A PHASE 3, RANDOMIZED OBSERVER-BLINDED STUDY TO EVALUATE THE IMMUNOGENICITY, SAFETY, AND TOLERABILITY OF 2 DOSES COMPARED TO 3 DOSES OF CLOSTRIDIUM DIFFICILE VACCINE IN ADULTS 50 YEARS OF AGE AND OLDER
Phase: PHASE3
Conditions: Clostridium Difficile Associated Disease
Sponsor: Pfizer

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A PHASE 3, RANDOMIZED, OBSERVER-BLINDED STUDY TO EVALUATE THE 
IMMUNOGENICITY, SAFETY, AND TOLERABILITY OF 2 DOSES COMPARED 
TO 3 DOSES OF 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:
Protocol Number:
B5091019
Phase:
3
Short Title: C difficile Vaccine 2- Versus 3-Dose Noninferiority Study
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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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Protocol 
Amendment 1
02 May 2019
Following regulatory consultation, the 
following were added:

A coprimary estimand of 
seroresponse difference at Month 7.

A secondary estimand of the 
seroresponse difference at Month 
12.

A noninferiority comparison of 
dosing regimens by age group. 
Increased the number of participants to 
support the analysis for the coprimary 
immunogenicity estimands in order to meet 
the study’s primary immunogenicity 
objective. The enrollment period has been 
extended to allow for the recruitment of the 
additional participants; therefore, the study 
duration has also increased.
Added a visit at Month 9 for 
immunogenicity blood draw to provide
more information on the immune response 
over time.
Original protocol
18 October 2018
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country heath authorities and institutional review boards (IRBs)/ethics committees 
(ECs).

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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities (SoA)...................................................................................13
2. INTRODUCTION ...............................................................................................................15
2.1. Study Rationale .......................................................................................................15
2.1.1. Mechanism of Action/Indication................................................................15
2.2. Background .............................................................................................................15
2.2.1. Clostridium difficile Disease Background..................................................15
2.2.2. Clostridium difficile Vaccine Development Rationale...............................17
2.2.3. Clostridium difficile Vaccine Candidate.....................................................17
2.2.3.1. Preclinical Development ...........................................................18
2.2.3.2. Clinical Development................................................................18
2.3. Benefit/Risk Assessment.........................................................................................20
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................22
4. STUDY DESIGN.................................................................................................................25
4.1. Overall Design.........................................................................................................25
4.1.1. Approximate Number of Participants.........................................................25
4.1.2. Approximate Duration of the Study ...........................................................25
4.1.3. Approximate Duration of Participation for Each Participant .....................25
4.2. Scientific Rationale for Study Design.....................................................................26
4.3. Justification for Dose ..............................................................................................26
4.4. End of Study Definition ..........................................................................................26
5. STUDY POPULATION......................................................................................................27
5.1. Inclusion Criteria.....................................................................................................27
5.2. Exclusion Criteria....................................................................................................28
5.2.1. Criteria for Temporary Delay of Vaccination ............................................29
5.3. Lifestyle Considerations..........................................................................................30

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5.3.1. Contraception..............................................................................................30
5.4. Screen Failures ........................................................................................................30
6. STUDY INTERVENTION..................................................................................................30
6.1. Study Intervention(s) Administered........................................................................31
6.1.1. Administration............................................................................................32
6.1.2. Medical Devices .........................................................................................33
6.2. Preparation/Handling/Storage/Accountability ........................................................33
6.2.1. Preparation and Dispensing........................................................................34
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................35
6.3.1. Allocation to Investigational Product .........................................................35
6.3.2. Blinding of Site Personnel..........................................................................35
6.3.3. Blinding of the Sponsor..............................................................................35
6.3.4. Breaking the Blind......................................................................................36
6.4. Study Intervention Compliance...............................................................................36
6.5. Concomitant Therapy..............................................................................................36
6.5.1. Recording Concomitant Vaccinations and Medications.............................36
6.5.2. Prohibited Concomitant Vaccinations and Medications.............................36
6.5.3. Permitted Concomitant Medications ..........................................................37
6.6. Dose Modification...................................................................................................37
6.7. Intervention After the End of the Study..................................................................37
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................37
7.1. Discontinuation of Study Intervention ....................................................................37
7.2. Participant Discontinuation/Withdrawal From the Study.......................................38
7.3. Lost to Follow-up....................................................................................................38
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................39
Visit 1: Month 0 – Vaccination 1 .........................................................................40
Visit 2: Month 1 –Vaccination 2 (28 to 42 Days After Visit 1) ...........................41
Visit 3: Month 2 - Telephone Contact (28 to 42 Days After Visit 2)...................43
Visit 4: Month 6 -Vaccination 3 (140 to 168 Days After Visit 2)........................43
Visit 5: Month 7 (28 to 42 Days After Visit 4).....................................................45
Visit 6: Month 9 (84 to 98 Days After Visit 4).....................................................45

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Visit 7: Month 12 (165 to 195 Days After Visit 4)...............................................46
Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction........................46
8.1. Efficacy Assessments..............................................................................................46
8.1.1. Immunogencity Assessments......................................................................46
8.2. Safety Assessments .................................................................................................47
8.2.1. Electronic Diary..........................................................................................47
8.2.1.1. Grading Scales...........................................................................48
8.2.1.2. Local Reactions.........................................................................48
8.2.1.3. Systemic Events ........................................................................49
8.2.1.4. Fever..........................................................................................49
8.2.2. Clinical Safety Laboratory Assessments ....................................................50
8.2.3. Biological Samples.....................................................................................50
8.2.4. Pregnancy Testing ......................................................................................50
8.3. Adverse Events and Serious Adverse Events..........................................................51
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......51
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................52
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................52
8.3.2. Method of Detecting AEs and SAEs ..........................................................52
8.3.3. Follow-up of AEs and SAEs.......................................................................52
8.3.4. Regulatory Reporting Requirements for SAEs...........................................52
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................53
8.3.5.1. Exposure During Pregnancy......................................................53
8.3.5.2. Exposure During Breastfeeding ................................................53
8.3.5.3. Occupational Exposure .............................................................53
8.3.6. Medical Device Incidents (Including Malfunctions)..................................54
8.3.6.1. Time Period for Detecting Medical Device Incidents...............54
8.3.6.2. Follow-up of Medical Device Incidents....................................54
8.3.6.3. Prompt Reporting of Medical Device Incidents to Sponsor .....54
8.3.6.4. Regulatory Reporting Requirements for Medical Device 
Incidents ............................................................................................55
8.3.7. Medication Errors .......................................................................................55

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8.4. Treatment of Overdose............................................................................................56
8.5. Pharmacokinetics ....................................................................................................56
8.6. Pharmacodynamics..................................................................................................56
8.7. Genetics...................................................................................................................56
8.7.1. Specified Genetics ......................................................................................56
8.8. Biomarkers ..............................................................................................................56
8.9. Health Economics ...................................................................................................57
9. STATISTICAL CONSIDERATIONS ................................................................................57
9.1. Estimands and Statistical Hypotheses.....................................................................57
9.2. Sample Size Determination.....................................................................................60
9.3. Populations for Analysis .........................................................................................62
9.4. Statistical Analyses .................................................................................................62
9.4.1. Immunogenicity Analyses ..........................................................................63
9.4.1.1. Analysis of the Primary Immunogenicity Endpoint..................64
9.4.1.2. Analysis of the Secondary Immunogenicity 
 
 Endpoints ...........................................65
9.4.2. Safety Analyses ..........................................................................................66
9.4.2.1. Analysis of  the Primary Safety Endpoints ...............................66
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................68
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............68
10.1.1. Regulatory and Ethical Considerations ....................................................68
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................68
10.1.2. Informed Consent Process ........................................................................69
10.1.3. Data Protection .........................................................................................70
10.1.4. Dissemination of Clinical Study Data ......................................................70
10.1.5. Data Quality Assurance ............................................................................71
10.1.6. Source Documents....................................................................................73
10.1.7. Study and Site Closure..............................................................................73
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10.1.8. Publication Policy.....................................................................................73
10.1.9. Sponsor’s Qualified Medical Personnel ...................................................74
10.2. Appendix 2: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................75
10.2.1. Definition of AE .......................................................................................75
10.2.2. Definition of SAE.....................................................................................76
10.2.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................77
10.2.4. Reporting of SAEs....................................................................................79
10.3. Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................80
10.3.1. Male Participant Reproductive Inclusion Criteria....................................80
10.3.2. Female Participant Reproductive Inclusion Criteria.................................80
10.3.3. Woman of Childbearing Potential (WOCBP) ..........................................80
10.3.4. Contraception Methods.............................................................................81
10.4. Appendix 4: Liver Safety: Suggested Actions and Follow-up Assessments ........84
10.5. Appendix 5: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting....................................................86
10.6. Appendix 6: Abbreviations ...................................................................................88
11. REFERENCES ..................................................................................................................91
LIST OF TABLES
Table 1.
Intended Numbers of Participants Included in the Study, by Age ...........25
Table 2.
Description of Study Intervention(s) ........................................................31
Table 3.
Local Reaction Grading Scale ..................................................................48
Table 4.
Systemic Event Grading Scale..................................................................49
Table 5.
Scale for Fever..........................................................................................50
Table 6.
Power Analysis (Primary Immunogenicity Objective: 
Noninferiority for GMC ratio)..................................................................61
Table 7.
Power Analysis (Primary Immunogenicity Objective: 
Noninferiority for Difference in Seroresponse)........................................61

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1. PROTOCOL SUMMARY 
1.1. Synopsis 
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, Estimands, and Endpoints
Primary Immunogenicity 
Objective
Coprimary Immunogenicity 
Estimands
Primary Immunogenicity 
Endpoint

To demonstrate the 
noninferiority of a 2-dose 
regimen of the C difficile
vaccine compared to a 3-dose 
regimen of the C difficile
vaccine. 

For each of toxin A– and toxin 
B–specific neutralizing antibody
levels: Adjusted geometric mean 
concentration (GMC) ratio, 
estimated by the ratio of the 
adjusted GMC (adjusted for
baseline concentration) for the 
2-dose regimen to the adjusted 
GMC for the 3-dose regimen, in 
participants receiving C difficile
vaccine and in compliance with 
the key protocol criteria 
(evaluable participants).

For each of toxin A– and toxin 
B–specific neutralizing antibody 
levels: Seroresponse difference, 
estimated by the difference 
between the 2-dose regimen 
and the 3-dose regimen in the 
percentage of participants 
achieving seroresponse, in 
participants receiving C difficile
vaccine and in compliance with 
the key protocol criteria 
(evaluable participants).
Seroresponse for each of toxin 
A– and toxin B– specific 
neutralizing antibody levels:
For both seronegative (baseline 
concentration < lower limit of 
quantitation [LLOQ]) and 
seropositive (baseline 
concentration ≥LLOQ) 
participants, seroresponse is 
achieved for a specific 
participant if that participant has 
at least a 4-fold rise from the 
baseline neutralizing antibody

C difficile toxin A– and toxin 
B–specific neutralizing 
antibody levels at Month 7 in 
each regimen.

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level following vaccination.
Primary Safety Objective
Primary Safety Estimands
Primary Safety Endpoints

To evaluate the safety of 
C difficile vaccine when 
administered to participants in 
a 2-dose regimen or a 3-dose 
regimen by assessing local 
reactions and systemic events, 
adverse events (AEs), and 
serious adverse events
(SAEs).

In participants receiving at least 
1 dose of investigational 
product, the incidence rate 
estimated by the percentage of 
participants reporting local 
reactions.

