and 4). One exception to this is that nonadjuvanted seasonal 
influenza vaccine and pandemic influenza vaccine can be given at least 14 days after, or at 
least 14 days prior to, the administration of investigational product.
Receipt of chronic systemic treatment with other known immunosuppressant medications, or 
radiotherapy, within 6 months before enrollment through conclusion of the study.
Receipt of systemic corticosteroids (20 mg/day of prednisone or equivalent) for 14 days is 
prohibited from 28 days prior to enrollment to Visit 5 (Month 7). 
Receipt of blood products or immunoglobulins within 6 months before enrollment through 
conclusion of the study.
Receipt of any other (nonstudy) investigational C difficile vaccine or C difficile mAb therapy
at any time prior to or during study participation is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated with 
investigational product administration are not permitted.  However, if a subject is taking a 
medication for another condition, even if it may have antipyretic or pain-relieving properties, 
it should not be withheld prior to study vaccination.
5.9.3. Permitted Concomitant Medications
The use of antipyretics and other pain medication to treat symptoms associated with 
investigational product administration or ongoing conditions is permitted.
Medication other than that described as prohibited in Section 5.9.2 required for treatment of 
preexisting stable conditions is permitted.
Inhaled, topical, or localized injections of corticosteroids (eg, intra-articular or intrabursal 
administration) are permitted.
6. STUDY PROCEDURES
6.1. Study Period
Throughout the study period, if a subject has had no study-related activity for at most 
1 month, the subject will receive an electronic reminder to confirm that he or she is still 
active in the study and to remind the subject to record when he or she experiences an 
unformed stool and to collect a sample when required (see Section 6.1.9 and Section 6.4).

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If the subject is unresponsive to the electronic reminder, the site staff should contact him or 
her by telephone. Site staff will be able to record that a subject is still active in the electronic 
diary (e-diary) vendor portal. In addition, all subjects will receive a reminder every 2 weeks 
to collect a stool sample should a diarrheal episode occur (3 or more diarrheal episodes,
Bristol type 5-7, within 24 hours).
Deaths will be recorded for the entire study duration, as follows:
a.
Occurring within 30 days of a diarrheal episode: death should be recorded on the relevant 
CRF page related to the diarrheal episode (see Section 6.1.9). In addition, dependent on 
the timing within the study, b or c below should also be followed.
b. Occurring between provision of informed consent and Visit 6: the underlying cause 
should be reported as an SAE (see Section 8.2.3) with death as the outcome.
c.
Occurring after Visit 6 and before the end of the study: the date and cause of death should 
be recorded on the relevant CRF page. For reporting requirements outside of the active 
collection period, see Section 8.1.4.1.
6.1.1. Visit 1: Month 0 – Vaccination 1
It is anticipated that the procedures below will be conducted in a stepwise manner; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination.

Obtain written informed consent prior to performing any protocol required procedures.

Record the subject’s demography (including date of birth, sex, race, and ethnicity). 

Conduct a clinical assessment, including review of medical history, to verify that all 
inclusion criteria, none of the exclusion criteria, and none of the temporary delay criteria 
are met (Section 4). Record medical history of significance, including the presence of 
chronic medical conditions. If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the subject, perform a physical 
examination and record the findings.

Record nonstudy vaccines as described in Section 5.9.1.

Measure and record the subject’s weight and height.

Measure and record the subject’s oral temperature.

For female subjects of childbearing potential, perform a urine pregnancy test and ensure 
the result is negative prior to vaccination (Section 7.5).

Discuss contraceptive use.

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
Ensure that all inclusion criteria, none of the exclusion criteria, and none of the temporary 
delay criteria are met (Section 4).

An appropriate site staff member (may be blinded or unblinded) will use the IRT system 
to obtain the subject’s randomization number and investigational product blinded carton 
number. 

Collect a blood sample of approximately 20 mL for immunogenicity testing (Section 7.3).

Unblinded site staff will prepare and administer investigational product. Investigational 
product will be administered by intramuscular injection into the upper deltoid muscle, 
preferably of the nondominant arm. The time of vaccination will be recorded.  Refer to 
the IP manual under separate cover for further instruction on this process.

The unblinded vaccine dispenser/administrator updates the investigational product 
accountability records.

Blinded study staff will observe the subject for at least 30 minutes after investigational 
product administration for any acute reactions. Any AEs noted during the observation 
period should be recorded in the CRF.

Record and report AEs and SAEs (relative to the time of vaccination) as described in
Section 8 and the schedule of activities.

Review the stool sample collection and shipping instructions with the subject and ensure 
the subject acknowledges understanding, including the requirement to contact the courier 
for sample collection (see Section 6.3).

Issue the stool collection kit and shipping box and provide instructions on their use 
(see Section 6.3).

Explain the communication technologies available for the study (which also allow for the 
completion of the e-diary), and assist the subject in downloading the study application 
(app) onto the subject’s own device or issue a provisioned device if required
(see Section 6.4).

Issue a measuring device for measurement of local reactions, and a digital thermometer 
for recording daily temperatures. Provide instructions on their use and recording.

Explain the e-diary platform to collect vaccine reactogenicity data and provide 
instructions on its completion. Ask the subject to complete the e-diary from Day 1 to 
Day 7, with Day 1 being the day of vaccination.

Ask the subject to contact the site staff or investigator immediately if he or she 
experiences 3 or more unformed stools (Bristol stool chart types 5-7) in any 24-hour 
period.

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
Ask the subject to contact the site staff or investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the subject to return for the next study visit.

Complete the source documents.

Complete the CRF.
6.1.2. Visit 2: Month 1 – Vaccination 2 (28 to 42 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination.

Review the subject’s e-diary data and follow up on any ongoing local reactions or 
systemic events.

Ensure that the subject continues to be eligible for the study and does not meet any of the 
withdrawal criteria as described in Section 6.2.

Discuss with the subject to determine whether any major protocol violations have 
occurred, as described in Section 6.2.1, and record in source documents.

Based on clinical evaluation, determine whether any AEs or SAEs have occurred since 
the last study visit.  Record and report findings as described in Section 8 and the schedule 
of activities.  Review AEs that were ongoing from the previous visit and record their stop 
dates or confirm if they are still continuing.

Record nonstudy vaccines as described in Section 5.9.1.

Measure and record the subject’s oral temperature.

For female subjects of childbearing potential, perform a urine pregnancy test and ensure 
the result is negative prior to vaccination (Section 7.5).

Discuss contraceptive use.

Ensure that none of the temporary delay criteria are met (Section 4.3).

An appropriate site staff member (may be blinded or unblinded) will use the IRT system 
to obtain the subject’s investigational product blinded carton number. 

Unblinded site staff will prepare and administer investigational product. Investigational 
product will be administered by intramuscular injection into the upper deltoid muscle, 
preferably of the nondominant arm. The time of vaccination will be recorded.  Refer to
the IP manual under separate cover for further instruction on this process.

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
The unblinded vaccine dispenser/administrator updates the investigational product 
accountability records.

Blinded study staff will observe the subject for at least 30 minutes after investigational 
product administration for any acute reactions.  Any AEs noted during the observation 
period should be recorded in the CRF.

Record and report AEs and SAEs (relative to the time of vaccination) as described in 
Section 8 and the schedule of activities.

Confirm that the subject understands the stool sample collection and shipping 
requirements, including the mechanism to contact the courier for sample collection 
(see Section 6.3). 

Ensure the subject has an available stool collection kit and shipping box and provide 
instructions on their use, as required (see Section 6.3).

Ensure the subject is comfortable with his or her chosen communication technology
(see Section 6.4).

Ensure the subject has an available measuring device for measurement of local reactions, 
and a digital thermometer for recording daily temperatures. If required, provide 
instructions on their use.

Confirm that the subject understands the reactogenicity reporting requirements. Remind 
the subject to complete the e-diary from Day 1 to Day 7, with Day 1 being the day of 
vaccination.  

Ask the subject to contact the site staff or investigator immediately if he or she 
experiences 3 or more unformed stools in any 24-hour period.

