A PHASE 3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLINDED STUDY TO EVALUATE THE LOT CONSISTENCY, SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF A CLOSTRIDIUM DIFFICILE VACCINE IN HEALTHY ADULTS 65 TO 85 YEARS OF AGE
Phase: PHASE3
Conditions: Clostridium Difficile Associated Disease
Sponsor: Pfizer

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A PHASE 3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLINDED 
STUDY TO EVALUATE THE LOT CONSISTENCY, SAFETY, TOLERABILITY,
AND IMMUNOGENICITY OF A CLOSTRIDIUM DIFFICILE VACCINE IN 
HEALTHY ADULTS 65 TO 85 YEARS OF AGE
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:
Not Applicable (N/A)
Protocol Number:
B5091008
Phase:
3
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version Date
Summary of Changes and Rationale
Protocol Amendment 1
08 Nov 2018
Clostridium difficile Disease Background, 
Section 1.2.1, has been updated to reflect 
the most recent therapy recommendations 
for the treatment of Clostridium difficile
infection (CDI), and a reference was 
added.
The secondary endpoints such as 
geometric mean fold rises (GMFRs) for 
neutralizing antibody were not intended to 
explore any additional aspects of the 
vaccine lot comparisons beyond those 
assessed for the primary objective.  
Therefore, the secondary objectives and 
endpoints were changed to exploratory 
objectives and endpoints in Sections 2 and
9.2.3.
To ensure that subjects continue to meet 
eligibility requirements at Visit 5, the 
Schedule of Activities and Procedures 
(Section 6.1.5) were updated.
Medical Device Complaint Reporting 
Requirements, Section 8.5, has been 
updated to incorporate the Protocol 
Administrative Change Letter (PACL),
dated 18 April 2018, that prevents
accidental unblinding.
Original protocol
08 Jan 2018
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).

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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
APPENDICES ...........................................................................................................................6
PROTOCOL SUMMARY.........................................................................................................7
SCHEDULE OF ACTIVITIES..................................................................................................9
1. INTRODUCTION ...............................................................................................................10
1.1. Mechanism of Action/Indication.............................................................................10
1.2. Background and Rationale ......................................................................................10
1.2.1. Clostridium difficile Disease Background..................................................10
1.2.2. Clostridium difficile Vaccine Development Rationale...............................11
1.2.3. Clostridium difficile Vaccine Candidate.....................................................12
1.2.3.1. Nonclinical Development..........................................................12
1.2.3.2. Clinical Development................................................................12
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................14
3. STUDY DESIGN.................................................................................................................14
3.1. Approximate Number of Subjects...........................................................................14
3.2. Approximate Duration of Subject Participation......................................................15
3.3. Approximate Duration of the Study........................................................................15
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................15
4.1. Inclusion Criteria.....................................................................................................15
4.2. Exclusion Criteria....................................................................................................16
4.3. Criteria for Temporarily Delaying Vaccine Administration...................................17
4.4. Lifestyle Requirements ...........................................................................................18
4.4.1. Contraception..............................................................................................18
4.5. Sponsor’s Qualified Medical Personnel..................................................................19
5. INVESTIGATIONAL PRODUCTS ...................................................................................19
5.1. Allocation to Investigational Product......................................................................19
5.2. Blinding of Site Personnel.......................................................................................20
5.3. Blinding of the Sponsor...........................................................................................20
5.4. Breaking the Blind ..................................................................................................20
5.5. Subject Compliance.................................................................................................21

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5.6. Vaccine Supplies.....................................................................................................21
5.6.1. Formulation and Packaging........................................................................21
5.6.1.1. Clostridium difficile Vaccine ....................................................21
5.6.1.2. Placebo ......................................................................................21
5.6.2. Preparation and Dispensing........................................................................21
5.6.3. Administration............................................................................................21
5.7. Investigational Product Storage ..............................................................................22
5.8. Investigational Product Accountability...................................................................23
5.8.1. Destruction of Investigational Product Supplies ........................................23
5.9. Concomitant Medication(s).....................................................................................23
5.9.1. Recording Concomitant Vaccinations and Medications.............................23
5.9.2. Prohibited Concomitant Vaccinations and Medications.............................23
5.9.3. Permitted Concomitant Medications ..........................................................24
6. STUDY PROCEDURES .....................................................................................................24
6.1. Study Period ............................................................................................................24
6.1.1. Visit 1: Month 0 – Vaccination 1 (Day 1) ..................................................24
6.1.2. Visit 2: Month 1 – Vaccination 2 (28 to 42 Days After Visit 1) ................26
6.1.3. Visit 3: Month 2 (28 to 42 Days After Visit 2)...........................................27
6.1.4. Visit 4: Month 6 – Vaccination 3 (140 to 168 Days After Visit 2) ............27
6.1.5. Visit 5: Month 7 (28 to 42 Days After Visit 4)...........................................29
6.1.6. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction..............29
6.2. Subject Withdrawal.................................................................................................29
7. ASSESSMENTS..................................................................................................................30
7.1. Safety Assessments .................................................................................................30
7.1.1. Electronic Diary..........................................................................................31
7.1.1.1. Grading Scales...........................................................................31
7.1.1.2. Local Reactions.........................................................................31
7.1.1.3. Systemic Events ........................................................................32
7.1.1.4. Fever..........................................................................................33
7.2. Immunogenicity Assessments.................................................................................33
7.3. Biological Samples..................................................................................................34
8. ADVERSE EVENT REPORTING......................................................................................34

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8.1. Requirements...........................................................................................................34
8.1.1. Additional Details on Recording Adverse Events on the CRF...................35
8.1.2. Eliciting Adverse Event Information..........................................................35
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................36
8.1.4. Time Period for Collecting AE/SAE Information......................................36
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................36
8.1.4.2. Recording Nonserious AEs and SAEs on the CRF...................36
8.1.5. Causality Assessment .................................................................................36
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................37
8.2. Definitions...............................................................................................................37
8.2.1. Adverse Events...........................................................................................37
8.2.2. Abnormal Test Findings .............................................................................38
8.2.3. Serious Adverse Events ..............................................................................38
8.2.4. Hospitalization............................................................................................39
8.3. Severity Assessment................................................................................................41
8.4. Special Situations ....................................................................................................41
8.4.1. Protocol-Specified Serious Adverse Events...............................................41
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................41
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................43
8.4.3.1. Exposure During Pregnancy......................................................43
8.4.3.2. Exposure During Breastfeeding ................................................44
8.4.3.3. Occupational Exposure .............................................................44
8.4.4. Medication Errors .......................................................................................45
8.4.4.1. Medication Errors......................................................................45
8.5. Medical Device Complaint Reporting Requirements .............................................46
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................46
9.1. Sample Size Determination.....................................................................................46
9.2. Immunogenicity Analysis .......................................................................................47
9.2.1. Immunogenicity Analysis Population.........................................................47
9.2.2. Analysis of the Primary Immunogenicity Endpoint...................................48
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9.3. Safety Analysis........................................................................................................49
9.4. Analysis Timing ......................................................................................................49
9.5. Data Monitoring Committee ...................................................................................49
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................50
11. DATA HANDLING AND RECORD KEEPING .............................................................51
11.1. Case Report Forms/Electronic Data Record .........................................................51
11.2. Record Retention...................................................................................................51
12. ETHICS..............................................................................................................................52
12.1. Institutional Review Board/Ethics Committee......................................................52
12.2. Ethical Conduct of the Study ................................................................................52
12.3. Subject Information and Consent..........................................................................52
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................53
13. DEFINITION OF END OF TRIAL...................................................................................53
13.1. End of Trial in All Participating Countries ...........................................................53
14. SPONSOR DISCONTINUATION CRITERIA ................................................................53
15. PUBLICATION OF STUDY RESULTS..........................................................................53
15.1. Communication of Results by Pfizer ....................................................................53
15.2. Publications by Investigators ................................................................................54
16. REFERENCES ..................................................................................................................56
LIST OF TABLES
Table 1.
Local Reaction Grading Scale ..............................................................................32
Table 2.
Systemic Event Grading Scale..............................................................................32
Table 3.
Scale for Fever......................................................................................................33
Table 4.
Power Analysis (Primary Immunogenicity Endpoint) .........................................47
APPENDICES
Appendix 1. Abbreviations......................................................................................................61

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PROTOCOL SUMMARY
Indication
Pfizer’s investigational Clostridium difficile vaccine (PF-06425090) is a prophylactic vaccine 
that is currently being investigated for the prevention of primary C difficile infection (CDI) in 
adults 50 years of age and older.
Objectives and Endpoints
Primary Immunogenicity Objective:
Primary Immunogenicity Endpoint:

To demonstrate that the immune responses induced by 
3 lots of C difficile vaccine are equivalent as measured 
by C difficile toxin A– and toxin B–specific 
neutralizing antibody levels 1 month after the third 
vaccination when administered in a 3-dose regimen to 
healthy adults 65 to 85 years of age.