In participants receiving at least 
1 dose of investigational 
product, the incidence rate 
estimated by the percentage of 
participants reporting systemic 
events.

In participants receiving at least 
1 dose of investigational 
product, the incidence rate 
estimated by the percentage of 
participants reporting 
nonserious AEs.

In participants receiving at least 
1 dose of investigational 
product, the incidence rate 
estimated by the percentage of 
participants reporting SAEs.

Local reactions (pain, 
erythema, and induration), as 
self-reported on e-diaries for 
up to 7 days following each
dose of investigational 
product in each regimen.

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 in 
each regimen.

Nonserious adverse events 
from signing of the informed 
consent document (ICD) to 1 
month after receipt of the last 
dose of investigational 
product in each regimen.

SAEs from signing of the 
ICD to 6 months after receipt 
of the last dose of 
investigational product in 
each regimen.

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Secondary Objective
Secondary Estimands
Secondary Endpoint

To demonstrate the 
noninferiority of a 2-dose 
regimen of the C difficile
vaccine compared to a 3-dose 
regimen of the C difficile
vaccine. 

For each of toxin A– and toxin 
B–specific neutralizing antibody
levels: Adjusted GMC ratio, 
estimated by the ratio of the 
adjusted GMC (adjusted for
baseline concentration) for the 
2-dose regimen to the adjusted 
GMC for the 3-dose regimen, in 
participants receiving C difficile
vaccine and in compliance with 
the key protocol criteria 
(evaluable participants).

For each of toxin A– and toxin 
B–specific neutralizing antibody 
levels: Seroresponse difference, 
estimated by the difference 
between the 2-dose regimen 
and the 3-dose regimen in the 
percentage of participants 
achieving seroresponse, in 
participants receiving C difficile
vaccine and in compliance with 
the key protocol criteria 
(evaluable participants).
Seroresponse for each of toxin 
A– and toxin B– specific 
neutralizing antibody levels:  
For both seronegative (baseline 
concentration < LLOQ) and 
seropositive (baseline 
concentration ≥LLOQ) 
participants, seroresponse is 
achieved for a specific 
participant if that participant has 
at least a 4-fold rise from the 
baseline neutralizing antibody
level following vaccination.

C difficile toxin A– and toxin 
B–specific neutralizing 
antibody levels at Month 12 
in each regimen.
Overall Design
This is a Phase 3, randomized, observer-blinded study to evaluate the immunogenicity, 
safety, and tolerability of a 2-dose regimen of C difficile vaccine compared to a 3-dose 
regimen of C difficile vaccine in adults 50 years of age and older.
Participants will be randomly assigned in parallel in a 1:1 ratio to receive C difficile vaccine 
(200 µg total toxoid) at Months 0, 1, and 6 (3-dose group) or at Months 0 and 6 (2-dose 
group). The participants in the 2-dose group will receive placebo (saline) at Month 1.

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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. 
 
 
 
 
 
Placebo (2-Dose Regimen Only)
The placebo will consist of a sterile normal saline solution for injection (0.9% sodium 
chloride injection, in a 0.5-mL dose) in a prefilled syringe (PFS) and will be provided by the 
sponsor to each study site.
Number of Participants
Approximately 1960 participants will be randomized into the study, such that approximately 
1568 (784 per vaccine group) evaluable participants complete the study. 
 
 
 
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Statistical Methods
The study sample size estimate is based on the evaluation of the primary immunogenicity 
objective of the study to demonstrate that the immune responses induced by 2 doses of 
C difficile vaccine (administered in a 0- and 6-month regimen) are noninferior to the immune 
responses induced by 3 doses of C difficile vaccine (administered in a 0-, 1-, and 6-month 
regimen) —by evaluating the toxin A– and toxin B–specific neutralizing antibody in terms of 
GMC ratios and the difference in percentage of participants achieving seroresponse, 1 month 
after the last investigational product administration. Seven hundred and eighty-four (784)
evaluable participants per group will provide an overall power of 90.5% to meet the primary 
objective of noninferiority of a 2-dose to a 3-dose regimen for both toxin A and toxin B, 
1 month after the last dose. The primary immunogenicity objective of noninferiority of the 
2-dose regimen compared with the 3-dose regimen will be achieved if (1) the lower limit of 
the 2-sided 95% confidence interval (CI) for the GMC ratio (2-dose/3-dose regimen) is >0.67
for both toxin A and toxin B, and (2) the lower limit of the 2-sided 95% CI for the difference 
in percentage of participants achieving seroresponse (2-dose minus 3-dose regimen) is 
> -10% for both toxin A and toxin B 1 month after the last vaccination.  The same criteria 
will be used for the secondary immunogenicity objective evaluation, which will be conducted
only after the primary immunogenicity objective is met.
Assuming a maximum study nonevaluable rate of 20% and a randomization ratio of 1:1, a 
total of 1960 participants need to be randomized in the study to meet the primary 
immunogenicity objectives. 
For each of toxin A– and toxin B–specific neutralizing antibody levels, the GMC ratio of the 
2-dose regimen to the 3-dose regimen at Month 7 and Month 12 will be evaluated by an
analysis of covariance (adjusted for baseline antibody concentrations) and the corresponding
95% CIs.  Two (2)-sided 95% CIs will be constructed by obtaining a CI for the mean of the 
logarithmically transformed assay results based on the Student t distribution, and 
transforming the confidence limits back to the original units. For each of the toxin A– and 
toxin B–specific neutralizing antibody levels, the difference between the 2-dose and 3-dose 
regimens in the percentage of participants achieving seroresponse at Month 7 and Month 12 
will be computed, along with 95% CIs, using the Miettinen and Nurminen method. 
Seroresponse will be considered achieved if a participant has at least a 4-fold rise from 
baseline in the respective antibody concentration following vaccination. Baseline 
concentration is defined as the antibody concentration results from the blood drawn before 
vaccine Dose 1. Antibody concentration values below the LLOQ or denoted as below the 
limit of quantitation (BLQ) will be set to 0.5 × LLOQ for analysis.
All safety and reactogenicity endpoints will be summarized as proportions of participants 
with events by vaccine group.  Additionally, exact 2-sided 95% CIs for proportions will be 
calculated using the Clopper-Pearson method.
1.2. Schema
Not applicable.

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1.3. Schedule of Activities (SoA)
The SoA table provides an overview of the protocol visits and procedures.  Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section 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 in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Visit ID
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit Description
Month 0
(Vax 1)
Month 1
(Vax 2)
Month 2
(Telephone 
Contact)
Month 6
(Vax 3)
Month 7
Month 9
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
84-98 Days 
After Visit 4
165-195 Days 
After Visit 4
Informed consenta
X
Demographya
X
Clinical assessment, including 
medical historya
X
Record nonstudy vaccinationsb
X
X
X
X
X
Measure and record height and 
weighta
X
Oral temperaturea
X
X
X
Urine pregnancy test (women of 
childbearing potential)a
X
X
X
Discuss contraceptive useb
X
X
X
X
Confirm eligibilityb
X
X
X
X
X
X
Review temporary delay criteriaa
X
X
X
Randomizationa
X
Blood draw for immunogenicity 
assessmentb
20 mL
20 mL
20 mL + 40 mLc
20 mLd
20 mLd
Vaccination
X
X
X
Postvaccination observation 
(30 minutes) and AE assessment
X
X
X

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Visit ID
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit Description
Month 0
(Vax 1)
Month 1
(Vax 2)
Month 2
(Telephone 
Contact)
Month 6
(Vax 3)
Month 7
Month 9
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
84-98 Days 
After Visit 4
165-195 Days 
After Visit 4
Issue e-diary, measuring device, 
and thermometer and provide 
instructions on their use, as 
required 
X
X
X
Record AEs
X
X
X
X
X
Xd
Xd
Record SAEs 
X
X
X
X
X
X
X
Telephone contact
X
Participant completes e-diary 
X
X
X
Review e-diary datae
Collect e-diary
X
Abbreviations: CRF = case report form; e-diary = electronic diary; Vax = vaccination; = ongoing/continuous event.
a.
Prior to vaccination.
b.
Prior to vaccination, if at a vaccination visit.
c.
Additional (optional) blood will be collected for the purposes of vaccine assay development.
d.
Any AEs occurring up to 48 hours after blood draw must be recorded in the CRF.
e.
E-diary data review is ongoing during participant e-diary data entry periods (7 days after each vaccination) via an internet-based portal.

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2. INTRODUCTION
2.1. Study Rationale 
The purpose of the study is to evaluate the immunogenicity, safety, and tolerability of a 
2-dose regimen of the C difficile vaccine compared to a 3-dose regimen of the C difficile
vaccine in adults 50 years of age and older. The study will recruit participants who may be at 
increased risk for developing CDI, and the study population, inclusion criteria, and exclusion 
criteria will be consistent with those of the Phase 3 B5091007 efficacy study, allowing direct 
immunological comparison.  Vaccine compliance (completion of a 3-dose vaccine series) has 
been challenging as evidenced, as an example, by human papillomavirus (HPV) 9 vaccine.1
It is expected that this would be especially challenging with a 3-dose vaccine regimen given 
in an adult population, which could have public health consequences. The C difficile vaccine 
program utilizes a 3-dose vaccine regimen at Months 0, 1, and 6 with a 200-g dose. The 
200-µg month regimen in our Phase 2 B5091009 study, our ongoing B5091007 efficacy
study, and our B5091008 lot-consistency study utilize this regimen and dose. 
A 2-dose vaccine regimen would presumably improve compliance. This study, therefore, 
will be a noninferiority study comparing a 3-dose regimen (Months 0, 1, and 6) with a 2-dose 
regimen (Months 0 and 6).
2.1.1. Mechanism of Action/Indication
Pfizer’s investigational C difficile vaccine (PF-06425090) is a prophylactic vaccine that is 
currently being investigated for the prevention of primary CDI in adults 50 years of age and 
older.
2.2. Background 
2.2.1. Clostridium difficile Disease Background
C difficile, a gram-positive, anaerobic, spore-forming bacillus, is the main cause of 
nosocomial infectious diarrhea in industrialized countries.2,3,4,5,6 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.7  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.8  As many as 50% or more of hospital patients 
colonized by C difficile are asymptomatic carriers.7
C difficile can produce 3 toxins, toxin A (TcdA), toxin B (TcdB), and binary toxin.9  TcdA 
and TcdB are the principal virulence factors for CDI,10 causing severe inflammation in the 
bowel.11,12  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.3,13

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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.14
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.12,15,16,17,18  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.12,19,20 Additional 
risk factors for recurrence include failure to mount an immune response to TcdA and/or 
TcdB and infection with a hypervirulent strain.21,22
Increased incidence and severity of the disease with associated complications, colectomy 
rates, and mortality have been observed over the last 10 to 20 years.23,24,25 In Europe, 
increased mortality, prolonged length of hospital stay, and incremental cost of hospitalization 
in association with CDI have been reported.26,27  A systematic review published in 2012 
reported 30-day mortality estimates in Europe ranging from 6.8% to 42%.27 In a surveillance 
study conducted in the United States, approximately 453,000 cases of CDI and 
approximately 29,000 deaths were reported in 2011.28  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.29,30
In the last decade, the numbers and severity of C difficile iatrogenic outbreaks in hospitals 
and nursing homes have increased.28,29,31  Key factors in this escalation include emergence of 
hypervirulent pathogenic strains such as BI/NAP1/027,32,33,34 increased use of antibiotics,35
improved detection methods, and increased exposure to spores in healthcare facilities.36
Metronidazole has been recommended as initial therapy since the late 1990s, but recent 
guidance issued by Infectious Diseases Society of America (IDSA) recommends either 
vancomycin or fidaxomycin as the first choice, and only if not available should 
metronidazole be used.7,22,37,38 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.20  European guidelines for treatment of CDI include fidaxomicin as an 
option for treatment of recurrence.22  Fecal transplantation has also been shown to be 
effective in some patients for the treatment of multiple recurrences of CDI.39,40  However, 
regulatory oversight of this method remains in development,41 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.42

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2.2.2. Clostridium difficile Vaccine Development Rationale
The increasing burden of CDI on patients and on the healthcare system demonstrates that 
prevention of CDI constitutes a significant unmet medical need.
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.21,43,44,45 Preclinical studies have 
shown that active immunization with inactivated toxins (“toxoids”) and passive 
immunization with antitoxin antibodies protect animals from lethal challenge.46,47,48   
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.49  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.50  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.51  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,52 indicating that a polyclonal antibody approach, 
such as elicited by active immunization with C difficile toxoids, may be more efficacious to 
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 is at least 
1 other vaccine in development that targets C difficile toxins. This is a recombinant fusion 
protein comprising fragments of the receptor-binding domains of TcdA and TcdB separated 
by a 4–amino acid linker53; this vaccine has been evaluated in a completed Phase 2 study.54
2.2.3. 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.

