Conditions: Clostridium Infections
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 140
Healthy volunteers: yes

Brief summary:
The purpose of this study is to generate safety, reactogenicity (assessment of any expected or unexpected side effect of the vaccine) and immunogenicity (ability to induce an immune response) data for the development of a candidate Clostridium difficile (C. difficile) vaccine that would protect against primary cases of Clostridium difficile infection (CDI) and CDI recurrence.

Clostridium difficile infection is a major cause of gastrointestinal illness with approximately 500,000 infections and the leading cause of gastroenteritis associated death with 29,000 deaths annually in the United States of America (USA). The emergence of extremely infectious varieties/types of C. difficile has contributed to increase the number and severity of CDI cases. In recent years, some countries (United Kingdom) have implemented hospital hygiene and other measures which resulted in significant reductions in the number of cases. The burden is, however, expected to remain significant until vaccination is available.

Detailed description:

Arms:
arm 1: Healthy male and female subjects, aged between and including 18 and 45 years old, who receive CDIFF antigen (Ag) vaccine administered intramuscularly in the deltoid, according to a 0, 1-month vaccination schedule. arm 2: Healthy male and female subjects, aged between and including 18 and 45 years old, who receive Placebo administered intramuscularly in the deltoid, according to a 0, 1-month vaccination schedule. arm 3: Healthy male and female subjects, aged between and including 50 and 70 years old, who receive CDIFF antigen (Ag) vaccine administered intramuscularly in the deltoid, according to a 0, 1-month vaccination schedule. A third dose of CDIFF Ag vaccine is to be administered to a subcohort of subjects aged 50-70 years, approximately 15 months after the administration of the second dose. arm 4: Healthy male and female subjects, aged between and including 50 and 70 years old, who receive CDIFF Ag + AS01B adjuvant vaccine administered intramuscularly in the deltoid, according to a 0, 1-month vaccination schedule. A third dose of CDIFF Ag + AS01B adjuvant vaccine is to be administered to a subcohort of subjects aged 50-70 years, approximately 15 months after the administration of the second dose. arm 5: Healthy male and female subjects, aged between and including 50 and 70 years old, who receive Placebo administered intramuscularly in the deltoid, according to a 0, 1-month vaccination schedule.

Interventions: intervention 1: C. difficile investigational vaccine based on the F2 antigen (GSK2904545A) intervention 2: C. difficile investigational vaccine based on the F2 antigen (GSK2904545A) adjuvanted with AS01B intervention 3: Placebo
Intervention descriptions: intervention 1: Subjects in CDIFF Ag 18 - 45 Years and CDIFF Ag 50 - 70 Years Groups will receive 2 or 3 doses (0.5 mL each) of CDIFF Ag vaccine.

The vaccine will be administered intramuscularly in the deltoid, at a 0, 1-month dose interval. The third dose will be administered approximately 15 months after the second dose. intervention 2: Subjects in CDIFF Ag + AS01B 50 - 70 Years Group will receive 2 or 3 doses (0.5 mL each) of CDIFF Ag + AS01B vaccine.

The vaccine will be administered intramuscularly in the deltoid, at a 0, 1-month dose interval. The third dose will be administered approximately 15 months after the second dose. intervention 3: Subjects will receive 2 doses (0.5 mL each) of Placebo, administered intramuscularly in the deltoid, at a 0, 1-month dose interval.

Protocol document:
Prot_000.pdf: 
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CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
1 
TITLE PAGE 
Protocol Title: A Phase I, Single-center, Randomized, Observer-blind, Placebo-controlled Study to 
Evaluate Safety, Reactogenicity and Immunogenicity of GSK¶VClostridium difficile Investigational 
Vaccine Based on the F2 Antigen With or Without AS01B Adjuvant, When Administered Intramuscularly 
According to a 0, 1-month Schedule to Healthy Adults Aged Between 18-45 Years and Between 
50-70 Years, Followed by an Additional Dose Administered in a Partial blind Manner Within an Interval 
of Approximately 15 Months After Dose 2, in a Subcohort of Subjects aged 50-70 Years 
Protocol Number: 208109 (CDIFF-004) 
Amendment Number: Amendment 04 
Product: GlaxoSmithKline Biologicals SA (GSK) Clostridium difficile investigational vaccine based on 
the F2 antigen (GSK2904545A) 
Short Title: Safety and Immunogenicity Study of G6.¶V Clostridium difficile Vaccine 2904545A When 
Administered in Healthy Adults Aged 18-45 Years and 50-70 Years 
Study Phase: I 
Sponsor Name: GlaxoSmithKline Biologicals SA 
Legal Registered Address: *OD[R6PLWK.OLQH%LRORJLFDOV6$5XHGHO¶,QVWLWXW5L[HQVDUW
Belgium 
Regulatory Agency Identifying Number(s): EudraCT number: 2018-002304-14 
Date of Protocol: 02 December 2021 
 
 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
2 
Sponsor Signatory: 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
Juan Pablo Yarzabal Rodriguez
Clinical and Epidemiology Project Lead (CEPL)
 
Date 
 
 
 
 
 
 
Medical Monitor name and contact information can be found in $SSHQGL[ 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Table 1 
Document History 
Document 
Date 
Substantial 
Region 
Amendment 04 
02 December 2021 
No 
Global 
Amendment 03 
18 May 2021 
Yes 
Global 
Amendment 02 
16 April 2020 
Yes 
Global 
Amendment 01 
12 December 2019 
Yes 
Global 
Original Protocol 
02 May 2019 
- 
- 
Amendment 04 (02 December 2021) 
This amendment is considered non-substantial based on the criteria defined in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither impacts the safety or physical/mental integrity of subjects nor the scientific 
value of the study. 
Overall Rationale for the Current Amendment: 
The CDIFF-004 (208109) study protocol was amended on 18 May 2021 (Protocol 
Amendment 03, approved by FAMHP on 25 August 2021) to introduce a third study vaccine 
dose, to be offered in a subcohort of subjects recruited in Step 4. Following approval of this 
amendment, the Sponsor would like to update accordingly one of the protocol exclusion criteria 
related to the lapse to consider, in case of administration of Shingrix. The update to be 
considered concerns the exclusion criterion 9 of the protocol which should state that the planned 
DGPLQLVWUDWLRQRI*6.¶V+HUSHV=RVWHUYDFFLQHPDUNHWHGDV6KLQJUL[RUDQDGMXYDQWHG
recombinant varicella zoster virus envelope gE subunit vaccine (HZ/su) should not occur within 
180 days before the first dose and within 180 days after the last dose of the study vaccine 
(instead of the second dose, as written in Protocol Amendment 03). 
The opportunity was also taken to do minor editorial corrections for typographical, grammar, and 
consistency errors. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
4 
Table 2 
Description of Changes in Amendment 04 
Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria 9 
It was clarified that the planned administration of *6.¶V
Herpes Zoster vaccine marketed as Shingrix or an 
adjuvanted recombinant varicella zoster virus envelope 
gE subunit vaccine (HZ/su) within 180 days before the 
first dose and 180 days after the last dose was not 
allowed. 
Updated the 
information to be 
in line with the 
additional third 
dose administration 
Sponsor Signatory 
Jeanne Marie Devaster replaced with Juan Pablo 
Yarzabal Rodriguez 
To mention the 
name of current 
signatory 
Amendment 03 (18 May 2021) 
This amendment is considered substantial based on the criteria defined in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it significantly impacts the safety of subjects and/or the scientific value of the study. 
Overall Rationale for the Current Amendment: 
Results from a recent interim analysis on data from subjects immunized with 2 doses of the F2 
antigen candidate (with or without the inclusion of an adjuvant ), showed an acceptable safety 
profile for both formulations. Analysis on immunogenicity showed that an anti-toxin (A/B) 
neutralizing antibodies (TNA) response can be elicited by the F2 adjuvanted formulation. 
However, a lower immune response post second dose was observed for anti Tox B TNA in 
subjects who had no quantifiable antibodies at baseline, indicating that a third vaccine dose may 
be necessary to reach higher level of antibodies. 
Published data from a Phase II study with another Clostridium difficile candidate1, using full 
Toxin A and B aluminum-based toxoids, showed similar trend in toxin neutralization assay 
values post second dose, also evidencing that a third dose induced very high response in 
seronegative subjects. 
The aim of this amendment is to offer a third dose of the vaccine to subjects recruited in the 
active groups of the last step of the study, to demonstrate if a similar kinetics in terms of 
anti-Toxin A/B TNA can be achieved with the F2 antigen formulation with or without an 
adjuvant. The purpose of this amendment is also to assess the safety and immunogenicity 
following the addition of a third dose in a subcohort of subjects aged 50-70 years, recruited in the 
Step 4 of the study. 
The details of Clinical Laboratory Sciences, Marburg were deleted from the protocol, as it would 
no longer be used for the study purposes. 
The COVID-19 guidance was updated to mention the most recent version applicable at the time 
of study conduct and the reporting period for pregnancies was updated to 24 hours from 2 weeks. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
5 
The opportunity was also taken to do minor editorial corrections for typographical, grammar, and 
consistency errors. 
Table 3 
Description of Changes in Amendment 03 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
1.1 Synopsis 
1.2 Schema 
4.1 Overall Design 
6.1 Study Treatment(s) 
Administered 
9.4.2.1 Primary Analyses 
Added information about an 
additional third dose to be given to 
subjects on active treatment 
To provide the information related to 
the proposed third dose 
1.1 Synopsis 
8.11 Study Procedures During 
Special Circumstances 
Updated version of EMA Guidance 
on the Management of Clinical Trials 
during the Coronavirus pandemic. 
To indicate the recent version, 
applicable to the study conduct 
1.1 Synopsis 
4.1 Overall Design 
9.4.2.2 Internal Safety Review 
Committee Evaluations 
9.7 Internal Safety Review 
Committee 
 
Clarified that an ad hoc iSRC meeting 
may happen in case of any safety 
concerns during Dose 3 
7RSURWHFWVXEMHFW¶VZHOIDUHDQG
safety 
1.1 Synopsis 
6.6.3 Blinding 
9.5 Interim Analyses 
9.8 Sequence of Analysis 
Added information about second 
interim analyses 
Added information about an 
additional analysis related to the third 
dose 
1.2 Schema 
1.3 Schedule of Activities 
3.0 Objectives and Endpoints 
8.3 Adverse Events 
8.8.2  Immunological Read 
outs 
Appendix 4 
Added information about additional 
days when the study assessments will 
be performed. 
Added information about additional 
assessments related to the third dose 
4.1 Overall Design 
Appendix 2 
Updated details of duration of study 
and Primary Completion Date 
Added definition of Study Conclusion 
for Individual Subjects 
Updated the information to be in line 
with the additional study processes 
related to the third dose 
administration 
4.1 Overall Design 
4.4 End of Study Definition 
Appendix 2 
Added definition of study conclusion 
for individual subjects. 
Updated the information to be in line 
with the additional study processes 
related to the third dose 
administration 
4.2.1 Rationale of Study 
Blinding 
6.6.3 Blinding 
Added details of partial blind. 
Updated the information to be in line 
with the additional study processes 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
6 
Section # and Name 
Description of Change 
Brief Rationale 
Appendix 2 
related to the third dose 
administration 
4.2.2 Rationale for 
Randomization and the Use of 
Placebo 
Added the rationale for excluding the 
subjects receiving placebo, from the 
third dose 
Since the additional dose 
administration is related to the 
demonstration of kinetics in terms of 
anti-Toxin A/Toxin B, the third dose 
will not be given to the subjects 
receiving placebo 
4.3 Justification of Dose 
Added justification of third dose 
Clarified why the additional dose is to 
be administered 
5.2 Exclusion Criteria 
Updated information for 
administration of a vaccine not 
foreseen by the study protocol 
7RSURWHFWVXEMHFW¶VZHOIDUHDQG
safety 
5.4 Screen Failures 
Updated the information for the 
screen failures related to Dose 3 
To differentiate between the screen 
failures related to previous 2 doses 
and the third dose 
6.8.1 Recording of 
Concomitant 
Medications/Products and 
Concomitant Vaccinations 
6.8.2 Concomitant 
Medications/Products/Vaccines 
That may Lead to the 
Elimination of a Subject From 
Per protocol Analyses 
Added details for concomitant 
medications during Dose 3 
7RSURWHFWVXEMHFW¶Vwelfare and 
safety 
9.3 Populations for Analyses 
Added information about analysis sets 
related to the Dose 3 
Updated the information to be in line 
with the additional study processes 
related to the third dose 
administration 
Appendix 2 
Updated definition of End of Study 
For clarification 
Appendix 5 
Deleted the details of Clinical 
Laboratory Sciences, Marburg 
This laboratory is no longer needed in 
the study 
Appendix 6 
Updated the time period for collecting 
and recording of adverse events 
Updated the information to be in line 
with the additional study processes 
related to the third dose 
administration 
Appendix 6 
Appendix 7 
Updated reporting period for 
pregnancies from 2 weeks to 24 hours 
The reporting period was updated in 
lines of the recent version of the 
applicable guidelines 
 
 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
7 
Amendment 02 (16 April 2020) 
This amendment is considered substantial based on the criteria defined in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it significantly impacts the safety of subjects and/or the scientific value of the study. 
Overall Rationale for the Current Amendment: 
This protocol Amendment 2 outlines measures that may be applicable during special 
circumstances (eg, COVID-SDQGHPLF7KHSXUSRVHRIWKHDPHQGPHQWLVWRSURWHFWVXEMHFW¶V
welfare and safety, and as far as possible ensure the potential benefit to the subject and promote 
data integrity. 
Table 4 
Description of Changes in Amendment 02 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Added section on study procedures 
during special circumstances. 
 
To SURWHFWVXEMHFW¶VZHOIDUHDQG
safety, and as far as possible ensure 
the potential benefit to the subject and 
promote data integrity. 
1.2 Schema 
1.3 Schedule of Activities 
4.1 Overall Design 
4.2.5 Rational for the Safety 
Monitoring Plan 
6.6.2 Treatment Allocation 
to the Subject 
8.0 Study Assessments and 
Procedures 
9.2 Sample Size 
Determination 
Added reference to Section 8.11 for 
study procedures to be considered 
during special circumstances. 
To SURWHFWVXEMHFW¶VZHOIDUHDQG
safety, and as far as possible ensure 
the potential benefit to the subject and 
promote data integrity. 
6.6.3 Blinding 
Added toll-free number for GSK 
helpdesk. 
Provided toll-free number to be dialed 
in case of emergency unblinding. 
8.0 Study Assessments and 
Procedures 
Added statement that the specific 
guidance from local public health and 
other competent authorities regarding 
the SURWHFWLRQRILQGLYLGXDOV¶ZHOIDUH
must be applied during special 
circumstances. For the duration of 
such special circumstances, certain 
study procedures may be implemented 
for enrolled subjects (refer to 
Section 8.11 for further details). 
To SURWHFWVXEMHFW¶VZHOIDUHDQG
safety, and as far as possible ensure 
the potential benefit to the subject and 
promote data integrity. 
8.3.8 Contact Information 
for Reporting of Serious 
Adverse Events, Adverse 
Events of Specific Interest, 
Updated study contact for reporting of 
holding rules. 
Added CRO back-up study contact 
information. 
To state that the Sponsor or Sponsor 
designee should be contacted for 
reporting of holding rules instead of 
the Local Medical Lead. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
8 
Section # and Name 
Description of Change 
Brief Rationale 
Pregnancies, and Study 
Holding Rules 
To provide additional back-up contact 
information for reporting of 
SAE/AESI and pregnancies. 
8.11 Study Procedures 
During Special 
Circumstances 
Added section on study procedures 
during special circumstances. 
 
To SURWHFWVXEMHFW¶VZHOIDUHDQG
safety, and as far as possible ensure 
the potential benefit to the subject and 
promote data integrity. 
AESI = adverse event of specific interest; CRO = Contract Research Organization; SAE = serious adverse event 
Amendment 01 (12 December 2019) 
Overall Rationale for the Amendment: 
An optional blood sample will be added for subjects in Step 4 at Day 61 (Visit 5). To better and 
deeply characterize the antibody response, monoclonal antibodies produced by antigen specific 
B-cells will be isolated from a subset of subjects in Step 4 at Day 61 (Visit 5). 
The selection of the subset will be based on the most pronounced response to the antigen of 
interest as determined by serological or cellular immunogenicity assessment.  
The sequence of the monoclonal antibodies might be retrieved from the analysis of the 
complementary DNA generated from immunoglobulin messenger RNA. The sequence of the 
most interesting antibodies might be used to generate recombinant monoclonal antibodies to be 
further characterized for their properties in fighting the infectious agent. 
This sequence may be used in the future for various possible applications, both for research and 
commercial purposes, to develop a new treatment that can help combat infectious diseases, such 
as generation of monoclonal antibodies that can be sold as therapeutic treatment. 
The opportunity was also taken to add clarifications on possible ambiguities within the protocol 
surrounding the processes of sample collection and other assessments, simplification of 
assessments based on feedback from the LQYHVWLJDWRU¶Vsite, and minor editorial corrections for 
typographical, grammar, and consistency errors. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
9 
Table 5 
Description of Changes in Amendment 01 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
9.5 Interim Analysis 
9.8 Sequence of Analysis 
Added that immunogenicity and 
reactogenicity data will also be used to 
perform the first analysis. 
To clarify that safety, immunogenicity, 
and reactogenicity data will be used to 
perform the first analysis. 
1.2 Schema 
1.3 Schedule of Activities 
8.8.1 Blood Sampling for 
Immunogenicity Response 
Assessment 
An optional blood sample was added 
for subjects in Step 4 at Day 61 
(Visit 5) for antibody determination. 
To indicate that an additional optional 
blood sample will be drawn from 
subjects in Step 4 on Day 61. This 
sample will be optional. PBMC may 
be used for the generation of 
monoclonal antibodies. 
6.6.2 Treatment Allocation 
to the Subject 
Added details regarding the allocation 
of subjects to study groups. 
To clarify how subjects of 2 different 
age groups will be sequentially 
enrolled into the study through 4 steps. 
Appendix 5 
Updated to indicate that the Neomed 
laboratory is now called Nexelis and is 
an outsourced laboratory. 
Neomed laboratory has changed into 
Nexelis. Nexelis is not a GSK 
Laboratory, but an outsourced 
laboratory. 
 
 
Correction of typographical error. 
 
 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
10 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................... 3
TABLE OF TABLES ........................................................................................................ 14
TABLE OF FIGURES ...................................................................................................... 15
1.0
PROTOCOL SUMMARY .................................................................................... 16
1.1
Synopsis ...................................................................................................... 16
1.2
Schema........................................................................................................ 21
1.3
Schedule of Activities ................................................................................. 24
2.0
INTRODUCTION ................................................................................................. 29
2.1
Study Rationale .......................................................................................... 29
2.2
Background ................................................................................................ 29
2.3
Benefit/Risk Assessment ............................................................................ 30
2.3.1
Risk Assessment ............................................................................ 31
2.3.2
Benefit Assessment ........................................................................ 32
2.3.3
Overall Benefit/Risk Conclusion .................................................... 32
3.0
OBJECTIVES AND ENDPOINTS ....................................................................... 33
4.0
STUDY DESIGN ................................................................................................... 35
4.1
Overall Design ............................................................................................ 35
4.2
Scientific Rationale for Study Design ........................................................ 37
4.2.1
Rationale for Study Blinding .......................................................... 37
4.2.2
Rationale for Randomization and the Use of Placebo ..................... 37
4.2.3
Rationale for the Use of F2 Fusion Protein Antigen ........................ 38
4.2.4
Rationale for the Use of AS01B Adjuvant ....................................... 38
4.2.5
Rationale for the Safety Monitoring Plan ........................................ 39
4.3
Justification for Dose ................................................................................. 39
4.4
End of Study Definition ............................................................................. 40
4.5
Dose Escalation Criteria ............................................................................ 40
4.6
Study Holding Criteria .............................................................................. 40
4.6.1
Study Holding Rules ...................................................................... 40
4.6.2
Procedure if the Study is Put on Hold ............................................. 45
5.0
STUDY POPULATION ........................................................................................ 46
5.1
Inclusion Criteria ....................................................................................... 46
5.2
Exclusion Criteria ...................................................................................... 46
5.3
Lifestyle Considerations............................................................................. 48
5.4
Screen Failures ........................................................................................... 49


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
11 
6.0
STUDY TREATMENT ......................................................................................... 50
6.1
Study Treatment(s) Administered ............................................................. 50
6.2
Contraindication to Subsequent Vaccination ........................................... 51
6.3
Criteria for Temporary Delay of Vaccination .......................................... 52
6.4
Intercurrent Medical Condition That May Lead to Elimination of 
a Subject From the Per-protocol Analysis ................................................ 52
6.5
Preparation/Handling/Storage/Accountability ......................................... 52
6.5.1
Replacement of Unusable Vaccinations .......................................... 53
6.6
Measures to Minimize Bias: Randomization and Blinding ...................... 53
6.6.1
Subject Identification ..................................................................... 53
6.6.2
Treatment Allocation to the Subject ............................................... 53
6.6.3
Blinding ......................................................................................... 54
6.7
Study Treatment Compliance .................................................................... 56
6.7.1
Treatment Strategy ......................................................................... 56
6.7.2
Warnings and Precautions .............................................................. 56
6.8
Concomitant Therapy ................................................................................ 56
6.8.1
Recording of Concomitant Medications/Products and 
Concomitant Vaccinations .............................................................. 56
6.8.2
Concomitant Medications/Products/Vaccines That may Lead 
to the Elimination of a Subject From Per-protocol Analyses ........... 57
6.9
Dose Modification ...................................................................................... 57
6.10
Treatment After the End of the Study ...................................................... 58
7.0
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ............................................................. 59
7.1
Discontinuation of Study Vaccine .............................................................. 59
7.2
Subject Discontinuation/Withdrawal From the Study ............................. 59
7.3
Lost to Follow-up ....................................................................................... 60
8.0
STUDY ASSESSMENTS AND PROCEDURES .................................................. 62
8.1
Efficacy Assessments .................................................................................. 62
8.2
Safety Assessments ..................................................................................... 62
8.2.1
Physical Examinations ................................................................... 63
8.2.2
Vital Signs ..................................................................................... 63
8.2.3
Clinical Safety Laboratory Assessments ......................................... 63
8.3
Adverse Events ........................................................................................... 64
8.3.1
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information ......................................... 66
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events ............................................................................................ 68
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ............. 68
8.3.4
Treatment of Adverse Events ......................................................... 69
8.3.5
Regulatory Reporting Requirements for Serious Adverse 
Events ............................................................................................ 69
8.3.6
Pregnancy ...................................................................................... 69
8.3.7
Subject Card................................................................................... 69


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
12 
8.3.8
Contact Information for Reporting of Serious Adverse 
Events, Adverse Events of Specific Interest, Pregnancies, 
and Study Holding Rules ................................................................ 70
8.4
Treatment of Overdose .............................................................................. 70
8.5
Pharmacokinetics ....................................................................................... 70
8.6
Pharmacodynamics .................................................................................... 70
8.7
Genetics ...................................................................................................... 70
8.8
Immunogenicity Assessment ...................................................................... 71
8.8.1
Laboratory Assays .......................................................................... 71
8.8.2
Immunological Read-outs .............................................................. 72
8.8.3
Immunological Correlates of Protection ......................................... 74
8.9
Biomarkers ................................................................................................. 74
8.10
Health Economics or Medical Resource Utilization and Health 
Economics ................................................................................................... 74
8.11
Study Procedures During Special Circumstances..................................... 74
9.0
STATISTICAL CONSIDERATIONS .................................................................. 75
9.1
Statistical Hypotheses ................................................................................ 75
9.2
Sample Size Determination ........................................................................ 75
9.3
Populations for Analyses............................................................................ 78
9.4
Statistical Analyses ..................................................................................... 79
9.4.1
Analysis of Demographics.............................................................. 79
9.4.2
Safety Analyses .............................................................................. 79
9.4.3
Analysis of Immunogenicity........................................................... 80
9.4.4
Missing Data .................................................................................. 81
9.5
Interim Analyses ........................................................................................ 81
9.6
Safety Review Team ................................................................................... 81
9.7
Internal Safety Review Committee ............................................................ 82
9.8
Sequence of Analysis .................................................................................. 82
10.0
REFERENCES ...................................................................................................... 84
11.0
APPENDICES ....................................................................................................... 86
Appendix 1
Abbreviations ............................................................................... 87
Appendix 2
Glossary of Terms ........................................................................ 89
Appendix 3
Regulatory, Ethical, and Study Oversight Considerations ......... 92
Regulatory and Ethical Considerations ......................................................... 92
Adequate Resources ..................................................................................... 92
Financial Disclosure ..................................................................................... 93
Insurance ..................................................................................................... 93
Informed Consent Process ............................................................................ 93
Data Protection ............................................................................................ 93
Administrative Structure .............................................................................. 94
Medical Monitor .......................................................................................... 94
Medical Oversight from GSK....................................................................... 94
Publication Policy ........................................................................................ 94


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
13 
Dissemination of Clinical Study Data ........................................................... 94
Data Quality Assurance ................................................................................ 95
Source Documents ....................................................................................... 96
Study and Study Center Closure ................................................................... 96
Appendix 4
Clinical Safety Laboratory Tests ................................................. 98
Appendix 5
Clinical Laboratories ................................................................... 99
Appendix 6
Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ................................. 100
Appendix 7
Contraceptive Guidance and Collection of Pregnancy 
Information .............................................................................................. 111
Appendix 8
Signature of Investigator............................................................ 114
 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
14 
TABLE OF TABLES 
Table 1
Document History .......................................................................................... 3
Table 2
Description of Changes in Amendment 04 ..................................................... 4
Table 3
Description of Changes in Amendment 03 ..................................................... 5
Table 4
Description of Changes in Amendment 02 ..................................................... 7
Table 5
Description of Changes in Amendment 01 ..................................................... 9
Table 6
Schedule of Activities (Refer to Section 8.11 for Study Procedures to 
be Considered During Special Circumstances) ............................................. 24
Table 7
Intervals Between Study Visits (Refer to Section 8.11 for Study 
Procedures to be Considered During Special Circumstances) ....................... 27
Table 8
Risk Assessment .......................................................................................... 31
Table 9
 Study Objectives and Endpoints .................................................................. 33
Table 10
Study Groups Foreseen in the Study (Refer to Section 8.11 for Study 
Procedures to be Considered During Special Circumstances) ...................... 36
Table 11
Holding Rules Assessed by the Investigator ................................................. 40
Table 12
Holding Rules Assessed During Internal Safety Review Committee 
Evaluations .................................................................................................. 41
Table 13
Toxicity Grading Scales for Hematology, Biochemistry, and 
Urinalysis Parameters Applicable for this Study ........................................... 44
Table 14
Description of Study Treatment .................................................................... 50
Table 15
Dosage and Administration of Study Treatment ........................................... 51
Table 16
Contact Information for Emergency Unblinding ........................................... 55
Table 17
Reporting Periods for Collecting Safety Information .................................... 65
Table 18
List of Potential Immune-mediated Diseases ................................................ 67
Table 19
Contact Information for Reporting of Serious Adverse Events, 
Adverse Events of Specific Interest, Pregnancies, and Study Holding 
Rules ............................................................................................................ 70
Table 20
Humoral Immunity (Antibody Determination) ............................................. 72
Table 21
Immunological Read-outs ............................................................................ 73
Table 22
95% Confidence Interval for 1 Proportion with 45 Subjects ......................... 75
Table 23
95% Confidence Intervals Based on Variability Assumptions of 
0.84-fold for Anti-Toxin A and 1.4-fold for Anti-Toxin B and on a 
Sample Size Including 36 Evaluable Subjects .............................................. 77
Table 24
Analysis Sets................................................................................................ 78
Table 25
Protocol-required Safety Laboratory Assessments ........................................ 98
 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
15 
TABLE OF FIGURES 
Figure 1
Study Design Overview (Refer to Section 8.11 for Study Procedures 
to be Considered During Special Circumstances) ......................................... 21
Figure 2
Evaluations Based on 10 Enrolled Subjects - Risk Assessment Curves 
for 1 Formulation Based on the Proposed Safety Holding Rules ................... 42
Figure 3
Evaluations Based on 45 Enrolled Subjects - Risk Assessment Curves 
for 1 Formulation Based on the Proposed Safety Holding Rules ................... 43
 
 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
16 
1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Phase I, Single-center, Randomized, Observer-blind, Placebo-controlled Study to 
Evaluate Safety, Reactogenicity and Immunogenicity of GSK¶VClostridium difficile Investigational 
Vaccine Based on the F2 Antigen With or Without AS01B Adjuvant, When Administered Intramuscularly 
According to a 0, 1-month Schedule to Healthy Adults Aged Between 18-45 Years and Between 
50-70 Years, Followed by an Additional Dose Administered in a Partial blind Manner Within an Interval 
of Approximately 15 Months After Dose 2, in a Subcohort of Subjects aged 50-70 Years 
Short Title: 6DIHW\DQGLPPXQRJHQLFLW\VWXG\RI*6.¶VClostridium difficile vaccine 2904545A when 
administered in healthy adults aged 18-45 years and 50-70 years 
Rationale: The purpose of this study is to generate safety and immunogenicity data for the development 
of a candidate Clostridium difficile (C. difficile) vaccine that would protect against primary cases of 
Clostridium difficile infection (CDI) and CDI recurrence. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
x 
To evaluate the safety and reactogenicity profile of 
the C. difficile F2 fusion protein when 
administered with or without AS01B adjuvant as 
IM doses according to a 0, 1-month schedule, in 
healthy adults aged between 18-45 years and 
between 50-70 years followed by an additional 
dose administered approximately 15 months after 
Dose 2 in a subcohort of subjects aged 
50-70 years, during the entire study period. 
x 
Solicited local and general symptoms. 
 
Occurrence of solicited local symptoms 
(any and Grade 3) within 7 days (Day 1 
to Day 7) after each vaccination, in all 
subjects and in all groups. 
 
Occurrence of solicited general 
symptoms (any, Grade 3, related, and 
Grade 3 related) within 7 days (Day 1 to 
Day 7) after each vaccination, in all 
subjects and in all groups. 
x 
Unsolicited AEs. 
 
Occurrence of unsolicited AEs (any, 
Grade 3, related, Grade 3 related, and 
those resulting in a medically attended 
visit) within 30 days (Day 1 to Day 30) 
after each vaccination, according to the 
MedDRA classification, in all subjects 
and in all groups. 
x 
SAEs. 
 
Occurrence of SAEs from Dose 1 (Day 1) 
up to study end, in all subjects and in all 
groups. 
x 
AEs of specific interest. 
 
Occurrence of AEs of specific interest 
(pIMDs) from Dose 1 up to study end, in 
all subjects and in all groups. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
17 
Objectives 
Endpoints 
x 
Laboratory parameters. 
 Occurrence of hematological (white 
blood cells, platelets count, and 
hemoglobin level) and biochemical 
(alanine aminotransferase, aspartate 
aminotransferase, creatinine, and uric 
acid) laboratory abnormalities at 
Screening, Days 8, 31, 38, 180, 390, 476, 
491, 498, and 670 and urinary laboratory 
abnormalities (protein, glucose, and 
blood) at Screening. (Grades will be 
based on the local laboratory normal 
ranges and derived from the FDA 
Toxicity Grading Scale for laboratory 
abnormalities). 
Secondary 
 
x 
To evaluate the humoral immunogenicity induced 
by IM doses of the C. difficile F2 fusion protein 
when administered with or without AS01B 
adjuvant according to a 0, 1-month schedule, in 
healthy adults aged between 18-45 years and 
between 50-70 years followed by an additional 
dose administered approximately 15 months after 
Dose 2 in a subcohort of subjects aged 
50-70 years, up to study end. 
x 
Humoral response to the investigational 
C. difficile F2 fusion protein when administered 
with or without AS01B adjuvant, at Days 1, 31, 61, 
180, 390, 491, 521 and 670. 
 