C difficile toxin A– and toxin B–specific neutralizing 
antibody levels for each lot, expressed as geometric 
mean concentrations (GMCs) (neutralization 
units/mL) at Month 7.
Primary Safety Objective:
Primary Safety Endpoints:

To evaluate the safety of C difficile vaccine when 
administered in a 3-dose regimen to healthy adults 65 
to 85 years of age, as measured by the number and 
percentage of subjects reporting local reactions and 
systemic events, adverse events, and serious adverse 
events.

Local reactions (pain, erythema, and induration), as 
self-reported in electronic diaries (e-diaries) for up to 
7 days following each dose of investigational 
product.

Systemic events (fever, vomiting, headache, fatigue, 
new or worsening muscle pain, and new or 
worsening joint pain), as self-reported in e-diaries for 
up to 7 days following each dose of investigational 
product.

Nonserious adverse events from signing of the 
informed consent document (ICD) to 1 month after 
receipt of the third dose of investigational product.

Serious adverse events from signing of the ICD to 
1 month after receipt of the third dose of 
investigational product.
Study Design
This is a Phase 3, placebo-controlled, randomized, observer-blinded study to evaluate the lot 
consistency, safety, tolerability, and immunogenicity of an aluminum hydroxide 
(AlOH)-containing C difficile vaccine (200 g total toxoid) administered as a 3-dose regimen 
at Months 0, 1, and 6 in healthy adults 65 to 85 years of age.
Subjects will be randomized into 1 of 4 groups in a 1:1:1:1 ratio (Lot 1: Lot 2: Lot 3: 
placebo).
Investigational Products
Clostridium difficile Vaccine
The investigational C difficile vaccine is toxoid based. C difficile toxin A and toxin B are 
inactivated by a combination of genetic mutations and chemical treatments. The vaccine is 

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provided as a sterile lyophilized powder in a dosage strength of 200 g/dose (total for 
toxoids A and B) given at Month 0, Month 1, and Month 6. The vaccine will be 
reconstituted with AlOH diluent immediately before use as instructed in the investigational 
product (IP) manual. The AlOH diluent is supplied as a 1-mg aluminum/mL (as AlOH) 
liquid suspension.
Placebo
The placebo will consist of a sterile normal saline solution for injection (0.9% sodium 
chloride injection, in a 0.5-mL dose) and will be provided by the sponsor to each study site.
Statistical Methods
The study sample size estimate is based on the study primary immunogenicity objective to 
demonstrate lot-to-lot consistency, by evaluating the toxin A– and toxin B–specific 
neutralizing antibody in terms of GMCs, 1 month after the third vaccination (Month 7). A 
2-fold equivalence margin is used as the criterion; 263 evaluable subjects per lot will provide 
an overall 90% power to declare equivalence between all 6 comparisons for both toxin A and 
toxin B.
Assuming a maximum study nonevaluable rate of 20%, a total of 1316 subjects need to be 
enrolled in the study to meet the primary objective, with a randomization ratio of 1:1:1:1 
(Lot 1: Lot 2: Lot 3: placebo).
The primary immunogenicity objective of the lot-to-lot consistency will be achieved if the 
2-sided 95% confidence intervals (CIs) on the GMC ratios for all 6 comparisons are within 
the interval (0.5, 2), for both toxin A and toxin B.
All safety and reactogenicity endpoints will be summarized as proportions of subjects with 
events by vaccine group.  Additionally, exact 2-sided 95% CIs for proportions will be 
provided as applicable.
For immunogenicity endpoints, GMCs and geometric mean fold rises (GMFRs) from 
baseline will be calculated by vaccine group along with the 95% CIs for both toxin A and 
toxin B.

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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  
Refer to the Study Procedures and Assessments sections of the protocol for detailed 
information on each procedure and assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities table, in order to conduct evaluations or assessments required to protect 
the well-being of the subject.
Visit ID
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit Description
Month 
0
(Vax 1)
Month 1
(Vax 2)
Month 2
(Phone 
Contact)
Month 6
(Vax 3)
Month 7
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
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
Discuss contraceptive useb
X
X
X
X
Confirm eligibilityb
X
X
X
X
X
Review temporary delay criteriaa
X
X
X
Randomizationa
X
Blood draw for immunogenicity assessmentb
X
Xc
Vaccination
X
X
X
Postvaccination observation
(at least 30 minutes) and AE assessment
X
X
X
Issue measuring device and thermometer, and 
provide instructions on their use, as required
X
X
X
Assist the subject with downloading the app, 
or issue provisioned device
X
Review e-diary completion requirements
X
X
X
Record AEs/SAEs
X
X
X
X
X
Telephone contact
X
Review e-diary datad
Collect e-diary
X
Abbreviations: e-diary = electronic diary; Vax = vaccination; = ongoing/continuous event.
a.
Prior to vaccination.
b.
Prior to vaccination, if at a vaccination visit.
c.
Any AEs occurring up to 48 hours after blood draw must be recorded on the case report form (CRF).
d.
E-diary data review is ongoing during subject e-diary data-entry periods (7 days after each vaccination) via 
an internet-based portal.

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

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care facilities, the cost of caring for patients experiencing CDI in the United States ranges 
from $1.1 to $4.8 billion annually.28,29
In the last decade, the numbers and severity of C difficile iatrogenic outbreaks in hospitals 
and nursing homes have increased.27,28,30  Key factors in this escalation include emergence of 
hypervirulent pathogenic strains such as BI/NAP1/027,31,32,33 increased use of antibiotics,34
improved detection methods, and increased exposure to spores in healthcare facilities.35
Metronidazole has been recommended as initial therapy since the late 1990s, but recent 
guidance issued by the Infectious Diseases Society of America (IDSA) recommends either 
vancomycin or fidaxomicin as the first choice, and metronidazole should be used only if they 
are not available.6,21,36,37  Fidaxomicin has been developed more recently and has been shown 
to be noninferior to vancomycin for treatment of CDI.  In addition, treatment with 
fidaxomicin was associated with a significantly lower rate of recurrence than was treatment 
with vancomycin.19  European guidelines for treatment of CDI include fidaxomicin as an 
option for treatment of recurrence.21  Fecal transplantation has also been shown to be 
effective in some patients for the treatment of multiple recurrences of CDI.38,39  However, 
regulatory oversight of this method remains in development,40 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.41
1.2.2. Clostridium difficile Vaccine Development Rationale
It is well established that humoral immune responses to C difficile toxins play a significant 
role in preventing a more severe outcome or a recurrence of the disease in humans.  Several 
clinical studies suggest a correlation between high serum concentrations of antitoxin A and B 
immunoglobulin G (IgG) (as measured by enzyme-linked immunosorbent assay [ELISA]) 
and protection from CDI or recurrence after primary CDI.20,42,43,44  Preclinical studies have 
shown that active immunization with inactivated toxins (“toxoids”) and passive 
immunization with antitoxin antibodies protect animals from lethal challenge.45,46,47  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.48  Results of human studies 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.49
To date, there is no approved vaccine to prevent primary or recurrent CDI.  There are at least 
2 other vaccines in development that target C difficile toxins.  A toxoid-based vaccine 
adjuvanted with aluminum hydroxide (AlOH) has been evaluated in Phase 1 and 2 
studies,50,51,52,53 and efficacy is currently being evaluated in a Phase 3 study.54  The other is a 
recombinant fusion protein comprising fragments of the receptor-binding domains of TcdA
and TcdB separated by a 4–amino acid linker;55 this vaccine has been evaluated in a 
completed Phase 2 study.56