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2.2.3.1. Preclinical Development
In preclinical 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 preclinical data generated by Pfizer in rhesus 
macaques support the use of a 3-dose regimen of the C difficile vaccine, with or without 
AlOH.
2.2.3.2. 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.55  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 
comprised mostly injection site pain, headache, and fatigue.  AEs were reported in all 
vaccine groups, with little difference in the number of participants between the dose groups 
and the placebo group or between vaccine formulations.  In participants who received the 
vaccine formulations, both the toxin A– and toxin B–specific neutralizing antibody GMCs 
increased substantially at 1 month after Dose 2 and after Dose 3 compared to baseline.  In the 
50- to 64-year age cohort, 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 participants 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.

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Study B5091003, a Phase 2 study, was conducted to assess 2 antigen dose levels (100 and 
200 g) of the toxoids alone reconstituted with sodium chloride (60 mM) diluent 
administered as a 3-dose regimen (Days 1, 8, and 30) in healthy adults 50 to 85 years of age.
However, recruitment and vaccinations were halted because of the occurrence of 7 cases of 
Grade 3 injection site redness after Dose 2.  Following the observed tolerability profile in 
Study B5091003, the decision was made to progress development of the 
aluminum-containing formulation into a second Phase 2 study, B5091009.
Study B5091009 (original planned stage up to 12 months after the third dose) was a Phase 2, 
placebo-controlled, randomized, observer-blinded study to assess the safety, tolerability, and 
immunogenicity of 2 antigen dose levels (100 μg and 200 μg total toxoid) of aluminum 
hydroxide–containing C difficile vaccine administered as a 3-dose regimen: either at Days 1, 
8, and 30 (day regimen) or at Months 0, 1, and 6 (month regimen) in participants at US sites.  
Results from the original planned stage of the study demonstrated that the 200-µg dose level 
was more immunogenic, as evidenced by numerically higher proportions of participants
achieving antibody levels prespecified thresholds, GMCs, and GMFRs, than the 100-µg 
dose level in both dosing regimens.  The month regimen resulted in numerically higher
post-Dose 3 immune response for both the 100-µg and 200-µg dose levels, particularly for 
toxin B in participants who were seronegative at baseline.  The immune responses by age 
group (65 to 69 years, 70 to 74 years, and 75 to 79 years) were similar to that of the 
combined age group (65 to 85 years) as determined by proportions of participants achieving 
both toxin A– and toxin B–specific neutralizing antibody levels specified thresholds,
GMCs, and GMFRs at 1 month after Dose 3 for the month regimen and 7 days after Dose 3 
for the day regimen. The number of participants 80 to 85 years of age was small and the 
interpretation of results for this age group should be conducted with caution.  Local reactions 
increased after Dose 2 for both regimens, but it was to a greater extent when it was 
administered at Day 8 in the day regimen, particularly at the 200-g dose level.  Rates of 
systemic events were similar between placebo and the 2 vaccine dose levels.  Overall, the AE 
profile observed in this study identified no untoward safety signals.  Overall, the C difficile
vaccine was highly immunogenic, was well tolerated, and exhibited an acceptable safety 
profile.
The extension phase of this study is ongoing to assess persistence of neutralizing antibody 
titers against toxins A and B for up to 4 years after Dose 3.
The ongoing Phase 3 efficacy study (B5091007) is a placebo-controlled, randomized (1:1, 
vaccine : placebo), observer-blinded, parallel-group study in participants 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.  

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The ongoing Phase 3 lot-consistency study (B5091008) is a placebo-controlled, randomized 
1:1:1:1 (Lot 1 : Lot 2 : Lot 3 : placebo), observer-blinded study to evaluate the lot 
consistency, safety, tolerability, and immunogenicity of the C difficile vaccine 200-g dose 
level administered at Months 0, 1, and 6 in healthy adults 65 to 85 years of age. This 
lot-to-lot study is being conducted to fulfill regulatory requirements for product licensure. 
Since commercial production of this vaccine will involve multiple manufacturing campaigns 
and multiple lot productions, it is imperative to demonstrate that vaccination from different 
lots yields similar responses within an acceptable margin.
The present study (B5091019) is a Phase 3, randomized, observer-blinded study to evaluate 
the immunogenicity, safety, and tolerability of a 3-dose C difficile vaccine regimen compared 
to a 2-dose C difficile vaccine regimen in adults 50 years of age and older. 
2.3. Benefit/Risk Assessment
C difficile is the main cause of nosocomial infectious diarrhea in industrialized 
countries.2,3,4,5,6 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.7 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 participants 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, 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. 

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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-μg dose level was more immunogenic than the 100-μg dose 
level.
Study B5091010, a first-in-Japanese participants study, was a Phase 1, placebo-controlled, 
randomized, observer-blinded study to assess the safety, tolerability (primary objectives), and 
immunogenicity (secondary objectives) of 2 antigen dose levels 
 
 in 2 different dosing regimens (Months 0, 1, and 6 [month 
regimen] or Days 1, 8, and 30 [day regimen]) in healthy Japanese adults, 65 to 85 years of 
age. The C difficile vaccine was well tolerated when administered in the 0-, 1-, and 6-month 
regimen with no unexpected AEs observed in this regimen, indicating a favorable safety 
profile in this elderly population of healthy Japanese adults 65 to 85 years of age when 
administered in the month regimen. There were 3 participants in the day regimen who 
reported severe local reactions, leading to the triggering of a stopping rule and 
discontinuation of subsequent enrollment and dosing in the day regimen; these local reactions 
resolved.  The proportion of participants reporting local reactions and systemic events was 
generally low across all vaccine groups in the month regimen. In both the month and day 
regimens, most events were of mild to moderate severity. There were no notable differences 
between the 100- or 200-μg dose groups observed within each regimen based on an 
evaluation of the proportion of participants reporting AEs, SAEs, or newly diagnosed chronic 
medical conditions (NDCMCs). 
Thus, C difficile vaccinations at a dose of 100 or 200 μg were generally well tolerated when 
given according to a Month 0, 1, and 6 regimen.
Pfizer considers that the available information from Studies B5091001, B5091009, and 
B5091010 with PF-06425090 supports a favorable benefit-risk profile for studies 
administrating 3 doses of the C difficile vaccine at dose levels up to 200 μg 
 
 as a potential prevention against CDI. It is expected that this would also apply to a 
2-dose regimen of the vaccine given 6 months apart, and especially so since the 
reactogenicity after Dose 2 (at Month 1 seen in all 3 studies, B5091001, B5091009, and 
B5091010) was the most pronounced. In addition, this is further supported by review of 
safety data from the B5091007 and B5091008 studies 
 
which 
has not identified a safety concern.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of C difficile vaccine may be found in the investigator’s brochure (IB), which 
is the single reference safety document (SRSD) for this study.
CCI
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3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Estimands
Endpoints
Primary Immunogenicity:
Coprimary Immunogenicity:
Primary Immunogenicity:

To demonstrate the 
noninferiority of a 2-dose 
regimen of the C difficile
vaccine compared to a 3-dose 
regimen of the C difficile
vaccine.

For each of toxin A– and toxin 
B–specific neutralizing antibody
levels: Adjusted GMC ratio, 
estimated by the ratio of the 
adjusted GMC (adjusted for
baseline concentration) for the 
2-dose regimen to the adjusted 
GMC for the 3-dose regimen, in 
participants receiving C difficile
vaccine and in compliance with 
the key protocol criteria 
(evaluable participants).

For each of toxin A– and toxin 
B–specific neutralizing antibody 
levels: Seroresponse difference, 
estimated by the difference 
between the 2-dose regimen 
and the 3-dose regimen in the 
percentage of participants 
achieving seroresponse, in 
participants receiving C difficile
vaccine and in compliance with 
the key protocol criteria 
(evaluable participants).
Seroresponse for each of toxin 
A– and toxin B– specific
neutralizing antibody levels: 
For both seronegative (baseline 
concentration < LLOQ) and 
seropositive (baseline 
concentration ≥LLOQ) 
participants, seroresponse is 
achieved for a specific 
participant if that participant has 
at least a 4-fold rise from the 
baseline neutralizing antibody 
level following vaccination.

C difficile toxin A– and toxin 
B–specific neutralizing 
antibody levels at Month 7 in 
each regimen.
Primary Safety:
Primary Safety:
Primary Safety:

To evaluate the safety of 
C difficile vaccine when 
administered to participants in 
a 2-dose regimen or a 3-dose 
regimen by assessing local 
reactions and systemic events, 
AEs, and SAEs.

In participants receiving at least 
1 dose of investigational 
product, the incidence rate 
estimated by the percentage of 
participants reporting local 
reactions.

In participants receiving at least 
1 dose of investigational 
product, the incidence rate 
estimated by the percentage of 

Local reactions (pain, 
erythema, and induration), as 
self-reported on e-diaries for 
up to 7 days following each 
dose of investigational product
in each regimen.

Systemic events (fever, 
vomiting, headache, fatigue, 
new or worsening muscle pain, 
and new or worsening joint 

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Objectives
Estimands
Endpoints
participants reporting systemic 
events.

In participants receiving at least 
1 dose of investigational 
product, the incidence rate 
estimated by the percentage of 
participants reporting 
nonserious AEs.

In participants receiving at least 
1 dose of investigational 
product, the incidence rate 
estimated by the percentage of 
participants reporting SAEs.
pain), as self-reported on e-
diaries for up to 7 days 
following each dose of 
investigational product in each 
regimen.

Nonserious AEs from signing 
of the ICD to 1 month after 
receipt of the last dose of 
investigational product in each 
regimen.

SAEs from signing of the ICD 
to 6 months after receipt of the 
last dose of investigational 
product in each regimen.
Secondary:
Secondary:
Secondary:

To demonstrate the 
noninferiority of a 2-dose 
regimen of the C difficile
vaccine compared to a 3-dose 
regimen of the C difficile
vaccine.a

For each of toxin A– and toxin 
B–specific neutralizing 
antibody levels: Adjusted GMC 
ratio, estimated by the ratio of 
the adjusted GMC (adjusted for
baseline concentration) for the 
2-dose regimen to the adjusted 
GMC for the 3-dose regimen, in 
participants receiving C difficile
vaccine and in compliance with 
the key protocol criteria 
(evaluable participants).