Serum neutralizing antibody titers 
anti-Toxin A and anti-Toxin B, as 
measured by TNA. 
 Serum antibody concentration 
anti-Toxin A and anti-Toxin B, as 
measured by ELISA. 
AE = adverse event; AS01B = an adjuvant system containing MPL, QS-21 and liposome (50 ȝJ03/DQG ȝJ
QS-21); C. difficile = Clostridium difficile; ELISA = enzyme-linked immunosorbent assay; FDA = Food and 
Drug Administration; GSK = GlaxoSmithKline Biologicals SA; IM = intramuscular; MedDRA = Medical 
Dictionary for Regulatory Activities; MPL = 3-O-desacyl-¶-monophosphoryl lipid A; pIMD = potential 
immune-mediated disease; QS-21 = Quillaja saponaria Molina, fraction 21 (Licensed by GSK from Antigenics 
Inc., a wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation); SAE = serious adverse event; 
TNA = toxin neutralization assay. 
Overall Design: 
This is a Phase I, first-in-human, single-center, randomized, observer-blind, placebo-controlled, study 
with 2 to 3 treatment groups per step in a 4-step staggered design in healthy subjects to generate safety, 
reactogenicity, and immunogenicity data for the development of a candidate C. difficile vaccine that 
would protect against primary cases of CDI and CDI recurrence. 
A 4-step staggered design will be used to ensure maximum safety of the participating subjects: 
x 
Step 1: Vaccination of approximately 20 subjects aged 18-45 years (approximately 10 subjects in the 
CDIFF antigen [Ag] group and approximately 10 subjects in the placebo group). An internal safety 
review committee (iSRC) will review all accumulating safety data after Dose 1 and then again after 
Dose 2. Vaccination in Step 2 will proceed in the absence of a safety concern detected by the iSRC on 
all accumulating safety data at the end of Step 1. 
x 
Step 2: Vaccination of approximately 20 subjects aged 50-70 years (approximately 10 subjects in the 
CDIFF Ag group and approximately 10 subjects in the placebo group). An iSRC will review all 
accumulating safety data after Dose 1 and then again after Dose 2. Vaccination in Step 3 will proceed 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
18 
in the absence of a safety concern detected by the iSRC on all accumulating safety data at the end of 
Step 2. 
x 
Step 3: Vaccination of approximately 30 subjects aged 50-70 years (approximately 10 subjects in the 
CDIFF Ag group, approximately 10 subjects in the CDIFF Ag + an adjuvant system containing 
3-O-desacyl-¶-monophosphoryl lipid A [MPL], QS-21 and liposome [50 ȝJ03/DQG ȝJ46-21] 
[AS01B] group, and approximately 10 subjects in the placebo group). An iSRC will review all 
accumulating safety data after Dose 1, and then again after Dose 2. Vaccination in Step 4 will proceed 
in the absence of a safety concern detected by the iSRC on all accumulating safety data at the end of 
Step 3. 
x 
Step 4: Vaccination of approximately 70 subjects aged 50-70 years (approximately 25 subjects in the 
CDIFF Ag group, approximately 35 subjects in the CDIFF Ag + AS01B group, and approximately 
10 subjects in the placebo group). An iSRC will review all accumulating safety data 3 weeks after the 
start of vaccination in Step 4 and then about every 3 weeks until all subjects have received Dose 1. In 
addition, the iSRC will review all safety data after Dose 2. A subcohort of subjects who have 
successfully completed all visits up to Visit 7, have received two doses on an active arm (ie, the 
subjects who received placebo will be excluded) do not meet any contraindication for subsequent 
vaccination, and still meet the eligibility criteria will receive a third dose after the iSRC has reviewed 
all the accumulating safety data at the end of Step 4 Dose 2. If there are any safety concerns observed 
during SRT reviews post Dose 3, an ad hoc iSRC meeting will take place to review the unblinded 
safety data. 
During all 4 steps, all subjects should be closely observed for at least 60 minutes after vaccination. 
For Steps 1, 2, and 3 only, all subjects should be vaccinated sequentially and at least 60 minutes apart to 
allow for monitoring of any acute events (eg, hypersensitivity reaction). 
During vaccination days of Steps 1, 2, and 3 (ie, Day 1 and Day 31), vaccination will be limited to a 
maximum of 10 subjects per day. In Step 4, there is no limit related to the number of subjects to be 
vaccinated per day. 
Number of Investigators and Study Centers: 
One Principal Investigator and 1 study center are expected to participate in this study. 
Number of Subjects: 
A total of 120 subjects aged 50±70 years (30 receiving placebo, 45 receiving CDIFF Ag and 45 receiving 
CDIFF Ag + AS01B) and 20 subjects aged 18-45 years (10 receiving placebo and 10 receiving CDIFF 
Ag) will be enrolled in this study. 
Treatment Groups and Duration: 
The duration of the study for each subject receiving 2 doses will be approximately 1 year (Visit 7) and 
each subject receiving 3 doses will be approximately 2 years (Visit 11). 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
19 
Study treatment will be administered as indicated below: 
Type of 
Contact and 
Timepoint 
Study Group 
Treatment Name 
Volume to be 
Administered 
Route 
Injection Site 
Location 
Lateralitya 
Visit 1 
(Day 1) 
Placebo 
Placebo 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag 
CDIFF Ag 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag + 
AS01B 
CDIFF Ag + 
AS01B 
0.5 mL 
IM 
Deltoid 
Nondominant 
Visit 3 
(Day 31) 
Placebo 
Placebo 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag 
CDIFF Ag 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag + 
AS01B 
CDIFF Ag + 
AS01B 
0.5 mL 
IM 
Deltoid 
Nondominant 
Visit 8 for 
Step 4 
(Day 491) 
CDIFF Ag 
CDIFF Ag 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag + 
AS01B 
CDIFF Ag + 
AS01B 
0.5 mL 
IM 
Deltoid 
Nondominant 
Ag = antigen; AS01B = an adjuvant system containing MPL, QS-21 and liposome (50 ȝJ03/DQG ȝJ46-21); 
IM = intramuscular; MPL = 3-O-desacyl-¶-monophosphoryl lipid A. 
a The nondominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the 
nondominant arm, an injection in the dominant arm may be performed. 
Study Procedures During Special Circumstances 
During special circumstances (eg, COVID-19 pandemic), the specific guidance from local public health 
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duration of such special circumstances, the following measures may be implemented for enrolled 
subjects: 
x 
Safety follow-up may be made by a telephone call, other means of virtual contact, or home visit, if 
appropriate. 
x 
Diary cards may be transmitted from and to the site by electronic means and/or conventional mail. 
x 
Biological samplHVPD\EHFROOHFWHGDWDGLIIHUHQWORFDWLRQRWKHUWKDQWKHVWXG\VLWHRUDWVXEMHFW¶V
home. Biological samples should not be collected if they cannot be processed in a timely manner or 
appropriately stored until the intended use. 
x 
If despite best efforts it is not possible to collect blood samples within the interval predefined in the 
protocol, then the interval for blood sampling may be extended up to a maximum length of 30 days 
before the next blood sampling. Impact on the per protocol set for analysis of immunogenicity will be 
determined on a case-by-case basis. 
x 
A limited number of subjects may be recruited in addition in the Step 4 in the active arms, should 
there be a high rate of missed visit and/or visit outside of planned interval and/or withdrawal due to 
the current exceptional and unpredictable circumstances. 
,WLVWKH,QYHVWLJDWRU¶VUHVSRQVLELOLW\WRLGHQWLI\DQDOWHUQDWHORFDWLRQ7KH,QYHVWLJDWRUVKRXOGHQVXUHWKDW
this alternate location meets International Council for Harmonisation Good Clinical Practice 
requirements, such as adequate facilities to perform study procedures, appropriate training of the staff and 
documented delegation of responsibilities in this location. This alternate location should be covered by 
proper insurance for the conduct of study on subjects by Investigator and staff at a site other than the 
designated study site. Refer to EMA Guidance on the Management of Clinical Trials during the 
COVID-19 (Coronavirus) pandemic (Version 4, 04 February 2021) for more details. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
20 
Statistical Methods: 
The statistical analyses will be performed in 3 steps: 
x 
The first interim analysis will be performed when all data up to 1 month after Dose 2, ie, Day 61 (ie, 
data that are as clean as possible) are available. The immunogenicity data available until Day 61, and 
the safety and reactogenicity data available at the time of this analysis will be described. At this point, 
the statistician will be unblinded for the analysis (ie, will have access to individual subject treatment 
assignments). The remaining study personnel will stay blinded (ie, will not have access to the 
individual subject treatment assignment) until study end. It is possible however, due to the limited 
sample size, that unblinding occurs for a few subjects having a specific adverse event (AE) or serious 
adverse event (SAE) (eg, an AE/SAE occurring only in a single group). Therefore, anyone having 
access to the analysis of Day 61 could become unblinded regarding those specific cases. The study 
will be considered as partial blind from this point onwards. Individual listings will be provided at the 
study end to the investigator. Subjects will be provided with information about the study arm, via the 
investigator at the study end. 
x 
The second interim analysis will be performed when all data up to 1 month after Dose 3, ie, Day 521 
(ie, data that are as clean as possible) are available. The immunogenicity data available until Day 521, 
and the safety and reactogenicity data available at the time of this analysis will be described. 
x 
The final analysis will be performed when all data up to study end are available. An integrated 
clinical study report containing all data will be written and made available to the Principal 
Investigator at that time. In addition, all previous analyses will be re-produced based on cleaned data 
at this point. Individual listings will only be provided at this stage. 
 
 
Internal Safety Review Committee: Yes 
As the investigational vaccine formulation will be administered to human for the first time, an iSRC will 
EHDSSRLQWHGLQDGGLWLRQWRWKHSURMHFW¶VH[LVWLQJ657DQGVDIHW\KROGLQJUXOHVKDYHEHHQGHILQHG.
CCI


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
21 
1.2 
Schema 
Figure 1 
Study Design Overview (Refer to Section 8.11 for Study Procedures to be Considered During Special 
Circumstances) 
 
 
 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
22 
 
Ag = antigen; AS01B = an adjuvant system containing MPL, QS-21 and liposome (50 ȝJ03/DQG ȝJ46-21); D = day; iSRC = internal safety review 
committee; MPL = 3-O-desacyl-¶-monophosphoryl lipid A; N = number of subjects; PBMC = peripheral blood mononuclear cell; QS-21 = Quillaja saponaria 
Molina, fraction 21 (Licensed by GSK from Antigenics Inc., a wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation); V = visit 
a 
As soon as the results from hematology and biochemistry analysis are available, Visit 1 (Day 1) should be scheduled. If the Investigator believes there is a 
reasonable justification to do so, screening procedures may be repeated (maximum 1 rescreening per subject is allowed). Only laboratory results from the 
Rescreening Visit, if it occurs, will be taken into consideration and recorded in the eCRF. Medical history, physical examination and review of 
inclusion/exclusion criteria must be repeated if a Rescreening Visit occurs. The subject can only be randomized once the Investigator receives the results and 
confirms the eligibility criteria 
b The iSRC will review all accumulating safety data 3 weeks after the start of vaccination in Step 4 and then about every 3 weeks until all subjects have 
received Dose 1. 
c Optional blood sampling for retesting, if deemed necessary by the Investigator. 
d An additional blood sample of approximately 40 mL will be collected from subjects in Step 4 at Visit 5. This sample will be optional. PBMC may be used for 
the generation of monoclonal antibodies. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
23 
e A subcohort of subjects who have successfully completed all visits up to Visit 7, have received two doses on an active arm (ie, the subjects who received 
placebo will not be considered for Dose 3) do not meet any contraindication for subsequent vaccination, and still meet the eligibility criteria will receive an 
additional dose ie, Dose 3.  
f  The iSRC will review all the accumulating safety data at the end of Step 4 Dose 2. If there are any safety concerns  observed during SRT reviews post Dose 3, 
an ad hoc iSRC meeting will take place to review the unblinded safety data.


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
24 
1.3 
Schedule of Activities 
Table 6 
Schedule of Activities (Refer to Section 8.11 for Study Procedures to be Considered During Special 
Circumstances) 
Type of contact 
Screeninga Visit 
1 
Visit 
2 
Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 
Screening 
for Dose 
3, Step 4 
Visit 8 
for Step 
4 
Visit 9 for 
Step 4 
Visit 10 
for Step 4 
Visit 11 for 
Step 4 
Timepoints 
Day -15 Day 1 Day 
8 
Day 31 Day 38 Day 61 Day 180 Day 390 Day 476 Day 491 
Day 498 
Day 521 
Day 670 
Informed consent 
Ɣ 












Informed consent addendum 
 



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Ɣ 




Check inclusion/exclusion 
criteria 
Ɣ
Ɣ
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Ɣ

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Collect demographic datab 
Ɣ
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Medical historyc 
Ɣ
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Physical examination 
Ɣ
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żd
Ɣe
żd
żd
żd
żd 
Ɣ 
Ɣe 
żd 
żd 
żd
Vital signs (systolic/diastolic 
blood pressure and heart rate) 
Ɣ 
Ɣe 
ż 
Ɣe 
ż 
ż 
ż 
ż 
Ɣ 
Ɣe 
ż 
ż 
ż 
Urine pregnancy testf 
Ɣ
Ɣe
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Ɣ 
Ɣe
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Measure/record height and 
weight 
Ɣ
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Check contraindications to 
subsequent vaccinationg 


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Ɣe

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Ɣe


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Body temperature 

Ɣe

Ɣe
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Ɣe
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Study group and treatment 
number allocation 

że
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Treatment number allocation 
for subsequent dose 

 

że 
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że
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CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
25 
Table 6 
Schedule of Activities (Refer to Section 8.11 for Study Procedures to be Considered During Special 
Circumstances) 
Type of contact 
Screeninga Visit 
1 
Visit 
2 
Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 
Screening 
for Dose 
3, Step 4 
Visit 8 
for Step 
4 
Visit 9 for 
Step 4 
Visit 10 
for Step 4 
Visit 11 for 
Step 4 
Timepoints 
Day -15 Day 1 Day 
8 
Day 31 Day 38 Day 61 Day 180 Day 390 Day 476 Day 491 
Day 498 
Day 521 
Day 670 
Recording of administered 
treatment number 

Ɣ

Ɣ



 
 
Ɣ



Vaccine administration 

Ɣ

Ɣ



 
 
Ɣ



Blood sampling for antibody 
determination (humoral 
immunogenicity) 
(approximately 20 mL) ± TNA 
and ELISA 

Ɣe

Ɣe

Ɣ
Ɣ
Ɣ 
 
Ɣe 
 
Ɣ 
Ɣ
Optional blood sample for 
PBMC isolation 
(approximately 40 mL) 




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Ɣk







Blood sampling for 
hematology and biochemical 
analysis (approximately 
5.5 mL)h, i 
Ɣ
Ɣe, j
Ɣ
Ɣe
Ɣ

Ɣ
Ɣ 
Ɣ 
Ɣe 
Ɣ 
 
Ɣ
Urine analysis (quantitative or 
semi-quantitative analysis) 
Ɣ






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Ɣ



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Record any concomitant 
medications/vaccinations 
Ɣ
Ɣe
Ɣ
Ɣe
Ɣ
Ɣ
Ɣ
Ɣ 
Ɣ 
Ɣe 
Ɣ 
Ɣ 
Ɣ
Record any intercurrent 
medical conditions 
Ɣ
Ɣe
Ɣ
Ɣe
Ɣ
Ɣ
Ɣ
Ɣ 
Ɣ 
Ɣe 
Ɣ 
Ɣ 
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Distribution of the subject card 
ż
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Distribution of paper diary 
cards 

ż
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ż
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ż
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CONFIDENTIAL 
Protocol 208109 (CDIFF-004) ± Amendment 04 
 
26 
Table 6 
Schedule of Activities (Refer to Section 8.11 for Study Procedures to be Considered During Special 
Circumstances) 
Type of contact 
Screeninga Visit 
1 
Visit 
2 
Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 
Screening 
for Dose 
3, Step 4 
Visit 8 
for Step 
4 
Visit 9 for 
Step 4 
Visit 10 
for Step 4 
Visit 11 for 
Step 4 
Timepoints 
Day -15 Day 1 Day 
8 
Day 31 Day 38 Day 61 Day 180 Day 390 Day 476 Day 491 
Day 498 
Day 521 
Day 670 
Return of paper diary cards 

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ż
ż
ż
ż
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ż
ż
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Diary card transcription by 
Investigator 

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Ɣ
Ɣ
Ɣ
Ɣ
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Ɣ
Ɣ
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Recording of solicited AE 
(Day 1 to Day 7) 

Ɣ
Ɣ
Ɣ
Ɣ
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

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Ɣ
Ɣ

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Recording of unsolicited AE 
(Day 1 to Day 30) 

Ɣ
Ɣ
Ɣ
Ɣ
Ɣ
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Ɣ
Ɣ
Ɣ
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Recording of SAEs (all, fatal, 
related to study vaccine) 

Ɣ
Ɣ
Ɣ
Ɣ
Ɣ
Ɣ
Ɣ 
Ɣ 
Ɣ 
Ɣ 
Ɣ 
Ɣ
Recording of SAEs related to 
study participation, or to a 
concurrent GSK 
medication/vaccine 
Ɣ
Ɣ
Ɣ
Ɣ
Ɣ
Ɣ
Ɣ
Ɣ 
Ɣ 
Ɣ 
Ɣ 
Ɣ 
Ɣ
Recording of AEs of specific 
interest (pIMDs) 

Ɣ
Ɣ
Ɣ
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Ɣ
Ɣ
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Ɣ 
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Ɣ
Recording of pregnancies 

Ɣ
Ɣ
Ɣ
Ɣ
Ɣ
Ɣ
Ɣ 
Ɣ 
Ɣ 
Ɣ 
Ɣ 
Ɣ
Study conclusion for individual 
subjects 







Ɣl 
 
 
 
 
Ɣm
AE = adverse event; D = Day; ELISA = enzyme-linked immunosorbent assay; eCRF = electronic case report form; GSK = GlaxoSmithKline Biologicals SA; 
iSRC = internal safety review committee; PBMC = peripheral blood mononuclear cell; pIMD = potential immune-mediated disease; SAE = serious adverse 
event; TNA = toxin neutralization assay. 
Note: The double-line border following Day 61 indicates the analyses which will be performed on all data (ie, data that are as clean as possible) obtained up to 
Day 61. 
Ɣ Used to indicate a study procedure that requires documentation in the individual eCRF. 


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ż Used to indicate a study procedure that does not require documentation in the individual eCRF. 
a If the Investigator believes there is a reasonable justification to do so, screening procedures may be repeated (maximum 1 rescreening per subject is allowed). 
Only laboratory results from the Rescreening Visit, if it occurs, will be taken into consideration and recorded in the eCRF. Medical history, physical 
examination and review of inclusion/exclusion criteria must be repeated if a Rescreening Visit occurs. The subject can only be randomized once the 
Investigator receives the results and confirms the eligibility criteria. 
b Date of birth, sex, and UDFHWREHUHFRUGHGLQWKHVXEMHFW¶VH&5) 
c Medical occurrences that begin before the start of study treatment but after obtaining informed consent will be recorded in tKHVXEMHFW¶VH&5) 
d Physical examination, if deemed necessary by the Investigator or delegate. 
e To be performed prior to vaccination. 
f 
A urine pregnancy test will be performed only for women of childbearing potential. 
g Contraindications to subsequent vaccinations are detailed in Section 6.2. 
h The following hematological (white blood cells, platelets count and hemoglobin) and biochemical (alanine aminotransferase, aspartate aminotransferase, 
creatinine, and uric acid) parameters will be assessed at all timepoints specified above. C-reactive protein will be assessed only during the two screening 
visits. 
i 
In case Grade 3 hematology or biochemistry parameter is observed, a retesting should be performed if deemed necessary by the Investigator, the iSRC, or the 
Sponsor. 
j 
Optional blood sampling for retesting, if deemed necessary by the Investigator. 
k An additional blood sample will be collected from subjects in Step 4 at Visit 5. This sample will be optional. PBMC may be used for the generation of 
monoclonal antibodies. 
l 
The study conclusion for subjects receiving 2 doses will be on Visit 7. 
m The study conclusion for subjects receiving 3 doses will be on Visit 11. 
 
Table 7 
Intervals Between Study Visits (Refer to Section 8.11 for Study Procedures to be Considered During Special 
Circumstances) 
Interval 
Optimal Length of Interval 
Allowed Interval 
6FUHHQLQJĺ9LVLW 1 (Day 1) 
1 to 15 days 
- 
Visit 1 (Day ĺ9LVLW 2 (Day 8) 
7 days 
7 to 9 days 
Visit 1 (Day ĺ9LVLW 3 (Day 31) 
30 days 
30 to 35 days 
Visit 3 (Day ĺ9LVLW 4 (Day 38) 
7 days 
7 to 9 days 
Visit 3 (Day ĺ9LVLW 5 (Day 61) 
30 days 
30 to 35 days 


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Visit 3 (Day ĺ9LVLW 6 (Day 180) 
149 days 
140 to 160 days 
Visit 3 (Day ĺ9LVLW 7 (Day 390) 
359 days 
350 to 395 days 
Visit 7 (Day ĺ Screening Dose 3 (Day 476) 
20 to 150 days 
- 
Screening Dose 3 (Day 476)ĺ9LVLWDay 491) 
1 to 15 days 
- 
Visit 8 (Day 491ĺ9LVLWDay 498) 
7 days 
7 to 9 days 
Visit 8 (Day 491ĺ9LVLW'D\521) 
30 days 
30 to 35 days 
Visit 8 (Day 491ĺ9LVLW'D\670) 
179 days 
170 to 190 days 


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2.0 INTRODUCTION 
2.1 
Study Rationale 
The purpose of this study is to generate safety, reactogenicity, and immunogenicity data for the 
development of a candidate Clostridium difficile (C. difficile) vaccine that would protect against 
primary cases of C. difficile infection (CDI) and CDI recurrence. 
2.2 
Background 
Clostridium difficile was characterized during the nineteen-seventies, but comprehensive 
epidemiological data were available since 2003 when large increases in incidence and mortality 
rates were observed in the United States of America (USA) and Europe. Since then there has 
been a steady increase in incidence of CDI, with subsequent increases in mortality, prolonged 
hospital stays with higher level care, and a substantial rise in healthcare costs.2 
Clostridium difficile infection is a major cause of gastrointestinal illness, with approximately 
500 000 infections and the leading cause of gastroenteritis associated death with 29 000 deaths 
annually in the USA. 2 The emergence of hypervirulent strains has contributed to increase the 
number and severity of CDI cases. In recent years, some countries (United Kingdom) have 
implemented hospital hygiene and bundle measures which resulted in significant reductions in 
the number of cases. The burden is, however, expected to remain significant until vaccination is 
available. 
Currently, the CDI burden is known in North America and Europe (data are scarce from other 
regions of the world) and predominantly affects the older adult population, with increased 
severity of infection resulting in a 4% to 13% mortality rate depending on the age and underlying 
comorbidities. In the USA alone, there had been an estimated 453 000 incident cases of CDI and 
29 300 deaths in 2011. 2 Treatment includes metronidazole and/or vancomycin and/or 
fidaxomicin, and complications such as toxic megacolon may require partial or full colectomy. 
Recurrences are reported in up to 25% of cases. Clostridium difficile is transmitted through 
ingestion of spores that germinate in the human intestine and become toxigenic. Virulent strains 
produce 2 toxins (Toxin A and Toxin B) with clear pathogenic role. Some newly emerging 
hypervirulent strains such as ribotype-027 or ribotype-078 produce greater quantities of Toxin A 
and Toxin B plus a binary toxin with a potentially important pathogenic role. 2  
In the US, from 1993 to 2009, hospital stays for patients with a primary CDI diagnosis have 
quadrupled. In 2009, CDI was associated with at least 1% of all hospital stays. The number of 
death certificates with enterocolitis due to C. difficile as the primary cause of death had 
multiplied by 10 from 1999 to 2008 in the USA. Similar trends were observed in Europe. 
The rise in CDI-related hospitalizations worldwide has indicated that the affected population 
appears to have evolved. Indeed, there is a growing number of healthy adults without significant 


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30 
medical comorbidities or prior antibiotic exposure who present with diarrheal symptoms and are 
diagnosed with CDI. In addition to that, emergence of community strains of C. difficile has been 
described. 
Up to 40% of CDI cases may be community-acquired. Patients suffering from 
community-acquired CDI tend to be younger and healthier, without previously described risk 
factors. 
The clinical burden associated with CDI is driven by morbidity and mortality in the hospitalized 
or institutionalized older adult population. Additional risk factors involve antibiotic use, 
comorbidities and to some extent, proton pump inhibitors. The economic burden is mainly driven 
by the increased length of stay and the cost of preventing dissemination within the institution 
(patient isolation and decontamination). Recently, the proportion of CDI occurring in patients 
outside the hospital setting has increased. Indeed, a large USA study demonstrated a community 
case incidence higher than previously reported. This supports the fact that the boundaries 
between hospital and community acquired CDI are becoming less distinct.3,4 
First line treatments for CDI include metronidazole and vancomycin for primary and recurrent 
cases. However, 25% to 30% of cases result in recurrence of disease, with case fatality rates in 
the range of 6% to 30%.2 A recently approved antibiotic (fidaxomicin) demonstrated 
noninferiority to vancomycin in initial clinical response rates but most importantly showed 
superiority in sustained response rate, ie, lower recurrence rate (15% versus 30% with 
vancomycin). Despite this, the uptake of fidaxomicin has been poor, due to concerns with its 
price as compared to vancomycin. 
Please refer to the current Investigator Brochure (IB) for information regarding the preclinical 
studies and the epidemiological information of C. difficile investigational vaccine 
(GSK2904545A). 
2.3 
Benefit/Risk Assessment 
Please refer to the current IB for the summary of potential risks and benefits of C. difficile 
investigational vaccine. 
The Sponsor will immediately notify the Principal Investigator if any additional safety or 
toxicology information becomes available during the study. 
This study will be performed in compliance with the protocol, International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) and applicable regulatory requirements. 
Aspects of the study concerned with the study treatment will meet the requirements of the 
European Union ± Good Manufacturing Practice. 


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2.3.1 
Risk Assessment 
The risk assessment and mitigation strategy for this study protocol are outlined in Table 8. 
Table 8 
Risk Assessment 
Important Potential/Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Investigational vaccine: Clostridium difficile investigational vaccine 
Theoretical risk of acquiring a 
vaccine-induced autoimmune disease 
after vaccination. 
Theoretical safety concerns have arisen 
from studies in which adjuvants have 
induced autoimmune diseases in 
various animal models and from 
literature reports that diverse 
FRPSRXQGVZLWK³DGMXYDQW´DFWLYLW\
could be associated with 
autoimmunity.5 
Close monitoring of pIMDs 
in clinical development 
programs using adjuvants 
systems. The potential risk 
of events of possible 
autoimmune etiology to 
occur is mentioned in the 
ICF. 
Hypersensitivity reactions (including 
anaphylaxis). 
Sudden potentially life-threatening 
allergic reactions to the vaccines are 
usually very rare. The first symptoms 
will usually occur shortly after the 
vaccination. In general, the symptoms 
can be treated successfully if the 
treatment is started quickly. 
Subjects with known 
hypersensitivity to any of 
the components of the 
vaccine are excluded from 
enrollment. 
For Steps 1, 2, and 3 only, 
all subjects should be 
vaccinated sequentially and 
at least 60 minutes apart to 
allow monitoring of any 
acute events (eg, 
hypersensitivity reaction). 
During all 4 steps, all 
subjects should be closely 
observed for at least 
60 minutes after vaccination. 
During vaccination days of 
Steps 1, 2, and 3 (ie, Day 1 
and Day 31), vaccination 
will be limited to maximum 
10 subjects per day. 
Study Procedures 
Injection site hemorrhage in 
individuals with thrombocytopenia or 
any other coagulation disorder. 
Injection site hemorrhage may occur at 
the injection site in populations at 
increased risk of hemorrhage, such as 
those with thrombocytopenia or 
acquired/hereditary coagulation 
disorders. 
The Investigators are 
informed of possible 
injection site hemorrhage in 
individuals with 
thrombocytopenia or any 
coagulation disorder 
following study treatment 
administration by 
information included in 
product labels or IB based 
on the following language in 
the company Core Safety 
,QIRUPDWLRQ³$VZLWKRWKHU
vaccines administered 


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Protocol 208109 (CDIFF-004) ± Amendment 04 
 
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Table 8 
Risk Assessment 
Important Potential/Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
intramuscularly, all study 
vaccine should be given 
with caution to individuals 
with thrombocytopenia or 
any coagulation disorder 
since bleeding may occur 
following an IM 
administration to these 
subjects.´ 
Risk from blood sampling. 
Blood sampling-associated risk of 
discomfort, syncope, dizziness, and 
infection at the injection site after or 
during venipuncture. 
Blood samples will be 
obtained by a trained 
professional and medical 
assistance will be available. 
IB = ,QYHVWLJDWRU¶V%URFKXUHICF = informed consent form; IM = intramuscular; pIMDs = potential 
immune-mediated diseases 
2.3.2 
Benefit Assessment 
Possible benefits include: 
x Contribution to the process of developing a C. difficile vaccine that would potentially provide 
protection in the future. 
x Medical assessment associated with this study (ie, physical examination, blood tests 
[hematology and biochemistry]) for the subjects enrolled. 
x Access to medical care. 
x Subjects receiving C. difficile investigational vaccine may potentially have the benefit of 
being protected against CDI. However, since the efficacy of the C. difficile investigational 
vaccine has not yet been assessed, it is not known whether it is effective in protecting 
humans. 
2.3.3 
Overall Benefit/Risk Conclusion 
The C. difficile investigational vaccine is currently in a very early stage of clinical development 
and no vaccine efficacy has been demonstrated in humans. Taking into account the measures 
taken to minimize risk to subjects participating in this study, the potential risks identified in 
association with the C. difficile investigational vaccine are justified by the potential benefits 
linked to the development of the C. difficile investigational vaccine. 


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3.0 OBJECTIVES AND ENDPOINTS 
Table 9 
 Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
x 
To evaluate the safety and reactogenicity profile of 
the C. difficile F2 fusion protein when 
administered with or without AS01B adjuvant as 
IM doses according to a 0, 1-month schedule, in 
healthy adults aged between 18-45 years and 
between 50-70 years followed by an additional 
dose administered approximately 15 months after 
Dose 2 in a subcohort of subjects aged 
50-70 years, during the entire study period. 
x 
Solicited local and general symptoms. 
 
Occurrence of solicited local symptoms 
(any and Grade 3) within 7 days (Day 1 
to Day 7) after each vaccination, in all 
subjects and in all groups. 
 
Occurrence of solicited general 
symptoms (any, Grade 3, related, and 
Grade 3 related) within 7 days (Day 1 to 
Day 7) after each vaccination, in all 
subjects and in all groups. 
x 
Unsolicited AEs. 
 