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The increasing burden of CDI on patients and on the healthcare system demonstrates that 
prevention of CDI constitutes a significant unmet medical need.
1.2.3. Clostridium difficile Vaccine Candidate
Pfizer’s C difficile vaccine candidate consists of a 1:1 mixture of C difficile toxoids A and B.  
The toxoids were derived from native toxins by genetic modification to decrease toxin 
activity, and chemical inactivation prior to final purification and formulation of the drug 
substance.
1.2.3.1. Nonclinical Development
In nonclinical experiments, Pfizer’s C difficile candidate vaccine was studied either alone or 
in combination with AlOH.  Using the standard hamster C difficile disease model, vaccine 
formulations with and without AlOH demonstrated a survival benefit, providing at least 90% 
protection from a lethal challenge with C difficile spores in the immunized hamsters.  In 
addition, pooled sera obtained from hamsters immunized with the C difficile vaccine 
formulated with AlOH neutralized secreted toxins from C difficile isolates representing 
diverse ribotypes/pulsed-field gel electrophoresis (PFGE) types, including hypervirulent 
strains, and covering >67% and >70% of the circulating strains in the United States and 
Europe, respectively. In nonhuman primates, Pfizer’s toxoid vaccine formulations with and 
without AlOH induced robust neutralizing antitoxin antibody responses to both TcdA and 
TcdB.  The nonclinical data generated by Pfizer in rhesus macaques support the use of a 
3-dose regimen of the C difficile vaccine, with or without AlOH.
1.2.3.2. Clinical Development
The B5091001 first-in-human study was a placebo-controlled, randomized, observer-blinded 
Phase 1 study that evaluated the safety, tolerability, and immunogenicity of Pfizer’s 
C difficile vaccine.  Three (3) antigen dose levels (50, 100, and 200 g) were assessed and 
administered either alone or in combination with AlOH at Months 0, 1, and 6 to healthy 
adults 50 to 85 years of age.57  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.  Adverse events (AEs) were 
reported in all vaccine groups, with little difference in the number of subjects between the 
dose groups and the placebo group or between vaccine formulations.  In subjects who 
received the vaccine formulations, both the toxin A– and toxin B–specific neutralizing 
antibody geometric mean concentrations (GMCs) increased substantially at 1 month after 
Dose 2 and after Dose 3 compared to baseline.  Potent antitoxin neutralizing responses were 
evident in immunized subjects in both age groups at Month 12.  Although there was no clear 
dose-level response pattern, the data suggest that both the antitoxin A– and 
antitoxin B-specific neutralizing responses were trending higher in the toxoid-only groups 
compared to the toxoid + AlOH groups.  Furthermore, the magnitude of the immune 
response was similar in the 2 age cohorts.
Based on these data, a Phase 2 study (B5091003) was initiated using a 3-dose regimen 
(Days 1, 8, and 30) and 2 antigen dose levels (100 and 200 g) of the toxoids alone 

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reconstituted with sodium chloride diluent.  However, recruitment and vaccinations were 
halted because of the occurrence of 7 cases of Grade 3 injection site redness after Dose 2.  In 
light of this observed tolerability profile, the decision was made to progress development of 
the AlOH-containing formulation into a second Phase 2 study. This Phase 2 study 
(B5091009) of the AlOH-containing formulation is ongoing to assess the safety, tolerability, 
and immunogenicity of 2 antigen dose levels (100 and 200 g) and two 3-dose regimens 
(Days 1, 8, and 30 and Months 0, 1, and 6).  A prespecified interim analysis of data up to 
Month 7 from this study demonstrated that the immunogenicity profile following 3 doses 
administered at Months 0, 1, and 6 was superior to that when the doses were administered at 
Days 1, 8, and 30. In addition, the 200-g dose level was more immunogenic than the 
100-g dose level. On this basis, it was decided to progress into Phase 3 development with 
the 200-g dose level administered at Months 0, 1, and 6.
The ongoing Phase 3 efficacy study (B5091007) is a placebo-controlled, randomized 
(1:1, vaccine:placebo), observer-blinded, parallel-group study in subjects 50 years of age or 
older who have an increased risk of CDI.  In the absence of an accepted immunological 
correlate of protection for CDI, vaccine efficacy (VE) will be determined by comparing the 
CDI incidence in recipients of the investigational vaccine with those receiving placebo.
The present study (B5091008) is a Phase 3, placebo-controlled, randomized, 
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.  The study seeks to recruit a relatively healthy 
population in an age category that is harmonized with the previous Phase 2 study 
(B5091009). The Phase 2 study provides significant information pertaining to 
immunological and safety responses, and immunological variability, particularly 1 month 
after Dose 3. 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.
Additional information for this compound may be found in the single reference safety
document (SRSD), which for this study is the investigator’s brochure (IB).

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Subjects withdrawn from the study after randomization will not be replaced, regardless of the 
reason for withdrawal.
3.2. Approximate Duration of Subject Participation
Subjects will be followed for 1 month after receipt of their third vaccination.  Therefore, 
individual subjects will participate in the study for approximately 7 months.
3.3. Approximate Duration of the Study
This study will be completed in approximately 16 months.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated ICD indicating that the subject has been 
informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, vaccination plan, and other study 
procedures.
3. Healthy adults 65 to 85 years of age at enrollment (signing of the ICD) as determined by 
medical assessment, and the clinical judgment of the investigator, to be eligible for the 
study. Subjects with preexisting chronic medical conditions determined to be stable may 
be included.
4. Male subjects or female subjects who are not of childbearing potential (ie, meet at least 1 
of the following criteria):
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause; status may be confirmed with a nonstudy serum follicle-stimulating hormone 
(FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c.
Have medically confirmed ovarian failure.

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All other female subjects (including female subjects with tubal ligations) are considered 
to be of childbearing potential.
5. Ability to be contacted by telephone during study participation.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or subjects 
who are Pfizer employees, including their family members, directly involved in the 
conduct of the study.
2. Participation in other studies involving investigational drug(s)/vaccine(s) within 28 days
prior to study entry through conclusion of the study.
3. Previous administration of an investigational C difficile vaccine or C difficile mAb 
therapy.
4. Proven or suspected prior episode of CDI.
5. Unstable chronic medical condition or disease requiring significant change in therapy or 
hospitalization for worsening disease within 8 weeks before receipt of investigational 
product.
6. Serious chronic medical disorders, including metastatic malignancy, severe chronic 
obstructive pulmonary disease (COPD) requiring supplemental oxygen, end-stage renal 
disease with or without dialysis, clinically unstable cardiac disease, or any other disorder 
that in the investigator’s opinion precludes the subject from participating in the study.
7. Any bleeding disorder or anticoagulant therapy that would contraindicate intramuscular 
injection.
8. Any contraindication to vaccination or vaccine components, including previous 
anaphylactic reaction to any vaccine or vaccine-related components.
9. Subjects who may be unable to respond to vaccination due to: 

Congenital or acquired immunodeficiency.

Receipt of systemic corticosteroids (20 mg/day of prednisone or equivalent) for 
14 days within 28 days of enrollment.

Receipt of chronic systemic treatment with other known immunosuppressant 
medications, or radiotherapy, within 6 months of enrollment.

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
Underlying bone marrow disorder such as myelodysplasia, myeloma, or 
myeloproliferative disorder, treated within the past year, or any history of bone 
marrow transplant.

Malignancy that required treatment with chemotherapy (including the use of 
adjunctive and hormonal therapy), immunotherapy, radiation therapy, or 
antineoplastic target therapies within the past 24 months.
10. Receipt of blood products or immunoglobulins within 6 months before enrollment 
through conclusion of the study.
11. Residence in a nursing home or other long-term care facility, or requirement for 
semiskilled nursing care or assisted living.  An ambulatory subject who lives in an 
autonomous manner in a retirement home or village is eligible for the trial.
12. A known infection with human immunodeficiency virus (HIV).
13. Other acute or chronic medical or psychiatric condition including recent (within the past 
year) or active suicidal ideation or behavioral or laboratory abnormality that may increase 
the risk associated with study participation or investigational product administration or 
may interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the subject inappropriate for entry into this study.
14. Female subjects of childbearing potential; pregnant female subjects; breastfeeding female 
subjects; fertile male subjects who are unwilling or unable to use a highly effective 
method of contraception as outlined in this protocol for the duration of the study and for 
at least 28 days after the last dose of investigational product.
4.3. Criteria for Temporarily Delaying Vaccine Administration
The following conditions are temporary or self-limiting and a subject may be vaccinated 
once the condition(s) has/have resolved and no other exclusion criteria are met:
1. Current febrile illness (oral temperature of 38.0C [100.4F]) or other acute illness 
within 48 hours prior to investigational product administration.
2. Subject has received seasonal or pandemic influenza vaccine within the previous 14 days 
or any other nonstudy vaccine within the previous 28 days before investigational product 
administration.
3. If systemic corticosteroids have been administered short term (7 days) for treatment of 
an acute illness, investigational product administration should be delayed until systemic 
corticosteroid use has been discontinued for at least 28 days. Inhaled, intra-
articular/intrabursal, or topical corticosteroids are permitted.
If a subject meets any delay criteria for vaccination, all study procedures, including blood 
sample collection relating to that visit, should be delayed until the day of vaccination.