For each of  toxin A– and toxin 
B–specific neutralizing 
antibody levels: Seroresponse 
difference, estimated by the 
difference between the 2-dose 
regimen and the 3-dose regimen 
in the percentage of participants 
achieving seroresponse, in 
participants receiving C difficile
vaccine and in compliance with 
the key protocol criteria 
(evaluable participants).
Seroresponse for each of toxin 
A– and toxin B– specific 
neutralizing antibody levels: 
For both seronegative (baseline 
concentration < LLOQ) and 
seropositive (baseline 
concentration ≥LLOQ) 
participants, seroresponse is 
achieved for a specific 
participant if that participant 
has at least a 4-fold rise from 

C difficile toxin A– and toxin 
B–specific neutralizing 
antibody levels at Month 12 in 
each regimen.

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Objectives
Estimands
Endpoints
the baseline neutralizing 
antibody level following 
vaccination.
a.
Noninferiority (NI) analysis for Month 12 will be performed only after the NI criteria are met in terms of 
the GMC ratio and the seroresponse difference at Month 7.
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4. STUDY DESIGN
4.1. Overall Design
This is a Phase 3, randomized, observer-blinded study to evaluate the immunogenicity, 
safety, and tolerability of a 2-dose C difficile vaccine regimen compared to a 3-dose 
C difficile vaccine regimen in adults 50 years of age and older.
Participants will be randomly assigned in parallel in a 1:1 ratio to receive one of the 
following dosing regimens according to the visit schedule: 

2-Dose: Participants will receive 1 dose of C difficile vaccine (200 g total toxoid per 
dose) at Visit 1 (Month 0) and Visit 4 (Month 6) and 1 dose of placebo (0.9% sodium 
chloride or normal saline) at Visit 2 (Month 1).

3-Dose: Participants will receive 1 dose of C difficile vaccine (200 g total toxoid per 
dose) at Visit 1 (Month 0), Visit 2 (Month 1), and Visit 4 (Month 6).
4.1.1. Approximate Number of Participants
Approximately 1960 participants will be randomized into the study, with a randomization 
ratio of 1:1 (2-dose C difficile vaccine : 3-dose C difficile vaccine).
To achieve a broad representation of age groups among those 50 years of age and older, 
randomization into an age cohort will be managed by the central randomization process. The 
targeted number of participants and age cohorts intended to be randomized is shown in 
Table 1. 
Table 1.
Intended Numbers of Participants Included in the Study, by Age
Age Category
Minimum Number for Inclusion
Maximum Number for Inclusion
50-59 years
Not limited
200 participants
60-69 years
200
Not limited
70 years
200
Not limited
4.1.2. Approximate Duration of the Study
It is estimated that this study will be completed in approximately 19 months.  It is anticipated 
that recruitment will be completed in approximately 7 months.
4.1.3. Approximate Duration of Participation for Each Participant
Participants will be followed from the time they sign the ICD until 6 months after receipt of 
their last vaccination.  Therefore, individual participants will participate in the study for 
approximately 12 months.

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4.2. Scientific Rationale for Study Design
The mechanism of action (MOA) for prevention of CDI is very well established, both 
preclinically and clinically, and is based on toxin-neutralizing antibodies.21,43-49
Demonstrating that the 2-dose vaccine regimen can generate comparable noninferior 
antibody responses compared with the 3-dose vaccine regimen provides the clinical rationale 
for a 2-dose vaccine regimen. This argument may be informed by the successful efficacy 
anticipated to be demonstrated in the pivotal B5091007 clinical endpoint efficacy study. 
Efficacy in Study B5091007 may be associated with an immunological profile after the third 
dose at 6 months in participants who received a 3-dose regimen at Months 0, 1, and 6. 
Therefore, if participants who received a 2-dose regimen at Months 0 and 6 achieve a 
noninferior comparable immunological response 1 month after their Month 6 dose compared
with the response achieved by the participants who received a 3-dose regimen 1 month after 
their third dose at Month 6, where efficacy against a clinical endpoint is established, one can 
infer that similar VEs would be seen with the 2-dose vaccine regimen and the 3-dose vaccine 
regimen. A similar approach was used in the HPV vaccine program, where efficacy was 
inferred in adolescents (9 to 15 years of age) based on an immunological profile comparable 
to the adult female population (16 to 26 years of age), in which efficacy had been 
established.1
4.3. Justification for Dose
Dose selection was derived from Study B5091009 where 2 doses (100 µg and 200 µg) and 2 
dosing regimens (Months 0, 1, and 6; and Days 1, 8, and 30) were compared against placebo.
The study demonstrated that the 200-g dose level was more immunogenic as evidenced by 
numerically higher proportions of participants achieving antibody levels threshold, GMCs, 
and GMFRs than those for the 100-g dose level in both dosing regimens; and that the month 
regimen resulted in a higher post–Dose 3 immune response for both the 100-g and 200-g 
dose levels.
Based on these results from Study B5091009, the dosing level to be used in Phase 3 studies is 
200 µg, and the regimen to be used is 3 doses administered by intramuscular (IM) injection at
Months 0, 1, and 6.
Hence, 200 g will be used for both the 2-dose regimen (at Months 0 and 6) and the 3-dose 
regimen (at Months 0, 1, and 6).
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed the last 
scheduled procedure shown in the schedule of activities (SoA).
End of study is defined as the date of the last visit of the last participant in the study.

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5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants 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 participant is suitable for this 
protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants 50 years of age or older at enrollment.

Refer to Appendix 3 for reproductive criteria for male (Section 10.3.1) and female 
(Section 10.3.2) participants.
Type of Participant and Disease Characteristics:
2. Willing and able to comply with scheduled visits, vaccination plan, and other study 
procedures.
3. Participants with an increased risk of future contact with healthcare systems by virtue of:

At least 1 inpatient hospitalization of 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 but 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 of 2 nights’ duration scheduled 37 days after 
randomization.

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Or participants who have received systemic (ie, oral or injected) antibiotics at any time in 
the previous 12 weeks.
4. Ability to be contacted by telephone during study participation.
Informed Consent:
5. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICD and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Pregnant female participants; breastfeeding female participants; positive urine pregnancy 
test for women of childbearing potential (WOCBP); and WOCBP who are, in the opinion 
of the investigator, sexually active and at risk for pregnancy and are unwilling or unable 
to use an effective method 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.
Medical Conditions:
2. Prior episode of CDI, confirmed by either laboratory test or diagnosis of 
pseudomembranous colitis at colonoscopy, at surgery, or histopathologically. 
3. Participants who may be unable to respond to vaccination due to:

Metastatic malignancy; or

End-stage renal disease (glomerular filtration rate <15 mL/min/1.73 m2 or on 
dialysis).

Any serious medical disorder that in the investigator’s opinion is likely to be fatal 
within the next 12 months.

Congenital or acquired immunodeficiency.
4. Known infection with human immunodeficiency virus (HIV).
5. Any bleeding disorder or anticoagulant therapy that would contraindicate IM injection.
6. Any contraindication to vaccination or vaccine components, including previous 
anaphylactic reaction to any vaccine or vaccine-related components. 

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7. Other acute or chronic medical or psychiatric condition including recent (within the past 
year) or active suicidal ideation or behavior or laboratory abnormality that may increase 
the risk associated with study participation or investigational product administration or 
may interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the participant inappropriate for entry into this study.
Prior/Concomitant Therapy:
8.
Previous administration of an investigational C difficile vaccine or C difficile mAb 
therapy.
9. Receipt of systemic corticosteroids (20 mg/day of prednisone or equivalent) for 
14 days within 28 days before enrollment.
10. Receipt of chronic systemic treatment with other known immunosuppressant
medications, or radiotherapy, within 6 months before enrollment.
11. Receipt of blood products or immunoglobulins within 6 months before enrollment.
Prior/Concurrent Clinical Study Experience:
12. 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).
Diagnostic Assessments:
Not applicable.
Other Exclusions:
13. 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 Pfizer 
employees, including their family members, directly involved in the conduct of the study.
5.2.1. Criteria for Temporary Delay of Vaccination
The following conditions are temporary or self-limiting and a participant 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 
within 48 hours prior to investigational product administration.
2. Participant has received seasonal or pandemic influenza vaccine within the previous 
14 days or any other 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 participant 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.
5.3. Lifestyle Considerations
No restrictions are required.
5.3.1. Contraception 
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods 
(see Appendix 3 [Section 10.3.4]) and will confirm that the participant has been instructed in 
its consistent and correct use.  At time points indicated in the SoA, the investigator or 
designee will inform the participant of the need to use highly effective contraception 
consistently and correctly and document the conversation and the participant’s affirmation in 
the participant’s chart (participants need to affirm their consistent and correct use of at least 
1 of the selected methods of contraception).  In addition, the investigator or designee will 
instruct the participant to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized.  A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities.  Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs recorded from signing the informed consent.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened under a different participant number if they meet eligibility criteria.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention.

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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.
6.1. Study Intervention(s) Administered
The investigational C difficile vaccine (PF-06425090) is toxoid based. C difficile toxin A 
and toxin B are inactivated by a combination of genetic mutations and chemical treatments.  
Participants randomized to the 2-dose regimen will receive 2 doses of C difficile vaccine 
(200 μg total toxoid per dose) and 1 dose of placebo (sterile normal saline solution, 0.9% 
sodium chloride).
Participants randomized to the 3-dose regimen will receive 3 doses of C difficile vaccine 
(200 μg total toxoid per dose).
Please refer to Table 2 below for the description of study intervention(s)s that will be 
administered.
Table 2.
Description of Study Intervention(s)
Intervention Name
PF-06425090
Placebo for PF-06425090
Regimen
C difficile vaccine (200 μg) 3-dose 
regimen and C difficile vaccine (200 
μg) 2-dose regimen
C difficile vaccine (200 μg) 2-dose 
regimen 
Type
Vaccine
Placebo
 
 
 
Unit Dose Strength(s)
200 μg/dose (0.5 mL)
0.9% sodium chloride (0.5 mL)
Dosage Level(s)
0.5-mL dose at Visits 1, 2, and 4 
(Months 0, 1, and 6) for 3-dose 
regimen
0.5-mL dose at Visits 1 and 4 
(Months 0 and 6) for 2-dose 
regimen
0.5-mL dose at Visit 2 (Month 1) 
for 2-dose regimen only
Route of Administration
Intramuscular
Intramuscular
Investigational Medicinal Product 
(IMP) and Noninvestigational 
Medicinal Product (NIMP)
IMP
IMP
CCI
CCI

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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.
6.1.1. Administration
All injections will be administered in the upper deltoid muscle, preferably of the 
nondominant arm, by the unblinded administrator.
Participants will be administered the following injections according to the dosing regimen to 
which the participant is randomized:
•
2-Dose:  Participants will receive 1 dose of C difficile vaccine (200 μg total toxoid per
dose) at Visit 1 (Month 0) and Visit 4 (Month 6) as well as 1 dose of placebo (0.9% 
sodium chloride or normal saline) at Visit 2 (Month 1).
•
3-Dose:  Participants will receive 1 dose of C difficile vaccine (200 μg total toxoid per 
dose) at Visit 1 (Month 0), Visit 2 (Month 1), and Visit 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.
CCI

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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 case report form (CRF).
6.1.2. Medical Devices 
In this study, medical devices being deployed will be vial adapter and PFS for C difficile
vaccine and PFS only for placebo (0.9% sodium chloride or normal saline).
Instructions for medical device use are provided in the IP manual.
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the unblinded study personnel throughout the study. 
Please refer to Section 8.3.6 for details.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature-monitored shipments. 
3. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business.
4. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).  All study 
interventions will be accounted for using an investigational product accountability 
form/record. 
CCI

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5. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual.
6. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
7. Study interventions should be stored in their original containers and in accordance 
with the labels. 
8. See the IP manual for storage conditions of the study intervention once reconstituted.
9. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken.  The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible.  Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention.  It will not be considered a protocol deviation if Pfizer 
approves the use of the study intervention after the temperature excursion. Use of the 
study intervention prior to Pfizer approval will be considered a protocol deviation. 
Specific details regarding the definition of an excursion and information the site 
should report for each excursion will be provided to the site in the IP manual. 
10. 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.
11. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (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.
Additional details about accountability, storage, destruction, and excursion reporting can be 
found in the IP manual.
6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the investigational product for 
administration.  Investigational product should be prepared and administered by an 
appropriately qualified and experienced unblinded member of the study staff.