Occurrence of unsolicited AEs (any, 
Grade 3, related, Grade 3 related, and 
those resulting in a medically attended 
visit) within 30 days (Day 1 to Day 30) 
after each vaccination, according to the 
MedDRA classification, in all subjects 
and in all groups. 
x 
SAEs. 
 
Occurrence of SAEs from Dose 1 (Day 1) 
up to study end, in all subjects and in all 
groups. 
x 
AEs of specific interest. 
 
Occurrence of AEs of specific interest 
(pIMDs) from Dose 1 up to study end, in 
all subjects and in all groups. 
x 
Laboratory parameters 
 Occurrence of hematological (white 
blood cells, platelets count, and 
hemoglobin level) and biochemical 
(alanine aminotransferase, aspartate 
aminotransferase, creatinine, and uric 
acid) laboratory abnormalities at 
Screening, Days 8, 31, 38, 180, 390, 476, 
491, 498, and 670 and urinary laboratory 
abnormalities (protein, glucose, and 
blood) at Screening. (Grades will be 
based on the local laboratory normal 
ranges and derived from the FDA 
Toxicity Grading Scale for laboratory 
abnormalities). 


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Table 9 
 Study Objectives and Endpoints 
Objectives 
Endpoints 
Secondary 
 
x 
To evaluate the humoral immunogenicity induced 
by IM doses of the C. difficile F2 fusion protein 
when administered with or without AS01B 
adjuvant according to a 0, 1-month schedule, in 
healthy adults aged between 18-45 years and 
between 50-70 years followed by an additional 
dose administered approximately 15 months after 
Dose 2 in a subcohort of subjects aged 
50-70 years, up to study end. 
x 
Humoral response to the investigational 
C. difficile F2 fusion protein when administered 
with or without AS01B adjuvant, at Days 1, 31, 61, 
180, 390, 491, 521 and 670. 
 
Serum neutralizing antibody titers 
anti-Toxin A and anti-Toxin B, as 
measured by TNA. 
 Serum antibody concentration 
anti-Toxin A and anti-Toxin B, as 
measured by ELISA. 
AE = adverse event; AS01B = an adjuvant system containing MPL, QS-21 and liposome (50 ȝJ03/DQG ȝJ
QS-21); C. difficile = Clostridium difficile; ELISA = enzyme-linked immunosorbent assay; FDA = Food and Drug 
Administration; GSK = GlaxoSmithKline Biologicals SA; IM = intramuscular; MedDRA = Medical Dictionary for 
Regulatory Activities; MPL = 3-O-desacyl-¶-monophosphoryl lipid A; pIMD = potential immune-mediated 
disease; QS-21 = Quillaja saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc., a wholly owned 
subsidiary of Agenus Inc., a Delaware, USA corporation); SAE = serious adverse event; TNA = toxin neutralization 
assay. 


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4.0 STUDY DESIGN 
4.1 
Overall Design 
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, including 
those specified in the outline in the schedule of activities (Section 1.3), are essential and required 
for study conduct. 
This is a Phase I, first-in-human, single-center, randomized, observer-blind, placebo-controlled, 
study with 2 to 3 treatment groups per step in a 4-step staggered design in healthy subjects to 
generate safety, reactogenicity, and immunogenicity data for the development of a candidate 
C. difficile vaccine that would protect against primary cases of CDI and CDI recurrence. 
The duration of the study for each subject receiving 2 doses will be approximately 1 year and for 
each subject receiving 3 doses will be of approximately 2 years. 
Primary completion date (PCD): Visit 11 (Day 670) (refer to Appendix 2 for the definition of 
PCD). 
Study conclusion for individual subjects: The study conclusion for subjects receiving 2 doses 
will be Visit 7 (Day 390) and for subjects receiving 3 doses will be Visit 11 (Day 670) (refer to 
Appendix 2 for the definition of EoS). 
A 4-step staggered design will be used to ensure maximum safety of the participating subjects 
(see Figure 1): 
x Step 1: Vaccination of approximately 20 subjects aged 18-45 years (approximately 
10 subjects in the CDIFF antigen [Ag] group and approximately 10 subjects in the placebo 
group). An internal safety review committee (iSRC) will review all accumulating safety data 
after Dose 1 and then again after Dose 2. Vaccination in Step 2 will proceed in the absence of 
a safety concern detected by the iSRC on all accumulating safety data at the end of Step 1. 
x Step 2: Vaccination of approximately 20 subjects aged 50-70 years (approximately 
10 subjects in the CDIFF Ag group and approximately 10 subjects in the placebo group). An 
iSRC will review all accumulating safety data after Dose 1 and then again after Dose 2. 
Vaccination in Step 3 will proceed in the absence of a safety concern detected by the iSRC 
on all accumulating safety data at the end of Step 2. 
x Step 3: Vaccination of approximately 30 subjects aged 50-70 years (approximately 
10 subjects in the CDIFF Ag group, approximately 10 subjects in the CDIFF Ag + an 
adjuvant system containing 3-O-desacyl-¶-monophosphoryl lipid A [MPL], QS-21 and 
liposome [50 ȝJ03/DQG ȝJ46-21] AS01B group, and approximately 10 subjects in the 
placebo group). An iSRC will review all accumulating safety data after Dose 1, and then 
after Dose 2. Vaccination in Step 4 will proceed in the absence of a safety concern detected 
by the iSRC on all accumulating safety data at the end of Step 3. 


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x Step 4: Vaccination of approximately 70 subjects aged 50-70 years (approximately 
25 subjects in the CDIFF Ag group, approximately 35 subjects in the CDIFF Ag + AS01B 
group, and approximately 10 subjects in the placebo group). An iSRC will review all 
accumulating safety data 3 weeks after the start of vaccination in Step 4 and then about every 
3 weeks until all subjects have received Dose 1. In addition, the iSRC will review all safety 
data after Dose 2 (refer to Section 8.11 for study procedures to be considered during special 
circumstances). A subcohort of subjects who have successfully completed all visits up to 
Visit 7, have received two doses on an active arm (ie, the subjects who received placebo will be 
excluded), do not meet any contraindication for subsequent vaccination, and still meet the 
eligibility criteria will receive a third dose after the iSRC has reviewed all the accumulating 
safety data at the end of Step 4 Dose 2. If there are any safety concerns observed during SRT 
reviews post Dose 3, an ad hoc iSRC meeting will take place to review the unblinded safety 
data. 
Refer to Section 9.6 for iSRC oversight. 
During all 4 steps, all subjects should be closely observed for at least 60 minutes after 
vaccination. 
For Steps 1, 2, and 3 only, all subjects should be vaccinated sequentially and at least 60 minutes 
apart to allow for monitoring of any acute events (eg, hypersensitivity reaction). 
During vaccination days of Steps 1, 2, and 3 (ie, Day 1 and Day 31), vaccination will be limited 
to a maximum of 10 subjects per day. In Step 4, there is no limit related to the number of 
subjects to be vaccinated per day. 
Table 10 
Study Groups Foreseen in the Study (Refer to Section 8.11 for Study 
Procedures to be Considered During Special Circumstances) 
Step 
Study Groups 
Number of Subjects 
Age (Minimum/Maximum) 
1 
Placebo 
10 
18-45 years 
CDIFF Ag 
10 
18-45 years 
2 
Placebo 
10 
50-70 years 
CDIFF Ag 
10 
50-70 years 
3 
Placebo 
10 
50-70 years 
CDIFF Ag 
10 
50-70 years 
CDIFF Ag + AS01B 
10 
50-70 years 
4 
Placebo 
10 
50-70 years 
CDIFF Ag 
25 
50-70 years 
CDIFF Ag + AS01B 
35 
50-70 years 


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Ag = antigen; AS01B = an adjuvant system containing MPL, QS-21 and liposome (50 ȝJ03/DQG ȝJ46-21); 
GSK = GlaxoSmithKline Biologicals SA; MPL = 3-O-desacyl-¶-monophosphoryl lipid A; QS-21 = Quillaja 
saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc., a wholly owned subsidiary of Agenus 
Inc., a Delaware, USA corporation) 
The Investigator is not permitted to start the administration of the next dose until receipt of the 
favorable outcome of the safety evaluation, documented and provided in writing (scanned and 
emailed), authorizing the Investigator to proceed. Moreover, if the Investigator becomes aware 
of a holding rule being met, he/she will suspend vaccination and will inform GlaxoSmithKline 
Biologicals SA (GSK) immediately (see Table 11 and Table 12). 
Refer to Section 4.6.1 for detailed description of holding rules and safety monitoring. 
4.2 
Scientific Rationale for Study Design 
4.2.1 
Rationale for Study Blinding 
Given the different appearance of the C. difficile investigational vaccines and placebo, double 
blinding is not possible, and the study will be conducted in an observer-blind manner. In an 
observer-blind study, the subject, the Contract Research Organization personnel, and the study 
center and Sponsor personnel involved in the clinical evaluation of the subjects are blinded while 
other study personnel may be aware of the treatment assignment. 
When all data up to Day 61 are available, a statistical analysis will be performed (first interim 
analysis). The immunogenicity data available until Day 61, and the safety and reactogenicity 
data available at the time of this analysis will be described. At this point, the statistician will be 
unblinded for the analysis (ie, will have access to individual subject treatment assignments). The 
remaining study personnel will stay blinded (ie, will not have access to the individual subject 
treatment assignment) until study end. It is possible however, due to the limited sample size, that 
unblinding occurs for a few subjects having a specific adverse event (AE) or serious adverse 
event (SAE) (eg, an AE/SAE occurring only in a single group). Therefore, anyone having access 
to the analysis of Day 61 could become unblinded regarding those specific cases. The study will 
be considered as partial blind from this point onwards. 
The third dose will be administered to the Step 4 subjects who received the active components, 
in a partial blind manner. The Investigator and the subjects will not have access to the treatment 
allocation up to study end (Day 390). After Day 390, only the subjects will remain fully blinded, 
while the Investigator will be partially blinded, as no placebo subjects will be included for 
Dose 3. 
Please refer to Appendix 2 for the definition of observer-blind and partial blind. 
4.2.2 
Rationale for Randomization and the Use of Placebo 
Randomized, placebo-controlled studies are widely considered to be the most rigorous method 
for the efficacy evaluation of treatments or prevention interventions. To be ethical, clinical 


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Protocol 208109 (CDIFF-004) ± Amendment 04 
 
38 
research requires balancing rigorous science with the protection of subjects. The use of placebo 
controls in studies for conditions with no effective treatment is widely accepted.6 Up to date, 
there is no established standard of care to prevent CDI. 
Likewise, the Declaration of Helsinki allows placebo controls and states: ³Where for compelling 
and scientifically sound methodological reasons the use of placebo is necessary to determine the 
efficacy or safety of an intervention and the patients who receive placebo will not be subjected to 
additional risks of serious or irreversible harm.´7 
Randomization is used to reduce bias of selection and the placebo group is included as a control 
for the reactogenicity, the safety and the immunogenicity assessments. 
The third dose of the vaccine is being given to the subjects recruited in the active groups of the 
last step of the study, to demonstrate if a similar kinetics in terms of anti-Toxin A/Toxin B can 
be achieved with the F2 antigen formulation with or without an adjuvant. Therefore, the third 
dose will not be given to the subjects receiving placebo. 
4.2.3 
Rationale for the Use of F2 Fusion Protein Antigen 
The F2 antigen is a fusion protein comprising the C-terminal portions of Toxin A and Toxin B. 
The rationale for selecting the C-terminal portions of Toxin A and Toxin B is based on the fact 
that these portions correspond to the binding domains of the toxins. 
Substantial evidences suggest a protective role of antitoxin antibodies. In humans, antibodies 
against C. difficile Toxin A and Toxin B have been reported to protect against CDI8,9,10,11 and 
recurrent episodes of CDI.12,13,14 There is evidence suggesting that antibodies to the C-terminal 
part of Toxin B can drive protection while data remain unclear on the protective role conferred 
by antibodies induced by the C-terminal part of Toxin A. 
4.2.4 
Rationale for the Use of AS01B Adjuvant 
As the C. difficile investigational vaccine is intended for subjects at risk for CDI who also may 
have an impaired immune system due to immunosenescence and/or comorbidities, the C. difficile 
investigational vaccine includes an adjuvant. Using an adjuvant might indeed help to induce a 
higher and longer-lasting immune response. 
The C. difficile investigational vaccine used in the present study will be adjuvanted with AS01B. 
AS01B is an adjuvant included in the *6.%LRORJLFDOV¶+HUSHV=RVWHUYDFFLQHPDUNHWHGDV 
Shingrix, which has recently received regulatory approvals in the US, Canada, Europe, and Japan 
for the prevention of shingles in adults aged 50 years and above. AS01B contains 50 ȝJRI03/
and 50 ȝJRI46-21 (a saponin molecule purified from the bark extract of Quillaja saponaria 
Molina, fraction 21 [Licensed by GSK from Antigenics Inc. a wholly owned subsidiary of 
Agenus Inc. a Delaware, USA corporation]). 


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Protocol 208109 (CDIFF-004) ± Amendment 04 
 
39 
4.2.5 
Rationale for the Safety Monitoring Plan 
The C. difficile investigational vaccine will be administered for the first time in humans therefore 
a 4-step staggered design will be used to allow evaluation of safety of the 2 formulations (with or 
without adjuvant) in a limited number of subjects before exposing a larger number of subjects to 
the C. difficile investigational vaccine (refer to Section 4.1). The C. difficile investigational 
vaccine without adjuvant will be first administered to subjects aged 18-45 years before 
administration to subjects aged 50-70 years (refer to Section 4.1 and to Figure 1). 
The C. difficile investigational vaccine without adjuvant will be administered to approximately 
55 subjects (approximately 10 subjects aged 18-45 years and approximately 45 subjects aged 
50-70 years), the C. difficile investigational vaccine with AS01B adjuvant will be administered to 
approximately 45 subjects aged 50-70 years and placebo will be administered to approximately 
40 subjects (approximately 10 subjects aged 18-45 years and approximately 30 subjects aged 
50-70 years) (refer to Section 8.11 for study procedures to be considered during special 
circumstances). 
For Steps 1, 2, and 3 only, vaccination will be limited to a maximum of 10 subjects per day. 
Subjects will be vaccinated sequentially, separated by a minimum interval of 60 minutes to allow 
for monitoring of any acute events (eg, hypersensitivity reaction). During all 4 steps, all subjects 
should be closely observed for at least 60 minutes after vaccination. 
Specific holding rules are defined to ensure well-controlled exposure to the C. difficile 
investigational vaccine (see Section 4.6.1). 
4.3 
Justification for Dose 
The F2 candidate antigen developed by GSK contains a portion of the amino acids sequence of 
the full-length C. difficile toxins. Another manufacturer developing a C. difficile vaccine based 
on the use of genetically detoxified full-length Toxin A and Toxin B, reported optimal 
immunogenicity data at a dose of 100 μg each (clinical trial: NCT01706367). The proposed dose 
of F2 antigen is defined to obtain an equivalent number of epitopes (included in F2 sequence) as 
reported in the Phase I study. 
Moreover, findings from the repeated dose toxicology study indicate that the investigational 
vaccine F2/AS01B was well tolerated when administered three times at two-week intervals. No 
safety risks were identified. Please refer to the current IB for more information regarding the 
preclinical studies of C. difficile investigational vaccine (GSK2904545A). 
In addition to these observations, pooled analyzes of AS01 adjuvanted vaccines in humans 
yielded that there is no safety concern for the administration of the same AS01 adjuvanted 
vaccine. Increase of reactogenicity is expected after dose 2 or dose 3 of the same adjuvanted 
vaccine. 


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40 
Based on these data, it is recognized that CDIFF F2 AS01B has an acceptable safety profile 
(reactogenicity). 
4.4 
End of Study Definition 
See Appendix 2 for the definition of EoS. 
Study conclusion for individual subjects: A subject is considered to have completed the study if 
he/she returns for the concluding visit/is available for the concluding contact (Visit 7 [Day 390] 
for subjects receiving 2 doses and Visit 11 [Day 670] for subjects receiving 3 doses) as described 
in the protocol. 
Global completion of the study is required in order to provide sufficient subjects as defined in 
Section 9.2. 
4.5 
Dose Escalation Criteria 
Not applicable. 
4.6 
Study Holding Criteria 
4.6.1 
Study Holding Rules 
The safety holding rules which will be assessed by the Investigator are defined in Table 11 and 
the safety holding rules which will be assessed by the iSRC are defined in Table 12. The toxicity 
grading scales for hematology, biochemistry, and urinalysis parameters applicable for this study 
are presented in Table 13. 
Table 11 
Holding Rules Assessed by the Investigator 
Holding Rule 
Event 
Number of Subjects 
1a 
Death or any life-threatening SAE. 
 
1b 
Any withdrawal from the study following a Grade 3 AE that cannot 
reasonably be attributed to a cause other than vaccination. 
 
1c 
Any SAE or fever >40°C (104°F) that cannot reasonably be attributed 
to a cause other than vaccination, or visible necrosis at the injection 
site, within the 7-day (Day 1 to Day 7) period after vaccination. 
 
AE = adverse event; SAE = serious adverse event. 


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Protocol 208109 (CDIFF-004) ± Amendment 04 
 
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Table 12 
Holding Rules Assessed During Internal Safety Review Committee 
Evaluations 
Holding Rule 
Event 
Percentage of 
Subjects 
2a 
Any Grade 3 solicited local AE (lasting 48 hours or more) in an 
investigational group, within the 7-day (Day 1 to Day 7) period after 
vaccination. 
SHUJURXS 
2b 
Any Grade 3 solicited general AE (lasting 48 hours or more) in an 
investigational group, that cannot reasonably be attributed to a cause 
other than vaccination, within the 7-day (Day 1 to Day 7) period after 
vaccination. 
SHUJURXS 
2c 
Any Grade 3 unsolicited AE in an investigational group, that cannot 
reasonably be attributed to a cause other than vaccination, within the 
7-day (Day 1 to Day 7) period after vaccination. 
SHUJURXS 
2d 
Any Grade 3 abnormality in prespecified hematological or biochemical 
laboratory parameters in an investigational group within the 7-day 
(Day 1 to Day 7) period after vaccination (refer to Table 13). 
SHUJURXS 
AE = adverse event. 
Figure 2 illustrates that, with 10 subjects per group: 
x For holding rules 1a, 1b, and 1c, using a cutoff of 1/10, there is more than 80% chance that 
the holding rule is met for a vaccine with a true incidence rate above 15% and there is more 
than 60% chance that the holding rule is not met for a vaccine with a true incidence rate 
below 5%. 
Since this holding rule will be assessed on a continuous basis by the Investigator, irrespective 
of the number of subjects enrolled, the statistical interpretation of this holding rule is less 
relevant. 
x For holding rules 2a, 2b, 2c, and 2d, using a cutoff of 2/10, there is more than 80% chance 
that the holding rule is met for a vaccine with a true incidence rate above 27% and there is 
more than 80% chance that the holding rule is not met for a vaccine with a true incidence rate 
below 8%. 
A similar figure is presented for 45 subjects per group (Figure 3). 


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Figure 2 
Evaluations Based on 10 Enrolled Subjects - Risk Assessment Curves for 
1 Formulation Based on the Proposed Safety Holding Rules 


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Figure 3 
Evaluations Based on 45 Enrolled Subjects - Risk Assessment Curves for 
1 Formulation Based on the Proposed Safety Holding Rules 


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Table 13 
Toxicity Grading Scales for Hematology, Biochemistry, and Urinalysis Parameters Applicable for this Study 
Discipline 
(System) 
Component 
Hematology 
(whole blood) 
Hemoglobin (gm/dL) - female 
Hemoglobin (gm/dL) - male 
Hemoglobin (gm/dL) - female change 
from baseline value 
Hemoglobin (gm/dL) - male change 
from baseline value 
White blood cells increase (cell/mm3) 
White blood cells decrease (cell/mm3) 
Platelets decrease (cell/mm3) 
Biochemistry 
(serum) 
Alanine aminotransferase 
(increase by factor) 
Aspartate aminotransferase 
(increase by factor) 
Creatinine (mg/dL) 
Uric acid 
Urinalysis 
(urine) 
Protein (mg/dL) 
CTCAE = Common Terminology Criteria for Adverse Events; FDA = Food and Drug Administration; iSRC = internal safety review committee; ULN = upper 
limit of the normal range 
7KHODERUDWRU\YDOXHVSURYLGHGLQWKHVHWDEOHVDUHWDNHQIURPWKH)'$*XLGDQFHIRU,QGXVWU\³7R[LFLW\*UDGLQJ6FDOHIRU+HDOWhy Adults and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials´, except for uric acid for which laboratory values are taken from CTCAE Version 4.15,16 
a In case Grade 3 hematology or biochemistry parameter is observed, a re-testing should be performed if deemed necessary by the Investigator, the iSRC, or the 
Sponsor. 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.


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4.6.2 
Procedure if the Study is Put on Hold 
If the Investigator detects 1 of the holding rules, he/she will immediately put the enrollment or 
the vaccination on hold and he/she will immediately inform the Sponsor and enter the data in the 
electronic case report form (eCRF), but all other procedures relating to safety and immunology 
will continue. In case 1 of the holding rules (1a, 1b, or 1c) is met, the iSRC will meet urgently 
and review the unblinded data. During this time the study will be kept on hold. The iSRC will 
inform the study Clinical Research and Development Lead (CRDL) who will inform the relevant 
bodies of the Sponsor about the outcome of the review and the recommendation on whether to 
suspend, modify, or continue the conduct of the study on all groups or on selected groups. The 
decision regarding the further conduct of the study will be documented and provided in writing 
to the Investigators. 
During this review period, the study will be temporarily stopped, while the decision is being 
made. In case of a decision to stop the study, a letter indicating the reason will be sent to the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the Investigator and 
to the Regulatory Agency by the Sponsor. 


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5.0 STUDY POPULATION 
5.1 
Inclusion Criteria 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity, regulatory acceptability of the study, or subject safety. Therefore, adherence 
to the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
1. Subjects who, in the opinion of the Investigator, can and will comply with the requirements 
of the protocol (eg, completion of the diary cards, return for Follow-up Visits). 
2. Written or witnessed/thumb print informed consent obtained from the subject prior to 
performance of any study specific procedure. 
3. For Step 1 only: A male or female between, and including, 18-45 years of age at the time of 
the first vaccination. 
4. For Steps 2, 3, and 4: A male or female between, and including, 50-70 years of age at the 
time of the first vaccination. 
5. Healthy subjects (ie, without progressive, unstable, or uncontrolled clinical conditions) as 
established by medical history (as verified by either a personal physician or medical 
practitioner, as appropriate) and clinical examination before entering into the study. 
6. Subjects free of any uncontrolled chronic illnesses as established by medical history and 
clinical examination before entering into the study. 
7. Female subjects of nonchildbearing potential may be enrolled in the study. 
 Nonchildbearing potential is defined as premenarche, current bilateral tubal ligation 
or occlusion, hysterectomy, bilateral ovariectomy, or postmenopause (refer to 
Appendix 7 for definitions of premenarche and postmenopause). 
Female subjects of childbearing potential may be enrolled in the study, if the subject (refer to 
Appendix 7 for definitions of woman of childbearing potential and adequate contraception): 
 Has practiced adequate contraception for 30 days prior to vaccination, and 
 Has a negative urine pregnancy test on the day of vaccination, and 
 Has agreed to continue adequate contraception during the entire treatment period and 
for 2 months after completion of the vaccination series. 
5.2 
Exclusion Criteria 
Deviations from exclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity, regulatory acceptability of the study, or subject safety. Therefore, adherence 
to the criteria as specified in the protocol is essential. 


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The following criteria should be checked at the time of study entry. If ANY exclusion criterion 
applies, the subject must not be included in the study. 
1. Health condition that, in the opinion of the Investigator, may interfere with optimal 
participation in the study or place the volunteer at increased risk of adverse events (AEs). 
Study clinicians, in consultation with the Principal Investigator will use clinical judgment on 
a case-by-case basis to assess safety risks under this criterion. The Principal Investigator will 
consult with the Medical Monitor as appropriate. 
2. Use of any investigational or nonregistered product (drug, vaccine, or medical device) other 
than the study vaccine(s) during the period starting 30 days before the first dose of study 
vaccine(s) (Day -29 to Day 1), or planned use during the study period. 
3. Any medical condition that in the judgment of the Investigator would make intramuscular 
(IM) injection unsafe and subjects under treatment with anticoagulant therapy. 
4. Chronic administration (defined as more than 14 consecutive days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 3 months 
prior to the first vaccination. For corticosteroids, this will mean prednisone 5 mg/day (for 
adult subjects), or equivalent. Inhaled and topical steroids are allowed. 
5. Administration of long-acting immune-modifying drugs at any time during the study period 
(eg, infliximab). 
6. Administration of immunosuppressive therapy, including chemotherapeutic agents used to 
treat cancer or other conditions, and treatments associated with organ or bone marrow 
transplantation or autoimmune disease. 
7. Administration of immunoglobulins and/or any blood products during the period starting 
3 months before the first vaccination of study treatment or planned administration during the 
study period. 
8. Planned administration/administration of a vaccine not foreseen by the study protocol in the 
period starting 6 weeks before the first vaccination and ending 6 weeks after the last 
vaccination, with the exception of inactivated influenza vaccine which can be administered 
up to 14 days before or from 30 days after the last study vaccination. 
In case an emergency mass vaccination for an unforeseen public health threat (eg, a 
pandemic) is recommended and/or organized by public health authorities outside the routine 
immunization program, the time period described above can be reduced if, necessary for that 
vaccine, provided it is used according to the local governmental recommendations and that 
the Sponsor is notified accordingly. 
9. Planned DGPLQLVWUDWLRQRI*6.¶V+HUSHV=RVWHUYDFFLQHPDUNHWHGDVShingrix or an 
adjuvanted recombinant varicella zoster virus envelope gE subunit vaccine (HZ/su) within 
180 days before the first dose and within 180 days after the last dose of the study vaccine. 
10. Planned elective surgery during the study period. 


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11. Concurrently participating in another clinical study, at any time during the study period, in 
which the subject has been or will be exposed to an investigational or a non-investigational 
vaccine/product (pharmaceutical product or device). 
12. Body mass index <19 kg/m2 or  kg/m2. 
13. Clinically relevant physical examination abnormalities. 
14. For subjects aged 18±45 years, Grade 2 or higher abnormal hematological, biochemical, and 
urinary parameters. 
15. For subjects aged 50±70 years, Grade 3 or higher abnormal hematological, biochemical, and 
urinary parameters. 
16. Documentation of current or prior episode of CDI. 
17. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on 
medical history and physical examination (no laboratory testing required). 
18. Recurrent history or uncontrolled neurological disorders or seizures. 
19. Family history of congenital or hereditary immunodeficiency. 
20. History of any reaction or hypersensitivity likely to be exacerbated by any component of the 
vaccines. 
21. Acute disease and/or fever at the time of enrollment. 
 )HYHULVGHILQHGDVWHPSHUDWXUH&)7KHSUHIHUUHGORFDWLRQIRU
measuring temperature in this study will be the oral cavity. 
 Subjects with a minor illness (such as mild diarrhea, mild upper respiratory infection) 
without fever may, be enrolled at the discretion of the Investigator. 
22. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, or renal 
functional abnormality, as determined by physical examination or laboratory screening tests. 
23. Pregnant or lactating female. 
24. History of intestinal bleeding or history of diverticular intestinal bleeding. 
25. Surgery for gastrointestinal malignancy in the period starting 3 months prior to the first 
vaccination. 
26. History of chronic alcohol consumption and/or drug abuse as deemed by the Investigator to 
render the potential subject unable/unlikely to provide accurate safety reports. 
27. Female planning to become pregnant or planning to discontinue contraceptive precautions. 
28. Documented human immunodeficiency virus-positive subject, known positivity for the 
surface Ag of the hepatitis B virus or known positive serologic test for the hepatitis C virus. 
29. Involvement in the planning and/or conduct of the study (applies to both GSK personnel 
and/or personnel at the study center). 
5.3 
Lifestyle Considerations 
No restrictions pertaining to lifestyle and/or diet beyond the details indicated in Section 5.2. 


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5.4 
Screen Failures 
Screen failures before first dose are defined as subjects who consent to participate in the clinical 
study but who are not subsequently randomly assigned to study treatment. Screen failures before 
third dose are defined as subjects who consent but did not receive the third dose. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure subjects 
to meet the Consolidated Standards of Reporting Trials publishing requirements and to respond 
to queries from regulatory authorities. Minimal information for screen failures before first dose 
includes demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs). Minimal information for screen failures before third dose includes screen failure details, 
eligibility criteria, and any SAEs. 
Upon completion of all screening procedures (refer to Section 1.3), the Investigator will review 
the inclusion/exclusion criteria for each subject. Subjects meeting all eligibility criteria will be 
enrolled in the study. Their screening information will be recorded in the eCRF. 
If the Investigator believes there is a reasonable justification to do so, screening procedures may 
be repeated (maximum 1 Rescreening per subject is allowed). 
Only laboratory results from the Rescreening Visit, if it occurs, will be taken into consideration 
and recorded in the eCRF. Medical history, physical examination and review of 
inclusion/exclusion criteria must be repeated if a Rescreening Visit occurs. The subject can only 
be randomized once the Investigator receives the results and confirms the eligibility criteria. 


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6.0 STUDY TREATMENT 
Study treatment is defined as a set of investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject. 
6.1 
Study Treatment(s) Administered 
Table 14 
Description of Study Treatment 
Treatment Name 
Vaccine Name 
Formulation 
Presentation 
Volume to be 
Administered 
Number of 
Doses 
Placebo 
NaCl 
NaCl = 150mM 
Clear liquid for 
suspension 
0.5 mL 
2 doses 
CDIFF Ag 
F2 
F2 antigen 
Lyophilized 
0.5 mL 
2 or 3 doses* 
 
NaCl 
NaCl = 150mM 
Clear liquid for 
suspension 
 
 
CDIFF Ag + AS01B 
F2 
F2 antigen 
Lyophilized 
0.5 mL 
2 or 3 doses* 
 
AS01B 
MPL = 50 μg; 
QS-21 = 50 μg; 
Liposomes 
Liquid in a 
monodose vial 
 
 
Ag = antigen; AS01B = an adjuvant system containing MPL, QS-21 and liposome (50 ȝg MPL and 50 ȝg QS-21); 
GSK = GlaxoSmithKline Biologicals SA; MPL = 3-O-desacyl-¶-monophosphoryl lipid A; QS-21 = Quillaja 
saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc., a wholly owned subsidiary of Agenus 
Inc., a Delaware, USA corporation) 
* a third dose will be administered to a subcohort of subjects in Step 4 


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Table 15 
Dosage and Administration of Study Treatment 
Type of 
Contact and 
Timepoint 
Study Group 
Treatment 
Name 
Volume to be 
Administered 
Route 
Injection Site 
Location 
Lateralitya 
Visit 1 
(Day 1) 
Placebo 
Placebo 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag 
CDIFF Ag 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag + 
AS01B 
CDIFF Ag + 
AS01B 
0.5 mL 
IM 
Deltoid 
Nondominant 
Visit 3 
(Day 31) 
Placebo 
Placebo 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag 
CDIFF Ag 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag + 
AS01B 
CDIFF Ag + 
AS01B 
0.5 mL 
IM 
Deltoid 
Nondominant 
Visit 8 
(Day 491) 
CDIFF Ag 
CDIFF Ag 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag + 
AS01B 
CDIFF Ag + 
AS01B 
0.5 mL 
IM 
Deltoid 
Nondominant 
Ag = antigen; AS01B = an adjuvant system containing MPL, QS-21 and liposome (50 ȝJ03/DQG ȝJ46-21); 
IM = intramuscular; MPL = 3-O-desacyl-¶-monophosphoryl lipid A. 
a The nondominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the 
nondominant arm, an injection in the dominant arm may be performed. 
For each subject, the Investigator is not permitted to start the administration of the next dose 
until receipt of the favorable outcome of the safety evaluation, documented and provided in 
writing (scanned and emailed), authorizing the Investigator to proceed. Moreover, if the 
Investigator becomes aware of a holding rule being met, he/she will suspend vaccination and will 
inform GSK immediately (see Table 11 and Table 12). 
Refer to Section 4.6.1 for detailed description of holding rules and safety monitoring. 
The subjects will be observed closely for at least 60 minutes following the administration of the 
vaccine(s), with appropriate medical treatment readily available in case of anaphylaxis and 
syncope. 
6.2 
Contraindication to Subsequent Vaccination 
Prior to receipt of additional study vaccination, subjects must be evaluated to confirm that they 
are eligible for subsequent vaccination. 
If subjects meet any of the original exclusion criteria or the criteria listed below, they should not 
receive additional vaccinations. However, the subjects should be encouraged to continue other 
study procedures at the discretion of the Investigator (Section 8.3.3). 
x Subjects who experience any SAE judged to be possibly or probably related to study vaccine 
or non-study vaccines, including hypersensitivity reactions. 