Ask the subject to contact the site staff or investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the subject to return for the next study visit.

Complete the source documents.

Complete the CRF.
6.1.3. Visit 3: Month 2 (28 to 42 Days After Visit 2)

Review the subject’s e-diary data and follow up on any ongoing local reactions or 
systemic events.

Ensure that the subject continues to be eligible for the study and does not meet any of the 
withdrawal criteria as described in Section 6.2.

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
Discuss with the subject to determine whether any major protocol violations have 
occurred, as described in Section 6.2.1, and record in source documents.

Based on clinical evaluation, determine whether any AEs or SAEs have occurred since 
the last study visit.  Record and report findings as described in Section 8 and the schedule 
of activities.  Review AEs that were ongoing from the previous visit and record their stop 
dates or confirm if they are still continuing. 

Record nonstudy vaccines as described in Section 5.9.1.

Collect a blood sample of approximately 20 mL for immunogenicity testing (Section 7.3).

Discuss contraceptive use.

Confirm that the subject understands the stool sample collection and shipping 
requirements, including the mechanism to contact the courier for sample collection 
(see Section 6.3). 

Ensure the subject has an available stool collection kit and shipping box and provide 
instructions on their use, as required (see Section 6.3).

Ensure the subject is comfortable with his or her chosen communication technology
(see Section 6.4).

Ask the subject to contact the site staff or investigator immediately if he or she 
experiences 3 or more unformed stools in any 24-hour period.

Ask the subject to contact the site staff or investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the subject to return for the next study visit.

Complete the source documents.

Complete the CRF.
6.1.4. Visit 4: Month 6 – Vaccination 3 (140 to 168 Days After Visit 2)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination.

Review the subject’s e-diary data and follow up on any ongoing local reactions or 
systemic events.

Ensure that the subject continues to be eligible for the study and does not meet any of the 
withdrawal criteria as described in Section 6.2.

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
Discuss with the subject to determine whether any major protocol violations have 
occurred, as described in Section 6.2.1, and record in source documents.

Based on clinical evaluation, determine whether any AEs or SAEs have occurred since 
the last study visit.  Record and report findings as described in Section 8 and the schedule 
of activities.  Review AEs that were ongoing from the previous visit and record their stop 
dates or confirm if they are still continuing. 

Record nonstudy vaccines and as described in Section 5.9.1.

Measure and record the subject’s oral temperature.

For female subjects of childbearing potential, perform a urine pregnancy test and ensure 
the result is negative prior to vaccination (Section 7.5).

Discuss contraceptive use.

Ensure that none of the temporary delay criteria are met (Section 4.3).

An appropriate site staff member (may be blinded or unblinded) will use the IRT system 
to obtain the subject’s investigational product blinded carton number. 

Unblinded site staff will prepare and administer investigational product. Investigational 
product will be administered by intramuscular injection into the upper deltoid muscle, 
preferably of the nondominant arm. The time of vaccination will be recorded.  Refer to 
the IP manual under separate cover for further instruction on this process.

The unblinded vaccine dispenser/administrator updates the investigational product 
accountability records.

Blinded study staff will observe the subject for at least 30 minutes after investigational 
product administration for any acute reactions.  Any AEs noted during the observation 
period should be recorded in the CRF.

Record and report AEs and SAEs (relative to the time of vaccination) as described in 
Section 8 and the schedule of activities.

Confirm that the subject understands the stool sample collection and shipping 
requirements, including the mechanism to contact the courier for sample collection 
(see Section 6.3). 

Ensure the subject has an available stool collection kit and shipping box and provide 
instructions on their use, as required (see Section 6.3).

Ensure the subject has an available measuring device for measurement of local reactions, 
and a digital thermometer for recording daily temperatures. If required, provide 
instructions on their use.

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
Ensure the subject is comfortable with his or her chosen communication technology
(see Section 6.4).

Remind the subject to complete the e-diary from Day 1 to Day 7, with Day 1 being the 
day of vaccination.

Ask the subject to contact the site staff or investigator immediately if he or she 
experiences 3 or more unformed stools in any 24-hour period.

Ask the subject to contact the site staff or investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the subject to return for the next study visit.

Complete the source documents.

Complete the CRF.
6.1.5. Visit 5: Month 7 (28 to 42 Days After Visit 4)

Review the subject’s e-diary data and follow up on any ongoing local reactions or 
systemic events.

Discuss with the subject to determine whether any major protocol violations have 
occurred, as described in Section 6.2.1, and record in source documents.

Based on clinical evaluation, determine whether any AEs or SAEs have occurred since 
the last study visit.  Record and report findings as described in Section 8 and the schedule 
of activities.  Review AEs that were ongoing from the previous visit and record their stop 
dates or confirm if they are still continuing. 

Record nonstudy vaccines and as described in Section 5.9.1.

Collect a blood sample of approximately 20 mL for immunogenicity testing (Section 7.3).

Confirm that the subject understands the stool sample collection and shipping 
requirements, including the mechanism to contact the courier for sample collection 
(see Section 6.3). 

Ensure the subject has an available stool collection kit and shipping box and provide 
instructions on their use, as required (see Section 6.3).

Ensure the subject is comfortable with his or her chosen communication technology
(see Section 6.4).

Ask the subject to contact the site staff or investigator immediately if he or she 
experiences 3 or more unformed stools in any 24-hour period.

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
Ask the subject to contact the site staff or investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the subject to return for the next study visit.

Complete the source documents.

Complete the CRF.
6.1.6. Visit 6: Month 12 (165 to 195 Days After Visit 4)

Visit 6 is intended to be conducted by telephone but, if desired, may be conducted in 
person.

Discuss with the subject to determine whether any major protocol violations have 
occurred, as described in Section 6.2.1, and record in source documents.

Following the provided script (found in the SRM), contact the subject by telephone to
determine whether any SAEs have occurred since the last study visit.  Record and report 
findings as described in Section 8 and the schedule of activities.  Review AEs that were 
ongoing from the previous visit and record their stop dates or confirm if they are still 
continuing.

Confirm that the subject understands the stool sample collection and shipping 
requirements, including the mechanism to contact the courier for sample collection 
(see Section 6.3). 

Ensure the subject has an available stool collection kit and shipping box and provide 
instructions on their use, as required (see Section 6.3).

Ensure the subject is comfortable with his or her chosen communication technology 
(see Section 6.4).

Ask the subject to contact the site staff or investigator immediately if he or she 
experiences 3 or more unformed stools in any 24-hour period.

Complete the source documents.

Complete the CRF.
6.1.7. Annual Retention Visits (Every 280 to 392 Days After Visit 5)
As the study is event driven, it is imperative that subjects remain engaged and comfortable 
with the study requirements. As the study duration increases, in-person retention visits will 
be used to facilitate this intent. 

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An annual retention visit should be arranged at the earliest opportunity for subjects already 
enrolled in the study, following approval of Amendment 3, and then every 280 to 392 days 
thereafter.
At the time of a retention visit:

At the first annual retention visit or potential CDI visit, whichever comes first following 
approval of Amendment 3, obtain written informed consent to the amendments in the
protocol.  

Discuss with the subject to determine whether any major protocol violations have 
occurred, as described in Section 6.2.1, and record in source documents.

Confirm that the subject understands the stool sample collection and shipping 
requirements, including the mechanism to contact the courier for sample collection 
(see Section 6.3). 

Ensure the subject has an available stool collection kit and shipping box and provide 
instructions on their use, as required (see Section 6.3).

Ensure the subject is comfortable with his or her chosen communication technology 
(see Section 6.4).

Ask the subject to contact the site staff or investigator immediately if he or she 
experiences 3 or more unformed stools in any 24-hour period.

Complete the source documents.

Complete the CRF.
6.1.8. Visit 7: End of Study

Discuss with the subject to determine whether any major protocol violations have 
occurred, as described in Section 6.2.1, and record in source documents.

Telephone the subject and advise him or her that the study has ended.