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6.3. Measures to Minimize Bias: Randomization and Blinding
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.  The study staff dispensing and administering the vaccine will be unblinded, but all 
other site study personnel, including the principal investigator and the participant, will be 
blinded.
6.3.1. Allocation to Investigational Product
Allocation of participants to vaccine groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR]) in a 
randomization ratio of 1:1.  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 participant number.  They will then be provided with 
a randomization number, and dispensable unit (DU) or container number.  The IRT system 
will provide a confirmation report containing the participant 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.
6.3.2. Blinding of Site Personnel
The principal investigator will assign the responsibility of the unblinded 
dispenser/administrator to persons who will not participate in the evaluation of any study 
participant.  More than 1 unblinded dispenser/administrator may be assigned per site.  
Members of the study site staff or clinic pharmacy should fulfill this role. Contact between 
the unblinded dispenser and study participants 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 participant and must not be allowed to see the investigational product container 
contents.
6.3.3. 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]; and unblinded clinician) will be 
unblinded for the duration of the study. Sponsor study team members will remain blinded 
until the snapshot for the interim analysis is taken (once all participants have completed Visit 
5 [Month 7]) and will be unblinded thereafter [see Section 9.5]. Laboratory personnel 
performing the serology assays will remain blinded to vaccine assigned/received throughout 
the study.

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6.3.4. Breaking the Blind 
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 participant.  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 CRF.
6.4. Study Intervention Compliance
All doses of investigational product will be administered by the appropriately designated 
unblinded study staff at the investigator site.
6.5. Concomitant Therapy
6.5.1. 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]).
6.5.2. Prohibited Concomitant Vaccinations and Medications
Receipt of the following prohibited vaccines and medications during the time periods listed 
below may exclude a participant from the per-protocol analysis, and may require 
vaccinations to be discontinued in that participant; however, it is anticipated that the 
participant would not be withdrawn from the study (see Section 7.2).
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). Exceptions to this are the seasonal influenza vaccine and 
pandemic influenza vaccine, which can be given at least 14 days prior to or 14 days after 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.

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
Prophylactic antipyretics and other pain medication to prevent symptoms associated 
with investigational product administration are not permitted.  However, if a 
participant 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. 
6.5.3. 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 6.5.2 required for 
treatment of preexisting stable conditions is permitted.

Inhaled, topical, or localized injections of corticosteroids (eg, intra-articular or 
intrabursal administration) are permitted.

Hormonal contraceptives that meet the requirements of this study are allowed to be 
used in participants who are WOCBP (see Appendix 3).
6.6. Dose Modification 
Not applicable.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Participant eligibility must be confirmed prior to each vaccination in order to continue in the 
study.
If a participant no longer meets the eligibility criteria during the vaccination period of the 
study, discontinuation of further vaccinations should be considered, but the participant may 
remain in the study.  If a participant is discontinued from vaccination and the participant
consents, safety follow-up will be conducted as per Section 8.3.1 (AEs will be collected for 
1 month after the last dose of investigational product and SAEs will be collected for 
6 months after the last dose of investigational product). 
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.

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7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons.
At the time of discontinuing, please refer to the study reference manual (SRM) and SoA for 
assessments to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed.
Participants should be questioned regarding their reason for withdrawal.  The participant will 
be permanently discontinued from the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples, but data already generated from the samples will continue to be available, and may 
be used to protect the integrity of existing analyses.  The investigator must document any 
such requests in the site study records.
If the participant withdraws from the study and also withdraws consent (see below) 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.
When a participant withdraws from the study because of an SAE, the SAE must be recorded 
on the CRF and reported on the Clinical Trial (CT) SAE Report.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
Withdrawal of Consent: 
Participants who request to discontinue receipt of study treatment will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of investigational product or also from study 
procedures and/or posttreatment study follow-up, and entered on the appropriate CRF page.  
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.

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The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA.  Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  

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When a protocol-required test cannot be performed, the investigator will document the 
reason for the missed test and any corrective and preventive actions that he or she has taken 
to ensure that required processes are adhered to as soon as possible.  The study team must 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.
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 participant’s demography (including date of birth, sex, race, and 
ethnicity). The full date of birth will be collected to critically evaluate the immune 
response and safety profile by age.

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 (Section 5.2.1) are met. 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 participant, 
perform a physical examination and record the findings.

Record nonstudy vaccines as described in Section 6.5.

Measure and record the participant’s weight and height. 

Measure and record the participant’s oral temperature.

For WOCBP, perform a urine pregnancy test and ensure the result is negative prior to 
vaccination (Section 8.2.4).

Discuss contraceptive use.

An appropriate site staff member (may be blinded or unblinded) will use the IRT 
system to obtain the participant’s randomization number and DU or container 
number.

Collect a blood sample of approximately 20 mL for immunogenicity testing 
(Section 8.1.1).

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
Unblinded site staff will prepare and administer investigational product. 
Investigational product will be administered by IM 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 participant 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 8.3 and the SoA.

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 participant to complete the e-diary from 
Day 1 to Day 7, with Day 1 being the day of vaccination.

Ask the participant to contact the site staff or investigator immediately if any 
significant illness or hospitalization occurs. 

Schedule an appointment for the participant to return for the next study visit. 

Complete the source documents. 

Complete the CRF. 
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 participant’s e-diary data and follow up on any ongoing local reactions or 
systemic events.

Ensure that the participant continues to be eligible for the study and does not meet 
any of the withdrawal criteria as described in Section 7.2.

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
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 8.3 and 
the SoA.  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 6.5.

Measure and record the participant’s oral temperature.

For WOCBP, perform a urine pregnancy test and ensure the result is negative prior to 
vaccination (Section 8.2.4).

Discuss contraceptive use.

Ensure that none of the temporary delay criteria are met (Section 5.2.1).

An appropriate site staff member (may be blinded or unblinded) will use the IRT 
system to obtain the participant’s investigational product blinded carton number. 

Unblinded site staff will prepare and administer investigational product. 
Investigational product will be administered by IM 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 participant 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 8.3 and the SoA.

Ensure the participant 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 participant understands the reactogenicity reporting requirements. 
Remind the participant to complete the e-diary from Day 1 to Day 7, with Day 1 
being the day of vaccination.

Ask the participant to contact the site staff or investigator immediately if any 
significant illness or hospitalization occurs. 

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
Schedule a telephone call for the next study visit. 

Complete the source documents. 

Complete the CRF. 
Visit 3: Month 2 - Telephone Contact (28 to 42 Days After Visit 2)

Contact the participant by telephone to determine whether any AEs or SAEs have 
occurred since the last study visit. Record and report findings as described in 
Section 8.3 and the SoA. Review AEs that were ongoing from the previous visit and 
record their stop dates or confirm if they are still continuing.

Follow up on any ongoing local reactions or systemic events.

Record nonstudy vaccines as described in Section 6.5.

Discuss contraceptive use.

Ensure that the participant continues to be eligible for the study and does not meet 
any of the withdrawal criteria as described in Section 7.2.

Ask the participant to contact the site staff or investigator immediately if any 
significant illness or hospitalization occurs. 

Schedule an appointment for the participant to return for the next study visit. 

Complete the source documents. 

Complete the CRF. 
Visit 4: Month 6 -Vaccination 3 (140 to 168 Days After Visit 2)

Review the participant’s e-diary data and follow up on any ongoing local reactions or 
systemic events.

Ensure that the participant continues to be eligible for the study and does not meet 
any of the withdrawal criteria as described in Section 7.2.

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 8.3 and 
the SoA.  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 6.5.

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
Collect a blood sample of approximately 20 mL for immunogenicity testing 
(Section 8.1.1).

Measure and record the participant’s oral temperature.

For WOCBP, perform a urine pregnancy test and ensure the result is negative prior to 
vaccination (Section 8.2.4).

Discuss contraceptive use.

Ensure that none of the temporary delay criteria are met (Section 5.2.1).

An appropriate site staff member (may be blinded or unblinded) will use the IRT 
system to obtain the participant’s investigational product blinded carton number. 

Unblinded site staff will prepare and administer investigational product. 
Investigational product will be administered by IM 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 participant 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 8.3 and the SoA.

Ensure the participant 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 participant understands the reactogenicity reporting requirements. 
Remind the participant to complete the e-diary from Day 1 to Day 7, with Day 1 
being the day of vaccination.

Ask the participant to contact the site staff or investigator immediately if any 
significant illness or hospitalization occurs. 

Schedule an appointment for the participant to return for the next study visit. 

Complete the source documents. 

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
Complete the CRF. 
Visit 5: Month 7 (28 to 42 Days After Visit 4)

Review the participant’s e-diary data and follow up on any ongoing local reactions or 
systemic events.

Collect the participant’s e-diary.

Ensure that the participant continues to be eligible for the study and does not meet 
any of the withdrawal criteria as described in Section 7.2.

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 8.3 and 
the SoA.  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 6.5.

Collect a blood sample of approximately 20 mL for immunogenicity testing 
(Section 8.1.1).

Collect an additional (optional) blood sample of approximately 40 mL for the 
purposes of vaccine assay development.

Ask the participant to contact the site staff or investigator immediately if any 
significant illness or hospitalization occurs. 

Schedule an appointment for the participant to return for the next study visit. 

Complete the source documents. 

Complete the CRF. 
Visit 6: Month 9 (84 to 98 Days After Visit 4)

Ensure that the participant continues to be eligible for the study and does not meet 
any of the withdrawal criteria as described in Section 7.2.

Based on clinical evaluation, determine whether any SAEs have occurred since the 
last study visit.  Record and report findings as described in Section 8.3 and the SoA.  
Review AEs that were ongoing from the previous visit and record their stop dates or 
confirm if they are still continuing.

Collect a blood sample of approximately 20 mL for immunogenicity testing 
(Section 8.1.1).

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
Ask the participant to contact the site staff or investigator immediately if any 
significant illness or hospitalization occurs. 

Schedule an appointment for the participant to return for the next study visit. 

Complete the source documents. 

Complete the CRF.
Visit 7: Month 12 (165 to 195 Days After Visit 4)

Based on clinical evaluation, determine whether any SAEs have occurred since the 
last study visit.  Record and report findings as described in Section 8.3 and the SoA.  
Review AEs that were ongoing from the previous visit and record their stop dates or 
confirm if they are still continuing.