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x Subjects who develop any new condition which, in the opinion of the Investigator, may pose 
additional risk to the subject if he/she continues to participate in the study. 
x Anaphylaxis following the administration of vaccines. 
x Grade 3 or higher abnormal hematological, biochemical, and urinary parameters. 
x Occurrence of a new potential immune-mediated disease (pIMD) or the exacerbation of an 
existing pIMD that, in the opinion of the Investigator, expose the subject to unacceptable risk 
from subsequent vaccination. In such cases, the Investigator should use his/her clinical 
judgment prior to administering the next dose of the vaccine(s)/product(s). Refer to 
Appendix 2 for the definition of pIMDs. 
6.3 
Criteria for Temporary Delay of Vaccination 
Vaccination may be postponed within the allowed time interval until transient circumstances 
cited below have been resolved. 
Acute disease and/or fever at the time of vaccination.  
x )HYHULVGHILQHGDVWHPSHUDWXUH&)7KHSUHIHUUHGORFDWLRQIRUPHDVXULQJ
temperature in this study will be the oral cavity. 
x Subjects with a minor illness (such as mild diarrhea, mild upper respiratory infection) 
without fever can be administered all vaccines. 
6.4 
Intercurrent Medical Condition That May Lead to Elimination of a 
Subject From the Per-protocol Analysis 
At each study visit subsequent to the first vaccination/the vaccination visit, it must be verified if 
the subject has experienced or is experiencing any intercurrent medical condition that may lead 
to elimination from the per-protocol analysis. If it is the case, the condition(s) must be recorded 
in the eCRF. 
Subjects may be eliminated from the Per-protocol Set for analysis of immunogenicity if, during 
the study, they incur a condition that has the capability of altering their immune response or are 
confirmed to have an alteration of their initial immune status. 
6.5 
Preparation/Handling/Storage/Accountability 
The study vaccine(s) must be stored at the respective label storage temperature conditions in a 
safe and locked place. Access to the storage space should be limited to authorized study 
personnel. The storage conditions will be assessed during prestudy activities under the 
responsibility of the Sponsor study contact. The storage temperature should be continuously 
monitored with calibrated (if not validated) temperature monitoring device(s) and recorded. 
Refer to the Module on Clinical Trial Supplies in the Study Procedures Manual (SPM) for more 
details on storage of the study vaccine(s). 


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A temperature excursion is any temperature that is not in range of the label storage temperature 
conditions. Temperatures outside the range of label storage temperature conditions must be 
reported and/or documented. Temperature excursion impacting study vaccine(s) must be 
reported and/or documented. 
In the frame of the reporting, the lack/absence of temperature monitoring documentation from a 
device meeting GSK requirements has to be considered as a temperature excursion. 
Study vaccine(s) that are impacted by a temperature excursion may not be used and must be 
quarantined at label storage conditions until usage approval has been obtained from/via the local 
study contact (eg, study center monitor). 
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on the 
temperature excursion reporting and usage decision process, packaging and accountability of the 
study vaccine(s). 
6.5.1 
Replacement of Unusable Vaccinations 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomization when applicable), at least 20% additional vaccine doses will be supplied to 
replace those that are unusable. 
The Investigator will use a System Built for Internet Randomization (SBIR) to obtain the 
replacement dose number. The replacement numbers will be allocated by component. The 
system will ensure, in a blind manner, that the replacement dose matches the formulation the 
subject was assigned to by randomization. 
6.6 
Measures to Minimize Bias: Randomization and Blinding 
6.6.1 
Subject Identification 
Subject identification numbers will be assigned sequentially to the subjects who have consented 
to participate in the study, according to the range of subject identification numbers allocated to 
the study center. 
6.6.2 
Treatment Allocation to the Subject 
Treatment numbers will be allocated by dose. 
The enrollment will be performed to ensure equal distribution of the population within the age 
strata (subjects 18-45 years of age versus subjects 50-70 years of age). 
Allocation of the subject to a study group at the study center will be performed using SBIR. As 
the study will enroll 2 age groups sequentially through 4 steps (Step 1: 18-45 years of age and 
Steps 2, 3, and 4: 50-70 years of age), the steps will be considered as stratification factors with a 
specific size and group ratio at each step (Step 1: 20 subjects with ratio 1:1 between CDIFF Ag 


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54 
and placebo alone; Step 2: 20 subjects with ratio 1:1 between CDIFF Ag and placebo alone, 
Step 3: 30 subjects with ratio 1:1:1 between CDIFF Ag, CDIFF Ag + AS01B and placebo; 
Step 4: 70 subjects with ratio 5:7:2 between CDIFF Ag, CDIFF Ag + AS01B and placebo). 
Within the 18-45 years age group, the randomization algorithm will use a minimization 
procedure accounting for gender (female, male), while within the 50-70 years age group, the 
randomization algorithm will use a minimization procedure accounting for age (50-59 years of 
age, 60-70 years of age) and gender (female, male). Minimization factors will have equal weight 
in the minimization algorithm. A minimum of 20% of each minimization factor category will be 
required to allow enrolling all categories within each minimization factor (refer to Section 8.11 
for study procedures to be considered during special circumstances).  
After obtaining the signed or witnessed/thumb printed and dated informed consent form (ICF) 
from the subject and having checked the eligibility of the subject, the study staff in charge of the 
vaccine administration will access SBIR. Upon providing the age (subjects 18-45 years of age 
versus subjects 50-70 years of age), the gender, and the subject identification number, the 
randomization system will determine the study group and will provide the treatment number to 
be used for the first dose. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
When SBIR is not available, please refer to the SBIR user guide or the SPM for specific 
instructions. 
6.6.2.1 
Treatment Number Allocation for Subsequent Doses 
For each dose subsequent to the first dose, the study staff in charge of the vaccine administration 
will access SBIR, provide the subject identification number, and the system will provide a 
treatment number consistent with the allocated study group. 
6.6.3 
Blinding 
Data will be collected in an observer-blind manner. By observer-blind, it is meant that during the 
course of the study, the vaccine recipient and those responsible for the evaluation of any study 
endpoint (eg, safety and reactogenicity) will all be unaware of which vaccine was administered. 
To do so, vaccine preparation and administration will be done by authorized medical personnel 
who will not participate in any of the study clinical evaluations. The Investigator and the subjects 
will not have access to the treatment allocation up to Day 390. 
The statistical analyses will be performed in 3 steps. Refer to Section 9.8 for controlled 
unblinding for the first and second interim analysis.  
The data for third dose will be collected in a partial blind manner. 


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55 
After Day 390, only the subjects will remain fully blinded. Those responsible for the evaluation 
of any study endpoint (eg, safety and reactogenicity) will be partially blinded, as no placebo 
subjects will be included for Dose 3. 
The laboratory in charge of the laboratory testing will be blinded to the treatment, and codes will 
be used to link the subject and study (without any link to the treatment attributed to the subject) 
to each sample. 
6.6.3.1 
Emergency Unblinding 
8QEOLQGLQJRIDVXEMHFW¶VLQGLYLGXDOWUHDWPHQWFRGHVKRXOGRFFXURQO\LQ the case of a medical 
emergency when knowledge of the treatment is essential for the clinical management or welfare 
of the subject. 
The emergency unblinding process consists of the automated internet-based system (SBIR) that 
allows the Investigator to havHXQUHVWULFWHGLPPHGLDWHDQGGLUHFWDFFHVVWRWKHVXEMHFW¶V
individual study treatment. 
As back-up process, the Investigator has the option of contacting a GSK Helpdesk (refer to 
Table 16) if he/she needs support to perform the unblinding (ie, he/she cannot access SBIR). 
Non-investigator physician (eg, physician from emergency room) or subject/care giver/family 
member can also request emergency unblinding either via the Investigator (preferred option) or 
via the GSK Helpdesk (back-up process). Contact details of Investigator and GSK Helpdesk are 
reported in the subject card. 
Table 16 
Contact Information for Emergency Unblinding 
GSK Helpdesk 
24-hour and 7-day availability 
The Helpdesk is available by phone, fax and email 
Toll-free number: 00 800 4344 1111 
Phone: +32(2)656 68 04 
Fax: +32(2)401 25 75 
email: rix.ugrdehelpdesk@gsk.com 
A subject PD\FRQWLQXHLQWKHVWXG\LIWKDWVXEMHFW¶VWUHDWPHQWDVVLJQPHQWLVXQEOLQGHG 
GSK Vaccines Clinical Safety and Pharmacovigilance staff may unblind the treatment 
assignment for any subject in case of Suspected Unexpected Serious Adverse Reaction (SUSAR) 
as well as in case of fatal or life-threatening cases. If the SAE requires that an expedited 
regulatory report be sent to 1 or more regulatory agencies, a copy of the report, identifying the 
VXEMHFW¶VWUHDWPHQWDVVLJQPHQWPD\EHVHQWWRInvestigators in accordance with local regulations 
and/or GSK policy. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
56 
6.7 
Study Treatment Compliance 
The prescribed dosage, timing, and mode of administration may not be changed. 
All dose administrations will be performed in the study center under the supervision of 
appropriately trained staff. 
6.7.1 
Treatment Strategy 
The study center staff is responsible for the ongoing safety and wellbeing of the subjects while 
they are in the study center. There is a paging system to alert the clinical staff to any area in the 
center where a subject may need medical attention. There is medical advice available by phone 
24 hours a day. In addition, if necessary, the clinical staff can contact further on-call physicians 
or public emergency services in the event of a serious medical event. 
6.7.2 
Warnings and Precautions 
As this is the first administration of study treatment to humans, all effects cannot be reliably 
predicted. The preclinical data suggest an acceptable safety margin. Facilities and staff for 
resuscitation and the treatment of other medical emergencies will be provided. 
6.8 
Concomitant Therapy 
6.8.1 
Recording of Concomitant Medications/Products and Concomitant Vaccinations 
At each study visit, the Investigator or delegate should question the subject about any 
medications/products taken and vaccinations received by the subject. 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the eCRF: 
x All concomitant medications/products, except vitamins and dietary supplements, 
administered between Day 1 and Day 61. 
x All concomitant medications/products, except vitamins and dietary supplements, 
administered between Day 491 and Day 521. 
x Any concomitant vaccination administered in the period starting 6 weeks before the first dose 
of study treatment and ending at the last study visit (Day -42 to Day 390 for subjects 
receiving 2 doses/Day 670 for subjects receiving 3 doses). 
x Prophylactic medication (ie, medication administered in the absence of ANY symptom and 
in anticipation of a reaction to the vaccination). 
An antipyretic is considered to be prophylactic when it is given in the absence of fever and any 
other symptom, to prevent fever from occurring (fever is defined as temperature 
&)UHJDUGOHVVWKHORFDWLRQRIPHDVXUHPHQW7KHSUHIHUUHGORFDWLRQIRUPHDVXULQJ
temperature in this study will be the oral cavity. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
57 
x Any concomitant medications/products/vaccines leading to the withdrawal or non-eligibility 
of the subject from the study (refer to Section 6.8.2). 
x Any concomitant medications/products/vaccines relevant to an SAE/pIMD to be reported as 
per protocol or administered during the study period for the treatment of an SAE/pIMD. In 
addition, concomitant medications relevant to SAEs and pIMDs need to be recorded on the 
expedited AE report. 
6.8.2 
Concomitant Medications/Products/Vaccines That may Lead to the Elimination 
of a Subject From Per-protocol Analyses 
The use of the following concomitant medications/products/vaccines will not require withdrawal 
RIWKHVXEMHFWIURPWKHVWXG\EXWPD\GHWHUPLQHDVXEMHFW¶VHYDOXDELOLW\LQWKHper-protocol 
analysis. See Section 9.3 for populations to be analyzed. 
x Any investigational or nonregistered product (drug or vaccine) other than the study 
vaccine(s) used during the study period. 
x Immunosuppressants or other immune-modifying drugs administered chronically (ie, more 
than 14 consecutive days in total) during the study period (until Day 390 for subjects 
receiving 2 doses and until Day 670 for subjects receiving 3 doses). For corticosteroids, this 
ZLOOPHDQSUHGQLVRQH5 mg/day (for adult subjects), or equivalent. Inhaled and topical 
steroids are allowed. 
x Long-acting immune-modifying drugs administered at any time during the study period (eg, 
infliximab). 
x A vaccine not foreseen by the study protocol administered during the period starting the day 
of the first vaccination and ending 6 weeks after the last vaccination*, with the exception of 
inactivated influenza vaccine which can be administered up to 14 days before or from 
30 days after the last study vaccination. 
* In case an emergency mass vaccination for an unforeseen public health threat (eg, a 
pandemic) is recommended and/or organized by public health authorities outside the routine 
immunization program, the time period described above can be reduced if, necessary for that 
vaccine, provided it is used according to the local governmental recommendations and that 
the Sponsor is notified accordingly. 
x Immunoglobulins and/or any blood products administered during the study period. 
x Drug and/or alcohol abuse. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.9 
Dose Modification 
Dose modifications are not planned or allowed in this study. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
58 
6.10 Treatment After the End of the Study 
During the study conclusion visit, the Investigator will ask each subject if they are interested in 
participating in a booster study/long-term study. If a subject is not interested in participating in 
the booster study/long-term study the reason for refusal will be documented, when available, in 
WKHVXEMHFW¶VH&5) 
The Sponsor will not provide any additional care to subjects after they completed the study. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
59 
7.0 DISCONTINUATION OF STUDY TREATMENT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL  
7.1 
Discontinuation of Study Vaccine 
$³ZLWKGUDZDO´IURPWKHVWXG\YDFFLQHVUHIHUVWRDQ\VXEMHFWZKRGRHVQRWUHFHLYHWKH
complete treatment, ie, when no further planned dose is administered from the date of 
withdrawal. A subject withdrawn from the study vaccine(s) may continue further study 
procedures (safety or immunogenicity) if planned in the study protocol, as deemed appropriate 
by the Investigator. 
Primary reason relative to premature discontinuation of the study vaccine(s) will be documented 
on the Vaccine Administration screen of the eCRF. The Investigator will document whether the 
decision to discontinue further vaccination was made by the subject himself/herself or by the 
Investigator, as well as which of the following possible reasons was responsible for withdrawal: 
x AEs requiring expedited reporting. 
x Nonserious AE (specify). 
x Unsolicited nonserious AE. 
x Solicited AE. 
x Not willing to be vaccinated. 
x Other (specify). 
7.2 
Subject Discontinuation/Withdrawal From the Study 
x A subject may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. 
x If the subject withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
x If a subject withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the study center study records. 
x See Section 1.3 for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. Should a subject request or decide 
to withdraw from the study, all efforts must be made to complete and report the observations 
as thoroughly as possible up to the date of withdrawal. Subjects withdrawing due to an AE 
should be followed up according to the Follow-up Visit. 
x Subjects withdrawn due to an AE will not be replaced. 
)URPDQDQDO\VLVSHUVSHFWLYHD³ZLWKGUDZDO´IURPWKHVWXG\UHIHUVWRDQ\VXEMHFWZKRdid not 
come back for the concluding visit foreseen in the protocol. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
60 
All data and samples collected until the date of withdrawal/last contact of the subject will be 
used for the analysis. 
$VXEMHFWLVFRQVLGHUHGD³ZLWKGUDZDO´IURPWKHVWXG\ZKHQQRVWXG\SURFHGXUHKDVRFFXUUHGQR
follow-up has been performed and no further information has been collected for this subject from 
the date of withdrawal/last contact. 
Investigators will make an attempt to contact those subjects who do not return for scheduled 
visits or follow-up. 
The primary reason for study withdrawal will be documented in the eCRF. The Investigator will 
document whether the decision to withdraw a subject from the study was made by the subject 
himself/herself or by the Investigator, as well as which of the following possible reasons was 
responsible for withdrawal: 
x AEs requiring expedited reporting. 
x Unsolicited nonserious AE. 
x Solicited AE. 
x Protocol deviation. 
x Withdrawal by subject, not due to an AE.* 
x Migrated/moved from the study area. 
x Lost to follow-up. 
x Sponsor study termination. 
x Other (specify). 
*In case a subject is withdrawn from the study because he/she has withdrawn consent, the 
Investigator will document the reason for withdrawal of consent, if specified by the subject, in 
the eCRF. 
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly distinguished 
from subjects who are withdrawn for other reasons. Investigators will follow subjects who are 
withdrawn from the study as result of an SAE/AE until resolution of the event (see 
Section 8.3.3). 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study center.  
The following actions must be taken if a subject fails to return to the study center for a required 
study visit: 
x The study center must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned visit 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
61 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
x Before a subject is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a 
certified letter to the subject¶VODVWNQRZQPDLOLQJDGGUHVVRUORFDOHTXLYDOHQWPHWKRGV
These contact attempts should be documented in the subject¶VPHGLFDOUHFRUG. 
x Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
62 
8.0 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in Section 1.3. 
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the subject(s) should discontinue study treatment. 
Adherence to the study design requirements, including those specified in Section 1.3, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable. 
3URFHGXUHVFRQGXFWHGDVSDUWRIWKHVXEMHFW¶VURXWLQHFOLQLFDOPDQDJHPHQWHJEORRGFRXQWDQG
obtained before signing of ICF may be utilized for screening or baseline purposes provided the 
procedure met the protocol-specified criteria and was performed within the timeframe defined in 
Section 1.3. 
Supplementary study conduct information not mandated to be present in this protocol is provided 
in the accompanying SPM. The SPM provides the Investigator and the study center personnel 
with administrative and detailed technical information that does not impact the safety of the 
subjects. 
The maximum amount of blood collected from each subject over the duration of the study, will 
not exceed 200 mL. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples (refer to Section 8.2.3 for blood sampling related to safety and 
to Section 8.8.1 for blood sampling related to immunogenicity assessment). 
During special circumstances (eg, COVID-19 pandemic), the specific guidance from local public 
KHDOWKDQGRWKHUFRPSHWHQWDXWKRULWLHVUHJDUGLQJWKHSURWHFWLRQRILQGLYLGXDOV¶ZHOIDUHPXVWEH
applied. For the duration of such special circumstances, certain study procedures may be 
implemented for enrolled subjects (refer to Section 8.11 for further details). 
8.1 
Efficacy Assessments 
Not applicable. 
8.2 
Safety Assessments 
Planned timepoints for all safety assessments are provided in Section 1.3. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
63 
8.2.1 
Physical Examinations 
x Physical examination of the subject, including assessment of oral body temperature. 
x Collected information needs to be recorded in the eCRF. 
x If the IQYHVWLJDWRUGHWHUPLQHVWKDWWKHVXEMHFW¶VKHDOWKRQWKHGD\RIYDFFLQDWLRQWHPSRUDULO\
precludes vaccination, the visit will be rescheduled within the protocol visit window. 
x Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate health 
care provider. 
8.2.2 
Vital Signs 
x Resting vital signs: systolic/diastolic blood pressure and heart rate after at least 10 minutes of 
rest. 
x Vital signs are to be taken before blood collection for laboratory tests and will consist of 
1 pulse and 1 blood pressure measurement.  
x Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
x Collected information needs to be recorded in the eCRF. 
8.2.3 
Clinical Safety Laboratory Assessments 
Approximately 5.5 mL of blood for hematology and biochemical analysis and approximately 
10 mL of urine for urinalysis will be collected from all subjects at the timepoints specified in 
Section 1.3. 
Please refer to Appendix 4 for a detailed description of the assays performed in the study. Please 
refer to Appendix 5 for the address of the clinical laboratories used for sample analysis. 
Hematology, biochemistry, and urine assessments will be performed in the IQYHVWLJDWRU¶V
laboratory as per local practice using standardized and validated procedures (Appendix 4). 
x The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with an underlying disease, unless 
MXGJHGE\WKH,QYHVWLJDWRUWREHPRUHVHYHUHWKDQH[SHFWHGIRUWKHVXEMHFW¶VFRQGLWLRQ 
x All laboratory tests with values considered clinically significant abnormal during 
participation in the study or within 30 days after the last dose of study treatment should be 
repeated until the values return to normal or baseline or are no longer considered 
significantly abnormal by the Investigator or Medical Monitor. Refer to Appendix 6 for 
clinical laboratory abnormal assessments qualified as AEs or SAEs. 
x If such values do not return to normal/baseline within a period of time judged reasonable by 
the Investigator, the etiology should be identified, and the Sponsor notified. 
x All protocol-required laboratory safety assessments, as defined in Appendix 4, must be 
conducted in accordance with the laboratory manual and Section 1.3. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
64 
8.3 
Adverse Events 
Please refer to Appendix 6 for safety definitions. 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
RUWKHSDUWLFLSDQW¶V legally authorized representative) or identified at the study visit. 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
subject to discontinue the study treatment (see Section 7.0). 
 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
65 
An overview of the protocol-required reporting periods for AEs, SAEs, AEs of specific interest, and pregnancies is given in Table 17. 
Table 17 
Reporting Periods for Collecting Safety Information 
 
Screening 
Visit 
1 
 
Visit 
2 
 
Visit 
3 
 
Visit 
4 
 
Visit 
5 
Visit 6 
Visit 7 
Scree
ning 
for 
Dose 3  
Visit 
8 for 
Step 
4 
Visit 
9 for 
Step 
4 
Visit 
10 
for 
Step 
4 
Visit 
11 
for 
Step 
4 
 
 
D1 
D7 
D8 
D30 
D31 
D37 
D38 
D60 
D61 
D180 
D390 
D476 
D491 
D498 
D521 
D670 
Solicited local 
and general 
AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs (all, fatal, 
related to study 
vaccine) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
study 
participation or 
concurrent 
GSK 
medication/vacc
ine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs of specific 
interest 
(pIMDs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; D = day; GSK = GlaxoSmithKline Biologicals SA; pIMDs = potential immune-mediated diseases; SAE = serious adverse event 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
66 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information 
All AEs and SAEs will be collected from the signing of the ICF until the Follow-up Visit at the 
timepoints specified in Section 1.3. 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, not the AE section. 
All SAEs will be recorded and reported via Expedited AE Reporting Form to the Sponsor or 
designee immediately and under no circumstance should this exceed 24 hours after the 
Investigator became aware of it, as indicated in Appendix 6. The Investigator will submit any 
updated SAE data to the Sponsor within 24 hours of it being available. 
A poststudy AE/SAE is defined as any event that occurs outside of the AE/SAE reporting period 
defined in Table 17. Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the Investigator learns of any SAE, including a death, at any time after a 
subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the study vaccine(s), the Investigator will promptly notify the Study Contact for 
Reporting SAEs. 
Refer to Appendix 6 for local (injection site) and general solicited AEs to be collected. 
At each vaccination visit, paper diary cards will be provided to the subject. The subject will be 
instructed to measure and record the oral body temperature, and any solicited local/general AEs 
(ie, on the day of vaccination and during the next 6 days) or any unsolicited AEs (ie, on the day 
of vaccination and during the next 30 days) occurring after vaccination. The subject will be 
instructed to return the completed diary card to the Investigator at the next study visit. 
Adverse events of specific interest (AESIs) for safety monitoring include pIMDs (refer to 
Appendix 2 for definition of pIMD). Adverse events that need to be recorded and reported as 
pIMDs include those listed in Table 18. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
67 
Table 18 
List of Potential Immune-mediated Diseases 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
x 
Cranial nerve neuropathy, 
including paralysis and 
paresis (eg, %HOO¶VSDOV\ 
x 
Optic neuritis. 
x 
Multiple sclerosis. 
x 
Transverse myelitis. 
x 
Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other variants. 
x 
Acute disseminated 
encephalomyelitis, including 
site specific variants, eg, 
noninfectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis. 
x 
Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome. 
x 
Demyelinating peripheral 
neuropathies including: 
 
Chronic inflammatory 
demyelinating 
polyneuropathy. 
 
Multifocal motor 
neuropathy. 
 
Polyneuropathies 
associated with 
monoclonal gammopathy. 
x 
Narcolepsy. 
x 
Systemic lupus 
erythematosus and 
associated conditions. 
x 
Systemic scleroderma 
(systemic sclerosis), 
including: 
 
Diffuse scleroderma. 
 
CREST syndrome. 
x 
Idiopathic inflammatory 
myopathies, including: 
 
Dermatomyositis.  
 
Polymyositis.  
x 
Antisynthetase syndrome. 
x 
Rheumatoid arthritis and 
associated conditions 
including:  
 
Juvenile idiopathic 
arthritis. 
 
6WLOO¶VGLVHDVH 
x 
Polymyalgia rheumatica. 
x 
Spondyloarthropathies, 
including:  
 
Ankylosing spondylitis.  
 
Reactive arthritis 
(Reiter¶s syndrome). 
 
Undifferentiated 
spondyloarthritis. 
 
Psoriatic arthritis. 
 
Enteropathic arthritis. 
x 
Relapsing polychondritis. 
x 
Mixed connective tissue 
disorder. 
x 
Gout. 
x 
Psoriasis. 
x 
Vitiligo. 
x 
Erythema nodosum. 
x 
Autoimmune bullous skin 
diseases (including pemphigus, 
pemphigoid, and dermatitis 
herpetiformis). 
x 
Lichen planus. 
x 
6ZHHW¶VV\QGURPH 
x 
Localized scleroderma 
(morphea). 
Vasculitis 
Blood disorders 
Others 
x 
Large vessels vasculitis 
including:  
 
Giant cell arteritis 
(temporal arteritis). 
 
Takayasu¶s arteritis.  
x 
Medium sized and/or small 
vessels vasculitis including:  
 
Polyarteritis nodosa. 
 
.DZDVDNL¶s disease.  
 
Microscopic polyangiitis.  
 
Wegener¶s 
granulomatosis 
(granulomatosis with 
polyangiitis).  
 
Churg±Strauss syndrome 
(allergic granulomatous 
x 
Autoimmune hemolytic 
anemia. 
x 
Autoimmune 
thrombocytopenia. 
x 
Antiphospholipid syndrome. 
x 
Pernicious anemia. 
x 
Autoimmune aplastic 
anemia. 
x 
Autoimmune neutropenia. 
x 
Autoimmune pancytopenia. 
x 
Autoimmune glomerulonephritis 
including: 
 
IgA nephropathy.  
 
Glomerulonephritis rapidly 
progressive.  
 
Membranous 
glomerulonephritis.  
 
Membranoproliferative 
glomerulonephritis.  
 
Mesangioproliferative 
glomerulonephritis. 
 
Tubulointerstitial nephritis 
and uveitis syndrome. 
x 
Ocular autoimmune diseases 
including: 
 
Autoimmune uveitis. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
68 
Table 18 
List of Potential Immune-mediated Diseases 
angiitis or eosinophilic 
granulomatosis with 
polyangiitis).  
 
%XHUJHU¶VGLVHDVH
(thromboangiitis 
obliterans).  
 
Necrotizing vasculitis 
(cutaneous or systemic).  
 
Antineutrophil 
cytoplasmic antibody 
positive vasculitis (type 
unspecified). 
 
Henoch-Schonlein 
purpura (IgA vasculitis).  
 
%HKFHW¶s syndrome. 
 
Leukocytoclastic 
vasculitis. 
 
Autoimmune retinitis. 
x 
Autoimmune myocarditis. 
x 
Sarcoidosis. 
x 
Stevens-Johnson syndrome. 
x 
6M|JUHQ¶VV\QGURPH 
x 
Alopecia areata. 
x 
Idiopathic pulmonary fibrosis. 
x 
Goodpasture syndrome. 
x 
5D\QDXG¶VSKHQRPHQRQ 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
x 
Autoimmune hepatitis. 
x 
Primary biliary cirrhosis. 
x 
Primary sclerosing 
cholangitis. 
x 
Autoimmune cholangitis. 
x 
Inflammatory bowel disease, 
including: 
 
&URKQ¶VGLVHDVH.  
 
Ulcerative colitis.  
 
Microscopic colitis.  
 