Instruct the subject how to return the study materials, including a provisioned device, if 
applicable.
6.1.9. At the Time of a Potential CDI Case (Follow-up Related to Each Diarrheal 
Episode)
When the subject experiences 3 or more unformed stools (Bristol stool chart types 5-7) in a 
24-hour period, having collected the third or subsequent stool for provision to the central 
laboratory, he or she is instructed to contact the site. This contact will trigger the following 
procedures that will include at least 1 in-person visit (eg, at the subject’s home, at the study 

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site, or in a medically attended setting) and may necessitate additional telephone follow-up 
with the subject. Information will be recorded in the CRF:

Collect a blood sample of approximately 20 mL (a minimum of 10 mL and up to 20 mL)
for immunogenicity testing (Section 7.3). Optimally, this should be collected within 
48 hours of the third unformed stool (Bristol stool chart types 5-7).

Record any AEs occurring up to 48 hours after the blood draw.

Collect the following information, including but not limited to:
o
Start and stop dates of the diarrheal episode.
o
Total number of unformed stools (Bristol stool chart types 5-7).
o
Type and result of any microbiological test performed locally for detection of 
C difficile and its toxins.
o
Concomitant medications received (see Section 5.9.1). 
o
Number and nature of any non–protocol-related medically attended visits up to 
1 month after the resolution of the episode.
o
Any new diagnosis (since enrollment) of metastatic malignancy, end-stage renal 
disease (glomerular filtration rate <15 mL/min/1.73 m2 or on dialysis), or infection 
with HIV.
o
If hospitalized: serum creatinine, serum albumin, total leukocyte count, results of 
microbiological tests performed for detection of stool pathogens other than C difficile, 
nonmicrobiological diagnostic procedures performed (eg, computed tomography
scan, endoscopy), length of stay, number of days spent in intensive care, requirement 
for mechanical ventilation, presence of renal failure, requirement for parenteral 
nutrition, surgical procedures performed.

Discuss with the subject to determine whether any major protocol violations have 
occurred, as described in Section 6.2.1, and record in source documents.
6.1.10. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 7.2.1.2), systemic event (Section 7.2.1.3), or fever 
(Section 7.2.1.4) is reported in the e-diary, a telephone contact should occur to ascertain 
further details and determine whether a site visit is clinically indicated.
If a suspected Grade 4 local reaction (Section 7.2.1.2), systemic event (Section 7.2.1.3), or 
fever (Section 7.2.1.4) is reported, a telephone contact or site visit should occur to confirm 
whether the event meets the criteria for Grade 4.

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6.2. Subject Withdrawal
Subject eligibility must be confirmed prior to each vaccination in order to continue in the 
study. 
If a subject no longer meets the eligibility criteria during the vaccination period of the study, 
discontinuation of further vaccinations should be considered, but the subject may remain in 
the study and be followed up per the schedule of activities. If a subject no longer meets the 
eligibility criteria after the vaccination period of the study, and is willing to remain in the 
study, the subject may do so and will be followed up per the schedule of activities.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return for a final visit, if applicable, 
and follow up with the subject regarding any unresolved AEs.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
6.2.1. Major Protocol Violations
In order to define the per-protocol analysis populations (Section 9.2), it is important to 
determine which subjects have experienced what may constitute a major protocol violation at 
any time during the study. At each study contact after Visit 1, site staff should record if any 
of the following has occurred:

Subject met exclusion criteria 1, 2, 6, 7, 8, 9, 12, and 13 (Section 4.2).

Subject in whom vaccination was not appropriately delayed following receipt of 
short-term (<14 days) systemic corticosteroids for treatment of an acute illness
(Section 4.3).

Subject received chronic systemic treatment with other known immunosuppressant 
medications, or radiotherapy, through the conclusion of the study (Section 5.9.2).

Subject received systemic corticosteroids (20 mg/day of prednisone or equivalent) for 
14 days through Visit 5 (Month 7) (Section 5.9.2). 

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
Receipt of blood products or immunoglobulins through the conclusion of the study
(Section 5.9.2). 
6.3. Stool Sample Collection
Stool samples (the third or subsequent unformed stool [Bristol stool chart types 5-7] in a 
24-hour period) will be collected in either the subject’s home or a medical setting 
(eg, hospital, nursing home).  Site staff will review the sample collection and shipping 
instructions with each subject and ensure that the subject understands the appropriate 
procedures for collecting and properly packaging stool samples.  All subjects will be 
provided with a stool sample collection kit and shipping box at Visit 1 and with replacement 
kits as needed throughout the study. For some subjects, assistance may be provided for stool 
collection from the subject’s own caregiver, healthcare assistants, community nurses, site 
staff, or equivalent, if required. 
The process for stool collection and transport to the processing center is detailed in the SRM.
6.4. Subject Communication and Use of Technology
In a study of this duration that is event-driven, it is vital to ensure that communication 
between the study site and the subject is maintained to ensure that endpoint events are not 
missed. This study will employ various methods, tailored to the individual subject, to ensure 
that communication is maintained and study information can be transmitted securely. Using 
appropriate technology, a communication pathway between the subject, the site, and the stool 
sample courier will be established. Subjects may be able to utilize their own devices to 
access this technology, or use a device provided by the sponsor. Traditional methods of 
telephone communication will also be available. The technology solution may facilitate:

Contact to the courier for stool sample shipping.

Contact to the investigator.

The subject to record individual unformed stools, and alert the subject of a third 
unformed stool in 24 hours (a diarrheal event).

An alert in the event a subject is hospitalized.

Access to study information, including stool collection instructions.

Visit reminders.

Reminders to ensure stool sample collection and shipping for diarrheal episodes.

Messages of thanks and encouragement from the study team.

A platform for recording local reactions and systemic events (e-diary).

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7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Efficacy Assessments
Any time during the study period that a subject experiences passage of 3 or more unformed 
stools (Bristol stool chart types 5-7) within 24 hours, the subject will be asked to collect the 
third or subsequent stool for provision to the central laboratory.  The subject will be provided 
with a sample collection kit and be instructed on how to package the sample.  The sample 
will be shipped to a processing laboratory.  The processing laboratory will prepare aliquots of 
the stool for later analysis at the central laboratory.
7.1.1. Central Laboratory Testing for Clostridium difficile
All diarrheal specimens submitted to the central laboratory will initially be tested by PCR to 
detect C difficile that harbors TcdB. PCR-positive samples will be tested in a second step for
presence of free toxins (Figure 1).
Figure 1.
Two-Step Testing Algorithm for Determination of Clostridium difficile
Infection Case Definition
Abbreviations: CDI = Clostridium difficile infection; PCR = polymerase chain reaction.

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7.1.1.1. Detection of Toxigenic Clostridium difficile by PCR
A commercially available, Food and Drug Administration (FDA)-approved and Conformité 
Européenne (CE)-marked assay will be used for the rapid detection of toxigenic C difficile
and for the presumptive identification of 027/NAP1/BI strains of toxigenic C difficile from 
the subjects’ stool samples.  The test is designed to detect the toxin B gene (tcdB) sequences 
associated with toxin-producing C difficile. PCR results and the corresponding action taken 
for the tested samples are outlined in Table 2.
Table 2.
Cepheid Xpert C. difficile/Epi Results
Result
Action
Toxigenic C difficile negative; 027 presumptive 
negative
Sample is reported as C difficile negative.  No further 
testing
Toxigenic C difficile positive; 027 presumptive 
negative
Test sample for the presence of free toxins
Toxigenic C difficile positive; 027 presumptive 
positive
Test sample for the presence of free toxins
Invalid
Sample is retested
Note: The Cepheid Xpert C. difficile/Epi is a test for detection and differentiation of Clostridium difficile and 
the epidemic 027 strain.
7.1.1.2. Detection of Free Toxins in the Stool Sample 
The assay used to detect presence of free toxins will be described in the laboratory manual
maintained by the sponsor.
7.1.2. Diagnosis of Pseudomembranous Colitis
The primary CDI case definition can also be met via a definitive demonstration of 
pseudomembranous colitis and corresponding stool sample that is positive for the toxin B 
gene (by PCR) as measured in the central laboratory. The diagnosis of pseudomembranous 
colitis could be made during colonoscopy or surgery or by histopathological examination.
7.2. Safety Assessments
Safety parameters will be assessed as described in the Schedule of Activities, Section 6, 
Section 8, and below. 
A clinical assessment, including medical history, will be performed on all subjects at Visit 1 
to establish a baseline. Significant medical history and observations from any physical 
examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.
Acute reactions within the first 30 minutes after investigational product administration will 
be assessed and documented in the AE CRF.