Collect a blood sample of approximately 20 mL for immunogenicity testing 
(Section 8.1.1).
Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 8.2.1.2), systemic event (Section 8.2.1.3), or fever 
(Section 8.2.1.4) 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 8.2.1.2), systemic event (Section 8.2.1.3), or 
fever (Section 8.2.1.4) is reported, a telephone contact or site visit should occur to confirm 
whether the event meets the criteria for Grade 4.  Only an investigator or medically qualified 
person is able to classify a participant’s local reaction as Grade 4. If a participant 
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 participant. The Grade 4 reaction 
must be recorded in the CRF and is not collected in the e-diary.
8.1. Efficacy Assessments
Not applicable.
8.1.1. Immunogencity Assessments
Both toxin A– and toxin B–specific neutralizing antibody levels will be measured. 
Approximately 20 mL (minimum of 10 mL and up to 20 mL) of blood will be collected 
(at Visit 1, Visit 4 [these must be prior to vaccination], Visit 5, Visit 6, and Visit 7) for each 
measurement to allow for adequate volume required for repeat testing or additional 
antigen-specific immunogenicity testing to be performed.
An additional (optional) 40 mL of blood at Visit 5 will be taken for the purposes of  vaccine 
assay development.

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Refer to the SRM for details regarding blood and serum sample management and storage.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.
A clinical assessment, including medical history, will be performed on all participants 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 8.3.
Acute reactions within the first 30 minutes after investigational product administration will 
be assessed and documented in the AE CRF.
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 8.2.1.
8.2.1. Electronic Diary
Participants 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 
investigational product administration. The e-diary allows recording of these assessments 
only within a fixed time window, thus providing the accurate representation of the 
participant’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 participant e-diary data-entry 
periods (7 days after each vaccination).
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 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.

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8.2.1.1. Grading Scales
The grading scales used in this study to assess local reactions and systemic events as 
described below are derived from the Food and Drug Administration (FDA) Center for 
Biologics Evaluation and Research (CBER) guidelines on toxicity grading scales for healthy 
adult volunteers enrolled in preventive vaccine clinical trials.56
8.2.1.2. Local Reactions
During the e-diary reporting period, participants 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 participant 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.  Pain at the vaccine injection site 
will be assessed by the participant 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 participant’s local reaction as 
Grade 4. If a participant 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 
participant. The Grade 4 reaction must be recorded in the CRF and is not collected in the 
e-diary.
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

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8.2.1.3. Systemic Events
During the e-diary reporting period, participants 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 participant 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 participant’s systemic event as 
Grade 4. If a participant 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 
participant. The Grade 4 reaction must be recorded in the CRF and is not collected in the 
e-diary.
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
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.
8.2.1.4. Fever
In order to record information on fever, a digital thermometer will be given to participants 
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 that 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.

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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 participant’s fever as Grade 4. If a 
participant 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 participant. The Grade 4 reaction 
must be recorded in the CRF and is not collected in the e-diary.
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)
8.2.2. Clinical Safety Laboratory Assessments
Clinical safety laboratory tests will not be performed in this study. 
If laboratory values from non–protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.3. Biological Samples 
Serum samples will be used only for scientific research.  Each sample will be labeled with a 
code so that the laboratory personnel testing the samples will not know the participant’s 
identity.  Samples that remain after performing assays outlined in the protocol may be stored 
by Pfizer.  Unless a time limitation is required by local regulations or ethical requirements, 
the samples will be stored for up to 15 years after the end of the study and then destroyed.  If 
allowed by the ICD, stored samples may be used for additional testing to better understand 
the immune responses to the vaccine(s) under study in this protocol, to inform the 
development of other products, and/or for vaccine-related assay work supporting vaccine 
programs.  No testing of the participant’s genetic material will be performed. 
The participant may request that his or her samples, if still identifiable, be destroyed at any 
time; however, any data already collected from those samples will still be used for this 
research.  The biological samples may be shared with other researchers as long as 
confidentiality is maintained and no testing of the participant’s genetic material is performed.
8.2.4. Pregnancy Testing 
Urine pregnancy tests must have a sensitivity of at least 25 mIU/mL.  Pregnancy tests will be 
performed in WOCBP at the times listed in the SoA, immediately before the administration 
of each vaccine dose. A negative pregnancy test result will be required prior to the 
participant’s receiving the investigational product.  Pregnancy tests may also be repeated if 

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requested by IRBs/ ECs or if required by local regulations.  In the case of a positive 
confirmed pregnancy, the participant will be withdrawn from administration of 
investigational product and from the study.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 2.
AEs will be reported by the participant or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative.
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study (see Section 7). 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving investigational product), through and including 
Visit 5 (Month 7) for AEs and through and including Visit 7 (Month 12) for SAEs.  
In addition, any AE occurring up to 48 hours after each blood draw (ie, after Visits 6 
[Month 9] and 7 [Month 12]) must be recorded on the CRF.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the CRF, not the AE section.
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.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.

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8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately and under no circumstance should this 
exceed 24 hours, as indicated in Appendix 2.  The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available.
SAEs occurring in a participant 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.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
During the active collection period, both nonserious AEs and SAEs are recorded on the CRF.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information 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 participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 2.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 

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sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/EC, if appropriate according to local 
requirements.
8.3.5. Exposure 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.
8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until Visit 7 (Month 12).
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 3.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. 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.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 

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information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Medical Device Incidents (Including Malfunctions)
Medical devices are being provided for use in this study for the purposes of administering 
investigational product.  In order to fulfill regulatory reporting obligations worldwide, the 
unblinded site staff are responsible for the detection and documentation of events meeting the 
definitions of incident or malfunction that occur during the study with such devices.
The definition of a medical device incident can be found in Appendix 5.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.3 and Appendix 3 of the protocol.
8.3.6.1. Time Period for Detecting Medical Device Incidents
Medical device incidents or malfunctions of the device that result in an incident will be 
detected, documented, and reported during all periods of the study in which the medical 
device is used.
If the investigator learns of any incident at any time after a participant has been discharged 
from the study, and such incident is considered reasonably related to a medical device 
provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device incidents is provided in Appendix 5.
8.3.6.2. Follow-up of Medical Device Incidents
All medical device incidents involving an AE will be followed and reported in the same 
manner as other AEs (see Section 8.3).  This applies to all participants, including those who 
discontinue study intervention.
The unblinded site staff are responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality of the 
incident.
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the unblinded site staff.
8.3.6.3. Prompt Reporting of Medical Device Incidents to Sponsor
Medical device incidents will be reported to the sponsor within 24 hours after unblinded site 
staff determines that the event meets the protocol definition of a medical device incident.
The Medical Device Incident Report Form will be sent to the sponsor by an electronic 
method.  If an electronic method is unavailable, then an alternative method should be 
utilized.

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The same individual will be the contact for the receipt of medical device reports and SAEs.
8.3.6.4. Regulatory Reporting Requirements for Medical Device Incidents
The unblinded site staff will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfill the legal responsibility to 
notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of incidents to the IRB/EC.
8.3.7. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength.
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
Medication errors include:

Medication errors involving participant 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 study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and 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.
Other examples include, but are not limited to:

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
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.
8.4. Treatment of Overdose
For this study, any dose of investigational product greater than 1 dose of investigational 
product within a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.  In the event of an overdose, 
the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs. 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.

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8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is 
outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
The primary objective of assessing noninferiority of the 2-dose regimen to the 3-dose 
regimen will be evaluated at 1 month after the last vaccination for each C difficile toxin A–
or toxin B–specific neutralizing antibody. The evaluable immunogenicity population will be 
used for the hypothesis testing to assess the primary immunogenicity objective.
The 2 null hypotheses (H0) for noninferiority are:
H01: ln(µ2) – ln(µ3) ≤ -ln(1.5) 
Where, for each of toxin A– and toxin B–specific neutralizing antibody, ln(µ2) and ln(µ3) are 
the means of the natural logarithm-transformed concentrations from participants receiving 
the 2-dose regimen and the 3-dose regimen, respectively, measured 1 month after the last 
vaccination with the C difficile vaccine (Month 7).  The analysis of covariance (adjusted for 
baseline concentration) will be used to test these null hypotheses, and corresponding 95% CIs
will be provided.  
and
H02: P2 – P3 ≤-10%
Where, for each of toxin A– and toxin B–specific neutralizing antibody, P2 and P3 are the 
seroresponse rates achieved by participants receiving the 2-dose regimen and the 3-dose 
regimen respectively, measured 1 month after the last vaccination with C difficile vaccine
(Month 7).  A participant achieves seroresponse if the participant has a 4-fold rise after 
vaccination. 
If the lower limit of the 2-sided 95% CI for the GMC ratio (2-dose/3-dose) is > 0.67 and the 
lower limit of the 2-sided 95% CI for the difference between the regimens (2-dose minus 
3-dose) in the percentage of participants achieving seroresponse is > -10% for both toxin A–
and toxin B–specific neutralizing antibodies, 1 month after the last vaccination, the primary 
objective of establishing noninferiority of the 2-dose regimen to the 3-dose regimen is met.  

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If this primary immunogenicity objective is met, the same null hypotheses for the secondary 
immunogenicity objective will be evaluated 6 months after the last vaccination.
Estimands
Endpoint
Estimands
Primary

Immunogenicity:  
For each of toxin A– and toxin B–specific neutralizing antibody levels: Adjusted GMC ratio, 
estimated by the ratio of the adjusted GMC at Month 7 (adjusted for baseline concentration),
for the 2-dose regimen to the adjusted GMC for the 3-dose regimen, in participants receiving 
C difficile vaccine and in compliance with the key protocol criteria (evaluable participants).
For each of  toxin A– and toxin B–specific neutralizing antibody levels: Seroresponse 
difference at Month 7, estimated by the difference between the 2-dose regimen and the 3-dose 
regimen in the percentage of participants achieving seroresponse, in participants receiving 
C difficile vaccine and in compliance with the key protocol criteria (evaluable participants).
Seroresponse for each of toxin A– and toxin B– specific neutralizing antibody levels: For both 
seronegative (baseline concentration < LLOQ) and seropositive (baseline concentration 
≥LLOQ) participants, seroresponse is achieved for a specific participant if that participant 
has at least a 4-fold rise from the baseline neutralizing antibody level following vaccination.
These estimands estimate the regimen effect in the hypothetical setting where participants 
follow the study schedules and protocol requirements as directed.  They address the primary 
immunogenicity objective of estimating the (maximum) potential difference between the 
2- and 3-dose regimens at 1 month post last vaccination, since the impact of noncompliance 
may diminish the observed difference between the 2 regimens (eg, when participants 
randomized to the 3-dose regimen receive only 2 doses).  Missing serology results will not be
imputed, as missing completely at random (MCAR) is assumed. 

Safety:

In participants receiving at least 1 dose of investigational product, the incidence rate 
estimated by the percentage of participants reporting local reactions.

In participants receiving at least 1 dose of investigational product, the incidence rate 
estimated by the percentage of participants reporting systemic events.

In participants receiving at least 1 dose of investigational product, the incidence rate 
estimated by the percentage of participants reporting nonserious AEs.

In participants receiving at least 1 dose of investigational product, the incidence rate 
estimated by the percentage of participants reporting SAEs.
Missing e-diary data will not be imputed; missing AE dates and missing AE severity will be 
handled according to the Safety Rulebook Summary developed by Pfizer.