Ulcerative proctitis. 
x 
Celiac disease. 
x 
Autoimmune pancreatitis. 
x 
Autoimmune thyroiditis 
(Hashimoto thyroiditis). 
x 
Grave¶VRU%DVHGRZ¶VGLVHDVH 
x 
Diabetes mellitus type 1. 
x 
$GGLVRQ¶VGLVHDVH 
x 
Polyglandular autoimmune 
syndrome. 
x 
Autoimmune hypophysitis. 
IgA = immunoglobulin A 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing intensity, causality and outcome of AEs and 
SAEs and the procedures for completing and transmitting SAE reports are provided in 
Appendix 6. 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
nonleading verbal questioning of the subjects is the preferred method to inquire about AE 
occurrence. 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits. All SAEs and AESIs will be followed until the event is resolved, stabilized, 
otherwise explained, or the subject is lost to follow-up. Further information on follow-up 
procedures is given in Appendix 6. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
69 
8.3.4 
Treatment of Adverse Events 
Treatment of any AE is at the sole discretion of the Investigator and according to current good 
medical practice. Any medication administered for the treatment of an SAE/AESIs should be 
UHFRUGHGLQ([SHGLWHG$GYHUVH(YHQW5HSRUWRIWKHVXEMHFW¶VeCRF (refer to Section 6.8). 
8.3.5 
Regulatory Reporting Requirements for Serious Adverse Events 
x Prompt notification of an SAE by the Investigator to the Sponsor is essential for meeting 
legal obligations and ethical responsibilities for the safety of subjects and the safety of a 
study treatment under clinical investigation. 
x The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and Investigators. 
x Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
x An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.6 
Pregnancy 
Female subjects of childbearing potential are to have a urine pregnancy test prior to any study 
vaccine administration. The study vaccine(s) may only be administered if the pregnancy test is 
negative. 
Note: Pregnancy test must be performed even if the subject is menstruating at the time of the 
study visit. 
See Appendix 7 for collection of pregnancy information. 
8.3.7 
Subject Card 
Study subjects must be provided with the address and telephone number of the main contact for 
information about the clinical study. 
The ,QYHVWLJDWRURUGHVLJQDWHPXVWWKHUHIRUHSURYLGHD³VXEMHFWFDUG´WRHDFKVXEMHFW,QDQ
emergency situation, this card serves to inform the responsible attending physician that the 
subject is in a clinical study and that relevant information may be obtained by contacting the 
Investigator. 
Subjects must be instructed to keep subject cards in their possession at all times during the study 
duration. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
70 
8.3.8 
Contact Information for Reporting of Serious Adverse Events, Adverse Events 
of Specific Interest, Pregnancies, and Study Holding Rules 
Table 19 
Contact Information for Reporting of Serious Adverse Events, Adverse 
Events of Specific Interest, Pregnancies, and Study Holding Rules 
Study Contact for Reporting of SAEs, AESIs, and Pregnancies: 
Refer to the local study contact information document. 
Study Contact for Reporting of Holding Rules: 
As soon as the Investigator is aware that a holding rule is met, he/she must immediately 
inform the Sponsor or Sponsor designee. 
Back-up Study Contact for Reporting SAEs, AESIs, and Pregnancies: 
24/24 hour and 7/7 day availability: 
IQVIA 
Email address: 208109safety@iqvia.com 
GSK Clinical Safety & Pharmacovigilance 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
Email address: Rix.CT-safety-vac@gsk.com 
AESI = adverse event of specific interest; SAE = serious adverse event. 
8.4 
Treatment of Overdose 
Not applicable. 
8.5 
Pharmacokinetics 
Not applicable. 
8.6 
Pharmacodynamics 
Not applicable. 
8.7 
Genetics 
Genetics are not evaluated in this study. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
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8.8 
Immunogenicity Assessment 
Blood Sampling for Immunogenicity Response Assessments 
All subjects from Steps 1, 2, 3, and 4 
A volume of approximately 20 mL of whole blood should be drawn for analysis of humoral 
immune response at each predefined timepoint specified in Section 1.3. After centrifugation, 
serum samples should be kept at ±20°C or below until shipment. Refer to the SPM for more 
details on sample storage conditions. 
Subjects from Step 4 who consented for the additional sampling 
For subjects who agreed to the optional blood sampling, a volume of approximately 40 mL of 
whole blood should be drawn for peripheral blood mononuclear cell (PBMC) isolation on 
Day 61 (Visit 5; refer to the schedule of activities in Section 1.3) and may be used for generation 
of monoclonal antibodies. The blood should be kept at the study center at a constant room 
temperature and it must not be centrifuged. Samples will be shipped at a constant room 
temperature (15 to 25°C) to the designated laboratory for PBMC separation to be performed 
within 18 hours. 
Refer to the SPM for more details on sample storage conditions. 
Monoclonal antibodies may be generated using the samples collected during the study and used 
for further research purposes as well as commercial use. 
Information on further investigations and their rationale can be obtained from GSK. 
Any sample testing will be done in line with the consent of the individual subject. 
8.8.1 
Laboratory Assays 
Please refer to Appendix 5 for the address of the clinical laboratories used for sample analysis. 
x Anti-Toxin A and anti-Toxin B neutralizing antibody titers will be measured by toxin 
neutralization assay (TNA) on serum samples, using different cell lines, at a GSK laboratory 
or in a laboratory designated by GSK using standardized and validated procedures 
(Table 20). 
x Anti-Toxin A and anti-Toxin B antibodies concentrations will be determined by 
enzyme-linked immunosorbent assay on serum sample at a GSK laboratory or in a laboratory 
designated by GSK using standardized and validated procedures (Table 20). 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
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Table 20 
Humoral Immunity (Antibody Determination) 
System 
Component 
Method 
Laboratory 
Serum 
Anti-Toxin A neutralizing 
antibodies (different cell lines) 
TNA 
 
GSKa or designated 
laboratory 
Anti-Toxin B neutralizing 
antibodies (different cell lines) 
Anti-Toxin A IgG 
ELISA 
Anti-Toxin B IgG 
ELISA = enzyme-linked immunosorbent assay; GSK = GlaxoSmithKline Biologicals SA; 
IgG = immunoglobulin G; TNA = toxin neutralization assay. 
a GSK laboratory refers to the Clinical Laboratory Sciences in Rixensart, Belgium, and Wavre, Belgium. 
Additional testing on the vaccine and/or on the disease under study may be performed within the 
framework of the study if deemed necessary for accurate interpretation of the data or should such 
assay(s) become available at GSK. These assays may not be represented in the 
objectives/endpoints of the study protocol. 
The GSK clinical laboratories have established a Quality System supported by procedures. The 
activities of GSK clinical laboratories are audited regularly for quality assessment by an internal 
(Sponsor-dependent) but laboratory-independent Quality Department. 
8.8.2 
Immunological Read-outs 
In case of insufficient blood sample volume to perform assays for all antibodies, the samples will 
be analyzed according to priority ranking provided in Table 21. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
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Table 21 
Immunological Read-outs 
Blood Sampling Timepoint 
Number of 
Subjects 
Component 
Components 
Priority Rank 
Type of Contact and Timepoint 
Visit 1 (Day 1) 
~140 
Anti-Toxin B neutralizing antibodies 
1 
Anti-Toxin A neutralizing antibodies 
2 
Anti-Toxin B immunoglobin G 
3 
Anti-Toxin A immunoglobin G 
4 
Visit 3 (Day 31) 
~140 
Anti-Toxin B neutralizing antibodies 
1 
Anti-Toxin A neutralizing antibodies 
2 
Anti-Toxin B immunoglobin G 
3 
Anti-Toxin A immunoglobin G 
4 
Visit 5 (Day 61) 
~140 
Anti-Toxin B neutralizing antibodies 
1 
Anti-Toxin A neutralizing antibodies 
2 
Anti-Toxin B immunoglobin G 
3 
Anti-Toxin A immunoglobin G 
4 
Visit 6 (Day 180) 
~140 
Anti-Toxin B neutralizing antibodies 
1 
Anti-Toxin A neutralizing antibodies 
2 
Anti-Toxin B immunoglobin G 
3 
Anti-Toxin A immunoglobin G 
4 
Visit 7 (Day 390) 
~140 
Anti-Toxin B neutralizing antibodies 
1 
Anti-Toxin A neutralizing antibodies 
2 
Anti-Toxin B immunoglobin G 
3 
Anti-Toxin A immunoglobin G 
4 
Visit 8 (Day 491) 
~60 
Anti-Toxin B neutralizing antibodies 
1 
Anti-Toxin A neutralizing antibodies 
2 
Anti-Toxin B immunoglobin G 
3 
Anti-Toxin A immunoglobin G 
4 
Visit 10 (Day 521) 
~50 
Anti-Toxin B neutralizing antibodies 
1 
Anti-Toxin A neutralizing antibodies 
2 
Anti-Toxin B immunoglobin G 
3 
Anti-Toxin A immunoglobin G 
4 
Visit 11 (Day 670) 
~50 
Anti-Toxin B neutralizing antibodies 
1 
Anti-Toxin A neutralizing antibodies 
2 
Anti-Toxin B immunoglobin G 
3 
Anti-Toxin A immunoglobin G 
4 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
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8.8.3 
Immunological Correlates of Protection 
No generally accepted immunological correlate of protection has been demonstrated so far for 
the Ag used in the C. difficile investigational vaccine. 
8.9 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.10 Health Economics or Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
8.11 
Study Procedures During Special Circumstances  
During special circumstances (eg, COVID-19 pandemic), the specific guidance from local public 
KHDOWKDQGRWKHUFRPSHWHQWDXWKRULWLHVUHJDUGLQJWKHSURWHFWLRQRILQGLYLGXDOV¶ZHOIDUHPXVWEH
applied. For the duration of such special circumstances, the following measures may be 
implemented for enrolled subjects: 
x 
Safety follow-up may be made by a telephone call, other means of virtual contact, or home 
visit, if appropriate. 
x 
Diary cards may be transmitted from and to the site by electronic means and/or conventional 
mail. 
x 
Biological samples may be collected at a different location* other than the study site or at 
VXEMHFW¶VKRPH%LRORJLFDOVDPSOHVVKRXOGQRWEHFROOHFWHGLIWKH\FDQQRWEHSURFHVVHGLQD
timely manner or appropriately stored until the intended use. 
x 
If despite best efforts it is not possible to collect blood samples within the interval 
predefined in the protocol (see Table 7), then the interval for blood sampling may be 
extended up to a maximum length of 30 days before the next blood sampling. Impact on the 
per protocol set for analysis of immunogenicity will be determined on a case-by-case basis. 
x 
A limited number of subjects may be recruited in addition in the Step 4 in the active arms, 
should there be a high rate of missed visit and/or visit outside of planned interval and/or 
withdrawal due to the current exceptional and unpredictable circumstances. 
*It is the InvestigaWRU¶VUHVSRQVLELOLW\WRLGHQWLI\DQDOWHUQDWHORFDWLRQ7KH,QYHVWLJDWRUVKRXOG
ensure that this alternate location meets ICH GCP requirements, such as adequate facilities to 
perform study procedures, appropriate training of the staff and documented delegation of 
responsibilities in this location. This alternate location should be covered by proper insurance for 
the conduct of study on subjects by Investigator and staff at a site other than the designated study 
site. Refer to EMA Guidance on the Management of Clinical Trials during the COVID-19 
(Coronavirus) pandemic (Version 4, 04 February 2021) for more details. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
75 
9.0 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
No formal statistical hypotheses are to be tested. 
9.2 
Sample Size Determination 
This study is a Phase I safety study to get preliminary safety and immunogenicity assessments of 
vaccine formulations in adults. 
The target will be to enroll a maximum of 140 healthy subjects (approximately 20 subjects aged 
18-45 years in Step 1, approximately 20 subjects aged 50-70 years in Step 2, approximately 
30 subjects aged 50-70 years in Step 3, and approximately 70 subjects aged 50-70 years in Step 4 
[refer to Table 10 and Figure 1]) (refer to Section 8.11 for study procedures to be considered 
during special circumstances). 
The sample size of 45 subjects aged 50-70 years in each active arm (CDIFF Ag or CDIFF Ag + 
AS01B) would provide a probability of 80% or 90% to observe at least 1 specific AE, if the true 
AE rate is 3.5% or 5.0%, respectively, in that group. 
Table 22 illustrates the precision on the percentage of subjects with symptoms following 
vaccination with 45 subjects vaccinated in each active arm. 
Table 22 
95% Confidence Interval for 1 Proportion with 45 Subjects 
Number of Subjects with a Symptom 
Percentage 
Exact 95% Confidence Interval 
Lower Limit 
Upper Limit 
0 
0.0% 
0.0% 
7.9% 
1 
2.2% 
0.1% 
11.8% 
2 
4.4% 
0.5% 
15.1% 
3 
6.7% 
1.4% 
18.3% 
4 
8.9% 
2.5% 
21.2% 
5 
11.1% 
3.7% 
24.1% 
6 
13.3% 
5.1% 
26.8% 
7 
15.6% 
6.5% 
29.5% 
8 
17.8% 
8.0% 
32.1% 
9 
20.0% 
9.6% 
34.6% 
10 
22.2% 
11.2% 
37.1% 
11 
24.4% 
12.9% 
39.5% 
12 
26.7% 
14.6% 
41.9% 


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Table 22 
95% Confidence Interval for 1 Proportion with 45 Subjects 
Number of Subjects with a Symptom 
Percentage 
Exact 95% Confidence Interval 
Lower Limit 
Upper Limit 
13 
28.9% 
16.4% 
44.3% 
14 
31.1% 
18.2% 
46.6% 
15 
33.3% 
20.0% 
49.0% 
16 
35.6% 
21.9% 
51.2% 
17 
37.8% 
23.8% 
53.5% 
18 
40.0% 
25.7% 
55.7% 
19 
42.2% 
27.7% 
57.8% 
20 
44.4% 
29.6% 
60.0% 
21 
46.7% 
31.7% 
62.1% 
22 
48.9% 
33.7% 
64.2% 
23 
51.1% 
35.8% 
66.3% 
24 
53.3% 
37.9% 
68.3% 
25 
55.6% 
40.0% 
70.4% 
26 
57.8% 
42.2% 
72.3% 
27 
60.0% 
44.3% 
74.3% 
28 
62.2% 
46.5% 
76.2% 
29 
64.4% 
48.8% 
78.1% 
30 
66.7% 
51.0% 
80.0% 
31 
68.9% 
53.4% 
81.8% 
32 
71.1% 
55.7% 
83.6% 
33 
73.3% 
58.1% 
85.4% 
34 
75.6% 
60.5% 
87.1% 
35 
77.8% 
62.9% 
88.8% 
36 
80.0% 
65.4% 
90.4% 
37 
82.2% 
67.9% 
92.0% 
38 
84.4% 
70.5% 
93.5% 
39 
86.7% 
73.2% 
94.9% 
40 
88.9% 
75.9% 
96.3% 
41 
91.1% 
78.8% 
97.5% 
42 
93.3% 
81.7% 
98.6% 
43 
95.6% 
84.9% 
99.5% 
44 
97.8% 
88.2% 
99.9% 


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77 
Table 22 
95% Confidence Interval for 1 Proportion with 45 Subjects 
Number of Subjects with a Symptom 
Percentage 
Exact 95% Confidence Interval 
Lower Limit 
Upper Limit 
45 
100.0% 
92.1% 
100.0% 
Exact 95% confidence interval computed based on Clopper-Pearson formula. 
Although key assumptions using GSK tests are not available at this stage, the variability values 
used in the statistical computations have been derived from the clinical data published by 
Sheldon (2016).17 The standard deviation (SD) log10 value of 0.84 and 1.4 have been used in the 
statistical calculations of the precision around the geometric mean fold-rise (GMFR) from 
prevaccination to postvaccination, respectively, for Toxin A and Toxin B.17 
Assuming 20% of nonevaluable subjects, 36 older adults in each active arm (CDIFF Ag or 
CDIFF Ag + AS01B) will be evaluable and included in the Per-protocol Set for analysis of 
immunogenicity. Table 23 illustrates the 95% confidence interval (CI) for various values of 
GMFR for Toxin A and Toxin B. 
Table 23 
95% Confidence Intervals Based on Variability Assumptions of 0.84-fold for 
Anti-Toxin A and 1.4-fold for Anti-Toxin B and on a Sample Size Including 
36 Evaluable Subjects 
Observed GMFR value 
Toxin A 
Toxin B 
10 
[5.20; 19.23] 
[3.36; 29.79] 
15 
[7.80; 28.85] 
[5.04; 44.68] 
20 
[10.40; 38.46] 
[6.715; 59.57] 
30 
[15.60; 57.69] 
[10.07; 89.36] 
40 
[20.80; 76.92] 
[13.43; 119.14] 
50 
[26.00; 96.15] 
[16.79; 148.93] 
GMFR = geometric mean fold-rise. 
Thirty subjects aged 50-70 years will be enrolled in the placebo group as control for safety. 
Ten additional subjects aged 18-45 years receiving CDIFF Ag and 10 subjects aged 18-45 years 
receiving placebo will be enrolled to evaluate safety and reactogenicity of the C. difficile F2 
fusion protein in young and healthy adults during the Step 1 of the staggered design (refer to 
Figure 1). 
A total of 120 subjects aged 50-70 years (30 receiving placebo, 45 receiving CDIFF Ag, and 
45 receiving CDIFF Ag + AS01B) and 20 subjects aged 18-45 years (10 receiving placebo and 
10 receiving CDIFF Ag) will be enrolled in this study. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
78 
9.3 
Populations for Analyses 
For purposes of analysis, the analysis sets in Table 24 are defined. 
Table 24 
Analysis Sets 
Analysis Set 
Description 
Enrolled Set 
All subjects who signed the ICF. 
Exposed Set 
All subjects who have received at least 1 dose of the study vaccine. 
The allocation in a group is done in function of the administered 
treatment. 
x 
Unsolicited Safety Set 
All subjects who received at least 1 dose of study treatment (Exposed 
Set) that report unsolicited AEs/report not having unsolicited AEs. 
x 
Solicited Safety Set 
All subjects who received at least 1 dose of the study treatment 
(Exposed Set) who have solicited safety data. 
x 
Subcohort Exposed Set 
All subjects who have received the Dose 3 on an active arm. 
Full analysis Set 
All subjects who received at least 1 dose of the study treatment and 
have postvaccination immunogenicity data. 
Per-protocol Set 
All subjects who received at least 1 dose of the study treatment to 
which they are randomized and have postvaccination data (Full 
Analysis Set) minus subjects with protocol deviations that lead to 
exclusion. The protocol deviations leading to exclusion of the 
subjects will be detailed in the SAP. 
Three Per-protocol Sets for analysis of immunogenicity will be 
derived. 
x 
Per-protocol Set for analysis of 
immunogenicity at Day 61 
(1-month post dose 2) 
x 
Per-protocol Set for analysis of 
immunogenicity at Day 180 
All subjects included in the Per-protocol Set, with no protocol 
deviations leading to exclusion until Day 61 and with at least 
1 immunogenicity data available at Day 61. 
 
All subjects included in the Per-protocol Set, with no protocol 
deviations leading to exclusion until Day 180 and with at least 
1 immunogenicity data available at Day 180 
x 
Per-protocol Set for analysis of 
immunogenicity at Day 390 
All subjects included in the Per-protocol Set, with no protocol 
deviations leading to exclusion until Day 390 and with at least 
1 immunogenicity data available at Day 390. 
Subcohort Per-protocol Set 
x 
Subcohort Per-protocol Set for 
analysis of immunogenicity at 
Day 521 in the Subcohort Set 
x 
Subcohort Per-protocol Set for 
analysis of immunogenicity at 
Day 670 in the Subcohort set 
 
 
All subjects included in the Per-protocol Set, who received the 
Dose 3 on an active arm, with no protocol deviations leading to 
exclusion until Day 521 and with at least 1 immunogenicity data 
available at Day 521. 
 
All subjects included in the Per-protocol Set, who received the 
Dose 3 on an active arm, with no protocol deviations leading to 
exclusion until Day 670 and with at least 1 immunogenicity data 
available at Day 670. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
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AE = adverse event; ICF = informed consent form; SAP = statistical analysis plan 
9.4 
Statistical Analyses 
9.4.1 
Analysis of Demographics 
Demographic characteristics (age at first study vaccination in years, gender, and ethnicity), 
cohort description, withdrawal status will be summarized by group using descriptive statistics: 
x Frequency tables will be generated for categorical variable such as gender. 
x Mean, median, and SD will be provided for continuous data such as age. 
9.4.2 
Safety Analyses 
9.4.2.1 
Primary Analyses 
The primary analysis will be performed on the Exposed Set. 
The percentage of subjects with at least 1 local AE (solicited and unsolicited), with at least 
1 general AE (solicited and unsolicited) and with any AE during the 7-day or the 30-day 
follow-up period will be tabulated with exact 95% CI after each vaccination and overall. The 
percentage of doses followed by at least 1 local AE (solicited and unsolicited), by at least 
1 general AE (solicited and unsolicited) and by any AE will be tabulated, overall vaccination 
course, with exact 95% CI. The same computations will be done for Grade 3, any AEs 
considered related to vaccination and any Grade 3 AEs considered related to vaccination. 
The percentage of subjects/doses reporting each individual solicited local and general AE during 
the 7-day follow-up period will be tabulated with exact 95% CI as follows: 
x Over the 2 or 3 doses, the percentage of subjects with the symptom and its exact 95% CI. 
x Over the 2 or 3 doses, the percentage of doses with the symptom and its exact 95% CI. 
x At each study dose (visit), the percentage of subjects with the symptom and its exact 95% CI. 
Occurrence of fever will be reported per 0.5°C cumulative iQFUHPHQWVDVIURP&DVZHOODV
the occurrence of fever >40°C/104°F with causal relationship to the study treatment. 
The verbatim reports of unsolicited symptoms will be reviewed by a physician and the signs and 
symptoms will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). Every verbatim term will be matched with the appropriate preferred term. The 
percentage of subjects with unsolicited AEs within 30 days after any doses with its exact 95% CI 
will be tabulated by group and by MedDRA preferred term. Similar tabulation will be done for 
Grade 3 unsolicited AEs, for unsolicited AEs that resulted in a medically attended visit, for 
Grade 3 and causally related unsolicited AEs and for unsolicited AEs causally related to 
vaccination. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
80 
The number of subjects who experienced at least 1 SAE or any AE of specific interest (pIMD) 
during the entire study period will be reported. 
For each group and for each hematology, biochemistry, and urinalysis parameter: 
x The percentage of subjects having hematology, biochemistry, and urinalysis results below or 
above the local laboratory normal ranges will be tabulated by timepoint. 
x The maximum grading from Screening up to Visit 5 (Day 61)/Visit 7 (Day 390) for subjects 
receiving 2 doses/Visit 11 (Day 670) for subjects receiving a third dose will be tabulated 
(grades will be based on local laboratory normal ranges and derived from Food and Drug 
Administration [FDA] *XLGDQFHWR,QGXVWU\³7R[LFLW\*UDGLQJ6FDOHIRU+HDOWK\$Gult and 
$GROHVFHQW9ROXQWHHUV(QUROOHGLQ3UHYHQWLYH9DFFLQH&OLQLFDO7ULDOV´ [refer to Table 13]). 
Those laboratory parameters not included in the FDA grading scale will not be graded). 
The percentage of subjects using concomitant medication (any medication, any antipyretic and 
any antipyretic taken prophylactically, respectively) during the 7-day follow-up period and 
during the 30-day follow-up period will be summarized by group after each vaccination and 
overall. 
Separate safety summaries for Subcohort Set may be generated as appropriate. 
9.4.2.2 
Internal Safety Review Committee Evaluations 
At each iSRC timepoint, a blinded review will be done by the GSK Safety Review Team (SRT) 
followed by an unblinded review of safety data by the iSRC. No individual clinical study report 
(CSR) will be written as a result of these safety evaluations. 
If there are any safety concerns observed during SRT reviews post Dose 3, an ad hoc iSRC 
meeting will take place to review the unblinded safety data. 
9.4.3 
Analysis of Immunogenicity 
The primary analysis will be based on the Per-protocol Set for analysis of immunogenicity. If, in 
any study group, the percentage of vaccinated subjects with serological results excluded from the 
Per-protocol Set for analysis of immunogenicity is 10% or more, a second analysis based on the 
Full Analysis Set will be performed. 
9.4.3.1 
Within Group Assessment 
For each study group, at each timepoint that blood samples are collected for humoral immune 
response and for each assay: 
x Percentage of subjects above the assay cutoff with their exact 95% CI will be tabulated. 
x Geometric mean concentrations/geometric mean titers and their 95% CI will be calculated. 
x Geometric mean fold-rise with their exact 95% CI will be tabulated. 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
81 
For each study group, at each blood sampling timepoint for humoral immune response after 
vaccination, and for each assay: 
x Antibody concentrations/titers will be investigated using Reverse Cumulative Curves. 
9.4.3.2 
Between Groups Assessment 
For the between group assessments, an analysis of covariance (ANCOVA) model will be fitted 
based on the subjects having a result at both the baseline and the considered timepoint. The 
model may include age and gender as covariate if the data allow. These comparative analyses 
will be exploratory with the aim to characterize the difference between the 2 investigational 
 
 
9.4.4 
Missing Data 
Data from subjects who withdraw from the study, including AEs and any follow-up, will be 
included in the analyses of primary and secondary outcomes. Missing data will not be imputed. 
9.5 
Interim Analyses 
A first interim analysis will be performed when all data up to 1 month after Dose 2, ie, Day 61 
(ie, data that are as clean as possible) are available. The immunogenicity data available until 
Day 61, and the safety and reactogenicity data available at the time of this analysis will be 
described. 
Second interim analysis will be performed when all data up to 1 month after Dose 3, ie, Day 521 
(ie, data that are as clean as possible) are available. The immunogenicity data available until 
Day 521, and the safety and reactogenicity data available at the time of this analysis will be 
described. 
All analyses are descriptive and with the aim to characterize the safety, reactogenicity, and 
immunogenicity data and therefore no statistical adjustment for interim analysis is required (refer 
to Section 9.8). 
9.6 
Safety Review Team 
7KHSURMHFW¶V657LQFOXGHVDVFRUHPHPEHUVWKH*6.%LRORJLFDOV¶&HQWUDO6DIHW\/HDGHUWKH
CRDL, Epidemiologist, Global Regulatory Lead and a Biostatistician of the project. The SRT is 
responsible for ongoing safety monitoring of the entire project and meets on a regular basis. The 
SRT will inform the iSRC about any potential safety concern relevant to the study (in a blinded 
way). 
CCI


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
82 
Before each iSRC safety evaluation in this study (see below), the SRT will review the same 
safety data, but in a blinded manner in order to keep all people involved in the conduct, cleaning 
and final analysis of the study blinded. 
9.7 
Internal Safety Review Committee 
As the investigational vaccine formulation will be administered to human for the first time, an 
L65&ZLOOEHDSSRLQWHGLQDGGLWLRQWRWKHSURMHFW¶V existing SRT and safety holding rules have 
been defined. 
This study will be overseen by an iSRC operating under a charter. Core members of the iSRC 
will include a GSK safety physician, a CRDL/CEPL, and a biostatistician who are not otherwise 
involved in the conduct of the project. The iSRC safety reviews will be conducted using 
unblinded data. Upon request, the iSRC has access to the subject randomization and reviews 
unblinded data. 
In Steps 1, 2, and 3, the iSRC will review all accumulating safety data after Dose 1 and then 
again after Dose 2, and in Step 4 the iSRC will review all accumulating safety data 3 weeks after 
the start of vaccination in Step 4 and then about every 3 weeks until all subjects have received 
Dose 1. If there are any safety concerns observed during SRT reviews post Dose 3, an ad hoc 
iSRC meeting will take place to review the unblinded safety data. 
The iSRC members will determine whether any of the predefined holding rules are met (refer to 
Section 4.6.1) or if there is any other safety signal. In this case, administration of the second 
vaccination will be immediately put on hold (refer to Section 4.6.2). If no safety signal is 
observed, the second vaccination will be administered to the subjects. At the end of each step, 
the iSRC will review all safety data from the entire step. The iSRC members will determine 
whether any of the predefined holding rules are met (refer to Section 4.6.1) or if there is any 
other safety signal. In this case, vaccination in the next step will be put on hold (refer to 
Section 4.6.2). If no safety signal is observed, vaccination in the next step will be performed 
(refer to Figure 1). 
9.8 
Sequence of Analysis 
The statistical analyses will be performed in 3 steps: 
x A first interim analysis will be performed when all data up to 1 month after Dose 2, ie, 
Day 61 (ie, data that are as clean as possible) are available. The immunogenicity data 
available until Day 61, and the safety and reactogenicity data available at the time of this 
analysis will be described. At this point, the statistician will be unblinded for the analysis (ie, 
will have access to individual subject treatment assignments). The remaining study personnel 
will stay blinded (ie, will not have access to the individual subject treatment assignment) 
until study end. It is possible however, due to the limited sample size, that unblinding occurs 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
83 
for a few subjects having a specific AE or SAE (eg, an AE/SAE occurring only in a single 
group). Therefore, anyone having access to the analysis of Day 61 could become unblinded 
regarding those specific cases. The study will be considered as partial blind from this point 
onwards. Individual listings will be provided at the study end to the investigator. Subjects 
will be provided with information about the study arm, via the investigator at the study end. 
x The second interim analysis will be performed when all data up to 1 month after Dose 3, ie, 
Day 521 (ie, data that are as clean as possible) are available. The immunogenicity data 
available until Day 521, and the safety and reactogenicity data available at the time of this 
analysis will be described. No individual listings will be provided. 
x The final analysis will be performed when all data up to study end are available. An 
integrated CSR containing all data will be written and made available to the Principal 
Investigator at that time. In addition, all previous analyses will be re-produced based on 
cleaned data at this point. Individual listings will only be provided at this stage. 
 
 
The final CSR will contain at least the final analyses of all primary and secondary endpoints. 
CCI


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
84 
10.0 REFERENCES 
1. Kitchin N, Remich SA, Peterson J, Peng Y, Gruber WC, Jansen KU, et al. A Phase 2 Study 
Evaluating the Safety, Tolerability, and Immunogenicity of Two 3-Dose Regimens of a 
Clostridium difficile Vaccine in Healthy US Adults Aged 65 to 85 Years. Clin Infect Dis. 
2020 Jan 1;70(1):1-10. 
2. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile Infection in the United 
States. N Engl J Med. 2015;372:825-34. 
3. Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin 
Infect Dis. 2012;55(2):S88-S92. 
4. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health 
care-associated infections. N Engl J Med. 2014;370:1198-1208. 
5. Perricone C, Colafrancesco S, Mazor RD, et al. Autoimmune/inflammatory syndrome 
induced by adjuvants (ASIA) 2013: Unveiling the pathogenic, clinical and diagnostic 
aspects. J Autoimmun. 2013;47:1-16. 
6. Millum J and Grady C. The Ethics of Placebo-controlled Trials: Methodological 
Justifications. Contemp Clin Trials. 2013;36(2):10.1016. 
7. World Medical Association. Declaration of Helsinki. 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-
medical-research-involving-human-subjects/(last accessed: 23 April 2018). 
8. Aronsson B, Granström M, Möllby R, et al. Serum antibody response to Clostridium difficile 
toxins in patients with Clostridium difficile diarrhoea. Infection. 1985;13:97-101. 
9. Warny M, Vaerman JP, Avesani V, et al. Human antibody response to Clostridium difficile 
toxin A in relation to clinical course of infection. Infect Immun. 1994;62:384-89. 
10. Kyne L, Warny M, Qamar A, et al. Asymptomatic carriage of Clostridium difficile and serum 
levels of IgG antibody against toxin A. N Engl J Med. 2000;342:390-97. 
11. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile 
infection and colonization. N Engl J Med. 2011;365:1693-703. 
12. Kyne L, Warny M, Qamar A, et al. Association between antibody response to toxin A and 
protection against recurrent Clostridium difficile diarrhoea. Lancet. 2001;357:189-93. 
13. Leav BA, Blair B, Leney M, et al. Serum anti-toxin B antibody correlates with protection 
from recurrent Clostridium difficile infection (CDI). Vaccine. 2010;28:965-69. 