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The safety parameters also include e-diary reports of local reactions and systemic events that 
occur in the 7 days after investigational product administration.  These prospectively 
collected occurrences of local reactions and systemic events are graded as described in
Section 7.2.1.
7.2.1. Electronic Diary
Subjects will be required to use an e-diary, based on appropriate technology, and will be 
asked to monitor and record local reactions and systemic events for 7 days following 
vaccination. The e-diary allows recording of these assessments only within a fixed time 
window, thus providing the accurate representation of the subject’s experience at that time.  
Data on local reactions and systemic events reported on the e-diary will be transferred 
electronically to a third-party vendor, where they will be available for review by investigators 
and the Pfizer clinicians at all times via an Internet-based portal. E-diary data review is 
ongoing during subject e-diary data-entry periods (7 days after each vaccination) via an 
Internet-based portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronically 
into Pfizer's database for analysis and reporting.  These data do not need to be reported by the 
investigator in the CRF as AEs.
Investigators (or designee) will be required to review the e-diary data online at frequent 
intervals as part of the ongoing safety review.
The investigator or designee must contact the subject in order to obtain stop dates for any 
ongoing local reactions or systemic events on the last day that the e-diary was completed.  
The stop dates should be documented in the source documents and the information entered in 
the CRF.
7.2.1.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as 
described below are derived from the FDA Center for Biologics Evaluation and Research 
(CBER) guidelines on toxicity grading scales for healthy adult volunteers enrolled in 
preventive vaccine clinical trials.62
7.2.1.2. Local Reactions
During the e-diary reporting period, subjects will be asked to assess redness, swelling, and 
pain at the injection site and to record the symptoms in the e-diary.  If a local reaction
persists beyond the end of the e-diary period following vaccination, the subject will be 
requested to report that information.  The investigator will enter this additional information in 
the CRF.
Redness and swelling will be measured and recorded in measuring device units (range: 1 to 
21) and then categorized during analysis as absent, mild, moderate, or severe based on the 
grading scale in Table 3.  Measuring device units can be converted to centimeters according 
to the following formula: 1 measuring device unit = 0.5 cm.  

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Pain at the vaccine injection site will be assessed by the subject as absent, mild, moderate, or 
severe according the grading scale in Table 3.
If a Grade 3 local reaction is reported in the e-diary, a telephone contact should occur to 
ascertain further details and determine whether a site visit is clinically indicated. Only an 
investigator or medically qualified person is able to classify a subject’s local reaction as 
Grade 4. If a subject experiences a confirmed Grade 4 local reaction, the investigator must
immediately notify the sponsor and, if it is determined to be related to the administration of 
the investigational product, further vaccinations will be discontinued in that subject.
Table 3.
Local Reaction Grading Scale
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Pain
Does not interfere 
with activity
Interferes with 
activity
Prevents daily activity Emergency room visit 
or hospitalization for 
severe pain
Erythema/
Redness
2.5 cm to 5.0 cm (5 to 
10 measuring device 
units)
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units)
>10 cm 
(21 measuring 
device units)
Necrosis or 
exfoliative dermatitis
Induration/
Swelling
2.5 cm to 5.0 cm (5 to
10 measuring device 
units)
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units)
>10 cm 
(21 measuring 
device units)
Necrosis
7.2.1.3. Systemic Events
During the e-diary reporting period, subjects will be asked to assess vomiting, headache, 
fatigue, new or worsening muscle pain, and new or worsening joint pain and to record the 
symptoms in the e-diary.  The symptoms will be assessed by the subject as absent, mild, 
moderate, or severe according to the grading scale in Table 4.
If a Grade 3 systemic event is reported in the e-diary, a telephone contact should occur to 
ascertain further details and determine whether a site visit is clinically indicated. Only an 
investigator or medically qualified person is able to classify a subject’s systemic event as 
Grade 4. If a subject experiences a confirmed Grade 4 systemic event, the investigator must
immediately notify the sponsor and, if it is determined to be related to the administration of 
the investigational product, further vaccinations will be discontinued in that subject.
Table 4.
Systemic Event Grading Scale
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Vomiting
1-2 times in 
24 hours
>2 times in 
24 hours
Requires IV 
hydration
Emergency room visit or 
hospitalization for 
hypotensive shock

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Table 4.
Systemic Event Grading Scale
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Headache
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
Emergency room visit or 
hospitalization for severe 
headache
Fatigue/ 
Tiredness
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
Emergency room visit or 
hospitalization for severe 
fatigue
New or 
worsening 
muscle pain
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
Emergency room visit or 
hospitalization for severe 
new or worsening muscle 
pain
New or 
worsening 
joint pain
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
Emergency room visit or 
hospitalization for severe 
new or worsening joint pain
Abbreviation: IV = intravenous.
7.2.1.4. Fever
In order to record information on fever, a digital thermometer will be given to subjects with 
instructions on how to measure oral temperature at home.  Temperature will be collected in 
the e-diary in the evening daily during the e-diary reporting period.  It will also be collected 
at any time during the e-diary data collection periods when fever is suspected.  Fever is 
defined as an oral temperature of 38.0C (100.4F).  The highest temperature for each day 
will be recorded in the e-diary. Temperature will be measured and recorded to 1 decimal 
place and then categorized during analysis according to the scale shown in Table 5.
If a Grade 3 fever is reported in the e-diary, a telephone contact should occur to ascertain 
further details and determine whether a site visit is clinically indicated. Only an investigator 
or medically qualified person is able to classify a subject’s fever as Grade 4. If a subject 
experiences a confirmed Grade 4 fever, the investigator must immediately notify the sponsor 
and, if it is determined to be related to the administration of the investigational product, 
further vaccinations will be discontinued in that subject.
Table 5.
Scale for Fever
Mild (Grade 1)
38.0-38.4C (100.4-101.1F)
Moderate (Grade 2)
38.5-38.9C (101.2-102.0F)
Severe (Grade 3)
39.0-40.0C (102.1-104.0F)
Potentially Life Threatening (Grade 4)
>40.0C (>104.0F)

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7.4. Other Assessments
At the time of a diarrheal episode, the site will complete a questionnaire with the subject to 
collect information on severity, duration, treatment of, and healthcare utilization associated 
with the episode.
7.5. Pregnancy Testing
For female subjects of childbearing potential, a urine pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed immediately before administration of each vaccine dose.  
A negative pregnancy test result is required before the subject may receive the investigational 
product. Pregnancy tests may also be repeated if requested by institutional review boards 
(IRBs)/ethics committees (ECs) or if required by local regulations. In the case of a positive 
confirmed pregnancy, the subject will be withdrawn from administration of investigational 
product but may remain in the study.
Urine pregnancy tests must be sensitive to at least 25 mIU/mL and will be conducted with the 
test kit provided by the sponsor in accordance with instructions provided in its package 
insert.  Subjects who have missed a menstrual period or who show an indeterminate or 
positive result on the qualitative point-of-service urine test may not further progress in the 
study until pregnancy is ruled out using further diagnostic testing (eg, a negative quantitative 
serum pregnancy test conducted at a certified laboratory).
CCI
CCI
CCI
CCI

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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious AEs; and (3) exposure to the investigational product under study during 
pregnancy or breastfeeding, and occupational exposure.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the investigational 
product under study during 
pregnancy or breastfeeding, and 
occupational exposure
All (regardless of whether associated 
with an AE), except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure (regardless of 
whether associated with an AE)
All observed or volunteered events regardless of vaccine group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  
CCI

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This time frame also applies to additional new (follow-up) information on previously 
forwarded reports.  In the rare situation that the investigator does not become immediately 
aware of the occurrence of an event, the investigator must report the event within 24 hours 
after learning of it and document the time of his/her first awareness of the event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology, and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject. In addition, each study subject will be questioned about the 
occurrence of AEs in a nonleading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.