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Endpoint
Estimands
Secondary
For each of toxin A– and toxin B–specific neutralizing antibody levels: Adjusted GMC ratio, 
estimated by the ratio of the adjusted GMC at Month 12 (adjusted for baseline concentration),
for the 2-dose regimen to the adjusted GMC for the 3-dose regimen, in participants receiving 
C difficile vaccine and in compliance with the key protocol criteria (evaluable participants).
For each of  toxin A– and toxin B–specific neutralizing antibody levels: Seroresponse 
difference at Month 12, estimated by the difference between the 2-dose regimen and the 
3-dose regimen in the percentage of participants achieving seroresponse, in participants 
receiving C difficile vaccine and in compliance with the key protocol criteria (evaluable 
participants).
Seroresponse for each of toxin A– and toxin B– specific neutralizing antibody levels: For both 
seronegative (baseline concentration < LLOQ) and seropositive (baseline concentration 
≥LLOQ) participants, seroresponse is achieved for a specific participant if that participant 
has at least a 4-fold rise from baseline neutralizing antibody level following vaccination.
These estimands estimate the regimen effect in the hypothetical setting where participants 
follow the study schedules and protocol requirements as directed.  They address the secondary 
objective of estimating the (maximum) potential difference between the 2- and 3-dose 
regimens at 6 months post last vaccination, since the impact of noncompliance may diminish 
the observed difference between the 2 regimens (eg, when participants randomized to the 
3-dose regimen receive only 2 doses).  Missing serology results will not be imputed, as 
MCAR is assumed. 

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9.2. Sample Size Determination
In order to meet the immunogenicity primary objective, the study sample size estimate is 
based upon the evaluation of the primary immunogenicity objective of the study to 
demonstrate that the immune responses induced by 2 doses of C difficile vaccine 
(administered in a 0- and 6-month regimen) are noninferior to the immune responses induced 
by 3 doses of C difficile vaccine (administered in a 0-, 1-, and 6-month regimen) – by 
evaluating the toxin A- and toxin B- specific neutralizing antibody in terms of GMC ratios 
and difference in the percentage of participants achieving seroresponse, 1 month after the last 
investigational product administration.  Regimen comparisons will be based on two primary 
endpoints: (1) the adjusted GMC ratio (adjusted for baseline antibody concentration); and (2) 
the difference in the percentage of participants achieving seroresponse, 1 month after the last
vaccination (Month 7), and the corresponding 95% CIs.  The noninferiority of a 2-dose 
regimen to a 3-dose regimen at 1 month after the last vaccine dose will be evaluated using a 
1.5-fold NI margin for the adjusted GMC ratio and a 10% NI margin for the difference in
seroresponse rates.  Pfizer has developed a new assay which will be used for serology testing 
in this study. The new assay was used to test Study B5091009 retrospectively, and the 
standard deviation was evaluated. Therefore, the computation of the sample size for the 
GMC ratio is based on (1) the standard deviations (0.794 for toxin A and 1.059 for toxin B) 
from Study B5091009 data tested by the new assay and (2) an assumption that the true mean 
difference between the 2 regimens for both toxin A– and toxin B–specific neutralizing 
antibody levels is no more than 0.2 on the logarithmic scale.  Similarly, the reference for the 
computation of the sample size for the difference in seroresponse rate is based on the 
percentage of seroresponse (4-fold rise from baseline) observed from Study B5091009, and 
an assumption that the true seroresponse rate for the 2-dose regimen is no more than 7% 
lower than the ones from the 3-dose regimen. A sample size of 784 evaluable participants 
per regimen will provide a power of 96.91% to declare the noninferiority of a 2-dose regimen 
to a 3-dose regimen for both toxin A and toxin B in terms of the GMC ratio, 1 month after
the last dose (see Table 6). The sample size will also provide a power of 93.43% to declare 
the noninferiority of a 2-dose regimen to a 3-dose regimen for both toxin A and toxin B in 
terms of the difference of percentage of participants achieving seroresponse, 1 month after 
the last dose (see Table 7).  Thus, the overall power to meet the study primary 
immunogenicity objective is 90.5%. 

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Table 6.
Power Analysis (Primary Immunogenicity Objective: Noninferiority for
GMC ratio)
Criteria
Neutralizing 
Antibody
Standard 
Deviation 
(Log Value)a
Assume 
Observed 
Log GMC 
Difference
Number of 
Evaluable 
Participants 
per Regimen
Powerb
Power to 
Meet NI for 
Both Toxins 
at 1 Month 
After Dose 3 
Lower limit of 
95% CI for 
GMC ratio 
(2 doses/3 doses) 
> 0.67
Toxin A
0.794
0.2
784
99.92%
96.91%
Toxin B
1.059
0.2
784
96.99%
Abbreviations: GMC = geometric mean concentration; NI = noninferiority.
a.
Reference Study B5091009 tested by new assay, 1 month after Dose 3.
b.
At 0.05 alpha level (2-sided).
Table 7.
Power Analysis (Primary Immunogenicity Objective: Noninferiority for
Difference in Seroresponse)
Criteria
Neutralizing 
Antibody
Observed % 
of 
seroresponse 
from 3-dose 
groupa
Assume % of 
seroresponse 
from 2-dose 
group
Number of 
Evaluable 
Participants 
per Regimen
Powerb
Power to 
Meet NI for 
Both Toxins 
at 1 Month 
After Dose 3 
Lower limit of 
95% CI for 
difference in
seroresponse 
rate (2 doses 
minus 3 doses) 
> -10%
Toxin A
91.8%
86%
784
96.14%
93.43%
Toxin B
93.7%
86%
784
97.18%
Note: Seroresponse = Participant achieves at least a 4-fold rise after the last vaccination 
a.
Reference Study B5091009.
b.
At 0.05 alpha level (2-sided).
If the primary immunogenicity objective is met, the secondary immunogenicity objective will 
be evaluated by the same criteria. For the secondary immunogenicity objective, if the 
noninferiority criterion for the GMC ratio is met at Month 12, then the evaluation of the 
difference between regimens in seroresponse at Month 12 will follow.  
A sufficient number of participants will be screened to achieve 1960 participants randomly 
assigned to investigational product and 1568 evaluable participants (assuming a maximum 
study nonevaluable rate of 20% and a randomization ratio of 1:1), for an estimated total of 
784 evaluable participants per vaccine group in order to meet the primary immunogenicity 
objectives. 

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9.3. Populations for Analysis
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICD.
Randomly assigned to 
investigational product
All participants who are assigned a randomization number in the IWR 
system.
Evaluable
All participants who are eligible, have received the investigational product 
to which they were randomized, have blood drawn for assay testing within 
the specified time frame, have valid and determinate assay results for either 
toxin A or toxin B for the proposed analysis time point, and have no major 
protocol violations.
For participants who have major protocol violations (eg, took concomitant 
medications/vaccines that may impact the immune response), all 
postviolation observations will be censored.
Participants who discontinue the study before reaching primary endpoint 
will be excluded from the primary analysis.    
Modified intent-to-treat (mITT)
All participants who are randomly assigned to investigational product and 
have received at least 1 vaccination and have at least 1 valid and determinate 
assay result for the proposed analysis.
Participants who discontinue the study before reaching the primary endpoint 
will be excluded from the analysis.    
Safety
All participants who are randomly assigned to investigational product and 
have received at least 1 dose of investigational product.  
For reactogenicity, it includes all participants who receive the dose and have 
the e-diary collected; an indicator variable for an e-diary completion status 
after each dose will be detailed in the SAP.
For safety, it includes all participants who receive at least 1 dose. Standard 
algorithms for handling missing AE dates and missing AE severity will be 
applied following the Safety Rulebook Summary developed by Pfizer.
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.  This section provides a summary of the planned 
statistical analyses of the primary and secondary endpoints.

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9.4.1. Immunogenicity Analyses
Endpoint
Statistical Analysis Methods
Primary
Adjusted GMC ratio of the 2-dose regimen to the 3-dose regimen for each of C difficile
toxin A– and toxin B–specific neutralizing antibody levels at Month 7 will be computed using
an analysis of covariance (adjusted for baseline antibody concentration); corresponding 95% 
CIs will be provided.  The GMC will be calculated as the mean of the assay results after 
making the logarithm transformation and then transforming the value back to its original 
scale.  Two (2)sided 95% CIs will be obtained by constructing a CI for the mean of the 
logarithmically transformed assay results based on the Student t distribution, and transforming 
the confidence limits back to the original units.
The difference between the 2-dose regimen and the 3-dose regimen in the percentage of 
participants achieving seroresponse will be computed, along with 95% CIs, for each of the 
C difficile toxin A– and toxin B–specific neutralizing antibody levels at Month 7.  For each of 
the toxin A- and toxin B-specific neutralizing antibody levels, for both seronegative (baseline 
concentration < LLOQ) and seropositive (baseline concentration ≥LLOQ) participants, 
seroresponse is defined as at least a 4-fold rise from the baseline neutralizing antibody 
following vaccination. Two (2)sided 95% CIs will be constructed by the Miettinen and 
Nurminen method. Baseline concentration is defined as the antibody concentration results 
from the blood drawn before vaccine Dose 1. Antibody concentration values below the 
LLOQ or denoted as BLQ will be set to 0.5 × LLOQ for analysis. This analysis is based on 
the evaluable population in order to provide a comparison of the 2 regimens that has the 
greatest chance of identifying a difference between the regimens with respect to 
immunogenicity, if a meaningful difference actually exists (ie, results of the regimen 
comparisons fail to establish noninferiority). A secondary analysis will be performed based 
on the mITT population. Participants will be summarized according to the vaccine group to 
which they were randomized. Missing serology data will not be imputed.  
Secondary
The secondary immunogenicity objective will be evaluated only after the primary 
immunogenicity objective is met.
Adjusted GMC ratio of the 2-dose regimen to the 3-dose regimen for each of C difficile
toxin A– and toxin B–specific neutralizing antibody levels at Month 12 will be computed 
using an analysis of covariance (adjusted for baseline antibody concentration); corresponding
95% CIs will be provided.  The GMC will be calculated as the mean of the assay results after 
making the logarithm transformation and then transforming the value back to its original 
scale.  Two (2)sided 95% CIs will be obtained by constructing a CI for the mean of the 
logarithmically transformed assay results based on the Student t distribution, and transforming 
the confidence limits back to the original units.
The difference between the 2-dose regimen and the 3-dose regimen in the percentage of 
participants achieving seroresponse will be computed, along with 95% CIs, for each of 
C difficile toxin A– and toxin B–specific neutralizing antibody levels at Month 12.  For each 
of toxin A- and toxin B-specific neutralizing antibody levels, for both seronegative (baseline 
concentration < LLOQ) and seropositive (baseline concentration ≥LLOQ) participants, 
seroresponse is defined as at least a 4-fold rise from the baseline neutralizing antibody 
following vaccination. Two (2)sided 95% CIs will be constructed by the Miettinen and 
Nurminen method. Antibody concentration values below the LLOQ or denoted as BLQ will 
be set to 0.5 × LLOQ for analysis.
This analysis is based on the evaluable population in order to provide a comparison of the 2
regimens that has the greatest chance of identifying a difference between the regimens with 
respect to immunogenicity, if a meaningful difference actually exists (ie, results of the 
regimen comparisons fail to establish noninferiority). A secondary analysis will be performed 
based on the mITT population. Participants will be summarized according to the vaccine 
group to which they were randomized. Missing serology data will not be imputed.  