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14. Lowry I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against 
Clostridium difficile toxins. N Engl J Med. 2010;362:197-205. 
15. )'$*XLGDQFHIRU,QGXVWU\³7R[LFLW\*UDGLQJ6FDOHIRU+HDOWK\$GXOWVDQG$GROHVFHQW
Volunteers Enrolled in Preventive Vaccine Clinical Trials.´ September 2007. 
16. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. June 2010. 
17. Sheldon E, Kitchinb N, Pengc Y, et al. A phase 1, placebo-controlled, randomized study of 
the safety, tolerability, and immunogenicity of a Clostridium difficile vaccine administered 
with or without aluminum hydroxide in healthy adults. Vaccine. 2016;34:2082±91. 
18. EMA Guideline on the exposure to medicinal products during pregnancy: need for post 
DXWKRULVDWLRQGDWD'RF5HI(0($&+03µDGRSWHG at Community level in 
May 2006; 
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guide
line/2009/11/WC500011303.pdf 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
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11.0 APPENDICES 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
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Appendix 1 
Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of specific interest 
Ag 
Antigen 
ANCOVA 
Analysis of Covariance 
AS01B 
An adjuvant system containing MPL, QS-21 and liposome 
(50 ȝJ03/DQG ȝJ46-21) 
CDI 
Clostridium difficile infection 
C. difficile 
Clostridium difficile 
CEPL 
Clinical and Epidemiology Project Lead 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CRDL 
Clinical Research and Development Lead 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTA 
Clinical Trial Application 
eCRF 
Electronic case report form 
ELISA 
Enzyme-linked immunosorbent assay 
EoS 
End of Study 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMFR 
Geometric mean fold-rise 
GSK 
GlaxoSmithKline Biologicals SA 
HRT 
Hormone replacement therapy 
IB 
,QYHVWLJDWRU¶VBrochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IM 
Intramuscular 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
iSRC 
Internal safety review committee 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPL 
3-O-desacyl-¶-monophosphoryl lipid A 
PBMC 
Peripheral blood mononuclear cell 
PCD 
Primary completion date 
pIMD 
Potential immune-mediated disease 
QS-21 
Quillaja saponaria Molina, fraction 21 (Licensed by GSK from 
Antigenics Inc., a wholly owned subsidiary of Agenus Inc., a 
Delaware, USA corporation) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBIR 
System Built for Internet Randomization 
SD 
Standard deviation 
SPM 
Study Procedures Manual 
SRT 
Safety Review Team 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TNA 
Toxin Neutralization Assay 
ULN 
Upper limit of normal 
USA 
United States of America 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
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Appendix 2 
Glossary of Terms 
Adverse Event: 
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use of a 
medicinal product, whether or not considered related to the 
medicinal product. 
An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or 
disease (new or exacerbated) temporally associated with the use 
of a medicinal product. 
Blinding: 
A procedure in which 1 or more parties to the study are kept 
unaware of the treatment assignment in order to reduce the risk 
of biased study outcomes. The level of blinding is maintained 
throughout the conduct of the study, and only when the data are 
cleaned to an acceptable level of quality will appropriate 
personnel be unblinded or when required in case of a serious 
adverse event. 
In a partial-blind study, the subject, the investigator, or anyone 
assessing the outcome is aware of the assignment in at least one 
treatment group but unaware of the treatment assignment(s) in 
one or more other treatment groups. 
In an observer-blind study, the subject and the study center and 
Sponsor personnel involved in the clinical evaluation of the 
subjects are blinded while other study personnel may be aware 
of the treatment assignment (see Section 6.6.3 for details on 
observer-blinded studies). 
Certified Copy: 
A copy (irrespective of the type of media used) of the original 
record that has been verified (ie, by a dated signature or by 
generation through a validated process) to have the same 
information, including data that describe the context, content, 
and structure, as the original. 
Eligible: 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
End of Study: 
(Synonym of End of 
Trial): 
For studies with collection of human biological samples, the 
End of Study is defined as last testing results released of 
samples collected at Visit 11 (Day 670)*. 
*In this case End of Study must be achieved no later than 
8 months after last subject last visit. 


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Essential Documents: 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of the data 
produced. 
Evaluable: 
Meeting all eligibility criteria, complying with the procedures 
defined in the protocol, and, therefore, included in the 
Per-protocol analysis (see Section 9.3 for details on criteria for 
evaluability). 
Immunological 
Correlate of Protection: 
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors that 
might increase susceptibility to the infectious agent. 
Investigational Vaccine: 
(Synonym of 
Investigational 
Medicinal Product) 
A pharmaceutical form of an active ingredient being tested in a 
clinical study, including a product with a marketing 
authorization when used 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. 
Investigator: 
A person responsible for the conduct of the clinical study at a 
study center. If a study is conducted by a team of individuals at 
a study center, the Investigator is the responsible leader of the 
team and may be called the Principal Investigator.  
The Investigator can delegate study-related duties and functions 
conducted at the study center to qualified individual or party to 
perform those study-related duties and functions. 
Potential 
Immune-mediated 
Disease: 
Potential immune-mediated diseases are a subset of adverse 
events that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest which may 
or may not have an autoimmune aetiology. 
Primary Completion 
Date: 
The date that the final subject was examined or received an 
intervention for the purpose of final collection of data for all 
primary outcomes, whether the clinical study was concluded 
according to the prespecified protocol or was terminated. 
Protocol Amendment: 
The International Council on Harmonisation defines a protocol 
amendment as: ³A written description of a change(s) to or 
formal clarification of a protocol.´ GSK further details this to 
include a change to an approved protocol that affects the safety 
of subjects, scope of the investigation, study design, or 
scientific integrity of the study. 
Randomization: 
Process of random attribution of treatment to subjects in order 
to reduce bias of selection. 


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Solicited Adverse 
Event: 
Adverse events to be recorded as endpoints in the clinical study. 
The presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a specified 
postvaccination follow-up period. 
Source Data: 
All information in original records and certified copies of 
original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and 
evaluation of the study. Source data are contained in source 
documents (original records or certified copies). 
Source Documents: 
Original documents, data, and records (eg, hospital records, 
clinical and office charts, laboratory notes, memoranda, 
subjects¶ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate 
copies, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories and at medico-technical 
departments involved in the clinical study). 
Study Vaccine: 
Any investigational vaccine being tested and/or any authorized 
use of a vaccine/placebo as a reference or administered 
concomitantly, in a clinical study that evaluates the use of an 
investigational vaccine. 
Study Conclusion for 
Individual Subjects: 
The study conclusion for subjects receiving 2 doses will be 
Visit 7 (Day 390) and for subjects receiving 3 doses will be 
Visit 11 (Day 670). 
Subject: 
Term used throughout the protocol to denote an individual who 
has been contacted in order to participate or participates in the 
clinical study, either as a recipient of the vaccine(s) or as a 
control. 
Treatment: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or placebo 
intended to be administered to a subject. 
Treatment Number: 
A number identifying a treatment to a subject, according to the 
treatment allocation. 
Unsolicited Adverse 
Event: 
Any adverse event reported in addition to those solicited during 
WKHFOLQLFDOVWXG\$OVRDQ\³VROLFLWHG´V\PSWRPZLWKRQVHW
outside the specified period of follow-up for solicited symptoms 
will be reported as an unsolicited adverse event. 


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Appendix 3 
Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
x This study will be conducted in accordance with the protocol and with: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
 Applicable ICH GCP Guidelines. 
 Applicable laws and regulations. 
x The protocol, protocol amendments, ICF or informed assent form, IB, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator for 
review and approval. These documents will be signed and dated by the Investigator before 
the study is initiated. 
x Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to subjects. 
x GSK will provide full details of the above procedures to the Investigator, either verbally, in 
writing, or both. 
x The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
 Providing oversight of the conduct of the study at the study center and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
x After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative Appendix 8 The study will not start 
at any study center at which the Investigator has not signed the protocol. 
Adequate Resources 
The Investigator is responsible for supervising any individual or party to whom the Investigator 
delegates study-related duties and functions conducted at the study center. 
If the Investigator/institution retains the services of any individual or party to perform study 
related duties and functions, the Investigator/institution should ensure this individual or party is 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
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qualified to perform those study-related duties and functions and should implement procedures to 
ensure the integrity of the study-related duties and functions performed and any data generated. 
Financial Disclosure 
Investigators and Sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interest prior initiation of the study center and 
at the end of the study. Investigators are responsible for providing an update of Financial 
Disclosure if their financial interest changes at any point during their participation in a study and 
for 1 year after completion of the study. 
Insurance 
The Sponsor has obtained liability insurance, which covers this study as required by local law 
and/or national regulations and/or ICH guidelines, whichever is applicable. The terms of the 
insurance will be kept in the study files. 
Informed Consent Process 
x The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorized representative and answer all questions regarding the study. 
x Subjects must be informed that their participation is voluntary. 
x Freely given and written or witnessed/thumb printed informed consent must be obtained from 
each subject, as appropriate, prior to participation in the study. 
x The content of ICF must meet the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act requirements, where 
applicable, and the IRB/IEC or study center. 
x The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
x Subjects must be reconsented to the most current version of the ICF(s) or an ICF addendum 
during their participation in the study. 
x A copy of the ICF(s) must be provided to the subject. 
x Subjects who are rescreened outside of the protocol screening interval are required to sign a 
new ICF. 
Data Protection 
x Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets 
that are transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.  


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x The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. 
x The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
x GSK will also ensure the protection of personal data of Investigator and the study center staff 
which will be collected within the frame and for the purpose of the study. 
Administrative Structure 
See Section 9.6 for information regarding the iSRC. 
Medical Monitor 
 
Phone: 
 
Medical Oversight from GSK 
, up to End of March 2021 and 
, as of April 2021. 
Publication Policy 
GSK aims to publish the results of this study in searchable, peer reviewed scientific literature. 
GSK will target to submit within 18 months from last subject last visit for interventional studies 
and from the completion of the analysis for noninterventional studies and follows the guidance 
from the International Committee of Medical Journal Editors. 
Dissemination of Clinical Study Data 
The key design elements of this protocol will be posted on the GSK Clinical Study Register and 
on publicly accessible registers including ClinicalTrials.gov. Where required, protocol 
summaries will also be posted on national or regional clinical trial registers or databases (eg, 
EudraCT database) in compliance with the applicable regulations. 
GSK also assures that results will be submitted to ClinicalTrials.gov within the required 
timeframe, in compliance with the current regulations mentioned in the table below. 
At the time of study results posting, the full study protocol and SAP will also be posted on 
ClinicalTrials.gov.  
In addition, for studies that are in scope of the EU Clinical Trial Directive, summaries of the 
results of GSK interventional studies (Phase I to IV) in adult population will be posted within 
defined timelines on the publicly available EU Clinical Trial Register.  
PPD
PPD
PPD
PPD


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
95 
If it is not possible to submit a summary of the results within the required timelines in the 
concerned EU member state, the summary of results shall be submitted as soon as it is available. 
In this case, the protocol shall specify when the results are going to be submitted, together with a 
justification. 
 
Clinicaltrial.gov 
EU 
Protocol summary 
Before enrollment of subjects 
As per CTA submission/before 
enrollment of subjects. 
Results summary 
Within 12 months of PCD (primary 
and safety endpoint results)/Within 
12 months of last subject last visita 
(for secondary endpoint results) 
Within 6 months (for pediatric 
population studies)/within 
12 months (for adult population 
studies) of EoSa. 
CTA = Clinical Trial Applications; EoS End of Study; PCD = primary completion date. 
a As defined in the study protocol. 
Under the framework of the SHARE initiative, anonymized patient-level data from GSK 
sponsored interventional studies that evaluate products will be made available within 6 months 
of this publication to independent researchers whose research proposals have been approved by 
an independent panel. Requests for access may be made through 
www.clinicalstudydatarequest.com. 
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the CSR, provided reasonable access to statistical tables, figures, 
and relevant reports. GSK will also provide the Investigator with the full summary of the study 
results. The Investigator is encouraged to share the summary results with the study subjects, as 
appropriate. 
Data Quality Assurance 
The Investigator should maintain a record of the location(s) of their respective essential 
documents including source documents. The storage system used during the study and for 
archiving (irrespective of the type of media used) should provide for document identification, 
version history, search, and retrieval. 
Essential documents for the study may be added or reduced where justified (in advance of study 
initiation) based on the importance and relevance to the study. When a copy is used to replace an 
original document (eg, source documents, eCRF), the copy should fulfil the requirements for 
certified copies.  
All subject data relating to the study will be recorded on printed or eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF.  


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The Investigator must maintain adequate and accurate source documents and study records that 
LQFOXGHDOOSHUWLQHQWREVHUYDWLRQVRQHDFKRIWKHVWXG\FHQWHU¶VVXEMHFWVWKDWVXSSRUWVWKH
information entered in the eCRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source documents or certified copies.  
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the source data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized study center personnel are attributable, legible, contemporaneous, 
original, accurate, and complete. Changes to source data should be traceable, should not obscure 
the original entry, and should be explained if necessary (eg, via an audit trail). Safety and rights 
of subjects must be protected and study be conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements.  
Study records and source documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the Investigator for 25 years from the issue of the final CSR/equivalent 
summary unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written notification 
to the Sponsor. 
Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Investigator should maintain a record of the location(s) of their source 
documents.  
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
Definition of what constitutes source data and source documents can be found in Appendix 2. 
Study and Study Center Closure 
GSK or its designee reserves the right to close the study center or terminate the study at any time 
for any reason at the sole discretion of GSK, provided there is sufficient notice given to account 
IRUSDWLHQW¶VVDIHH[LWIURPVWXG\SDUWLFLSDWLRQ6WXG\center regular closure will be upon study 
completion. A study center is considered closed when all required data/documents and study 
supplies have been collected and a study center closure visit has been performed. 


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The Investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center by the Sponsor or Investigator may include but 
are not limited to: 
x Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor¶VSURFHGXUHVRU*&3JXLGHOLQHV. 
x Inadequate recruitment of subjects by the Investigator. 
x Discontinuation of further study treatment development. 
 


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Appendix 4 
Clinical Safety Laboratory Tests  
The tests detailed in Table 25 will be performed by the local laboratory. Refer to Appendix 5 for 
GSK laboratories. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in Section 5.0 
of the protocol. 
The Investigator is not allowed to do extra testing on samples outside of what has been agreed 
upon by the ethics committees. 
Table 25 
Protocol-required Safety Laboratory Assessments 
System 
Discipline 
Component 
Scale 
Timepoints 
Method 
Laboratory 
Whole 
blood 
Hematology 
Leukocytes 
(white blood 
cells) 
Quantitative 
Screening 
Visit 2 (Day 8) 
Visit 3 (Day 31) 
Visit 4 (Day 38) 
Visit 6 (Day 180) 
Visit 7 (Day 390) 
Screening for 
Dose 3 (Day 476) 
Visit 8 (Day 491) 
Visit 9 (Day 498) 
Visit 11 (Day 670) 
As per 
local 
practice 
Local 
laboratory 
Platelet count 
Hemoglobin 
Serum 
Biochemistry 
Alanine 
aminotransferase 
Quantitative 
Screening 
Screening for 
Dose 3 (Day 476) 
Visit 8 (Day 491) 
Visit 9 (Day 498) 
Visit 11 (Day 670) 
 
Aspartate 
aminotransferase 
Creatinine 
Urate/uric acid 
C-reactive 
protein 
Urine 
Urinalysis 
Erythrocytes 
(red blood cells) 
Quantitative/ 
semi-quantitative 
Screening 
Screening for 
Dose 3 (Day 476) 
 
Protein 
Glucose 


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Appendix 5 
Clinical Laboratories 
GlaxoSmithKline Biologicals SA laboratories: 
Laboratory 
Address 
*6.%LRORJLFDO¶V&OLQLFDO/DERUDWRU\
Sciences, Rixensart  
Biospecimen Reception-B7/44 
Rue de l¶Institut, 89 
B-1330 Rixensart 
Belgium  
*6.%LRORJLFDO¶VClinical Laboratory 
Sciences, Wavre-Nord Noir Epine 
Avenue Fleming, 20 
B-1300 Wavre 
Belgium 
 
Outsourced Laboratory: 
Laboratory 
Address 
Nexelis 
525, Cartier Ouest Laval 
Quebec Canada H7V 3S8 
Nexelis 
 
,QYHVWLJDWRU¶V/RFDO/DERUDWRU\ 
Laboratory 
Address 
CEVAC Core Laboratory 
University of Ghent 
185 De Pintelaan, 
GENT 
Oost-Vlaanderen 9000 
Belgium 
 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
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Appendix 6 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
x 
An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the 
use of a study treatment, whether or not considered related to the study treatment. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
study treatment. 
 
Events Meeting the Adverse Event Definition 
x 
Significant or unexpected worsening or exacerbation of the condition/indication under study. 
x 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
x 
New conditions detected or diagnosed after study vaccine administration even though it may have been 
present before the start of the study. 
x 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
x 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study vaccine or a 
concomitant medication (overdose per se will not be reported as an AE/SAE). 
x 
Signs, symptoms temporally associated with study vaccine(s) administration. 
x 
Pre or posttreatment events that occur as a result of protocol-mandated procedures (ie, invasive 
SURFHGXUHVPRGLILFDWLRQRIVXEMHFW¶Vprevious therapeutic regimen). 
x 
Medically attended visits related to AEs (eg, hospital stays, physician visits and emergency room 
visits). 
$GYHUVHHYHQWVWREHUHFRUGHGDVHQGSRLQWVVROLFLWHG$(VDUHGHVFULEHGEHORZXQGHU³6ROLFLWHG$GYHUVH
Events.´$OOother AEs will be recorded as UNSOLICITED AEs. 
 
Events NOT Meeting the Adverse Event Definition 
x 
Situations where an untoward medical occurrence did not occur (eg, social and/or convenience 
admission to a hospital, admission for routine examination). 
x 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 
x 
Pre-existing conditions or signs and/or symptoms present in a subject prior to the first study 
vaccination. These events will be recorded in the Medical History section of the eCRF. 
 
Definition of Serious Adverse Event 
An SAE is any untoward medical occurrence that: 
a) Results in death 
b) Is life-threatening 


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Protocol 208109 (CDIFF-004) - Amendment 04 
 
101 
The term ³life-threatening´ LQWKHGHILQLWLRQRI³VHULRXV´UHIHUVWRDQHYHQWLQZKLFKWKHVXEMHFWZDVDWULVN
of death at the time of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe. 
c) Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the subject has been admitted at the hospital or emergency 
ZDUGIRUREVHUYDWLRQDQGRUWUHDWPHQWWKDWZRXOGQRWKDYHEHHQDSSURSULDWHLQWKHSK\VLFLDQ¶VRIILFHRULQ
an outpatient setting. Complications that occur during hospitalization are also considered AEs. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event will also be considered 
VHULRXV:KHQLQGRXEWDVWRZKHWKHU³KRVSLWDOL]DWLRQ´RFFXUUHGRUZDVQHFHVVDU\WKH$(VKRXOGEH
considered serious. 
Hospitalization for elective treatment of a pre-existing condition (known or diagnosed prior to informed 
consent signature) that did not worsen from baseline is NOT considered an AE. 
d) Results in disability/incapacity 
7KHWHUPGLVDELOLW\PHDQVDVXEVWDQWLDOGLVUXSWLRQRIDSHUVRQ¶VDELOLW\WRFRQGXFWQRUPDOOLIHIXQFWLRQV 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect in the offspring of a study subject 
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the other outcomes listed in the above definition. These should also be considered serious. Examples of 
such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization. 
 
Solicited Adverse Events 
a) Solicited local (injection site) AEs. 
x 
Pain at injection site. 
x 
Redness at injection site. 
x 
Swelling at injection site. 
b) Solicited general AEs. 
x 
Fatigue. 
x 
Fever. 
x 
Gastrointestinal symptoms.* 
x 
Headache. 
x 
Myalgia. 
x 
Shivering. 
x 
Arthralgia. 
*Gastrointestinal symptoms include nausea, vomiting, diarrhea, and/or abdominal pain. 
Note: Subjects will be instructed to measure and record the oral body temperature in the evening. Should 
additional temperature measurements be performed at other times of day, subjects will be instructed to 
record the highest temperature in the diary card. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
102 
 
Unsolicited Adverse Events 
An unsolicited AE is an AE that was not solicited using a Subject Diary and that was spontaneously 
communicated by subjects who has signed the informed consent. 
Potential unsolicited AEs may be medically attended (defined as symptoms or illnesses requiring 
hospitalization, or emergency room visit, or visit to/by a health care provider) or were of concern to the 
subjects. In case of such events, subjects will be instructed to contact the study center as soon as possible to 
report the event(s). The detailed information about the reported unsolicited AEs will be collected by the 
qualified study center SHUVRQQHOGXULQJWKHLQWHUYLHZDQGZLOOEHGRFXPHQWHGLQWKHVXEMHFW¶VUHFRUGV 
Unsolicited AEs that are not medically attended nor perceived as a concern by subjects will be collected 
during interview with the subjects and by review of available medical records at the next visit. 
 
Adverse Events of Specific Interest 
Potential immune-mediated Diseases 
x 
Potential immune-mediated diseases are a subset of AESIs that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune 
etiology (refer to Table 18 for a list of pIMDs). 
x 
However, the Investigator will exercise his/her medical and scientific judgment in deciding whether 
other diseases have an autoimmune origin (ie, pathophysiology involving systemic or organ-specific 
pathogenic autoantibodies) and should also be recorded as a pIMD. 
When there is enough evidence to make any of the above diagnoses, the AE must be reported as AESI. 
Symptoms, signs or conditions which might (or might not) represent the above diagnoses, should be 
recorded and reported as AEs but not as AESI until the final or definitive diagnosis has been determined, 
and alternative diagnoses have been eliminated or shown to be less likely. 
 
Clinical Laboratory Parameters and Other Abnormal Assessments Qualifying as Adverse 
Events or Serious Adverse Events 
In absence of diagnosis, abnormal laboratory findings (eg, clinical chemistry, hematology, urinalysis) or 
other abnormal assessments that are judged by the Investigator to be clinically significant will be recorded 
as AE or SAE if they meet the definition of an AE or SAE. Clinically significant abnormal laboratory 
findings or other abnormal assessments that are present at baseline and significantly worsen following the 
start of the study will also be reported as AEs or SAEs. However, clinically significant abnormal laboratory 
findings or other abnormal assessments that are associated with the disease being studied, unless judged by 
the IQYHVWLJDWRUDVPRUHVHYHUHWKDQH[SHFWHGIRUWKHVXEMHFW¶VFRQGLWLRQRUWKDWDUHSUHVHQWRUGHWHFWHGDW
the start of the study and do not worsen, will not be reported as AEs or SAEs. 
The Investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal 
laboratory finding or other abnormal assessment is clinically significant. 
In case of invalid or missing results or clinically significant abnormal laboratory findings that cannot be 
reasonably explained (eg, due to a pre-existing or current medical condition), the Investigator will be 
recommended to recall the subject in a timely manner (preferably within 7 days after IQYHVWLJDWRU¶V
awareness/assessment of the abnormal findings, if applicable) for a repeat test to confirm the result. 
 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
103 
Pregnancy 
Female subjects who are pregnant or lactating at the time of vaccination must not receive additional doses 
of study vaccine(s) but may continue other study procedures at the discretion of the Investigator. 
While pregnancy is not considered an AE or SAE, any adverse pregnancy outcome or complication or 
elective termination of a pregnancy for medical reasons will be recorded and reported as an AE or a SAE. 
Note: The pregnancy should always be recorded on an electronic pregnancy report. 
The following should alZD\VEHFRQVLGHUHGDV6$(DQGZLOOEHUHSRUWHGDVGHVFULEHGLQ³3URPSW5HSRUWLQJ
RI6HULRXV$GYHUVH(YHQWV3UHJQDQFLHVDQG2WKHU(YHQWV´DQG³&RPSOHWLRQDQG7UDQVPLVVLRQRI
3UHJQDQF\5HSRUWVWR*6.´ 
x 
Spontaneous pregnancy loss, including: 
 
spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of gestation). 
 
ectopic and molar pregnancy. 
 
stillbirth (intrauterine death of fetus after 22 weeks of gestation). 
1RWHWKHZHHNV¶FXWRIILQJHVWDWLRQDODJHLVEDVHGRQ:orld Health Organization-International 
Classification of Diseases 10 noted in the European Medicines Agency Guideline on pregnancy exposure 
[EMA, 2006]. It is recognized that national regulations might be different. 
x 
Any early neonatal death (ie, death of a live born infant occurring within the first 7 days of life).  
x 
Any congenital anomaly or birth defect identified in the offspring of a study subject (either during 
pregnancy, at birth or later) regardless of whether the fetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the products of 
conception after elective or spontaneous abortion. 
Furthermore, any SAE occurring as a result of a poststudy pregnancy AND considered by the Investigator 
to be reasonably related to the study vaccine(s) will be reported to GSK as described in ³5HSRUWLQJRI
Serious Adverse Events, Pregnancies, and Other Events.´ While the Investigator is not obligated to actively 
seek this information from former subjects, he/she may learn of a pregnancy through spontaneous 
reporting. 
 
Detecting and Recording Adverse Events, Serious Adverse Events and Pregnancies 
A paper diary hereafter referred to as Subject Diary will be used in this study to capture solicited AEs. The subject 
should be trained on how and when to complete each field of the Subject Diary. 
The subjects will be instructed to contact the Investigator immediately should the subjects manifest any signs or 
symptoms they perceive as serious. 
Subject Diary training should be directed at the individual(s) who will perform the measurements of AEs and who 
will enter the information into the Subject Diary. This individual may not be the subject, but if a person other than 
the subject enters information into the Subject DLDU\WKLVSHUVRQ¶VLGHQWLW\PXVWEHGRFXPHQWHGLQWKHSubject 
DLDU\VXEMHFW¶VVRXUFHUHFRUG$Q\LQGLYLGXDOWKDWPDNHVHQWULHVLQWRWKHSubject Diary must receive training on 
completion of the Subject Diary at the time of the visit when Subject Diary is dispensed. This training must be 
GRFXPHQWHGLQWKHVXEMHFW¶VVRXUFHUHFRUG 
x 
Collect and verify completed diary cards during discussion with the subject on Visit 7. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
104 
x 
Any unreturned diary cards will be sought from the subject through telephone call(s) or any other convenient 
procedure. 
The Investigator will transcribe the collected information into the eCRF in English. 
 
Time Period for Detecting and Recording Adverse Events, Serious Adverse Events, and Pregnancies 
x 
All solicited AEs during 7 days following administration of each dose of study vaccine(s) (Day 1 to 
Day 7) must be recorded in the eCRF, irrespective of intensity or whether or not they are considered 
vaccination-related. 
x 
All other AEs during 30 days following administration of each dose of study vaccine(s) (Day 1 to 
Day 30) must be recorded in the appropriate section of the eCRF, irrespective of intensity or whether 
or not they are considered vaccination-related. 
x 
The time period for collecting and recording SAEs will begin at the first receipt of study vaccine(s) 
and will end 359 days following administration of the last dose of study vaccine(s) for each subject 
receiving 2 doses and 6 months following administration of the last dose of study vaccine(s) for each 
subject receiving 3 doses. See ³5HSRUWLQJRI6HULRXV$GYHUVH(YHQWV3UHJQDQFLHVDQG2WKHU(YHQWV´ 
for instructions on reporting of SAEs. 
x 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from the time of 
the first receipt of study vaccine. 
x 
In addition to the above-mentioned reporting requirements and in order to fulfil international reporting 
obligations, SAEs that are related to study participation (ie, protocol-mandated procedures, invasive 
tests, a change from existing therapy) or are related to a concurrent GSK medication/vaccine will be 
collected and recorded from the time the subject consents to participate in the study until she/he is 
discharged from the study. 
x 
The time period for collecting and recording pregnancies will begin at the first receipt of study 
vaccine(s) and will end 359 days following administration of the last dose of study vaccine(s) each 
subject receiving 2 doses and 6 months following administration of the last dose of study vaccine(s) for 
each subject receiving 3 doses. See ³5HSRUWLQJRI6HULRXV$GYHUVH(YHQWV3UHJQDQFLHVDQG2WKHU
(YHQWV´ for instructions on reporting of pregnancies. 
x 
The time period for collecting and recording of AESIs will begin at the first receipt of study vaccine(s) 
and will end 359 days following administration of the last dose of study vaccine(s) each subject 
receiving 2 doses and 6 months following administration of the last dose of study vaccine(s) for each 
subject receiving 3 doses. See ³5HSRUWLQJRI$GYHUVH(YHQWVRI6SHFLfic ,QWHUHVWWR*6.´ for 
instructions on reporting of AESIs. 
Evaluation of Adverse Events and Serious Adverse Events 
Active questioning to detect AEs and SAEs: 
x 
As a consistent method of collecting AEs, the subject should be asked nonleading questions such as: 
³+DYH\RXIHOWGLIIHUHQWLQDQ\ZD\VLQFHUHFHLYLQJWKHYDFFLQHVRUVLQFHWKHSUHYLRXVYLVLW"´ 
x 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, 
hospital progress notes, laboratory and diagnostics reports) relative to the event. The Investigator will 
then record all relevant information regarding an AE/SAE in the eCRF. The Investigator is not allowed 
WRVHQGSKRWRFRSLHVRIWKHVXEMHFW¶VPHGLFDOUHFords to GSK instead of appropriately completing the 
eCRF. However, there may be instances when copies of medical records for certain cases are requested 
by GSK. In this instance, all subject identifiers will be blinded on the copies of the medical records 
prior to submission to GSK. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
105 
x 
The Investigator will attempt to establish a diagnosis pertaining to the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE/SAE 
and not the individual signs/symptoms. 
Assessment of Adverse Events: 
Assessment of Intensity 
The intensity of the following solicited AEs will be assessed as described in the table below: 
Adverse Event 
Intensity grade 
Parameter 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
106 
a Fever is defined as temperature 38.0°C/100.4°F. The preferred location for measuring temperature in 
this study will be the oral cavity. 
The Investigator will assess the maximum intensity that occurred over the duration of the event for all 
unsolicited AEs (including SAEs) recorded during the study. The assessment will be based on the 
,QYHVWLJDWRU¶VFOLQLFDOMXGJPHQW 
The intensity should be assigned to 1 of the following categories: 
 
 An event is defined 
DV³VHULRXV´ZKHQLWPHHWVRIWKHSUHGHILQHGRXWFRPHVDVGHVFULEHGLQ³'HILQLWLRQRI6HULRXV$GYHUVH
Events.´ 
Assessment of Causality 
The Investigator is obligated to assess the relationship between study vaccine(s) and the occurrence of each 
AE/SAE using clinical judgment. In case of concomitant administration of multiple vaccines, if possible, 
the Investigator should specify if the AE could be causally related to a specific vaccine administered (ie, 
investigational, control/placebo or co-administered vaccine). When causal relationship to a specific 
vaccine(s) cannot be determined, the Investigator should indicate the AE to be related to all products. 
Alternative plausible causes, such as natural history of the underlying diseases, concomitant therapy, other 
risk factors, and the temporal relationship of the event to the study vaccine(s) will be considered and 
investigated. The Investigator will also consult the IB and/or Summary of Product Characteristics and/or 
Prescribing Information for marketed products to determine his/her assessment. 
There may be situations when an SAE has occurred and the Investigator has minimal information to 
include in the initial report to GSK. However, it is very important that the Investigator always makes an 
assessment of causality for every event prior to submission of the Expedited Adverse Events Report to 
GSK. The Investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is 1 of the criteria used when 
determining regulatory reporting requirements. 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.
CCI


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
107 
All solicited local (injection site) reactions will be considered causally related to vaccination. Causality of 
all other AEs should be assessed by the Investigator using the following question: 
Is there a reasonable possibility that the AE may have been caused by the study vaccine? 
YES: There is a reasonable possibility that the study vaccine(s) contributed to the AE. 
NO: There is no reasonable possibility that the AE is causally related to the administration of the study 
vaccine(s). There are other, more likely causes and administration of the study vaccine(s) is not suspected 
to have contributed to the AE. 
,IDQHYHQWPHHWVWKHFULWHULDWREHGHWHUPLQHGDV³VHULRXV´VHH³'HILQLWLRQRI6HULRXV$GYHUVH(YHQWV´), 
additional examinations/tests will be performed by the Investigator in order to determine ALL possible 
contributing factors for each SAE. 
Possible contributing factors include: 
x 
Medical history. 
x 
Other medication. 
x 
Protocol required procedure. 
x 
Other procedure not required by the protocol. 
x 
Lack of efficacy of the vaccine, if applicable. 
x 
Erroneous administration. 
x 
Other cause (specify). 
Assessment of Outcome 
The Investigator will assess the outcome of all unsolicited AEs (including SAEs) recorded during the study 
as: 
x 
Recovered/resolved. 
x 
Recovering/resolving. 
x 
Not recovered/not resolved. 
x 
Recovered with sequelae/resolved with sequelae. 
x 
Fatal (SAEs only). 
 