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8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any study-
related procedure and/or receiving investigational product). All AEs are collected through 
and including Visit 5 (Month 7). Additionally, SAEs are collected between Visit 5 (Month 
7) through Visit 6 (Month 12), as elicited by telephone.
In addition, any AE occurring up to 48 hours after each subsequent blood draw (ie, after 
Visit 5 [Month 7] and at the time of a diarrheal episode) must be recorded on the CRF.
Diarrheal episode AEs must also be recorded on the CRF throughout the study.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety. If an SAE is reported after subject Visit 6, all the 
requirements will apply, including the respect of the reporting timelines as if the SAE 
occurred within the reporting period.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Nonserious AEs and SAEs on the CRF
During the active collection period, both nonserious AEs and SAEs are recorded on the CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
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If the investigator does not know whether or not the investigational product caused the event, 
then the event will be handled as “related to investigational product” for reporting purposes, 
as defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records.
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

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
Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.

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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.
Medical device complaints may meet the SAE reporting requirement criteria (see the Medical 
Device Complaint Reporting Requirements section).  An incident is any malfunction (ie, the 
failure of a device to meet its performance specifications or to perform as intended; 
performance specifications include all claims made in the labeling for the device) that, 
directly or indirectly, might lead to or might have led to the death of a subject, or user, or of 
other persons, or to a serious deterioration in their state of health.  
A serious injury that can cause a serious deterioration in state of health can include:

A life-threatening illness, even if temporary in nature;

A permanent impairment of a body function or permanent damage to a body 
structure; 

A condition necessitating medical or surgical intervention to prevent the above 
2 bulleted items;
Examples: clinically relevant increase in the duration of a surgical procedure; a 
condition that requires hospitalization or significant prolongation of existing 
hospitalization;

Any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;

Fetal distress, fetal death, or any congenital abnormality or birth defects.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.

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Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.

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8.3. Severity Assessment
GRADE 
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, SEVERE, or LIFE-THREATENING to describe the maximum intensity of the 
AE. For purposes of consistency, these intensity grades are defined as follows:
1
MILD
Does not interfere with subject's usual function.
2
MODERATE
Interferes to some extent with subject's usual function.
3
SEVERE
Interferes significantly with subject's usual function.
4
LIFE-
THREATENING
Life-threatening consequences; urgent intervention indicated.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database.
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to assess LFTs because a subject 
presents with clinical signs/symptoms, such LFT results should be managed and followed as 
described below.
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same laboratory
sample).  In rare instances, by the time TBili elevations are detected, AST/ALT values might 
have decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 

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elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:
o
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).
o
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × 
ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase, and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 

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collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed during 
his partner’s pregnancy.
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).

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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  
In the case of a live birth, the structural integrity of the neonate can be assessed at the time of 
birth.  In the event of a termination, the reason(s) for termination should be specified and, if 
clinically possible, the structural integrity of the terminated fetus should be assessed by gross
visual inspection (unless preprocedure test findings are conclusive for a congenital anomaly 
and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.

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An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.  
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Other examples include, but are not limited to:

The administration of expired investigational product;

The administration of an incorrect investigational product;

The administration of an incorrect dosage;

The administration of investigational product that has undergone temperature 
excursion from the specified storage range, unless it is determined by the sponsor that 
the investigational product under question is acceptable for use.
Such medication errors occurring to a study subject are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.

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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Medical Device Complaint Reporting Requirements
All medical device complaints, regardless of whether the medical device complaint is 
associated with an AE, will be reported by a member of unblinded site staff as described in the 
IP manual.  This includes potential incidents or malfunctions associated with the use of a 
medical device product.  An incident or malfunction is an event that might have led to death 
or serious deterioration in health, or if it occurred again might lead to death or serious 
deterioration in health.
Pfizer is to be notified of all medical device complaints within 24 hours of the investigator’s 
awareness of the event.
9. DATA ANALYSIS/STATISTICAL METHODS
The methodology for summary and statistical analyses of the data collected in this study is 
outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor. The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment. Supplemental analyses of the 
primary, secondary, immunogenicity, and safety data may be performed as required for local 
regulatory jurisdictions (for example, analyses by age, sex, ethnicity, risk status prior to 
vaccination) and will be prespecified in the SAP. 
The SAP will be finalized prior to any analyses being undertaken.
9.1. Sample Size Determination
This study is placebo-controlled, event-driven, and randomized with a 1:1 randomization 
ratio between subjects receiving C difficile vaccine and placebo.
With assumptions of a true adjusted VE of 66.5% after 3 doses of investigational product, 
66 first primary CDI cases (meeting case definition 1 in the per-protocol-3 population 
Section 2.1.1 and Section 9.2.1) will provide 89.8% power to conclude true VE of >20%,
taking into consideration 3 interim analyses (Section 9.5) during the study.  
The early efficacy stopping boundaries are based on a GS design65 utilizing a single-binomial 
distribution, conditional on a total of 66 cases, assuming true VE of 66.5%, with 3 interim 
analyses at 30, 40 and 50 cases.65  The same gamma[-2] alpha spending function that was 
used for the original statistical design is also used for this modified statistical design.  

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As this is an event-driven and GS study, the total enrollment number may vary depending on 
the assumptions of incidence rate of the primary endpoint, true VE, and potential early stop 
for efficacy or futility. 
Update as Part of Amendment 2 (January 2019):
Based on the ongoing blinded review of pooled primary CDI events, the annual CDI 
incidence rate in the placebo group may be different from the assumed rate in the 
power calculation during the initial study design. Additional enrollment may be 
needed in order to maintain the study power of 90% (106 first primary CDI cases in 
the final analysis) to reject the null hypothesis of VE ≤20%. Assuming a true VE of 
60% after 3 doses of investigational product and the true annual CDI rate in the 
placebo group of 0.552% to 0.516%, which is 8 to 14% lower than the previously
assumed 0.6%, an additional 1369 to 2566 subjects may be needed to ensure the 
required number of first primary CDI cases. 
In light of this, it is planned to enroll approximately 1700 additional subjects, giving a 
total of approximately 17,476 subjects. The pooled primary CDI event rate for the 
total population will continue to be monitored by the study team in a blinded manner 
and a further adjustment to enrollment may be required.
Update as Part of Amendment 4 (July 2020):
The statistical design is being modified to perform all the analyses with fewer cases 
than originally planned.  Two (2) additional interim analyses will be included based 
on the estimated disease rate from the blinded data review, and the assumption 
regarding true VE is modified to 68%, and is further adjusted to 66.5% after 3 doses 
of investigational product because of the impact of actual specificity (99.1%) and 
sensitivity (95.7%) of Pfizer’s cell cytotoxicity neutralization assay.66  
The pooled primary CDI event rate for the total population will continue to be 
monitored by the study team in a blinded manner and a further adjustment to 
enrollment may be required.
As specified in Section 3.1, the pooled primary CDI event rates in different age groups, 
inclusion criteria subgroups, CCI61 subgroups, and other baseline factors will be monitored in 
a blinded manner. Once the specified minimum numbers in each age group have been 
achieved, if a substantially higher pooled CDI event rate is observed in some subgroups, the 
intention may be to stop enrollment in lower-risk subgroups and complete enrollment with 
the higher-risk subgroups thereafter. This is mainly to help to achieve the targeted total 
number of first primary cases in a timely manner. As none of the potential adjustments will 
be based on the observed VE of the ongoing study, and the targeted total number of first 
primary CDI cases will remain the same, the distribution of the test statistic for the primary 
endpoint under the null hypothesis will not be affected and no alpha adjustment will be 
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For the second primary hypothesis test, it is expected that more than 66 cases for the final 
analysis will occur after 2 or more doses because of the nature of the endpoint.  Any 
additional first primary CDI cases occurring in the interval between Doses 2 and 3 will result 
in greater than 90% power to conclude true VE of >20% after 2 or more doses of vaccine 
assuming the vaccine first successfully demonstrates VE of >20% following 3 doses of 
vaccine.
9.2. Efficacy Analysis
All of the following VE analyses assume correct classification of suspected CDI cases for all 
case definitions.
Five (5) analysis populations (per-protocol-2, per-protocol-3, mITT-1, mITT-2, and mITT-3) 
will be defined for VE analyses.