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4.4. Lifestyle Requirements
4.4.1. Contraception
All fertile male subjects who are, in the opinion of the investigator, sexually active and at risk 
for pregnancy with their partner(s) must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the vaccination period and for at 
least 28 days after the last dose of investigational product.  The investigator or his or her 
designee, in consultation with the subject, will confirm that the subject has selected an 
appropriate method of contraception for the individual subject and his partner from the 
permitted list of contraception methods (see below) and will confirm that the subject has 
been instructed in its consistent and correct use.  At time points indicated in the 
schedule of activities, the investigator or designee will inform the subject of the need to use 
highly effective contraception consistently and correctly and document the conversation and 
the subject’s affirmation in the subject’s chart (subjects need to affirm their consistent and 
correct use of at least 1 of the selected methods of contraception).  In addition, the 
investigator or designee will instruct the subject to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the male 
subject’s female partner plans to remain on the same treatment throughout the entire 
study and has been using that hormonal contraceptive for an adequate period of time to 
ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, gel, 
film, cream, or suppository).  For countries where spermicide is not available or condom 
plus spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
6. Female partner who meets the criteria for nonchildbearing potential, as described below:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or

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
Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause.
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study reference manual (SRM).
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. INVESTIGATIONAL PRODUCTS
For the purposes of this study, and per International Council for Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational products are C difficile vaccine and placebo (saline). Since 
the appearance of these investigational products is not identical, the study is 
observer-blinded.  The 3 lots of C difficile vaccine will appear identical and all site personnel 
will be blinded to lot allocation.
5.1. Allocation to Investigational Product
Allocation of subjects to vaccine groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR]) in a 
randomization ratio of 1:1:1:1 to each of the lots and control group.  Study personnel (either 

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blinded or unblinded) will be required to enter or select information including but not limited 
to the user’s identification (ID) and password, the protocol number, and the subject number.  
They will then be provided with a randomization number, vaccine assignment, and 
dispensable unit (DU) or container number.  The IRT system will provide a confirmation 
report containing the subject number, randomization number, and DU or container number 
assigned.  The confirmation report must be retained by the unblinded dispenser in the 
unblinded site files.
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system.
5.2. Blinding of Site Personnel
In this observer-blinded study, the study staff dispensing and administering the vaccine will 
be unblinded, but all other site study personnel, including the principal investigator and the 
subject, will be blinded.
The principal investigator will assign the responsibility of the unblinded 
dispensers/administrators to persons who will not participate in the evaluation of any study 
subject.  To ensure adequate coverage, at least 2 unblinded dispensers/administrators will be 
assigned per site. Members of the study site staff or clinic pharmacy should fulfill these 
roles.  Contact between the unblinded dispensers and study subjects should be kept to a 
minimum.  The investigator, study coordinator, and any site staff other than the unblinded 
dispensers/administrators must not be allowed to know the investigational product assigned 
to any study subject and must not be allowed to see the investigational product container 
contents.
5.3. Blinding of the Sponsor
Those study team members who are involved in ensuring that protocol requirements for 
investigational product handling, allocation, and administration are fulfilled at the site 
(eg, the unblinded Pfizer clinician [separate from the study team], clinical research associates 
[CRAs]) will be unblinded for the duration of the study. All other study team members and 
all laboratory personnel performing the serology assays will remain blinded to vaccine 
assigned/received throughout the study.
5.4. Breaking the Blind
The study will be subject and investigator blinded.
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process.  Blinding codes should be 
broken only in exceptional circumstances when knowledge of the actual vaccine assignment 
is absolutely essential for further management of the subject.  Investigators are encouraged to 
discuss with a member of the study team if they believe that unblinding is necessary.  When 
the blinding code is broken, the reason must be fully documented and entered on the case 
report form (CRF).

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5.5. Subject Compliance
All doses of investigational product will be administered by the appropriately designated 
unblinded study staff at the investigator site.
5.6. Vaccine Supplies
5.6.1. Formulation and Packaging
5.6.1.1. Clostridium difficile Vaccine
The investigational C difficile vaccine is toxoid based. C difficile toxin A and toxin B are 
inactivated by a combination of genetic mutations and chemical treatments.  The vaccine is 
provided as a sterile lyophilized powder in a dosage strength of 200 g/dose (total for 
toxoids A and B).  The vaccine will be reconstituted with AlOH diluent immediately before
use as instructed in the investigational product (IP) manual.  The AlOH diluent is supplied as 
a 1-mg aluminum/mL (as AlOH) liquid suspension.
Blinded, sealed cartons will contain 1 single-use vial of C difficile vaccine lyophilized 
powder for reconstitution and 1 single-dose syringe of AlOH diluent.  The total volume of 
resuspended vaccine to be injected is 0.5 mL per dose.
The investigational products will be provided by the sponsor to each study site.  
Investigational product and diluent will be packed and labeled by Pfizer or its designee as 
investigational product in accordance with current guidelines and applicable local and legal 
regulatory requirements.  For detailed information on the antigenic components of the 
investigational product, please refer to the IB.
5.6.1.2. Placebo
The placebo will consist of a sterile normal saline solution for injection (0.9% sodium 
chloride injection, in a 0.5-mL dose) and will be provided by the sponsor to each study site. 
The placebo will be packaged within cartons labeled by Pfizer or its designee in accordance 
with current guidelines and applicable local and legal regulatory requirements.  Blinded, 
sealed cartons will contain 1 single-dose syringe of placebo.  Refer to the IP manual for 
details regarding the preparation and dispensing of placebo.
5.6.2. Preparation and Dispensing
Refer to the IP manual for instructions on how to prepare the investigational product for 
administration.  Investigational product should be prepared and dispensed by an 
appropriately qualified and experienced unblinded member of the study staff.
5.6.3. Administration
All injections will be administered in the upper deltoid muscle, preferably of the 
nondominant arm, by the unblinded administrator.  The size of the needle used for 
administration will be based on the subject's weight at the time of enrollment.  Refer to the IP 
manual for additional information.

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Subjects will receive 1 dose of C difficile vaccine/placebo at Visits 1 (Month 0), 2 (Month 1), 
and 4 (Month 6).
Standard vaccination practices must be observed and vaccine must not be injected into blood 
vessels.  Appropriate medication and other supportive measures for management of an acute 
hypersensitivity reaction should be available in accordance with local guidelines for standard 
immunization practices.
Administration of investigational products should be performed by an appropriately 
qualified, Good Clinical Practice (GCP)-trained, and vaccine-experienced member of the 
study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacist, or 
medical assistant) as allowed by local, state, and institutional guidance.
Investigational product administration details will be recorded on the CRF.
5.7. Investigational Product Storage
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.
See the IP manual for storage conditions of the product once reconstituted.
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
The investigational vaccine, AlOH diluent, and placebo will be shipped at +2C to +8C to 
each study site after required regulatory and legal documents have been received by the 
sponsor. Upon receipt at the study site, the products should be immediately transferred to a 
+2C to +8C temperature-monitored refrigerator for storage.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all nonworking days upon return to normal operations.  The operation of the 
temperature-monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.

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Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
5.8. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
5.8.1. Destruction of Investigational Product Supplies
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.9. Concomitant Medication(s)
5.9.1. Recording Concomitant Vaccinations and Medications
Subjects will be asked to provide a history with the name(s) and date(s) for all vaccinations 
received from 28 days prior to enrollment until completion of the study.  No additional 
concomitant medications will be recorded.
5.9.2. Prohibited Concomitant Vaccinations and Medications
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 anticoagulant therapy that would contraindicate intramuscular injection from 
enrollment through the last dose of investigational product.
Receipt of chronic systemic treatment with known immunosuppressant medications, or 
radiotherapy, within 6 months before enrollment through conclusion of the study is 
prohibited.