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Endpoint
Statistical Analysis Methods
9.4.1.1. Analysis of the Primary Immunogenicity Endpoint
For immunogenicity analysis, the evaluable immunogenicity population and the mITT 
population will be used for the analysis. Participants will be included in the vaccine group 
according to their randomization at Dose 1. The primary objective will be evaluated by an
analysis of covariance to compute the GMC ratio, adjusted for baseline antibody 
concentration, of the 2-dose regimen to the 3-dose regimen at 1 month after the last dose for 
each C difficile toxin A– and toxin B–specific neutralizing antibody; and by the difference 
between the regimens in the percentage of participants achieving seroresponse at 1 month 
after the last dose for each C difficile toxin A– and toxin B–specific neutralizing antibody.
If the lower limit of 2-sided 95% CI for the GMC ratio (2-dose/3-dose regimen) is > 0.67 for 
both toxin A– and toxin B–specific neutralizing antibody concentrations, and the lower limit 
of the 2-sided 95% CI for the difference in the percentage of participants achieving 
seroresponse (2-dose minus 3-dose regimen) is > -10% for both toxin A– and toxin B–
specific neutralizing antibodies, 1 month after the last vaccination, the primary objective of 
establishing noninferiority of the 2-dose regimen to the 3-dose regimen is met.  
CCI

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9.4.1.2. Analysis of the Secondary Immunogenicity 
 
Endpoints
If the primary objective is met, the secondary immunogenicity objective will be evaluated by 
the GMC ratio first and then by the difference in percentage of participants achieving 
seroresponse at 6 months after the last vaccination for each C difficile toxin A–and toxin B–
specific neutralizing antibody, based on the evaluable immunogenicity population and the
mITT population.  
If the lower limit of the 2-sided 95% CI for the GMT ratio (2-dose/3-dose regimen) is > 0.67 
at Month 12 for both toxin A– or toxin B–specific neutralizing antibody concentrations, and 
the lower limit of the 2-sided 95% CI for the difference in the percentage of participants 
achieving seroresponse (2-dose minus 3-dose regimen) is > -10% at Month 12 for both 
toxin A– and toxin B–specific neutralizing antibody levels, the secondary immunogenicity 
objective of noninferiority of the 2-dose regimen to the 3-dose regimen 6 months after the
last dose is met.
CCI
CCI

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9.4.2. Safety Analyses
All safety analyses will be performed on the safety population.
Endpoint
Statistical Analysis Methods
Primary
•
The point estimate and the exact 2-sided 95% CI will be calculated using the 
Clopper-Pearson method for the percentage of participants reporting each event for each 
vaccine group.
•
A 3-tier approach will be used to summarize AEs. For both tier 1 and tier 2 events, the 
95% CIs for the difference between the 2-dose regimen group and the 3-dose regimen 
group in the percentage of participants reporting the events, will be calculated using the 
test statistic proposed by Miettinen and Nurminen; in addition, for tier 1 events, the 
asymptotic p-values will also be presented for the difference in the percentage of 
participants reporting the events, based on the same test statistic and under the 
assumption that the test statistic is asymptotically normally distributed.
The safety analyses are based on safety population. Participants will be summarized 
according to the vaccine they actually received. Missing e-diary data will not be imputed;
missing AE dates and missing AE severity will be handled according to the Safety Rulebook 
Summary developed by Pfizer.
Secondary
•
N/A
9.4.2.1. Analysis of  the Primary Safety Endpoints
For safety analysis, the safety population will be used, and participants will be analyzed 
according to the investigational product received.  A descriptive summary will be presented 
for each vaccine group.  
The proportions of participants reporting local reactions at the injection site (pain, erythema, 
and induration), and systemic events (fever, vomiting, headache, fatigue, new or worsening 
muscle pain, and new or worsening joint pain) on any day within the 7-day period after 
vaccination will be descriptively summarized by vaccine group and by each vaccination.  
Severities of local reactions and systemic events reported after each vaccination will also be 
descriptively summarized by vaccine group.  Exact 2-sided 95% CIs will be presented with 
the proportions.
AEs and SAEs will be categorized according to Medical Dictionary for Regulatory Activities 
(MedDRA) terms.  AEs will be summarized by vaccine group from the signing of the ICD to 
1 month after receipt of the third dose of investigational product.  SAEs will be summarized 
by vaccine group from the signing of the ICD to 6 months after receipt of the third dose of 
investigational product, and throughout the entire study.  In general, all summaries will 
present the number and percentage of participants experiencing at least 1 event and the 
number of events for each vaccine group, and the exact 2-sided 95% CIs.
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, IB, and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is 
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 

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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.
Participants must be informed that their participation is voluntary.  Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant.

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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code.  
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred.  All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code.  The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity.  In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study 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 addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
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 
product, regardless of the geographical location in which the study is conducted. US Basic 
Results are generally 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 participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.

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EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (clinical study report [CSR] synopses in which any 
data that could be used to identify individual participants have 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.
Documents Within Marketing Authorization Packages/Submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods.  Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.5. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.

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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  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.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor.  The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor 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 participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 

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submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available.
Definition of what constitutes source data can be found in the SRM.
10.1.7. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon 
study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after end of the study (or 
study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission.  This allows the sponsor to protect proprietary information and to 

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provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.9. 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 SRM.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant 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 
participant’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 participant 
directly, and if a participant calls that number, he or she will be directed back to the 
investigator site.

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10.2. Appendix 2: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.2.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, electrocardiogram [ECG], radiological scans, vital sign measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either an increase in frequency 
and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent.  Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the investigator to be more severe than expected 
for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the procedure is 
the AE.

Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to 
a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or detected at the start 
of the study that do not worsen.

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10.2.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk 
of death at the time of the event.  It does not refer to an event that hypothetically might have caused death if it 
were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or outpatient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious.  When 
in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from baseline is not
considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.

This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained 
ankle) which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate 
in other situations such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition.  These events should 
usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse.

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10.2.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF and for reporting serious 
adverse 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. 
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.
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
None
All (and exposure during 
pregnancy [EDP] supplemental 
form for EDP)  

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostic reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical records to 
Pfizer Safety in lieu of completion of the CT SAE Report Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested by Pfizer 
Safety.  In this case, all participant identifiers, with the exception of the participant number, will be 
redacted on the copies of the medical records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information.  Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities.

Severe: An event that prevents normal everyday activities.  An AE that is assessed as severe should not 
be confused with an SAE.  Severe is a category utilized for rating the intensity of an event; and both 
AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe.

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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 participant's usual function.
2
MODERATE
Interferes to some extent with participant's usual function.
3
SEVERE
Interferes significantly with participant's usual function.
4
LIFE-THREATENING
Life-threatening consequences; urgent intervention indicated.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and each occurrence 
of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well 
as the temporal relationship of the event to study intervention administration will be considered and 
investigated.

The investigator will also consult the IB and/or product information, for marketed products, in his/her 
assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal information to 
include in the initial report to the sponsor.  However, it is very important that the investigator always 
make an assessment of causality for every event before the initial transmission of the SAE data to the 
sponsor.

The investigator may change his/her opinion of causality in light of follow-up information and send an 
SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.

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.  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.

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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the sponsor to elucidate the nature and/or 
causality of the AE or SAE as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other healthcare professionals.

If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide Pfizer Safety with a copy of any postmortem findings including 
histopathology.  

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of the 
information.
10.2.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to transmit this 
information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is acceptable with a copy 
of the CT SAE Report Form sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to complete and sign the 
CT SAE Report Form pages within the designated reporting time frames.

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10.3. Appendix 3: Contraceptive Guidance and Collection of Pregnancy Information
10.3.1. Male Participant Reproductive Inclusion Criteria
In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly effective 
methods below in Section 10.3.4).
10.3.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.3.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), as described below, during the intervention period 
and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate any study intervention(s).  The 
investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.3.3. Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.

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For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female:

A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.3.4. Contraception Methods
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Hormone-releasing intrauterine system (IUS).
4. Bilateral tubal occlusion.
5. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.

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6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

oral;

intravaginal;

transdermal;

injectable.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.
8. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
Collection of Pregnancy Information
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.

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If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’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 participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery 
(see below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
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 participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.

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10.4. Appendix 4: Liver Safety: Suggested Actions and Follow-up Assessments 
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 participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants 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 
participant 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 
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 
participant’s individual baseline values and underlying conditions.  Participants 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:

Participants 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 participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

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
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 participant 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 for suspected cases of 
Hy’s law, additional 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, and alkaline phosphatase.  Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected.  Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum sample for acetaminophen drug and/or protein adduct levels 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.

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10.5. Appendix 5: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6.1.2) for the list of sponsor 
medical devices.
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics and/or performance of a 
device as well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, 
might lead to or might have led to the death of a participant/user/other person or to a serious deterioration 
in his/her state of health.

Not all incidents lead to death or serious deterioration in health.  The nonoccurrence of such a result might 
have been due to other fortunate circumstances or to the intervention of healthcare personnel.
It is sufficient that:

An incident associated with a device happened.
AND

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness;

Permanent impairment of body function or permanent damage to body structure;

Condition necessitating medical or surgical intervention to prevent one of the above;

Fetal distress, fetal death, or any congenital abnormality or birth defects.
Examples of Incidents

A participant, user, caregiver, or healthcare professional is injured as a result of a medical device failure or 
its misuse.

A participant’s study intervention is interrupted or compromised by a medical device failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to medical device failure.

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Documenting Medical Device Incidents
Medical Device Incident Documentation

Any medical device incident occurring during the study will be documented in the participant’s medical 
records, in accordance with the investigator’s normal clinical practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE CRF page will be 
completed as described in Appendix 2.

The form will be completed as thoroughly as possible and signed by the investigator before transmittal to 
the sponsor or designee.

It is very important that the investigator provides his/her assessment of causality (relationship to the 
medical device provided by the sponsor) at the time of the initial AE or SAE report and describes any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a medical device where 
such action is necessary to prevent recurrence of an incident.  This includes any amendment to the device 
design to prevent recurrence.

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10.6. Appendix 6: Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
AE
adverse event
AIOH
aluminium hydroxide
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the level of quantitation
CBER
Center for Biologics Evaluation and Research
CDI
Clostridium difficile infection
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CONSORT
Consolidated Standards of Reporting Trials
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
clinical trial
DILI
drug-induced liver injury
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
e-diary
electronic diary
 
EDP
exposure during pregnancy
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
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
GMC
geometric mean concentration
GMFR
geometric mean fold rise
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
H0
null hypothesis
CCI
CCI

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Abbreviation
Term
HPV
human papillomavirus
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
IDSA
Infectious Diseases Society of America
IgG
immunoglobulin G
IM
intramuscular
IMP
investigational medicinal product
IND
investigational new drug application
INR
international normalized ratio
IP manual
investigational product manual
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
hormone-releasing intrauterine system
IWR
interactive Web-based response
LFT
liver function test
LLOQ
lower limit of quantitation
mAb
monoclonal antibody
MCAR
missing completely at random
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MOA
mechanism of action
N/A
not applicable
NDCMC
newly diagnosed chronic medical condition
NI
noninferiority
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
PCD
primary completion date
PFGE
pulsed-field gel electrophoresis
PFS
prefilled syringe
PT
prothrombin time
RCDC
reverse cumulative distribution curve
SAE
serious adverse event
SAP
statistical analysis plan
SoA
schedule of activities
SOP
standard operating procedure
SRM
study reference manual
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction

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Abbreviation
Term
TBili
total bilirubin
TcdA
Clostridium difficile toxin A
TcdB
Clostridium difficile toxin B
ULN
upper limit of normal
US
United States
VE
vaccine efficacy
WOCBP
woman/women of childbearing potential

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