The per-protocol-2 population will include all randomized subjects who received at 
least 2 doses of the investigational product to which they were randomized and had 
no major protocol violations up to and including 14 days after Dose 2.

The per-protocol-3 population will include all randomized subjects who received all 
3 doses of the investigational product to which they were randomized and had no 
major protocol violations up to and including 14 days after Dose 3. 

The mITT-1 population will include all randomized subjects who received at least 
1 dose of investigational product.

The mITT-2 population will include all randomized subjects who received at least 
2 doses of investigational product. 

The mITT-3 population will include all randomized subjects who received all 3 doses 
of investigational product. 
The per-protocol-2 and per-protocol-3 populations will be the primary populations for 
efficacy analyses accounting for the time interval after dosing as given in Table 6 and will be 
used for analyzing VE endpoints.  The mITT-1, mITT-2, and mITT-3 populations will be 
supportive populations for efficacy analyses and will be used for analyzing VE endpoints 
from immediately or 14 days after receipt of each dose of investigational product.
9.2.1. Analysis of the Primary Endpoints
VE is defined as VE = 100 × (1 – IRR), where IRR is the infection rate ratio, the calculated 
ratio of first primary CDI incidence between the C difficile vaccine group and the placebo 
group. VEi will be evaluated separately after 3 and after 2 doses. The 2 primary efficacy 
hypotheses are (in order of fixed-sequence testing):
1. H03: VE3 20% vs Ha3: VE3 >20%, and
2. H02: VE2 20% vs Ha2: VE2 >20%.

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where H0i and Hai represent null hypothesis and alternative hypothesis, and VEi (i = 2, 3) 
represents VE after at least 2 doses and after all 3 doses, respectively. For subjects with 
multiple primary CDI cases, only the first primary case will contribute to the VE calculation 
in each hypothesis test.
The primary efficacy hypotheses will be tested by a 1-sided test for VE >20% by a 
fixed-sequence testing procedure, with testing order of H03 followed by H02 using the 
approach described in Chan and Bohidar,63 accounting for follow-up time after vaccination.  
Statistical inference will be based on the lower alpha-adjusted confidence interval (CI) for 
VE3. and VE2. 
If the study continues after all 3 of the interim analyses, once 66 first primary cases after 
3 doses have accumulated for the final analysis, the hypothesis test H03 will be performed 
first, and the null hypothesis H03 will be rejected if there are 20 or fewer cases observed in 
the C difficile vaccine group (corresponding to a 2-sided lower bound of 96.4% exact CI 
>20%), assuming equal follow-up times. The lower bound of the 2-sided 96.4% exact CI 
corresponds to α=0.018 (one-sided) used for final testing in a GS design with a gamma(-2) 
efficacy boundary. Only if the hypothesis H03 is rejected, then hypothesis testing for H02 will 
be performed, at the same significance level for VE2 for the final analysis. The statistical 
success criterion for H02 also corresponds to the lower bound of the 2-sided 96.4% CI for VE 
being >20%. If there is failure to reject the hypothesis H03, the hypothesis test H02 will not be 
performed. 
The statistical analysis specifications for the primary endpoints are summarized in Table 6.
Table 6.
Statistical Analysis Specifications for the Primary Endpoints
Primary
Endpoints
Time Period for 
Case Accrual 
CDI Case 
Definition 
Analysis 
Population 
Hypothesis 
Testinga
Statistical 
Testing Method
CDI incidence of a 
first primary
episode per 1000 
person-years of 
follow-up
From 14 days after 
receipt of third 
dose of 
investigational 
product onwards
1
Per-protocol-3
(primary)
H03
Exact binomial, 
incidence rate 
CDI incidence of a 
first primary 
episode per 1000 
person-years of 
follow-up
From 14 days after 
receipt of third 
dose of 
investigational 
product onwards
1
mITT-3
(supportive)
H03
Exact binomial, 
incidence rate 
CDI incidence of a 
first primary 
episode per 1000 
person-years of 
follow-up
From immediately 
after receipt of 
third dose of 
investigational 
product onwards
1
mITT-3
(supportive)
H03
Exact binomial, 
incidence rate 
CDI incidence of a 
first primary 
episode per 1000 
person-years of 
follow-up
From 14 days after 
receipt of second 
dose of 
investigational 
product onwards
1
Per-protocol-2
(primary)
H02
Exact binomial,
incidence rate 

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Table 6.
Statistical Analysis Specifications for the Primary Endpoints
Primary
Endpoints
Time Period for 
Case Accrual 
CDI Case 
Definition 
Analysis 
Population 
Hypothesis 
Testinga
Statistical 
Testing Method
CDI incidence of a 
first primary 
episode per 1000 
person-years of 
follow-up
From 14 days after 
receipt of second 
dose of 
investigational 
product onwards
1
mITT-2
(supportive)
H02
Exact binomial,
incidence rate 
CDI incidence of a 
first primary 
episode per 1000 
person-years of 
follow-up
From immediately 
after receipt of 
second dose of 
investigational 
product onwards
1
mITT-2
(supportive)
H02
Exact binomial,
incidence rate 
Abbreviations: CDI = Clostridium difficile infection; mITT = modified intent-to-treat.
a.
For the per-protocol populations, hypotheses H02 and H03 will be tested in the fixed order of H03 followed 
by H02.
9.2.1.1. Multiplicity Control for the Primary Endpoints
There are 2 primary efficacy hypotheses; H03, followed by H02, if H03 is rejected. The study 
will be considered successful if H03 is rejected.
There are 2 sources of multiplicity in the study. First, there are repeated analyses of the 
primary hypothesis H03, at the interim and final analyses. Alpha adjustment due to the 
planned interim analyses is explained in Section 9.5. The second source of multiplicity is the 
existence of multiple primary hypotheses. The overall type I error rate for all primary 
hypotheses is controlled by the fixed -sequence testing procedure as described in 
Section 9.2.1. Testing hypothesis H02 will be considered as final analysis at the type I error 
of 0.018 only if H03 is rejected and a decision is made to proceed to the final analysis. 
9.2.2. Analysis of the Secondary Endpoints
9.2.2.1. Analysis of the Secondary Efficacy Endpoints
The analyses of the secondary efficacy endpoints will be performed based on a variety of 
CDI case definitions, detailed in Section 2.1, after the primary objectives are met. For the 
endpoints that combine data for subjects who fulfill case definition 1 and subjects who fulfill
case definition 3, or case definitions 2 and 4, each subject will contribute only once to the 
analysis.
In the evaluation of the efficacy of 2 doses of C difficile vaccine, only cases starting after the 
receipt of the second dose but prior to the receipt of the third dose of investigational product
will contribute to the VE calculation. 
In order to control overall Type I error, and specifically the Type I error for the evaluation of 
the secondary objectives, an alpha level of 0.018 (one-sided) for the final analysis is split 
equally (the Bonferroni correction, alpha = 0.009, for each family evaluation) for the 
evaluation of the secondary objectives between the 3-dose family and the 2-dose family 
(at-least-2-dose/only-2-dose), after primary objectives are met.