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Receipt of systemic corticosteroids (20 mg/day of prednisone or equivalent) for 14 days is 
prohibited from 28 days prior to enrollment until completion of the study.
Receipt of chemotherapy for a malignancy (including the use of adjunctive and hormonal 
therapy), immunotherapy, radiation therapy, or antineoplastic target therapies within the past 
24 months until completion of the study.
Receipt of blood products or immunoglobulins within 6 months before enrollment through 
conclusion of the study is prohibited.
Prophylactic antipyretics and other pain medication to prevent symptoms associated with 
investigational product administration are not permitted.  However, if a subject is taking a 
medication for another condition, even if it may have antipyretic or pain-relieving properties, 
it should not be withheld prior to study vaccination.
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.
5.9.3. Permitted Concomitant Medications
The use of antipyretics and other pain medication to treat symptoms associated with 
investigational product administration or ongoing conditions is permitted.
Medication, other than that described as prohibited in Section 5.9.2, required for treatment of 
preexisting stable conditions is permitted.
Inhaled, topical, or localized injections of corticosteroids (eg, intra-articular or intrabursal 
administration) are permitted.
6. STUDY PROCEDURES
6.1. Study Period
6.1.1. Visit 1: Month 0 – Vaccination 1 (Day 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination.

Obtain written informed consent prior to performing any protocol-required procedures.

Record the subject’s demography (including date of birth, sex, race, and ethnicity).  The 
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 
are met (Section 4). Record medical history of significance, including the presence of 
chronic medical conditions.  If the clinical assessment indicates that a physical 

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examination is necessary to comprehensively evaluate the subject, perform a physical 
examination and record the findings.

Record nonstudy vaccines as described in Section 5.9.1.

Measure and record the subject’s weight and height.

Measure and record the subject’s oral temperature.

Discuss contraceptive use.

Ensure that all inclusion criteria, none of the exclusion criteria, and none of the temporary 
delay criteria are met (Section 4).

An appropriate site staff member (may be blinded or unblinded) will use the IRT system 
to obtain the subject’s randomization number and investigational product blinded carton 
number.

Collect a blood sample of approximately 20 mL for immunogenicity testing (Section 7.2).

Unblinded site staff will prepare and administer investigational product. Investigational 
product will be administered by intramuscular injection into the upper deltoid muscle, 
preferably of the nondominant arm. The time of vaccination will be recorded.  Refer to 
the IP manual under separate cover for further instruction on this process.

The unblinded vaccine dispenser/administrator updates the investigational product 
accountability records.

Blinded study staff will observe the subject for at least 30 minutes after investigational 
product administration for any acute reactions. Any AEs noted during the observation 
period should be recorded in the CRF.

Record and report AEs and serious adverse events (SAEs) (relative to the time of 
vaccination) as described in Section 8 and the schedule of activities.

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 requirements for the completion of the e-diary and assist the subject in 
downloading the study application (app) onto the subject’s own device or issue a 
provisioned device (see Section 7.1). Provide instructions and ask the subject to 
complete the e-diary from Day 1 to Day 7, with Day 1 being the day of vaccination.

Ask the subject to contact the site staff or investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the subject to return for the next study visit.

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
Complete the source documents.

Complete the CRF.

Review the e-diary data online following vaccination to evaluate subject compliance and 
as part of the ongoing safety review.
6.1.2. Visit 2: Month 1 – Vaccination 2 (28 to 42 Days After Visit 1)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination.

Review the subject’s e-diary data and follow up on any ongoing local reactions or 
systemic events.

Ensure that the subject continues to be eligible for the study and does not meet any of the 
withdrawal criteria as described in Section 6.2.

Based on clinical evaluation, determine whether any AEs or SAEs have occurred since 
the last study visit.  Record and report findings as described in Section 8 and the 
schedule of activities.  Review AEs that were ongoing from the previous visit and record 
their stop dates or confirm if they are still continuing.

Record nonstudy vaccines as described in Section 5.9.1.

Measure and record the subject’s oral temperature.

Discuss contraceptive use.

Ensure that none of the temporary delay criteria are met (Section 4.3).

An appropriate site staff member (may be blinded or unblinded) will use the IRT system 
to obtain the subject’s investigational product blinded carton number.

Unblinded site staff will prepare and administer investigational product. Investigational 
product will be administered by intramuscular injection into the upper deltoid muscle, 
preferably of the nondominant arm. The time of vaccination will be recorded.  Refer to 
the IP manual under separate cover for further instruction on this process.

The unblinded vaccine dispenser/administrator updates the investigational product 
accountability records.

Blinded study staff will observe the subject for at least 30 minutes after investigational 
product administration for any acute reactions.  Any AEs noted during the observation 
period should be recorded in the CRF.

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
Ensure the subject has an available measuring device for measurement of local reactions, 
and a digital thermometer for recording daily temperatures. If required, provide 
instructions on their use.

Confirm that the subject understands the reactogenicity reporting requirements. Remind 
the subject to complete the e-diary from Day 1 to Day 7, with Day 1 being the day of 
vaccination.

Ask the subject to contact the site staff or investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the next study visit.

Complete the source documents.

Complete the CRF.
6.1.3. Visit 3: Month 2 (28 to 42 Days After Visit 2)

Contact the subject 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 and the 
schedule of activities.  Review AEs that were ongoing from the previous visit and record 
their stop dates or confirm if they are still continuing.

Follow up on any ongoing local reactions or systemic events.

Ensure that the subject continues to be eligible for the study and does not meet any of the 
withdrawal criteria as described in Section 6.2.

Record nonstudy vaccines as described in Section 5.9.1.

Discuss contraceptive use.

Ask the subject to contact the site staff or investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the subject to return for the next study visit.

Complete the source documents.

Complete the CRF.
6.1.4. Visit 4: Month 6 – Vaccination 3 (140 to 168 Days After Visit 2)
It is anticipated that the procedures below will be conducted in a stepwise manner; ensure 
that procedures listed prior to administration of the vaccine are conducted prior to 
vaccination.

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
Review the subject’s e-diary data and follow up on any ongoing local reactions or 
systemic events.

Ensure that the subject continues to be eligible for the study and does not meet any of the 
withdrawal criteria as described in Section 6.2.

Based on clinical evaluation, determine whether any AEs or SAEs have occurred since 
the last study visit.  Record and report findings as described in Section 8 and the 
schedule of activities.  Review AEs that were ongoing from the previous visit and record 
their stop dates or confirm if they are still continuing.

Record nonstudy vaccines and as described in Section 5.9.1.

Measure and record the subject’s oral temperature.

Discuss contraceptive use.

Ensure that none of the temporary delay criteria are met (Section 4.3).

An appropriate site staff member (may be blinded or unblinded) will use the IRT system 
to obtain the subject’s investigational product blinded carton number.

Unblinded site staff will prepare and administer investigational product. Investigational 
product will be administered by intramuscular injection into the upper deltoid muscle, 
preferably of the nondominant arm. The time of vaccination will be recorded.  Refer to 
the IP manual under separate cover for further instruction on this process.

The unblinded vaccine dispenser/administrator updates the investigational product 
accountability records.

Blinded study staff will observe the subject for at least 30 minutes after investigational 
product administration for any acute reactions.  Any AEs noted during the observation 
period should be recorded in the CRF.

Ensure the subject has an available measuring device for measurement of local reactions, 
and a digital thermometer for recording daily temperatures. If required, provide 
instructions on their use.

Remind the subject to complete the e-diary from Day 1 to Day 7, with Day 1 being the 
day of vaccination.

Ask the subject to contact the site staff or investigator immediately if any significant 
illness or hospitalization occurs.

Schedule an appointment for the subject to return for the next study visit.

Complete the source documents.

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
Complete the CRF.
6.1.5. Visit 5: Month 7 (28 to 42 Days After Visit 4)

Review the subject’s e-diary data and follow up on any ongoing local reactions or 
systemic events.

Collect the subject’s e-diary device, if applicable.

Ensure that the subject continues to be eligible for the study and does not meet any of the 
withdrawal criteria as described in Section 6.2.

Based on clinical evaluation, determine whether any AEs or SAEs have occurred since 
the last study visit.  Record and report findings as described in Section 8 and the 
schedule of activities.  Review AEs that were ongoing from the previous visit and record 
their stop dates or confirm if they are still continuing.

Record nonstudy vaccines as described in Section 5.9.1.

Collect a blood sample of approximately 20 mL for immunogenicity testing (Section 7.2).  
Any AEs occurring up to 48 hours after blood draw must be recorded on the CRF.

Complete the source documents.