Medically Attended Visits 
For each solicited and unsolicited symptom the subject experiences, the subject will be asked if he/she 
received medical attention defined as hospitalization, or an otherwise unscheduled visit to or from medical 
personnel for any reason, including emergency room visits. This information will be recorded in the eCRF. 
 
Reporting of Serious Adverse Events, Pregnancies, and Other Events 
Prompt Reporting of Serious Adverse Events, Pregnancies, and Other Events to GSK 
x 
SAEs that occur in the time period defined in ³'HWHFWLQJDQG5HFRUGLQJ$GYHUVH(YHQWV6HULRXV
$GYHUVH(YHQWVDQG3UHJQDQFLHV´ will be reported promptly to GSK within the timeframes described 
in the table below, once the Investigator determines that the event meets the protocol definition of an 
SAE. 
x 
Pregnancies that occur in the time period defined in ³'HWHFWLQJDQG5HFRUGLQJ$GYHUVH(YHQWV
6HULRXV$GYHUVH(YHQWVDQG3UHJQDQFLHV´ will be reported promptly to GSK within the timeframes 
described in the table below, once the Investigator becomes aware of the pregnancy. 
x 
AESIs that occur in the WLPHSHULRGGHILQHGLQ³'HWHFWLQJDQG5HFRUGLQJ$GYHUVH(YHQWV6HULRXV
$GYHUVH(YHQWVDQG3UHJQDQFLHV´will be reported promptly to GSK within the timeframes described 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
108 
in the table below, once the Investigator determines that the event meets the protocol definition of a 
AESIs. 
Timeframes for submitting SAEs, pregnancy, and other events reports to GSK: 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hoursa,c 
Electronic Expedited 
Adverse Events Report 
24 hoursa 
Electronic Expedited 
Adverse Events Report 
Pregnancies 
24 hoursa 
Electronic pregnancy 
report 
24 hoursa 
Electronic pregnancy report 
AESIs 
(pIMDs) 
24 hoursb,c 
Electronic Expedited 
Adverse Events Report 
24 hoursa 
Electronic Expedited 
Adverse Events Report 
AESI = adverse event of specific interest; pIMD = potential immune-mediated disease; SAE = serious 
adverse event 
a Timeframe allowed after receipt or awareness of the information. 
b Timeframe allowed once the Investigator determines that the event meets the protocol definition of an 
AESI. 
c The Investigator will be required to confirm review of the SAE/AESI FDXVDOLW\E\WLFNLQJWKH³UHYLHZHG´
box in the electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/AESI. 
Serious Adverse Events Requiring Expedited Reporting to GSK 
x 
Once an Investigator becomes aware that an SAE has occurred in a study subject, the Investigator (or 
designate) must complete the information in the electronic Expedited Adverse Events Report WITHIN 
24 HOURS. The report will always be completed as thoroughly as possible with all available details of 
the event. Even if the Investigator does not have all information regarding an SAE, the report should 
still be completed within 24 hours. Once additional relevant information is received, the report should 
be updated WITHIN 24 HOURS. 
x 
The Investigator will always provide an assessment of causality at the time of the initial report. The 
,QYHVWLJDWRUZLOOEHUHTXLUHGWRFRQILUPWKHUHYLHZRIWKH6$(FDXVDOLW\E\WLFNLQJWKH³UHYLHZHG´ER[
in the electronic Expedited Adverse Events Report within 72 hours of submission of the SAE. 
Back-up System in Case the Electronic Reporting System Does Not Work 
x 
If the electronic reporting system does not work, the Investigator (or designate) must complete, then 
date and sign a paper Expedited Adverse Events Report and fax it to the Study Contact for Reporting 
SAEs (refer to the Sponsor Information) or to GSK Clinical Safety and Pharmacovigilance department 
within 24 hours. 
This back-up system should only be used if the electronic reporting system is not working and NOT if the 
system is slow. As soon as the electronic reporting system is working again, the Investigator (or designate) 
must complete the electronic Expedited Adverse Events Report within 24 hours. The final valid 
information for regulatory reporting will be the information reported through the electronic SAE reporting 
system. 
Completion and Transmission of Pregnancy Reports to GSK 
x 
Once the Investigator becomes aware that a subject is pregnant, the Investigator (or designate) must 
complete the required information onto the electronic pregnancy report WITHIN 24 hours. 
Note: Conventionally, the estimated gestational age of a pregnancy is dated from the first day of the 
last menstrual period of the cycle in which a woman conceives. If the last menstrual period is uncertain 
or unknown, dating of estimated gestational age and the estimated date of delivery should be estimated 
by ultrasound examination and recorded in the pregnancy report. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
109 
5HSRUWLQJRI$(6,¶VWR*6. 
x 
Once an AESI is diagnosed (serious or nonserious) in a study subject, the Investigator (or designate) 
must complete the information in the electronic Expedited Adverse Events Report WITHIN 
24 HOURS after he/she becomes aware of the diagnosis. The report allows specify that the event is an 
AESI and whether it is serious or nonserious. The report will always be completed as thoroughly as 
possible with all available details of the event, in accordance with the AESIs standard questionnaire 
provided. Even if the Investigator does not have all information regarding an AESI, the report should 
still be completed within 24 hours. Once additional relevant information is received, the report should 
be updated WITHIN 24 HOURS. 
x 
The Investigator will always provide an assessment of causality at the time of the initial report. The 
Investigator will be required to confirm the review of the AESI causality by ticking the ³reviewed´ box 
in the electronic Expedited Adverse Events Report within 72 hours of submission of the AESI. 
Updating of Serious Adverse Events, Pregnancy, and Adverse Events of Specific Interest 
Information After Removal of Write Access to the SXEMHFW¶VElectronic Case Report Form 
When additional SAE, pregnancy, or AESI information is received after removal of the write access to the 
VXEMHFW¶VH&5)QHZRUXSGDWHGLQIRUPDWLRQVKRXOGEHUHFRUGHGRQWKHDSSURSULDWHSDSHUUHSRUWZLWKDOO
changes signed and dated by the Investigator. The updated report should be faxed to the Study Contact for 
Reporting SAEs (refer to the Sponsor Information) or to GSK Clinical Safety and Pharmacovigilance 
GHSDUWPHQWZLWKLQWKHGHVLJQDWHGUHSRUWLQJWLPHIUDPHVVSHFLILHGLQ³7LPHIUDPHVIRUVXEPLWWLQJ6$(V
SUHJQDQF\DQGRWKHUHYHQWVUHSRUWVWR*6.´ 
 
Follow-up of Adverse Events, Serious Adverse Events, and Pregnancies 
Follow-up of Adverse Events, Serious Adverse Events During the Study 
x 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject and 
provide additional relevant information on thHVXEMHFW¶VFRQGLWLRQWR*6.ZLWKLQKRXUVIRU6$(V
refer to: Timeframes for submitting SAEs, pregnancy, and other events reports to GSK). 
x 
All SAEs and AESIs (serious or nonserious) documented at a previous visit and designated as not 
recovered/not resolved or recovering/resolving will be reviewed at subsequent visits until the last visit 
of the subject. 
x 
All AEs documented at a previous visit and designated as not recovered/not resolved or 
recovering/resolving will be reviewed at subsequent visits/contacts until 30 days after the last 
vaccination. 
Follow-up After the Subject is Discharged from the Study 
The Investigator will follow subjects: 
x 
With SAEs, AESIs (serious or nonserious), or subjects withdrawn from the study as a result of an AE, 
until the event has resolved, subsided, stabilized, disappeared, or until the event is otherwise explained, 
or the subject is lost to follow-up. 
If the Investigator receives additional relevant information on a previously reported SAE, he/she will 
provide this information to GSK using an electronic Expedited Adverse Events Report and/or pregnancy 
report as applicable. 
GSK may request that the Investigator performs or arranges the conduct of additional clinical 
examinations/tests and/or evaluations to elucidate as fully as possible the nature and/or causality of the AE 
or SAE. The Investigator is obliged to assist. If a subject dies during participation in the study or during a 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
110 
recognized follow-up period, GSK will be provided with any available postmortem findings, including 
histopathology. 
Follow-up of Pregnancies 
x 
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end of the 
pregnancy, whether full-term or premature, information on the status of the mother and child will be 
forwarded to GSK using the electronic pregnancy report and the Expedited Adverse Events Report if 
applicable. Generally, the follow-XSSHULRGGRHVQ¶WQHHGWREHORQJHUWKDQWR weeks after the 
estimated date of delivery. 
x 
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is an SAE, it 
should always be reported as SAE. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
111 
Appendix 7 
Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
 
Women in the following categories are not considered women of childbearing potential 
x Premenarchal 
Menarche is the onset of menses for the first time in a young female and is preceded by 
several changes associated with puberty including breast development and pubic hair growth. 
Menarche usually occurs within 1 to 2 years of breast development, thelarche. However, a 
young female can become pregnant before her first menses. Thus, a conservative definition 
of nonchildbearing potential in a premenarcheal female is a young female who has not yet 
entered puberty as evidenced by lack of breast development (palpable glandular breast 
tissue). 
x Premenopausal female with 1 of the following: 
 Documented hysterectomy. 
 Documented bilateral salpingectomy. 
 Documented bilateral oophorectomy. 
Note: 'RFXPHQWDWLRQFDQFRPHIURPWKHVWXG\FHQWHUSHUVRQQHO¶V review of the 
VXEMHFW¶VPHGLFDOUHFRUGVPHGLFDOH[DPLQDWLRQRUPHGLFDOKLVWRU\LQWHUview. 
x Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormone replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient. 
x Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
nonhormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
112 
Contraception Guidance 
x Female subjects of childbearing potential are eligible to participate if they agree to use an 
adequate contraception consistently and correctly according to the methods listed in GSK list 
of highly effective contraceptive methods provided below: 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb 
x 
Oral. 
x 
Intravaginal. 
x 
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulationb 
x 
Injectable. 
Highly Effective Methods That Are User Independent a  
x 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb. 
x 
Intrauterine device. 
x 
Intrauterine hormone-releasing system. 
x 
Bilateral tubal occlusion. 
Vasectomized Partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
Male partner VWHULOL]DWLRQSULRUWRWKHIHPDOHVXEMHFW¶VHQWU\LQWRWKHVWXG\DQGWKLVmale is the sole partner for that 
subject (WKHLQIRUPDWLRQRQWKHPDOHVWHULOLW\FDQFRPHIURPWKHVWXG\FHQWHUSHUVRQQHO¶VUHYLHZRIWKHVXEMHFW¶V
medical records; medical examination and/or semen analysis, or medical history interview provided by her or her 
partner). 
Sexual Abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs
to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject. 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized during 
the treatment period and for at least 2 months after the last dose of study treatment.  
 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
113 
Collection of Pregnancy Information 
Female subjects who become pregnant 
x Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  
x Information will be recorded on the appropriate form and submitted to GSK within 24 hours 
RIOHDUQLQJRIDVXEMHFW¶VSUHJQDQF\ 
x Subject will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on subject and neonate, which will be forwarded to GSK. 
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the estimated 
delivery date.  
x Any termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for procedure.  
x While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.  
x A spontaneous abortion is always considered to be an SAE and will be reported as such. 
x Any SAE occurring as a result of a poststudy pregnancy which is considered reasonably 
related to the study treatment by the Investigator, will be reported to GSK as described in 
³5HSRUWLQJRI6HULRXV$GYHUVH(YHQWV3UHJQDQFLHVDQG2WKHU(YHQWV.´ While the 
Investigator is not obligated to actively seek this information in former study subjects, he or 
she may learn of an SAE through spontaneous reporting.  
Any female subject who becomes pregnant while participating will discontinue study treatment. 


CONFIDENTIAL 
Protocol 208109 (CDIFF-004) - Amendment 04 
 
114 
Appendix 8 
Signature of Investigator 
PROTOCOL TITLE: A Phase I, Single-center, Randomized, Observer-blind, Placebo-controlled 
Study to Evaluate Safety, Reactogenicity and Immunogenicity of GSK¶VClostridium difficile 
Investigational Vaccine Based on the F2 Antigen With or Without AS01B Adjuvant, When 
Administered Intramuscularly According to a 0, 1-month Schedule to Healthy Adults Aged 
Between 18-45 Years and Between 50-70 Years, Followed by an Additional Dose Administered 
in a Partial blind Manner Within an Interval of Approximately 15 Months After Dose 2, in a 
Subcohort of Subjects aged 50-70 Years 
PROTOCOL NO: 
208109 (CDIFF-004) 
VERSION:  
 
Amendment 04 
This protocol is a confidential communication of GlaxoSmithKline Biologicals SA. I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol. I will 
also work consistently with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with Good Clinical Practices and the applicable laws and 
regulations. Acceptance of this document constitutes my agreement that no unpublished 
information contained herein will be published or disclosed without prior written approval from 
the Sponsor. 
Instructions to the Investigator:  Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to Sponsor or CRO. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:      __________________________            Date:  ________ 
Printed Name:                                ___________________________ 
Investigator Title:                           ___________________________ 
 
Name/Address of Center:               
___________________________ 
 
 
 
 
 
___________________________ 
 
 
 
 
 
___________________________ 


Protocol Amendment (Study Level) - 4 - Final Deliverable including Sponsor
Signature - 06-Dec-2021
Electronic Signature Manifestation
This page is a manifestation of the electronic signature(s) used in compliance with the organization's
electronic signature policies and procedures.
Page 115 - Object 1000551A0000000052466A13
Signer Full Name
Meaning of Signature
Date and Time
Document Approval (I certify that I have the education,
training and experience to perform this task)
06 Dec 2021
08:31:17 UTC
PPD

SAP_001.pdf: 
Statistical Analysis Plan Amendment 3
Study ID:  208109
Official Title of Study: A Phase I, Single-center, Randomized, Observer-blind, 
Placebo-controlled Study to Evaluate Safety, Reactogenicity and Immunogenicity of 
GSK’s Clostridium difficile Investigational Vaccine Based on the F2 Antigen With or 
Without AS01B Adjuvant, When Administered Intramuscularly According to a 0, 1-
month Schedule to Healthy Adults Aged Between 18-45 Years and Between 50-70 
Years, Followed by an Additional Dose Administered in a Partial blind Manner Within 
an Interval of Approximately 15 Months After Dose 2, in a Subcohort of Subjects aged 
50-70 Years
NCT number: NCT04026009
Date of Document: 01 Oct 2021


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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 1 of 34 
STATISTICAL ANALYSIS PLAN 
208109 (CDIFF-004) 
A PHASE I, SINGLE-CENTER, RANDOMIZED, OBSERVER-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE SAFETY, REACTOGENICITY AND 
IMMUNOGENICITY OF 
S CLOSTRIDIUM DIFFICILE INVESTIGATIONAL 
VACCINE BASED ON THE F2 ANTIGEN WITH OR WITHOUT AS01B ADJUVANT, 
WHEN ADMINISTERED INTRAMUSCULARLY ACCORDING TO A 0, 1-MONTH 
SCHEDULE TO HEALTHY ADULTS AGED BETWEEN 18-45 YEARS AND 
BETWEEN 50-70 YEARS, FOLLOWED BY AN ADDITIONAL DOSE 
ADMINISTERED IN A PARTIAL BLIND MANNER WITHIN AN INTERVAL OF 
APPROXIMATELY 15 MONTHS AFTER DOSE 2, IN A SUBCOHORT OF SUBJECTS 
AGED 50-70 YEARS 
AUTHOR: 
 
VERSION NUMBER AND DATE: V3.0, 27SEP2021 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 2 of 34 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE - AUTHORS 
 
 
Name 
Signature 
Date 
Author: 
 
 
 
 
Position: 
Biostatistician 
 
Company: 
IQVIA RDS Inc. 
 
 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 3 of 34 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE - APPROVAL 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, 
authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
 
 
 
 
Position: 
Lead Statistician  BSP Early Clinical Statistics 
 
Company: 
GSK Vaccine 
 
Approved By: 
 
 
 
 
Position: 
 
 
Company: 
 
 
Approved By: 
 
 
 
 
Position: 
 
 
Company: 
 
 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 4 of 34 
MODIFICATION HISTORY 
 
Listed below are modifications made to the SAP after the signed approval(s).  
 
Unique 
Identifier 
for this 
Version
Date of the 
Document 
Version
Author
Significant Changes from  
Previous Authorized Version
1.0 
01AUG2019 
 
Not Applicable  First Version
2.0 
12JAN2021 
 
COVID-19 impact related text added 
within various sections 
 
 
  
3.0 
27SEP2021 
 
Added information about an additional 
third dose to be given to subjects on 
active treatment due to protocol 
amendment 03 dated 18MAY2021 
Added information about second 
interim analyses 
Added information about analysis sets 
related to the Dose 3 
 
 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 5 of 34 
TABLE OF CONTENTS  
1. INTRODUCTION................................................................................................................................8 
2. 
.........................................................................................................................8 
2.1. 
Primary Objective ........................................................................................................................................8 
2.2. 
Secondary Objectives ..................................................................................................................................8 
3. STUDY DESIGN..................................................................................................................................8 
3.1. 
General Description .....................................................................................................................................8 
3.2. 
Schedule of Events..................................................................................................................................... 12 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 12 
3.4. 
Treatment Allocation to the Subject .......................................................................................................... 12 
4. 
....................................................................................................................13 
4.1. 
Internal Safety Review Committee (iSRC) .................................................................................................. 13 
4.2. 
Safety Review Team (SRT) ......................................................................................................................... 13 
4.3. 
Interim Analysis ......................................................................................................................................... 13 
4.4. 
Final Analysis ............................................................................................................................................. 14 
5. 
SETS ..............................................................................................................................15 
5.1. 
Enrolled Set ............................................................................................................................................... 15 
5.2. 
Exposed Set ............................................................................................................................................... 15 
5.2.1. 
Unsolicited Safety Set ...............................................................................................................................15 
5.2.2. 
Solicited Safety Set ...................................................................................................................................15 
5.2.3. 
Subcohort Exposed Set .............................................................................................................................15 
5.3. 
Full Analysis Set ......................................................................................................................................... 15 
5.4. 
Per-protocol Set ........................................................................................................................................ 16 
5.4.1. 
Per-protocol Set for analysis of immunogenicity at Day 61 .....................................................................16 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 6 of 34 
5.4.2. 
Per-protocol Set for analysis of immunogenicity at Day 180 ...................................................................16 
5.4.3. 
Per-protocol Set for analysis of immunogenicity at Day 390 ...................................................................16 
5.5. 
Subcohort Per-protocol Set ....................................................................................................................... 16 
5.5.1. 
Subcohort Per-protocol Set for analysis of immunogenicity at Day 521 ..................................................16 
5.5.2. 
Subcohort Per-protocol Set for analysis of immunogenicity at Day 670 ..................................................16 
5.6. 
COVID-19 Set ............................................................................................................................................. 17 
6. 
CONSIDERATIONS.....................................................................................................17 
6.1. 
Summary Statistics .................................................................................................................................... 18 
6.2. 
Treatment Summarization ......................................................................................................................... 18 
6.3. 
Precision .................................................................................................................................................... 18 
6.4. 
Reference Start Date and Study Day .......................................................................................................... 19 
6.4.1. 
Attributing events to vaccine doses .........................................................................................................20 
6.5. 
Baseline ..................................................................................................................................................... 20 
6.6. 
Common Calculations ................................................................................................................................ 20 
6.7. 
Software Versions ..................................................................................................................................... 20 
7. 
ATIONS .............................................................................................21 
7.1. 
Missing data .............................................................................................................................................. 21 
7.1.1. 
Dates .........................................................................................................................................................21 
7.1.2. 
Laboratory Data ........................................................................................................................................21 
7.1.3. 
Adverse Events .........................................................................................................................................22 
7.2. 
Data Derivation ......................................................................................................................................... 23 
7.2.1. 
Body Mass Index .......................................................................................................................................23 
7.2.2. 
Age at vaccination in years .......................................................................................................................23 
7.2.3. 
Onset day ..................................................................................................................................................23 
7.2.4. 
Duration of events ....................................................................................................................................23 
7.2.5. 
Counting rules for combining solicited and unsolicited adverse events ..................................................23 
7.2.6. 
Counting rules for occurrences of solicited adverse events .....................................................................24 
7.2.7. 
Geometric mean titers (GMTs) .................................................................................................................24 
8. 
.........................................................................................................24 
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Page 7 of 34 
9. 
DRAWALS .......................................................................................25 
10. 
ISTICS..........................................25 
11. 
............................................................................................................25 
11.1. 
Deviations Related to Study Conduct ..................................................................................................... 25 
11.2. 
Deviations Related to Immunogenicity Analysis .................................................................................... 26 
12. 
.......................................................................................................................27 
13. MEDICATIONS................................................................................................................................27 
14. 
.............................................................................................27 
15. 
SIS...................................................................................................27 
15.1. 
Exploratory Analysis .............................................................................................................................. 29 
16. 
......................................................................................................................29 
16.1. 
Adverse Events ...................................................................................................................................... 29 
16.1.1. 
Adverse Events  Leading to Discontinuation from Study or from Treatment...........................................31 
16.1.2. 
Serious Adverse Events .............................................................................................................................31 
16.1.3. 
Derivation .................................................................................................................................................31 
16.2. 
Safety Laboratory Evaluations ............................................................................................................... 31 
16.2.1. 
Grading for Laboratory Data .....................................................................................................................32 
16.3. 
Vital Signs .............................................................................................................................................. 32 
16.4. 
COVID-19 ............................................................................................................................................... 32 
17. 
...........................................................................32 
18. REFERENCES...................................................................................................................................34 
 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 8 of 34 
1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of 
safety and immunogenicity data at first (interim), second (interim) and final analyses for Protocol 
208109 (CDIFF-004). It describes the data to be summarized and analyzed, including specifics of the 
statistical analyses to be performed. This statistical analysis plan (SAP) is based on protocol 
amendment 03 dated 18 May 2021. The iSRC/SRT analyses will be described in a separate document. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
To evaluate the safety and reactogenicity profile of the C. difficile F2 fusion protein when administered 
with or without AS01B adjuvant as 2 intra-muscular (IM) doses according to a 0, 1-month schedule, in 
healthy adults aged between 18-45 years and between 50-70 years followed by an additional dose 
administered approximately 15 months after Dose 2 in a subcohort of subjects aged 50-70 years, 
during the entire study period 
2.2. SECONDARY OBJECTIVES 
To evaluate the humoral immunogenicity induced by 2 IM doses of the C. difficile F2 fusion protein 
when administered with or without AS01B adjuvant according to a 0, 1-month schedule, in healthy 
adults aged between 18-45 years and between 50-70 years followed by an additional dose 
administered approximately 15 months after Dose 2 in a subcohort of subjects aged 50-70 years, up to 
study end  
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a Phase I, first-in-human, single-center, randomized, observer-blind, placebo-controlled, study 
with 2 to 3 treatment groups per step in a 4-step staggered design in healthy subjects to generate 
safety, reactogenicity, and immunogenicity data for the development of a candidate C. difficile vaccine 
that would protect against primary cases of CDI and CDI recurrence. 
A 4-step staggered design will be used to ensure maximum safety of the participating subjects: 
Step 1: Vaccination of approximately 20 subjects aged 18-45 years (approximately 10 subjects in the 
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Page 9 of 34 
CDIFF antigen [Ag] group and approximately 10 subjects in the placebo group). An internal safety 
review committee (iSRC) will review all accumulating safety data after Dose 1 and then again after 
Dose 2. Vaccination in Step 2 will proceed in the absence of a safety concern detected by the iSRC on 
all accumulating safety data at the end of Step 1. 
Step 2: Vaccination of approximately 20 subjects aged 50-70 years (approximately 10 subjects in the 
CDIFF Ag group and approximately 10 subjects in the placebo group). An iSRC will review all 
accumulating safety data after Dose 1 and then again after Dose 2. Vaccination in Step 3 will proceed 
in the absence of a safety concern detected by the iSRC on all accumulating safety data at the end of 
Step 2. 
Step 3: Vaccination of approximately 30 subjects aged 50-70 years (approximately 10 subjects in the 
CDIFF Ag group, approximately 10 subjects in the CDIFF Ag + an adjuvant system containing 
3-O-desacyl- -monophosphoryl lipid A [MPL], QS-21 and liposome [50 
 
-21] 
[AS01B] group, and approximately 10 subjects in the placebo group). An iSRC will review all 
accumulating safety data after Dose 1 and then again after Dose 2. Vaccination in Step 4 will proceed 
in the absence of a safety concern detected by the iSRC on all accumulating safety data at the end of 
Step 3. 
Step 4: Vaccination of approximately 70 subjects aged 50-70 years (approximately 25 subjects in the 
CDIFF Ag group, approximately 35 subjects in the CDIFF Ag + AS01B group, and approximately 
10 subjects in the placebo group). An iSRC will review all accumulating safety data 3 weeks after the 
start of vaccination in Step 4 and then about every 3 weeks until all subjects have received Dose 1. In 
addition, the iSRC will review all safety data after Dose 2. A subcohort of subjects who have 
successfully completed all visits up to Visit 7, have received two doses on an active arm (ie, the 
subjects who received placebo will be excluded) do not meet any contraindication for subsequent 
vaccination, and still meet the eligibility criteria will receive a third dose after the iSRC has reviewed all 
the accumulating safety data at the end of Step 4 Dose 2. If there are any safety concerns observed 
during SRT reviews post Dose 3, an ad hoc iSRC meeting will take place to review the unblinded safety 
data. 
During all 4 steps, all subjects should be closely observed for at least 60 minutes after vaccination. For 
Steps 1, 2, and 3 only, all subjects should be vaccinated sequentially and at least 60 minutes apart to 
allow for monitoring of any acute events (eg, hypersensitivity reaction). During vaccination days of 
Steps 1, 2, and 3 (ie, Day 1 and Day 31), vaccination will be limited to a maximum of 10 subjects per 
day. A total of 120 subjects aged 50  70 years (30 receiving placebo, 45 receiving CDIFF Ag and 
45 receiving CDIFF Ag + AS01B) and 20 subjects aged 18-45 years (10 receiving placebo and 10 receiving 
CDIFF Ag) will be enrolled in this study. The duration of the study for each subject receiving 2 doses will 
be approximately 1 year (Visit 7) and each subject receiving 3 doses will be approximately 2 years (Visit 
11).  
Study treatment will be administered as indicated below: 
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Page 10 of 34 
Type of 
Contact and 
Timepoint 
Study Group 
Treatment 
Name 
Volume to be 
Administered 
Route 
Injection Site 
Location 
Lateralitya 
Visit 1 
(Day 1) 
Placebo 
Placebo 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag 
CDIFF Ag 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag + 
AS01B 
CDIFF Ag + 
AS01B 
0.5 mL 
IM 
Deltoid 
Nondominant 
Visit 3 
(Day 31) 
Placebo 
Placebo 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag 
CDIFF Ag 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag + 
AS01B 
CDIFF Ag + 
AS01B 
0.5 mL 
IM 
Deltoid 
Nondominant 
Visit 8 for 
Step 4 
(Day 491) 
CDIFF Ag 
CDIFF Ag 
0.5 mL 
IM 
Deltoid 
Nondominant 
CDIFF Ag + 
AS01B 
CDIFF Ag + 
AS01B 
0.5 mL 
IM 
Deltoid 
Nondominant 
Ag = antigen; AS01B = an adjuvant system containing MPL, QS-21 and liposome (50 
50 
-21); IM = intramuscular; 
MPL = 3-O-desacyl-
-monophosphoryl lipid A. 
a 
The nondominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the nondominant arm, an 
injection in the dominant arm may be performed. 
Table A: 
Study Design Overview 
 
 
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Page 11 of 34 
 
Table B: 
Intervals between Study Visits 
Interval 
Optimal Length of Interval 
Allowed Interval 
Screening 
 
1 to 15 days 
- 
Visit 1 (Day 1) 
 
7 days 
7 to 9 days 
Visit 1 (Day 1) 
 
30 days 
30 to 35 days 
Visit 3 (Day 31) 
 
7 days 
7 to 9 days 
Visit 3 (Day 31) 
 
30 days 
30 to 35 days 
Visit 3 (Day 31) 
 
149 days 
140 to 160 days 
Visit 3 (Day 31) 
 
359 days 
350 to 395 days 
Visit 7 (Day 390) 
3 (Day 476) 
20 to 150 days 
- 
Screening Dose 3 (Day 476) 
8 (Day 491) 
1 to 15 days 
- 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 12 of 34 
Visit 8 (Day 491) 
498) 
7 days 
7 to 9 days 
Visit 8 (Day 491) 
521) 
30 days 
30 to 35 days 
Visit 8 (Day 491) 
670) 
179 days 
170 to 190 days 
 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 1.3, Table 5 of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
Given the staggered enrolment, step is used as stratification factor in the randomization algorithm. 
Step will be used as a covariate in the inferential analysis. 
The sponsor has decided not to perform ELISA assay in the study. All references to concentrations from 
ELISA have been deleted from the last approved SAP in this document. 
3.4. TREATMENT ALLOCATION TO THE SUBJECT 
Treatment numbers will be allocated by dose. 
The enrolment will be performed to control the distribution of the population within the age strata 
(subjects 18-45 years of age versus subjects 50-70 years of age) and within each step (step 1 to step 4). 
Allocation of the subject to a study group at the study center will be performed using SBIR (a 
randomization system on internet). Within the 18-45 years age and step 1 strata, the randomization 
algorithm will use a minimization procedure accounting for gender (female, male), while within the 
50-70 years age and step 2 to step 4 strata, the randomization algorithm will use a minimization 
procedure accounting for age (50-59 years of age, 60-70 years of age) and gender (female, male). 
Minimization factors will have equal weight in the minimization algorithm. 
After obtaining the signed or witnessed/thumb printed and dated informed consent form (ICF) from 
the subject and having checked the eligibility of the subject, the study staff in charge of the vaccine 
administration will access SBIR. At each step, upon providing the age (subjects18-45 years of age 
versus subjects 50-70 years of age), the gender, and the subject identification number, the 
randomization system will determine the study group and will provide the treatment number to be 
used for the first dose. 
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Page 13 of 34 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. When SBIR is not available, please refer to the SBIR user guide or the study 
procedures manual (SPM) for specific instructions. 
4. PLANNED ANALYSES 
4.1. INTERNAL SAFETY REVIEW COMMITTEE (ISRC) 
As the investigational vaccine formulation will be administered to human for the first time, an iSRC will 
be appointed. This study will be overseen by an iSRC operating under a charter. Please refer to iSRC 
charter for details. 
4.2. SAFETY REVIEW TEAM (SRT) 
The SRT is responsible for ongoing safety monitoring of the entire project and meets on a regular basis. 
The SRT will inform the iSRC about any potential safety concern relevant to the study (in a blinded 
way).  
Before each iSRC safety evaluation in this study (see above), the SRT will review the same safety data, 
but in a blinded manner to keep all people involved in the conduct, cleaning and final analysis of the 
study blinded. Please refer to iSRC charter for details. 
4.3. INTERIM ANALYSIS 
A first analysis will be performed when all data up to Day 61 (ie, data that are as clean as possible) are 
available. The immunogenicity data available until Day 61, and the safety and reactogenicity data 
available   at the time of this analysis will be summarized based on unblinded treatment groups. At this 
point, the IQVIA statistical team, including those responsible for creating the programs to produce the 
outputs for the Interim Analysis, will be unblinded for the analysis (ie, will have access to individual 
subject treatment assignments). Whenever it is needed after the interim analyses, the GSK statistical 
team may have access to individual subject treatment and data. 
The remaining study personnel will stay blinded (ie, will not have access to the individual subject 
treatment assignment) until study end. It is possible however, due to the limited sample size, that 
unblinding occurs for a few subjects having a specific AE or SAE  (eg, an AE/SAE occurring only in a 
single group). Therefore, anyone having access to the analysis of Day 61 could become unblinded 
regarding those specific cases. The study will be considered as partial-blind from this point onwards. 
Subjects will be provided with information about the study arm, via the investigator at the study end. 
Note: In a partial-blind study, the subject, the investigator, or anyone assessing the outcome is aware 
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Page 14 of 34 
of the assignment in at least one treatment group but unaware of the treatment assignment(s) in one 
or more other treatment groups. Individual listings will be provided at the study end to the 
investigator. 
The second interim analysis will be performed when all data up to 1 month after Dose 3, ie, Day 521 
(ie, data that are as clean as possible) are available. The immunogenicity data available until Day 521, 
and the safety and reactogenicity data available at the time of this analysis will be described. No 
individual listings will be provided. 
Given the multitude of the immunogenicity assays (TNA with different cell lines), the interim analysis 
may be performed in several parts upon the availability of assay results (until Day 61 or Day 521). The 
first part will include the available immunogenicity assay results (until Day 61 or Day 521) and safety 
data available. The subsequent parts will include only additional data results of immunogenicity assays 
that become available later. Any immunogenicity data (until Day 61 or Day 521) that become available 
at the end of the study will be included in the final (end of study) analysis.  
All analyses are descriptive and with the aim to characterize the safety and immunogenicity data and 
therefore no statistical adjustment for interim analysis is required.  
Derivations and definitions for the interim analyses will be based on those required for the final 
analysis contained in this analysis plan, unless deviations are stated within the text.  
All tables presenting summary statistics planned for final analysis will be generated at the time of 
interim analyses, only for the primary cohort (exposed set for safety and per protocol set/full analysis 
set for immunogenicity analyses). No unblinded individual subject listings and listing tables will be 
generated at the time of interim analyses.  
 