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Furthermore, within each family, the endpoints will be evaluated sequentially; that is, the 
subsequent endpoint is evaluated only if the criteria are met for the previous endpoints.
The analysis and the success criteria for the secondary objective evaluation are outlined 
below:
•
For evaluating C difficile vaccine in reducing the incidence of CDI cases, the lower 
limit (LL) of 98.2% CI (2-sided) for VE > 0.
•
For evaluating the efficacy of Pfizer’s C difficile vaccine in reducing the severity of 
CDI in terms of the duration, the upper limit (UL) of 98.2% CI (2-sided) < 0 for the 
difference in mean duration of CDI between the vaccine group and the control group.
•
For evaluating the efficacy of Pfizer’s C difficile vaccine in reducing the severity of 
CDI in terms of the risk ratio, the UL of 98.2% CI (2-sided) < 1.0 for the ratio of the 
proportion of subjects experiencing CDI who have a non-protocol-related medically 
attended visit in the vaccine group to the proportion of the subjects in the control
group.
 
 
 
 
 
 
 
 
 
 
 
9.4. Safety Analysis
The safety population will include all subjects who receive at least 1 dose of investigational 
product. The safety population for reactogenicity analysis after each dose will include
subjects who received that dose and have e-diary information available. For safety analysis, 
subjects will be analyzed according to the investigational product received.
CCI
CCI

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AEs will be categorized according to Medical Dictionary for Regulatory Activities 
(MedDRA) and will be summarized by vaccine group. All summaries of AEs will show the 
number and percentage of subjects experiencing at least 1 event and the number of events for 
each vaccine group. Two (2)-sided 95% CIs based on the Clopper-Pearson method will be 
presented for (S)AE percentages.
A 3-tier approach will be used to summarize AEs. Under this approach, AEs are classified 
into 1 of 3 tiers:

Tier 1 events: These are prespecified events of clinical importance and are maintained 
in a list in the product’s Safety Review Plan.

Tier 2 events: These are events that are not tier 1 but are “common.” A MedDRA 
preferred term is defined as a tier 2 event if there is an incidence of at least 1% in any 
vaccine group.

Tier 3 events: These are events that are neither tier 1 nor tier 2 events.
The Miettinen and Nurminen method64 will be used to derive the 95% CI for the risk 
difference between C difficile vaccine and placebo for the above tier 1 and tier 2 events. The 
p-value from Miettinen and Nurminen method will also be provided for tier 1 events.
9.4.1. Reactogenicity 
The proportion of subjects reporting local reactions at the injection site and systemic events 
on any day within the 7-day period after vaccination will be descriptively summarized by 
vaccine group.
Severities of local reactions and systemic events reported after each vaccination will also be 
descriptively summarized by vaccine group. Two (2)-sided 95% CIs based on the 
Clopper-Pearson method will be presented with the proportions. 
9.5. Interim Analysis
Three (3) planned formal interim analyses will be performed by the independent statistical 
team (IST) to assess whether there is overwhelming efficacy or futility with respect to the 
end-of-study success criterion.
The first, second, and third interim analyses are planned after 30, 40, and 50 first primary 
CDI cases have occurred from 14 days after receipt of the third dose of investigational 
product, respectively. The data cutoff date will be the calendar date of the confirmed 30th, 
40th, or 50th cases of first primary CDI occurring 14 days after the third dose by the central 
laboratory. Only the first primary efficacy endpoint will be examined. The statistical 
hypotheses testing (H03) will be performed on interim data; H02 will be tested if H03 is 
rejected and a decision is made to proceed the final analysis

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The early efficacy stopping boundary is derived on a GS design65 (utilizing a single-binomial 
distribution, conditional on the total number of 66 cases, with 3 interim analyses at 45% 
[30 out of 66], 61% [40 out of 66], and 76% [50 out of 66] of information and a gamma[-2]
alpha spending function).
The GS design from EAST (software package for clinical trial design) is based on normal 
approximation to binomial distribution, and EAST was used as a starting point to calculate 
GS design boundaries. Those were later converted into discrete boundaries (expressed as 
numbers of cases rather than proportions of cases coming from a vaccine group, given the 
total number of cases).
If there are 6 or fewer cases observed in the C difficile vaccine group out of a total of 30 first
primary cases (point estimate of VE ≥75.0% and corresponding to a lower bound of 2-sided
98.8% exact CI >20%), the null hypothesis in H03 will be rejected, the C difficile vaccine will 
be deemed efficacious, and a full analysis of the data will be conducted. 
If there are 9 or fewer cases observed in the C difficile vaccine group out of a total of 40 first 
primary cases in the second interim analysis (point estimate of VE ≥71.0% and 
corresponding to a lower bound of 2-sided 98.8% exact CI >20%), the null hypothesis in H03
will be rejected, the C difficile vaccine will be deemed efficacious, and a full analysis of the 
data may be conducted.  
If there are 13 or fewer cases observed in the C difficile vaccine group out of a total of 
50 first primary cases in the third interim analysis (point estimate of VE ≥64.9% and 
corresponding to a lower bound of 2-sided 98.2% exact CI >20%), the null hypothesis in H03
will be rejected, the C difficile vaccine will be deemed efficacious, and a full analysis of the 
data may be conducted.  
Of note, using the lower bound of a 2-sided 98.8% CI corresponds to α=0.006 (one-sided) 
used for the first and second interim analyses; the lower bound of a 2-sided 98.2% CI 
corresponds to α=0.009 (one-sided) for the third interim analysis.
The probabilities of stopping the trial for success are 44.3% at interim analysis 1 (ie, observe 
6 cases in the C difficile vaccine group), 15.0% at interim analysis 2 (ie, observe 9 cases in 
the C difficile vaccine group), and 17.1% at interim analysis 3 (ie, observe 13 cases in the 
C difficile vaccine group) if the true VE is 70%. 
Study futility at each interim analysis will be evaluated based on the pre-identified case split 
(C difficile vaccine vs placebo) by analysis of conditional power (CP) approach. The 
conditional probability of study success at the final analysis with observed VE of at least 
59.6% (19 out of 66 cases) is calculated based on an assumed case split in the C difficile
vaccine group and the assumption that an adjusted true VE of 66.5% remains for the rest of 
the study. The case split for futility is 11 versus 19 for IA1 (corresponding to a CP cutoff of 
50% at 30 cases), 13 versus 27 for IA2 (corresponding to a CP cutoff of 60% at 40 cases),
and 16 versus 34 for IA3 (corresponding to a CP cutoff of 60% at 50 cases).

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These futility boundaries may be subject to change to reflect subsequent program-related 
decisions by the Sponsor.  
The probability of stopping the trial because of futility is 6.6% at interim analysis 1 
(ie, observe ≥11 cases in the C difficile vaccine group), 5.8% at interim analysis 2
(ie, observe ≥13 cases in the C difficile vaccine group), and 2.0% at interim analysis 3 
(ie, observe ≥16 cases in the C difficile vaccine group), if the true VE is 70%.
The overall probability of success is at least 84.8% if the true VE is 70%.
Additional futility assessments for the study might be carried out at the time of external data 
monitoring committee (E-DMC) meetings. Full details of the futility assessment will be 
provided in the SAP.
There is no impact on the overall type I error rate for futility analyses performed for the 
study.
Additional design operating characteristics (stopping boundary based on the number of cases 
observed in the C difficile vaccine group; the probabilities of stopping for efficacy and 
futility given assumed various VEs with a 1:1 randomization ratio) are listed in Table 7.
Table 7.
Statistical Design Operating Characteristics
Interim Analysis #1
(Total Cases = 30)
Interim Analysis #2
(Total Cases = 40)
Interim Analysis #3
(Total Cases = 50)
Final Analysis
(Total Cases = 66)
Vaccine 
Efficacy 
(%)
Probability 
of Success
(Cases in 
C difficile
Vaccine 
Group 6)
Probability 
of Failure
(Cases in 
C difficile
Vaccine 
Group 
11)
Probability 
of Success
(Cases in 
C difficile
Vaccine 
Group 9)
Probability 
of Failure
(Cases in 
C difficile
Vaccine 
Group 
13)
Probability 
of Success
(Cases in 
C difficile
Vaccine 
Group 13)
Probability
of Failure
(Cases in 
C difficile
Vaccine 
Group 
)
Probability 
of Success 
(Cases in 
C difficile
Vaccine 
Group 
20)
Probability 
of Failure 
(Cases in 
C difficile
Vaccine 
Group 21)
Overall 
Probability 
of Success
0
20
50
60
0.0007
0.0047
0.0838
0.2039
0.9506
0.8512
0.4152
0.2146
0.0002
0.0017
0.0397
0.0909
0.0416
0.1066
0.2032
0.1490
0.0003
0.0029
0.0721
0.1424
0.0050
0.0211
0.0709
0.0557
0.0002
0.0033
0.0739
0.1134
0.0014
0.0085
0.0410
0.0300
0.0014
0.0126
0.2696
0.5507
70
0.4427
0.0656
0.1496
0.0583
0.1711
0.0202
0.0845
0.0080
0.8479
80
0.7765
0.0067
0.1207
0.0063
0.0730
0.0015
0.0149
0.0003
0.9852
Note: Assumes 95.7% assay sensitivity and 99.1% assay specificity.  Assumes equal follow-up times between 
vaccine groups.