Complete the CRF.
6.1.6. Unscheduled Visit for a Grade 3 or Suspected Grade 4 Reaction
If a Grade 3 local reaction (Section 7.1.1.2), systemic event (Section 7.1.1.3), or fever 
(Section 7.1.1.4) is reported in the e-diary data, a telephone contact should occur to ascertain 
further details and determine whether a site visit is clinically indicated.
If a suspected Grade 4 local reaction (Section 7.1.1.2), systemic event (Section 7.1.1.3), or 
fever (Section 7.1.1.4) 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 subject’s local reaction as Grade 4.
6.2. Subject Withdrawal
Subject eligibility must be confirmed at each visit by an appropriate member of the 
investigator's study team as described in Sections 4 and 5.9.2.  If a subject is discontinued 
from vaccination and the subject consents, safety follow-up will be conducted for 1 month 
after the last dose of vaccine.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 

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inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return for a final visit, if applicable, 
and follow up with the subject regarding any unresolved AEs.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Safety Assessments
Safety parameters will be assessed as described in the schedule of activities, Section 6, 
Section 8, and below.
A clinical assessment, including medical history, will be performed on all subjects at Visit 1 
to establish a baseline. Significant medical history and observations from any physical 
examination, if performed, will be documented in the CRF.
AEs and SAEs are collected, recorded, and reported as defined in Section 8.
Acute reactions within the first 30 minutes after investigational product administration will 
be assessed and documented in the AE CRF.
The safety parameters also include e-diary reports of local reactions and systemic events that 
occur within 7 days after investigational product administration.  These prospectively 
collected occurrences of local reactions and systemic events are graded as described in 
Section 7.1.1.

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7.1.1. Electronic Diary
Subjects will be required to use an e-diary, based on appropriate technology, and will be 
asked to monitor and record local reactions and systemic events from Day 1 to Day 7, with 
Day 1 being the day of vaccination, following each vaccination. The e-diary allows 
recording of these assessments only within a fixed time window, thus providing the accurate 
representation of the subject’s experience at that time.  Data on local reactions and systemic 
events reported on the e-diary will be transferred electronically to a third-party vendor, where 
they will be available for review by investigators and the Pfizer clinicians at all times via an 
internet-based portal. E-diary data review is ongoing during subject e-diary data-entry 
periods (from Day 1 to Day 7, with Day 1 being the day of vaccination) via an internet-based 
portal.
At intervals agreed to by the vendor and Pfizer, these data will be transferred electronically 
into Pfizer's database for analysis and reporting.  These data do not need to be reported by the 
investigator in the CRF as AEs.
Investigators (or designee) will be required to review the e-diary data online at frequent 
intervals as part of the ongoing safety review.
The investigator or designee should obtain stop dates for any ongoing local reactions or 
systemic events on the last day that the e-diary was completed.  The stop dates should be 
documented in the source documents and the information entered in the CRF.
7.1.1.1. 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.58
7.1.1.2. Local Reactions
During the e-diary reporting period, subjects will be asked to assess redness, swelling, and 
pain at the injection site and to record the symptoms in the e-diary.  If a local reaction 
persists beyond the end of the e-diary period following vaccination, the subject will be 
requested to report that information.  The investigator will enter this additional information in 
the CRF.
Redness and swelling will be measured and recorded in measuring device units (range: 1 to 
21) and then categorized during analysis as absent, mild, moderate, or severe based on the 
grading scale in Table 1.  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 subject as absent, mild, moderate, or severe according the grading 
scale in Table 1.
If a Grade 3 local reaction is reported in the e-diary, the site should contact the subject by 
telephone to ascertain further details and determine whether a site visit is clinically indicated. 

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

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Table 2.
Systemic Event Grading Scale
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Fatigue/
Tiredness
No interference 
with activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room visit or 
hospitalization for severe 
fatigue
New or 
worsening 
muscle pain
No interference 
with activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room visit or 
hospitalization for severe new 
or worsening muscle pain
New or 
worsening 
joint pain
No interference 
with activity
Some interference 
with activity
Significant; prevents 
daily activity
Emergency room visit or 
hospitalization for severe new 
or worsening joint pain
Abbreviation: IV = intravenous.
7.1.1.4. Fever
In order to record information on fever, a digital thermometer will be given to subjects with 
instructions on how to measure oral temperature at home.  Temperature will be collected in 
the e-diary in the evening daily during the e-diary reporting period.  It will also be collected 
at any time during the e-diary data collection periods 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 3.
If a Grade 3 fever is reported in the e-diary, a telephone contact should occur to ascertain 
further details and determine whether a site visit is clinically indicated. Only an investigator 
or medically qualified person is able to classify a subject’s fever as Grade 4. If a subject 
experiences a confirmed Grade 4 fever, the investigator must immediately notify the sponsor 
and, if it is determined to be related to the administration of the investigational product, 
further vaccinations will be discontinued in that subject.  The Grade 4 reaction must be 
recorded in the CRF.
Table 3.
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)
7.2. Immunogenicity Assessments
Serum samples will be obtained for immunogenicity testing at Visit 1 (Month 0, immediately 
before Dose 1) and Visit 5 (Month 7, 1 month after Dose 3).

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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 to 
allow for adequate volume required for repeat testing or additional antigen-specific 
immunogenicity testing to be performed.
Refer to the SRM for details regarding serum sample management and storage.
7.3. 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 subject’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 subject’s genetic material will be performed.
The subject 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 subject’s genetic material is performed.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) nonserious AEs; and (3) exposure to the investigational product under study during 
pregnancy or breastfeeding, and occupational exposure.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the investigational 
product under study during 
pregnancy or breastfeeding, and 
occupational exposure
All (regardless of whether associated 
with an AE), except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure (regardless of 
whether associated with an AE)
All observed or volunteered events regardless of vaccine group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.

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

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8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including 
Visit 5 (Month 7).
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Nonserious AEs and SAEs on the CRF
During the active collection period, both nonserious AEs and SAEs are recorded on the CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 

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investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records.
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to:

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

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

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

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

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

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sample).  In rare instances, by the time TBili elevations are detected, AST/ALT values might 
have decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:
o
Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).
o
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase, and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 

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

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

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

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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Medical Device Complaint Reporting Requirements
All medical device complaints, regardless of whether the medical device complaint is 
associated with an AE, will be reported by a member of the unblinded site staff as described 
in the IP manual.  This includes potential incidents or malfunctions associated with the use of 
a medical device product.  An incident or malfunction is an event that might have led to 
death or serious deterioration in health, or if it occurred again might lead to death or serious 
deterioration in health.
Pfizer is to be notified of all medical device complaints within 24 hours of the investigator’s 
awareness of the event.
9. DATA ANALYSIS/STATISTICAL METHODS
A detailed methodology for summary and statistical analysis of the data collected in this 
study will be documented in a statistical analysis plan (SAP), which will be finalized before 
the start of any analyses and will be maintained by the sponsor. This document may modify 
the plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition and/or its analysis will be reflected both in the amended protocol and in the SAP. 
The SAP amendment will follow the protocol amendment.
9.1. Sample Size Determination
In order to meet the immunogenicity primary objective, the study sample size estimate is 
based upon the evaluation of lot-to-lot consistency on the toxin A– and toxin B–specific 
neutralizing antibody in terms of GMCs, 1 month after the third vaccination (Month 7). A 
2-fold equivalence margin is used for the study. Assuming the inherent difference for toxin 
A– and toxin B–specific neutralizing antibody responses is no more than 0.2 (in logarithmic 
scale) between any 2 lots, and the common standard deviations for toxin A– and toxin 
B-specific neutralizing antibodies are 0.899 and 1.485 (natural log value), respectively (based 
on the standard deviations for toxin A and toxin B at Month 7 in Study B5091009), a sample 
size of 263 evaluable subjects per lot will provide an overall 90% power to declare 
equivalence between all 6 comparisons for both toxin A and toxin B (see Table 4).

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Table 4.
Power Analysis (Primary Immunogenicity Endpoint)
Criteria
Neutralizing 
Antibody
Standard 
Deviation 
(Log Value)
Assume 
Observed 
Log GMC 
Difference
Number of 
Evaluable 
Subjects per 
Lot
Powera
Overall Power 
(3 Comparisons 
for Each Toxin)
95% CI for 
GMC ratio 
(any 2 lots) 
is between 
0.5 and 2.0
Toxin A
0.899
0.2
263
>99.99%
>99.99%
Toxin B
1.485
0.2
263
96.72%
90.47%
Overall power (to meet equivalence for both toxin A and toxin B)
90.47%
a.
Using a 2-fold equivalence margin for GMC ratios at a 2-sided, 0.05 alpha level.
Assuming a maximum nonevaluable rate of approximately 20%, a total of 1316 subjects need 
to be enrolled to meet the primary objective, with a randomization ratio of 1:1:1:1 (Lot 1: 
Lot 2: Lot 3: placebo).
9.2. Immunogenicity Analysis
The immunogenicity data will be summarized according to the vaccine group (active vaccine 
and placebo) as received in the evaluable immunogenicity population, and according to the 
vaccine group as randomized in the modified intent-to-treat (mITT) population.  Subjects 
receiving vaccine who did not follow their randomization assignment will be excluded from 
the evaluable immunogenicity population.
The C difficile toxin A– and toxin B–specific neutralizing antibody levels at each blood 
sampling time point will be summarized by GMCs (any C difficile toxin A– or toxin 
B-specific neutralizing antibody level that is below the lower limit of quantitation [LLOQ] 
will be assigned as 0.5 × LLOQ) and the associated 95% confidence intervals (CIs).  The 
GMC will be calculated as the mean of the assay results after making the logarithm 
transformation and then back transformation to its original scale.  Two (2)-sided 95% CIs 
will be constructed by back transformation of the CI for the mean of the logarithmically 
transformed assay results computed based on the Student’s t distribution.
Exact 2-sided 95% CIs will be compiled using the Clopper-Pearson method for any 
proportions of subjects with C difficile toxin A– or toxin B–specific neutralizing antibody 
level cutoff (LLOQ).
9.2.1. Immunogenicity Analysis Population
An evaluable immunogenicity population and a mITT population will be defined for the 
immunogenicity analyses separately.  The evaluable immunogenicity population will be the 
primary population for the immunogenicity analyses.
In general, the evaluable immunogenicity population will include all subjects who are 
eligible, receive the investigational product to which they are 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, and have no major protocol deviations.  

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clinician who is independent of the study team) and will not be permitted access to the 
randomization assignments until the database is locked and unblinded.
The E-DMC will review safety data at defined intervals as specified in the charter. The 
E-DMC may conduct additional meetings to review safety data at other time points during 
the study, at its discretion, or at the request of the sponsor. In addition, as determined by the 
sponsor clinician, the E-DMC may meet on an ad hoc basis to evaluate any SAEs related to 
vaccination, or related AEs that may jeopardize further subject participation, in order to 
determine that the study may be continued safely.
After each meeting, the E-DMC will make recommendations that may include the following: 
continue the study with or without modification; or pause or stop vaccination for safety or 
other reasons.
The recommendations made by the E-DMC to alter the conduct of the study will be 
forwarded to Pfizer for final decision. Pfizer will forward such decisions, which may include 
summaries of aggregate analyses of endpoint events and of safety data that are not endpoints, 
to regulatory authorities, as appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and GCPs are being followed.  The monitors may review source documents to 
confirm that the data recorded on CRFs are accurate.  The investigator and institution will 
allow Pfizer monitors/auditors or its agents and appropriate regulatory authorities direct 
access to source documents to perform this verification.  This verification may also occur 
after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the institutional review board (IRB)/ethics committee (EC), and/or to quality 
assurance audits performed by Pfizer, or companies working with or on behalf of Pfizer, 
and/or to inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.

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

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

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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in All Participating Countries
End of trial in all participating countries is defined as database lock.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
C difficile vaccine at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 28 days.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 

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Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 

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all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.

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16. REFERENCES
1.
Guerrant RL, Hughes JM, Lima NL, Crane J. Diarrhea in developed and developing 
countries: magnitude, special settings, and etiologies. Rev Infect Dis. 
1990;12(suppl 1):S41-S50.
2.
Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med. 
1994;330(4):257-262.
3.
Kyne L, Kelly CP. Prospects for a vaccine for Clostridium difficile. BioDrugs. 
1998;10(3):173-181.
4.
McFarland LV. Epidemiology of infectious and iatrogenic nosocomial diarrhea in a 
cohort of general medicine patients. Am J Infect Control. 1995;23(5):295-305.
5.
Magill SS, Edwards JR, Bamberg W, et al; for the Emerging Infections Program 
Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey Team. 
Multistate point-prevalence survey of health care–associated infections. N Engl J Med. 
2014;370(13):1198-1208.
6.
Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium 
difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of 
America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect 
Control Hosp Epidemiol. 2010;31(5):431-455.
7.
Aslam S, Hamill RJ, Musher DM. Treatment of Clostridium difficile-associated disease: 
old therapies and new strategies. Lancet Infect Dis. 2005;5(9):549-557.
8.
Kuehne SA, Collery MM, Kelly ML, Cartman ST, Cockayne A, Minton NP. 
Importance of toxin A, toxin B, and CDT in virulence of an epidemic Clostridium 
difficile strain. J Infect Dis. 2014;209(1):83-86.
9.
Voth DE, Ballard JD. Clostridium difficile toxins: mechanism of action and role in 
disease. Clin Microbiol Rev. 2005;18(2):247-263.
10.
Sunenshine RH, McDonald LC. Clostridium difficile-associated disease: new challenges 
from an established pathogen. Cleve Clin J Med. 2006;73(2):187-197.
11.
Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 
2015;372(16):1539-1548.
12.
Bartlett JG. Antibiotic-associated diarrhea. N Engl J Med. 2002;346(5):334-339.
13.
Mayo Clinic Staff. Diseases & conditions: C. difficile infection. 
http://www.mayoclinic.org/diseases-conditions/c-difficile/basics/symptoms/con-
20029664.  16 July 2013.  Accessed 27 February 2016.

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14.
Bauer MP, Notermans DW, van Benthem BHB, et al; for the ECDIS Study Group. 
Clostridium difficile infection in Europe: a hospital-based survey. Lancet. 
2011;377(9759):63-73.
15.
Bartlett JG, Gerding DN. Clinical recognition and diagnosis of Clostridium difficile
infection. Clin Infect Dis. 2008;46(suppl 1):S12-S18.
16.
Pepin J, Valiquette L. Cossette B. Mortality attributable to nosocomial Clostridium 
difficile–associated disease during an epidemic caused by a hypervirulent strain in 
Quebec. Can Med Assoc J. 2005;173(9):1037-1041.
17.
Simor AE. Diagnosis, management, and prevention of Clostridium difficile infection in 
long-term care facilities: a review. J Am Geriatr Soc. 2010;58(8):1556-1564.
18.
Gerding DN, Muto CA, Owens RC Jr. Treatment of Clostridium difficile infection. Clin 
Infect Dis. 2008;46(suppl 1):S32-S42.
19.
Louie TJ, Miller MA, Mullane KM, et al; for the OPT-80-003 Clinical Study Group. 
Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med.
2011;364(5):422-431.
20.
Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin 
A and protection against recurrent Clostridium difficile diarrhoea. Lancet. 
2001;357(9251):189-193.
21.
Debast SB, Bauer MP, Kuijper EJ; on behalf of the Committee. European Society of 
Clinical Microbiology and Infectious Diseases: update of the treatment guidance 
document for Clostridium difficile infection. Clin Microbiol Infect. 2014; 
20(suppl 2):1-26.
22.
Ricciardi R, Rothenberger DA, Madoff RD, Baxter N. Increasing prevalence and 
severity of Clostridium difficile colitis in hospitalized patients in the United States. Arch 
Surg. 2007;142(7):624-131.
23.
Khanna S, Pardi DS. The growing incidence and severity of Clostridium difficile
infection in inpatient and outpatient settings. Exp Rev Gastroenterol Hepatol.
2010;4(4):409-416.
24.
Shivashankar R, Khanna S, Kammer PP, et al. Clinical factors associated with 
development of severe-complicated Clostridium difficile infection. Clin Gastroenterol 
Hepatol. 2013;11(11):1466-1471.
25.
Hensgens MPM, Goorhuis A, Dekkers OM, van Benthem GHB, Kuijper EJ. All-cause 
and disease-specific mortality in hospitalized patients with Clostridium difficile
infection: a multicenter cohort study. Clin Infect Dis. 2013;56(8):1108-1116.