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Should the actual amount of information observed at interim analysis be more than the 
planned information capture for each interim analysis, the first targeted primary cases will be 
used for the analysis. 
9.6. Data Monitoring Committee
This study will use an E-DMC. 
The E-DMC will be responsible for ongoing monitoring of VE, futility, and safety of subjects 
in the study according to the charter. The E-DMC may review unblinded data during closed 
meeting sessions; however, the sponsor will remain blinded and will not be permitted access 
to the randomization assignments until the database is locked.
The E-DMC will review efficacy/futility and safety data at defined intervals as specified in 
the charter. The E-DMC may conduct additional meetings to review safety data at other time 
points during the study, at its discretion, or at the request of the sponsor. In addition, as 
determined by the sponsor clinician, the E-DMC may meet on an ad hoc basis to evaluate 
any SAEs related to vaccination, or related AEs that may jeopardize further subject 
participation, in order to determine that the study may be continued safely.
The E-DMC will work in association with the IST in order to conduct both the safety and 
futility/efficacy evaluations. The IST will include statistician(s) and programmer(s) who are 
independent of the sponsor and who have unrestricted access to the randomization 
assignments during the study. The IST will perform statistical analysis and prepare 
unblinded data and reports to provide to the E-DMC for assessment in accordance with the 
E-DMC charter. The IST will report the outcome of the planned futility checks (only 
whether the futility rule has been passed or not) to the sponsor and the E-DMC separately.
After each meeting, the E-DMC will make recommendations that may include the following: 
continue the study with or without modification, pause or stop vaccination for safety or other 
reasons, or pause or stop the study for efficacy or futility (assessed at an efficacy/futility 
meeting only).
The recommendations made by the E-DMC to alter the conduct of the study will be 
forwarded to Pfizer for final decision. Information on the current efficacy cases (numbers
occurring in the C difficile vaccine and placebo groups) will not be disclosed until a decision 
is made to permanently stop the study. Pfizer will forward such decisions, which may 
include summaries of aggregate analyses of endpoint events and of safety data that are not 
endpoints, to regulatory authorities, as appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and 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.

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During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.

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11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
ICDs, copies of all CRFs, safety reporting forms, source documents, and detailed records of 
treatment disposition, and adequate documentation of relevant correspondence (eg, letters, 
meeting minutes, and telephone call reports).  The records should be retained by the 
investigator according to the ICH guidelines, according to local regulations, or as specified in 
the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer.
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, ICDs, and other relevant documents, eg, recruitment advertisements, if 
applicable, from the IRB/EC.  All correspondence with the IRB/EC should be retained in the 
investigator file.  Copies of IRB/EC approvals should be forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.

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When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The investigator
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed. The investigator 
will retain the original of each subject's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.
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 a Member State
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as database lock.

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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 
C difficile vaccine at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 28 days.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.

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www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed. If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication. However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
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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26.
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Zhou Y, Burnham CAD, Hink T, et al. Phenotypic and genotypic analysis of 
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Kotloff KL, Wasserman SS, Losonsky GA, et al.  Safety and immunogenicity of 
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Aboudola S, Kotloff KL, Kyne L, et al.  Clostridium difficile vaccine and serum 
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Anonymous. Study of candidate Clostridium difficile toxoid vaccine (Cdiffense) in 
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Tian JH, Fuhrmann SR, Kluepfel-Stahl S, Carman RJ, Ellingsworth L, Flyer DC.  A 
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Anonymous. Dose-confirmation, immunogenicity and safety study of the Clostridium 
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Sheldon E, Kitchin N, Peng Y, et al. A phase 1, placebo-controlled, randomized study 
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Appendix 1. Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AE
adverse event
AlOH
aluminum hydroxide
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATLAS
age, treatment with systemic antibiotics during Clostridium difficile
infection therapy, leukocyte count, serum albumin, and serum creatinine
CBER
Center for Biologics Evaluation and Research
CCI
Charlson Comorbidity Index
CDI
Clostridium difficile infection
CE
Conformité Européenne
CI
confidence interval
CK
creatine kinase
CP
conditional power
CRA
clinical research associate
CRF
case report form
CSA
clinical study agreement
CT
clinical trial
CTA
clinical trial application
DILI
drug-induced liver injury
DU
dispensable unit
EC
ethics committee
e-diary
electronic diary
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
ELISA
enzyme-linked immunosorbent assay
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GMFR
geometric mean fold rise
GS
group-sequential
HIV
human immunodeficiency virus 
IB
investigator's brochure
ICD
informed consent document 

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Abbreviation
Term
ICH
International Conference on Harmonisation
ID
identification
IgG
immunoglobulin G
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRR
infection rate ratio
IRT
interactive response technology
IST
independent statistical team
IUD
intrauterine device
IWR
interactive Web-based response
LFT
liver function test
LL
lower limit
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
N/A
not applicable
PCD
primary completion date
PCR
polymerase chain reaction
PFGE
pulsed-field gel electrophoresis
PI
principal investigator 
PT
prothrombin time 
SAE
serious adverse event
SAP
statistical analysis plan
SRM
study reference manual
SRSD
single reference safety document
TBili
total bilirubin
TcdA
Clostridium difficile toxin A
TcdB
Clostridium difficile toxin B
UL
upper limit
ULN
upper limit of normal
US
United States
VE
vaccine efficacy

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Appendix 2. Bristol Stool Chart

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Appendix 3. France Appendix
This appendix applies to study sites located in France.
1.
GCP Training
Prior to enrollment of any subjects, the investigator and any subinvestigators will complete 
the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP Training”) or 
training deemed equivalent by Pfizer. Any investigators who later join the study will 
complete the Pfizer GCP Training or equivalent before performing study-related duties. For 
studies of applicable duration, the investigator and subinvestigators will complete Pfizer GCP 
Training or equivalent every three years during the term of the study, or more often if there 
are significant changes to the ICH GCP guidelines or course materials.
2.
Investigational Product
No subjects or third-party payers will be charged for investigational product.

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Appendix 4. Japan Appendix
The following supplementary text should be read in conjunction with the B5091007 protocol:

An oral temperature of 37.5C meets the definition of a current febrile illness in the 
criteria for temporarily delaying vaccine administration described in Section 4.3 for 
subjects enrolled in Japan.

For the 2nd bulleted part of inclusion criterion 4, it is clarified that in Japan, subjects may 
be enrolled if, in the previous 12 months, they have had at least 2 emergency room visits 
for urgent or acute care.

For the 3rd bulleted part of inclusion criterion 4, (under protocol amendments 1, 2, and 3) 
it is clarified that in Japan that “primary and/or secondary care visits” may have been 
undertaken in any type of healthcare facilities (primary, secondary [or tertiary]) for care 
directed by a physician.  Note; Pharmacy and/or mental health visits do not count toward 
the 10 outpatient visits required under this criterion.

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