PF-06425090 (Clostridium difficile Vaccine)
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26.
Wiegand PN, Nathwani D, Wilcox MH, Stephens J, Shelbaya A, Haider S. Clinical and 
economic burden of Clostridium difficile infection in Europe: a systematic review of 
healthcare-facility-acquired infection. J Hosp Infect. 2012;81(1):1-14.
27.
Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the 
United States. N Engl J Med. 2015;372(9):825-834.
28.
Dubberke E. Clostridium difficile infection: the scope of the problem. J Hosp Med. 
2012;7(suppl 3):S1-S4.
29.
Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin 
Infect Dis. 2012;55(suppl 2):S88-S92.
30.
Gerding DN, Lessa FC. The epidemiology of Clostridium difficile infection inside and 
outside health care institutions. Infect Dis Clin North Am. 2015;29(1):37-50.
31.
Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional 
outbreak of Clostridium difficile–associated diarrhea with high morbidity and mortality. 
N Engl J Med. 2005;353(23):2442-2449.
32.
McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene–variant strain 
of Clostridium difficile. N Engl J Med. 2005;353(23):2433-2441.
33.
Pepin J, Valiquette L, Alary ME, et al. Clostridium difficile-associated diarrhea in a 
region of Quebec from 1991 to 2003: a changing pattern of disease severity. Can Med 
Assoc J. 2004;171(5):466-472.
34.
Gerding DN. Clindamycin, cephalosporins, fluoroquinolones, and Clostridium difficile–
associated diarrhea: this is an antimicrobial resistance problem. Clin Infect Dis. 
2004;38(5):646-648.
35.
Kyne L, Farrell RJ, Kelly CP. Clostridium difficile. Gastroenterol Clin North Am. 2001; 
30(3):753-777.
36.
Gerding DN, Johnson S. Management of Clostridium difficile infection: thinking inside 
and outside the box. Clin Infect Dis. 2010;51(11):1306-1313.
37.
McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for 
Clostridium difficile infection in adults and children: 2017 update by the Infectious 
Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of 
America (SHEA). Clin Infect Dis. 2018;66(7):987-994.
38.
Mattila E, Uusitalo-Seppala R, Wuorela M, et al. Fecal transplantation, through 
colonoscopy, is effective therapy for recurrent Clostridium difficile infection. 
Gastroenterology. 2012;142(3):490-496.

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39.
van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for 
recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415.
40.
Anonymous. Guidance for industry: enforcement policy regarding investigational new 
drug requirements for use of fecal microbiota for transplantation to treat Clostridium 
difficile infection not responsive to standard therapies. US Food and Drug 
Administration (FDA), US Department of Health and Human Services. 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformati
on/Guidances/Vaccines/ucm361379.htm.  July 2013. Accessed 27 February 2016.
41.
Dubberke ER, Carling P, Carrico R, et al. Strategies to prevent Clostridium difficile
infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol.
2014;35(6):628-645.
42.
Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile
and serum levels of IgG antibody against toxin A. N Engl J Med. 2000;342(6):390-397.
43.
Warny M, Vaerman JP, Avesani V, Delmee M. Human antibody response to 
Clostridium difficile toxin A in relation to clinical course of infection. Infect Immun.
1994;62(2):384-389.
44.
Gupta SB, Mehta V, Dubberke ER, et al. Antibodies to toxin B are protective against 
Clostridium difficile infection recurrence. Clin Infect Dis. 2016;63(6):730-734.
45.
Babcock GJ, Broering TJ, Hernandez HJ, et al. Human monoclonal antibodies directed 
against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. 
Infect Immun. 2006;74(11):6339-6347.
46.
Torres JF, Lyerly DM, Hill JE, Monath TP. Evaluation of formalin-inactivated 
Clostridium difficile vaccines administered by parenteral and mucosal routes of 
immunization in hamsters. Infect Immun. 1995;63(12):4619-4627.
47.
Giannasca PJ, Zhang ZX, Lei WD, et al. Serum antitoxin antibodies mediate systemic 
and mucosal protection from Clostridium difficile disease in hamsters. Infect Immun. 
1999;67(2):527-538.
48.
Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against 
Clostridium difficile toxins. N Engl J Med. 2010;362(3):197-205.
49.
Merck & Co., Inc. Pivotal Phase 3 studies of bezlotoxumab, Merck’s investigational 
antitoxin to prevent Clostridium difficile infection recurrence, met primary endpoint. 
http://www.mercknewsroom.com/news-release/research-and-development-
news/pivotal-phase-3-studies-bezlotoxumab-mercks-investigation.  September 2015.  
Accessed 24 March 2016.
50.
Greenberg RN, Marbury TC, Foglia G, Warny M.  Phase I dose finding studies of an 
adjuvanted Clostridium difficile toxoid vaccine. Vaccine. 2012;30(13):2245-2249.

PF-06425090 (Clostridium difficile Vaccine)
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51.
Kotloff KL, Wasserman SS, Losonsky GA, et al.  Safety and immunogenicity of 
increasing doses of a Clostridium difficile toxoid vaccine administered to healthy adults.  
Infect Immun. 2001;69(2):988-995.
52.
Aboudola S, Kotloff KL, Kyne L, et al.  Clostridium difficile vaccine and serum 
immunoglobulin G antibody response to toxin A.  Infect Immun. 2003;71(3):1608-1610.
53.
Ghose C, Kelly CP. The prospect for vaccines to prevent Clostridium difficile infection.  
Infect Dis Clin North Am. 2015;29(1):145-162.
54.
Anonymous. Study of candidate Clostridium difficile toxoid vaccine (Cdiffense) in 
subjects at risk for C difficile infection. Sanofi Pasteur Inc. ClinicalTrials.gov. 
https://www.clinicaltrials.gov/ct2/show/NCT01887912.   December 2015. Accessed 
27 February 2016.
55.
Tian JH, Fuhrmann SR, Kluepfel-Stahl S, Carman RJ, Ellingsworth L, Flyer DC.  A 
novel fusion protein containing the receptor binding domains of C. difficile toxin A and 
toxin B elicits protective immunity against lethal toxin and spore challenge in 
preclinical efficacy models.  Vaccine. 2012;30(28):4249-4258.
56.
Anonymous. Dose-confirmation, immunogenicity and safety study of the Clostridium 
difficile vaccine candidate VLA84 in healthy adults aged 50 years and older. Phase II 
study. Valneva Austria GmbH. ClinicalTrials.gov.  
https://www.clinicaltrials.gov/ct2/show/NCT02316470.   October 2015.  Accessed 
27 February 2016.
57.
Sheldon E, Kitchin N, Peng Y, et al. A phase 1, placebo-controlled, randomized study 
of the safety, tolerability, and immunogenicity of a Clostridium difficile vaccine 
administered with or without aluminum hydroxide in healthy adults. Vaccine.
2016;34(18):2082-2091.
58.
Food and Drug Administration (FDA) Center for Biologics Evaluation and Research 
(CBER). Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Rockville, MD: 
CBER; September 2007.

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Appendix 1. Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AE
adverse event
AlOH
aluminum hydroxide
ALT
alanine aminotransferase
AST
aspartate aminotransferase
CBER
Center for Biologics Evaluation and Research
CDI
Clostridium difficile infection
CI
confidence interval
CK
creatine kinase
COPD
chronic obstructive pulmonary disease
CRA
clinical research associate
CRF
case report form
CSA
clinical study agreement
CT
clinical trial 
DILI
drug-induced liver injury
DU
dispensable unit
EC
ethics committee
e-diary
electronic diary
E-DMC
external data monitoring committee
EDP
exposure during pregnancy
ELISA
enzyme-linked immunosorbent assay
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GMC
geometric mean concentration
GMFR
geometric mean fold rise
HIV
human immunodeficiency virus 
IB
investigator's brochure
ICD
informed consent document 
ICH
International Council for Harmonisation
ID
identification
IDSA
Infectious Diseases Society of America
IgG
immunoglobulin G
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product

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Abbreviation
Term
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IWR
interactive Web-based response
LFT
liver function test
LLOQ
lower limit of quantitation
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
N/A
not applicable
PCD
primary completion date
PFGE
pulsed-field gel electrophoresis
PI
principal investigator 
PT
prothrombin time 
RCDC
reverse cumulative distribution curves
SAE
serious adverse event
SAP
statistical analysis plan
SRM
study reference manual
SRSD
single reference safety document
TBili
total bilirubin
TcdA
Clostridium difficile toxin A
TcdB
Clostridium difficile toxin B
ULN
upper limit of normal
US
United States
VE
vaccine efficacy

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