 
4.4. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following 
sponsor authorization of this Statistical Analysis Plan, database lock, and unblinding of treatment. The 
final analysis will be performed when all data up to study end are available.  
An integrated (final) CSR containing all data will be written and made available to the Principal 
Investigator at that time. The final CSR will contain at least the final analyses of all primary and 
secondary endpoints. In addition, all previous analyses will be re-produced based on cleaned data at 
this point. Individual listings will only be provided at this stage.  
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5. ANALYSIS SETS 
5.1. ENROLLED SET 
The enrolled set will contain all eligible subjects who provide informed consent for this study. Subjects 
in this population will be used for disposition summaries. 
5.2. EXPOSED SET  
The exposed set will contain all subjects who have received at least 1 dose of study treatment and will 
be analyzed according to treatment received. Subjects with invalid informed consent or fraudulent 
data will be excluded from this cohort. Subjects in this population will be used for demographic and 
dosing summaries. 
The allocation in a group is done in function of the first administered treatment: 
5.2.1. 
UNSOLICITED SAFETY SET 
The unsolicited safety set will contain all subjects who have received at least 1 dose of study treatment 
(included in the Exposed Set) that report unsolicited AEs or report not having unsolicited AEs. 
5.2.2. 
SOLICITED SAFETY SET 
The solicited safety set will contain all subjects who received at least 1 dose of the study treatment 
(included in the Exposed Set) who have solicited safety data. 
5.2.3. 
SUBCOHORT EXPOSED SET 
The subcohort exposed set will contain all subjects who have received the Dose 3 on an active arm. 
5.3. FULL ANALYSIS SET  
The full analysis set will contain all subjects who received at least 1 dose of the study treatment to 
which they are randomized and have postvaccination immunogenicity data.  
The allocation in a group is done in function of the first treatment as per randomization.  
The Full Analysis Set will be performed if the percentage of vaccinated subjects with serological results 
excluded from the Per-protocol Set for analysis of immunogenicity is 10% or more. 
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5.4. PER-PROTOCOL SET   
The per-protocol set will contain all subjects included in the full analysis set minus subjects with 
protocol deviations that lead to exclusion. The protocol deviations leading to exclusion of the subjects 
are described in Section 11.2. Three Per-protocol Sets for analysis of immunogenicity will be derived: 
5.4.1. 
PER-PROTOCOL SET FOR ANALYSIS OF IMMUNOGENICITY AT DAY 61 
The analysis set will contain all subjects included in the Per-protocol Set, with no protocol deviations 
leading to exclusion until Day 61 and with at least 1 immunogenicity data available at Day 61. 
5.4.2. 
PER-PROTOCOL SET FOR ANALYSIS OF IMMUNOGENICITY AT DAY 180 
The analysis set will contain all subjects included in the Per-protocol Set, with no protocol deviations 
leading to exclusion until Day 180 and with at least 1 immunogenicity data available at Day 180. 
5.4.3. 
PER-PROTOCOL SET FOR ANALYSIS OF IMMUNOGENICITY AT DAY 390 
The analysis set will contain all subjects included in the Per-protocol Set, with no protocol deviations 
leading to exclusion until study end (Day 390) and with at least 1 immunogenicity data available at Day 
390. 
5.5. SUBCOHORT PER-PROTOCOL SET   
5.5.1. 
SUBCOHORT PER-PROTOCOL SET FOR ANALYSIS OF IMMUNOGENICITY AT DAY 521 
The analysis set will contain all subjects included in the Per-protocol Set, who received the Dose 3 on 
an active arm, with no protocol deviations leading to exclusion until Day 521 and with at least 1 
immunogenicity data available at Day 521. 
5.5.2. 
SUBCOHORT PER-PROTOCOL SET FOR ANALYSIS OF IMMUNOGENICITY AT DAY 670 
The analysis set will contain all subjects included in the Per-protocol Set, who received the Dose 3 on 
an active arm, with no protocol deviations leading to exclusion until Day 670 and with at least 1 
immunogenicity data available at Day 670. 
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5.6. COVID-19 SET   
The analysis set will contain all subjects included in the exposed set who were not able to go to the site 
for the Visit 5 (Day 61) on schedule, due to study being paused during COVID-19, and as a result, had 
their immunogenicity samples collected outside of the protocol specified interval. This analysis set will 
be used for additional descriptive summaries of immunogenicity variables. 
 
* The safety/reactogenicity analysis will be first performed on the exposed set. If >=10% of subjects 
have missing information for unsolicited symptoms, then the analyses on the unsolicited safety set will 
be performed. 
** Analysis in this set will be performed if the percentage of vaccinated subjects with serological 
results excluded from the Per-protocol Set for analysis of immunogenicity is 10% or more 
6. GENERAL CONSIDERATIONS 
The safety summaries, data listings and figures as well as the statistical analysis of the variables will be 
the responsibility of the study biostatistician at IQVIA. 
Analysis 
Enrolled 
Set 
Exposed 
Set 
Un- 
solicited 
Safety 
Set* 
Solicited 
Safety 
Set 
Full 
Analysis 
Set** 
Per-protocol 
(PP) Set 
Subcohort 
PP Set 
COVID-19 
Set 
PP 
Set 
Day 
61 
PP 
Set 
Day 
180
PP 
Set 
Day 
390
PP 
Set 
Day 
521 
PP 
Set 
Day 
670 
Subject 
Disposition 
 
 
 
 
 
 
 
 
 
 
Baseline 
Assessments 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
 
 
 
 
 
 
 
 
 
Exposure 
 
 
 
 
 
 
 
 
 
 
Immunogenicity 
Analysis 
 
 
 
 
 
 
Protocol 
Deviations 
 
 
 
Adverse Events
 
 
 
Other Safety 
(lab, vitals) 
 
 
 
 
 
 
 
 
 
 
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6.1. SUMMARY STATISTICS 
For qualitative variables, the population size (N for sample size and n for available data) and the 
percentage (of available data) for each class of the variable will be presented.  Quantitative variables 
will be summarized using descriptive statistics, including N (with data available), Nmiss (with missing 
data), mean, standard deviation (SD), coefficient of variation (CV%), median, Q1, Q3, minimum, and/or 
maximum values.  Geometric mean will be included for immunogenicity parameters, where applicable. 
Coefficient of variation will not be presented for change from baseline results.  
The exact two-sided 95% CIs for a proportion within a group will be calculated using the Clopper-
Pearson exact method. 
The geometric mean antibody titers (GMTs) calculations will be performed by taking the anti-log of the 
mean of the log10 titer transformations. Confidence interval for geometric means will be derived by 
raising 10 to the confidence interval associated with mean of log10 values i.e. CI of geometric mean = 
10^(CI for the mean of log10 values). All subjects with data will be considered. Subjects whose 
antibody titers are below the cut-off of the assay will be given an arbitrary value of half the cut-off for 
the purpose of GMT calculation.  
6.2. TREATMENT SUMMARIZATION 
In general, data will be presented for each treatment group: 
Age 
Treatment 
50-70 Y 
CDIFF Ag + AS01B 
CDIFF Ag 
Placebo 
18-45 Y 
CDIFF Ag 
Placebo 
Data for all study subjects combined will also be presented when appropriate. Analysis by age in older 
adult cohort will be performed by age strata (50-59 years old and 60-70 years old) for the descriptive 
immunogenicity analyses if at least 6 subjects are available in these subgroups and in at least one 
active arm.  
6.3. PRECISION 
Safety data (vital signs, laboratory parameters) and immunogenicity data will be reported to the same 
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Page 19 of 34 
precision as the source data.  
For the reporting of descriptive statistics, the mean, median, Q1, Q3, standard deviation, standard 
error and confidence intervals will be presented to one digit more precision than the source data. The 
minimum and maximum will be presented to the same precision as the source data.  Coefficient of 
variation (%) will always be reported to 1 decimal place. P-values, if any, shall be reported to four 
decimal places or as <0.0001. 
The number of decimals used when displaying geometric mean titers (GMT) and their confidence limits 
is shown in the following table: 
GMT value 
Number of decimals to display 
<0.1 
3 
>=0.1 and <10 
2 
>=10 and <1000 
1 
>=1000 
0 
When multiple categories of GMT/GMC values are present in the same table, the number of decimals 
displayed should match that of the smallest category (i.e. the one with the higher number of 
decimals). GMFR or GMT/GMC ratios and their confidence limits will be displayed with 2 decimals 
regardless of the actual values. 
6.4. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/stop day of 
assessments and events.  
Reference start date is defined as the day of the first dose of study vaccination, (Day 1 is the day of the 
first dose of study treatment) and will appear in every listing where an assessment date or event date 
appears.  
 
If the date of the event is on or after the reference date, then:  
Study Day = (date of event  reference date) + 1. 
 
If the date of the event is prior to the reference date, then:  
Study Day = (date of event  reference date). 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations 
will appear partial or missing in the listings. Refer to Section 7.1.1 for rules applicable on partially 
completed dates when used in calculations. 
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Page 20 of 34 
6.4.1. 
ATTRIBUTING EVENTS TO VACCINE DOSES  
The dose relative to an event is the most recent study dose given to a subject prior to the start of a 
given event. For example, if the start date of an adverse event is between Dose 1 and Dose 2, the 
relative dose will be Dose 1. 
If an event starts on the same day as a study dose, the relative dose will be derived from the additional 
information provided in the CRF using the contents of the flag indicating if the event occurred before 
 selected, the relative dose for the event will be the one 
event will be the dose prior to this one. Where applicable, the event will be classified a
-
 
6.5. BASELINE 
Baseline is defined as the last scheduled non-missing measurement taken prior to dosing and will 
correspond to Day 1, predose for immunogenicity assessments, hematology and biochemistry, and 
vital signs.  However, if a subject is missing the planned baseline result, the previous non-missing 
evaluation will become the baseline value.  
6.6. COMMON CALCULATIONS 
For quantitative safety measurements (e.g. vital signs, laboratory parameters), change from baseline 
will be calculated as: 
 
Test Value (after baseline)  Baseline Value 
For immunogenicity measurements, change from baseline will be calculated as: 
 
Test Value (after baseline)/Baseline Value 
6.7. SOFTWARE VERSIONS 
All derivations, statistical analyses, summaries, graphs and listings will be generated using SAS version 
9.4 or higher (SAS Institute, Inc., Cary, North Carolina).  
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Page 21 of 34 
7. STATISTICAL CONSIDERATIONS 
7.1. MISSING DATA 
Missing immunogenicity data will be handled as described in Section 15. Following imputation will be 
used for statistical calculations (and not for subject listings): 
7.1.1. 
DATES  
When partially completed birth dates (i.e. with missing day or month) are used in calculations, the 
following standard rules will be applied: 
- 
A missing day will be replaced by 15 
- 
A missing day and month will be replaced by June 30th 
The following exceptions apply: 
- 
Adverse event start dates with missing day: 
o If the event starts in the same month as at least one of the study doses, the contents of 
AE.AESTRTPT (the flag indicating if the event occurred before or after vaccination) will be 
selected, the imputed date will be one day before  the first (or only) study dose given 
during that month. 
- 
Adverse event start dates with missing day and month: 
o If the event starts in the same year as at least one of the study doses, the contents of 
AE.AESTRTPT (the flag indicating if the event occurred before or after vaccination) will be 
selected, the imputed date will be one day before  the first (or only) study dose given 
during that year. 
All other cases of incomplete AE or concomitant medication/vaccination start date will follow the 
standard rules as outlined in Section 6.4.  
7.1.2. 
LABORATORY DATA 
Missing laboratory results will not be replaced. 
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7.1.3. 
ADVERSE EVENTS 
Solicited Adverse Events: 
Daily recording of solicited adverse events: For symptom screens indicating the presence or absence of 
solicited adverse events, the following rules are applicable: 
 
- 
Denominators for the summary of local (or general) solicited adverse events will be 
calculated using the number of subjects who respond 
concerning the occurrence of local (or general) adverse events. 
 
- 
When a specific solicited adverse event is marked as having not occurred following a 
specific vaccination (i.e. SDTM CE.CEOCCUR=N for the specified post-vaccination period 
for the adverse event in question), all daily measurements will be imputed as Grade 0. 
 
- 
When a specific solicited adverse event is marked as having occurred following a specific 
vaccination (i.e. SDTM CE.CEOCCUR=Y for the specified post-vaccination period for the 
adverse event in question), any missing daily recordings will be given imputed values to 
allow them t
adverse event summary tables. 
 
- 
When the occurrence of a specific solicited adverse event is not present (i.e. SDTM 
CE.CEOCCUR is neither Y nor N for the specified post-vaccination period for the symptom 
in question) but the group of solicited adverse events (local or general) is marked as 
having occurred (i.e. SDTM CE.CEOCCUR=Y), all missing daily recordings will be given 
ws but not to specific grade 
rows of the solicited adverse event summary tables. 
 
The following table shows how subjects contribute to each category for a specific solicited adverse event 
over the Day X to Day Y post-vaccination period: 
Solicited adverse event 
category 
Subjects included in the calculation of the numerator 
Any 
All subjects with at least one occurrence of the adverse event at grade 1, 
grade 2, or grade 3 between Day X and Day Y or with the adverse event 
marked as present and at least one missing daily recording between Day X 
and Day Y 
At least grade 1 
All subjects with at least one occurrence of the adverse event at grade 1, 
grade 2, or grade 3 between Day X and Day Y 
At least grade 2 
All subjects with at least one occurrence of the adverse event at grade 2 or 
grade 3 between Day X and Day Y 
At least grade 3 
All subjects with at least one occurrence of the adverse event at grade 3 
between Day X and Day Y 
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Page 23 of 34 
 
Unsolicited adverse events 
Unsolicited adverse event summaries are including serious adverse events unless specified otherwise.  
Missing severity, relationship with study vaccine, and outcome of unsolicited adverse events will not be 
istical listings. 
7.2. DATA DERIVATION 
7.2.1. 
BODY MASS INDEX 
BMI (kg/ m2) = weight (kg)/ height (m)2 
7.2.2. 
AGE AT VACCINATION IN YEARS 
When age at vaccination is to be displayed in years, it will be calculated as the number of complete 
calendar years between the date of birth and the date of vaccination. For example: 
DOB = 10SEP1983, Date of vaccination = 09SEP2018 -> Age = 34 years 
DOB = 10SEP1983, Date of vaccination = 10SEP2018 -> Age = 35 years 
7.2.3. 
ONSET DAY 
The onset day for an event (e.g. AE, medication, vaccination) is the number of days between the last 
study vaccination and the start date of the event. This is 1 for an event occurring on the same day as a 
vaccination (and reported as starting after vaccination) 
7.2.4. 
DURATION OF EVENTS 
The duration of an event with a start and end date will be the number of days between the start and end 
dates plus one day, i.e. an event that starts on 03MAR2018 and ends on 12MAR2018 has a duration of 
10 days. 
 
The duration of solicited events will be calculated as the sum of the individual days with the symptom 
reported at grade 1 or higher. 
7.2.5. 
COUNTING RULES FOR COMBINING SOLICITED AND UNSOLICITED ADVERSE EVENTS 
For output combining solicited and unsolicited adverse events, all serious adverse events will be 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 24 of 34 
considered general events  since the administration site flag is not included in the expedited adverse 
event CRF pages. 
 
Multiple events with the same preferred term which start on the same day are counted as only one 
occurrence. 
7.2.6. 
COUNTING RULES FOR OCCURRENCES OF SOLICITED ADVERSE EVENTS 
When the occurrences of solicited adverse events are summarized, each event recorded as having 
occurred during a specific period will be counted as only one occurrence regardless of the number of 
days on which it occurs. 
 
For a given subject and the analysis of solicited symptoms within 7 days post-vaccination, missing or non-
evaluable measurements will not be replaced. Therefore the analysis of the solicited will include only 
vaccinated subjects for doses with documented safety data (i.e., symptom screen completed). More 
specifically the following rules will be used:  
- 
Subjects who documented the absence of a solicited symptom after one dose will be 
considered not having that symptom after that dose. 
- 
Subjects who documented the presence of a solicited symptom and fully or partially 
recorded daily measurement over the solicited period will be included in the summaries 
at that dose and classified according to their maximum observed daily recording over the 
solicited period. 
- 
Subjects who documented the presence of a solicited symptom after one dose without 
having recorded any daily measurement will be assigned to the lowest intensity category  
at that dose (i.e. 38°C for fever or grade 1 for other symptoms). 
- 
Doses without symptom sheets documented will be excluded.  
7.2.7. 
GEOMETRIC MEAN TITERS (GMTS)  
Geometric Mean Titer (GMT) calculations are performed by taking the inverse logarithm of the mean 
of the log titer transformations. Antibody titers below the cut-off of the assay will be given an arbitrary 
value of half the cut-off of the assay for the purpose of GMT calculation. The cut-off value will be 
defined by the laboratory before the analysis. 
8. OUTPUT PRESENTATIONS 
The templates provided with this SAP describe the presentations for this study and therefore the 
format and content of the summary tables, figures and listings to be provided by IQVIA Biostatistics. 
Some minor modifications may be necessary to the planned design of tables, figures, and listings to 
accommodate data collected during the actual study conduct. 
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9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this study. Subject disposition will 
be tabulated for each study treatment and for all subjects combined with the number of subjects who 
are randomly assigned to treatment, complete the study, prematurely discontinue, and the reason for 
early discontinuation.  A listing will present dates of completion or early withdrawal and the reason for 
early discontinuation, if applicable, for each subject.   
Listings of inclusion/exclusion criteria responses, study protocol deviations, treatment randomization 
and study treatment administration will be provided. 
A listing of subjects whose trial participation was impacted by COVID-19 will be presented along with 
the description of the impact. Number of subjects who discontinued study drug or study due to COVID-
19 infection or issues related to the COVID-19 pandemic will be summarized. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Individual subject demographics and baseline characteristics (medical history and results from 
pregnancy tests) will be presented in listings.   
Demographic characteristics such as age, sex, race, ethnicity, height, weight, and body mass index 
(BMI) will be summarized and tabulated by treatment and for all subjects overall.  Descriptive statistics 
(mean, median and standard deviation) will be presented for age, height, weight, and BMI.  Frequency 
counts and percentages will be presented for sex, race, ethnicity, age group (50-59 years old and 60-70 
years old) and step.   
No statistical testing will be carried out for demographic or other baseline characteristics. 
11. PROTOCOL DEVIATIONS 
11.1. DEVIATIONS RELATED TO STUDY CONDUCT 
A protocol deviation is any noncompliance with the clinical trial protocol, good clinical practice (GCP), 
or Manual of Procedure requirements. The noncompliance may be either on the part of the subject, 
the site PI, or the study site staff.  
Any subject enrolled who does not meet eligibility criteria will be considered an enrollment deviation.  
Protocol deviations will be listed including a classification of minor, major, or critical as determined by 
clinical staff.  Any protocol deviation related to study conduct that is assessed as COVID-19 related will 
be clearly identified in the outputs and clinical study report. 
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11.2. DEVIATIONS RELATED TO IMMUNOGENICITY ANALYSIS 
Changes to the procedures or events, which may impact the quality of the immunogenicity data, will 
be considered significant protocol deviations and will be described within the clinical study report. 
These changes or events will include any circumstances that will alter the evaluation of the 
immunogenicity results. Examples include, but may not be limited to, sample processing errors that 
lead to inaccurate immunogenicity results, and/or inaccurate dosing.  
Subjects may be eliminated from the per-protocol Set for analysis of immunogenicity if, during the 
study, they incur a condition that has the capability of altering their immune response or are 
confirmed to have an alteration of their initial immune status. Subjects may also be eliminated from 
the per-protocol set based on usage of certain concomitant medications/products/vaccines as 
described in Section 6.8.2 of the protocol. Such scenarios will be discussed by the study team and 
decision to exclude a subject and/or data from the Per-protocol analysis set (Day 61, Day 180 and Day 
390) or subcohort per-protocol analysis set (Day 521 and Day 670) will be taken on a case-by-case 
basis.  
Other deviations (not a comprehensive list) leading to elimination from the per-protocol set are: 
- 
Invalid informed consent 
- 
Fraudulent data 
- 
randomization code broken 
- 
dose volume insufficient 
- 
vaccination not according to protocol 
- 
vaccine dose storage conditions (temperature deviation) 
- 
vaccine administered out of expiry date 
- 
violation of inclusion/exclusion criteria 
- 
interval between doses 
- 
interval between post vaccination blood sampling and previous dose 
- 
two doses not in the same treatment group 
- 
concomitant infection related to study vaccine or not related to study vaccine that 
may alter the immune response 
- 
serology result at post vaccination dose 2 not available for all assays (blood sample not 
available or result not available) 
Protocol Deviation Management Plan (PDMP) describes the complete list of elimination codes that 
could lead to exclusion from the per-protocol set. 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
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12. MEDICAL HISTORY 
Medical History coded using MedDRA Version 22.0 will be presented for the exposed set. Medical 
history for subjects assessed as probable, confirmed or suspected case of COVID-19 will be 
summarized. 
13. MEDICATIONS 
Medication usage coded using the GSK Drug Dictionary Version 1.6 will be presented for the exposed 
set. 
 
 Prior  medications are medications which started and stopped prior to the first dose of study 
treatment.  
 
Concomitant  medications are medications which were taken during the treatment period, or 
specifically:  
o 
started after the first dose of study treatment or  
o 
started prior to the first dose of study medication and were continued after the first dose 
of study treatment  
The percentage of subjects using concomitant medications (any medication, any antipyretic and any 
antipyretic taken prophylactically, respectively) during the 7-day follow-up period and during the 30-
day follow-up period will be summarized by group after each vaccination and overall. 
14. STUDY MEDICATION EXPOSURE 
Exposure to study treatment as the number of doses administered will be presented for each 
treatment. Exposure for subjects assessed as probable, confirmed or suspected case of COVID-19 will 
be summarized separately. 
15. IMMUNOGENICITY ANALYSIS 
The primary analysis will be based on the Per-protocol Set for analysis of immunogenicity. If, in any 
study group, the percentage of vaccinated subjects with serological results excluded from the Per-
protocol Set for analysis of immunogenicity is 10% or more, a second analysis based on the Full 
Analysis Set will be performed. 
The analysis of subjects receiving Dose 3 on an active arm will be based on the Subcohort Per-protocol 
Set for analysis of immunogenicity. 
Numerical serology results will be derived from the content of IS.ISORRES in the SDTM dataset. For 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 28 of 34 
assays with a specific cut-off, the following derivation rules apply: 
IS.ISORRES 
Derived value 
-off 
cut-off/2 
-off 
value 
-off 
cut-off/2 
-off 
value 
is < cut-off 
cut-off/2 
-off 
value 
All other cases 
missing 
 
The following immunogenicity variables will be assessed: 
- 
Anti-Toxin A neutralizing antibody titers (using HT29 cell line) 
- 
Anti-Toxin B neutralizing antibody titers (using HCT116 cell line) 
A listing of collection dates and times for the immunogenicity variables will be presented for subjects 
within each treatment group. For each test method, the neutralizing antibody titers from TNA assay 
will be listed and summarized by treatment groups across all scheduled timepoints during entire study.  
For each study group, each age group (18-45 Y versus 50-70 Y) and/or subcohort (as applicable), at 
each timepoint that blood samples are collected for humoral immune response and for each assay: 
- 
Percentage of subjects above the assay cutoff with their exact 95% CI will be tabulated 
- 
Geometric mean titers and their 95% CI will be calculated 
- 
Geometric mean fold-rise with their exact 95% CI will be tabulated 
- 
Percentage of subjects with >=2, 4, 8, 16, 32, 64 fold-rise from baseline for each assay 
- 
Percentage of subjects with >=2, 4, 8, 16, 32, 64 fold-rise from baseline for both anti-Tox A and 
anti-Tox B for neutralizing titers  
- 
Antibody titers will be investigated using Reverse Cumulative Curves 
The same tabulations will be performed by age 50-59 Y versus 60-70 Y and by serostatus at baseline 
(above or equal to cut-off versus below the cut-off) [if at least 6 subjects are available in these sub-
group and in at least one active arm] 
Linear mixed model with repeated measures will be used to perform pairwise comparison between 
groups in anti-toxin A neutralizing antibody titers and anti-toxin B neutralizing antibody titers at Day 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 29 of 34 
31, Day 61, Day 180 and Day 390. The model will use fixed effects for treatment, time point, step, 
treatment×time point, baseline value as covariate, and a repeated time point effect within a subject 
under a unstructured covariance matrix. Variance between the groups will not be considered equal. 
Age and gender will be included in the model as covariates if the data allow. Additional covariance 
structures and suitable transformation (e.g. log) may be explored to attain convergence and meet 
model assumptions, respectively. This analysis will be performed on the age stratum 50-70 year old 
adults.  
A similar linear mixed model will be used to evaluate the difference between treatments for subjects 
who received the 3rd dose except the model will not include a fixed effect for step.
 
 
 
Descriptive summaries planned for immunogenicity variables (titers) described above will additionally 
be presented for COVID-19 analysis set. 
15.1. EXPLORATORY ANALYSIS 
16. SAFETY OUTCOMES 
There will be no statistical comparisons between the treatment groups for safety data, unless 
otherwise specified with the relevant section.  
16.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using Medical Dictionary for Regulatory Activities (MedDRA) central 
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CCI
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STATISTICAL ANALYSIS PLAN: PROTOCOL 208109 (CDIFF-004) 
Page 30 of 34 
coding dictionary, Version 22.0. 
The percentage of subjects with at least 1 local AE (solicited and unsolicited), with at least 1 general AE 
(solicited and unsolicited) and with any AE during the 7-day or the 30-day follow-up period will be 
tabulated with exact 95% CI after each vaccination and overall.  
The percentage of doses followed by at least 1 local AE (solicited and unsolicited), by at least 1 general 
AE (solicited and unsolicited) and by any AE will be tabulated, overall vaccination course, with exact 
95% CI. The same computations will be done for Grade 3, any AEs considered related to vaccination, 
any Grade 3 AEs considered related to vaccination and any AEs resulting in a medically attended visit. 
The percentage of subjects/doses reporting each individual solicited local and general AE during the 
7-day follow-up period will be tabulated with exact 95% CI as follows: 
 
Over the 2 or 3 doses, the percentage of subjects with the symptom and its exact 95% CI. 
 
Over the 2 or 3 doses, the percentage of doses with the symptom and its exact 95% CI. 
 
At each study dose (visit), the percentage of subjects with the symptom and its exact 95% CI. 
occurrence of fever >40°C/104°F with causal relationship to the study treatment. 
The verbatim reports of unsolicited symptoms will be reviewed by a physician and the signs and 
symptoms will be coded per the Medical Dictionary for Regulatory Activities (MedDRA). Every 
verbatim term will be matched with the appropriate preferred term. The percentage of subjects with 
unsolicited AEs within 30 days after any doses with its exact 95% CI will be tabulated by group and by 
MedDRA preferred term. Similar tabulation will be done for Grade 3 unsolicited AEs, for unsolicited 
AEs that resulted in a medically attended visit, for Grade 3 and causally related unsolicited AEs and for 
unsolicited AEs causally related to vaccination. These tabulations will include SOC and SOC/PT 
analyses. 
The number of subjects who experienced at least 1 SAE or any AE of specific interest (potential 
immune mediated disease) within 30 days after any dose, from dose 1 until 30 days post last dose and 
during the entire study period will be reported. 
The following summaries for COVID-19 infections will be presented: 
 
Number of subjects with an AE of suspected, probable or confirmed assessment of COVID-19 
infection 
 
Number of subjects who had a COVID-19 diagnosis test performed and the number of subjects 
with positive, negative or indeterminate results 
 
Incidence of COVID-19 as AEs and SAEs 
 
Summary of severity, duration and outcome of AEs related to COVID-19 
 
Incidence of AEs over the course of trial (pre and during pandemic) 
 
Incidence of AEs by age and gender over the course of trial (pre and during pandemic) 
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D oc u m e nt:  
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A ut h or: 
 
V ersi o n N u m b er: 
3. 0  
 
 
V ersi o n D at e: 
2 7 S E P 2 0 2 1  
T e m pl at e N o:  C S _ T P _ B S 0 1 6  R e visi o n 5 
R ef er e nc e:  C S _ WI _ B S 0 0 5 
Eff ectiv e D at e: 0 1 A pr 2 0 1 8 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All Ri g ht s R e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
 
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL 2 0 8 1 0 9 ( C DI F F- 0 0 4) 
P a g e 3 1 of 3 4  
Ev e nts o bs er v e d o n or aft er 0 1 D E C 2 0 1 9 will b e d e e m e d t o occ ur d uri n g t h e p a n d e mic w hil e t h e e v e nts 
o bs erv e d pri or t o 0 1 D E C 2 0 1 9 will b e c o nsi d er e d pr e- p a n d e mic. 
1 6. 1. 1.  
A D V E R S E E V E N T S  L E A DI N G T O D I S C O N TI N U A TI O N F R O M S T U D Y O R F R O M T R E A T M E N T  
A dv ers e ev e nts l e a di n g t o p er m a n e nt disc o nti n u ati o n fr o m st u dy will b e i d e ntifi e d b y usi n g t h e 
v ari a bl e p ert ai ni n g t o o utc o m e t h e A dv ers e E v e nts p a g e of t h e ( e) C R F, a n d list e d. A Es l e a di n g t o 
disc o nti n u ati o n fr o m tr e at m e nt will b e list e d.  
1 6. 1. 2.  
S E RI O U S A D V E R S E E V E N T S  
S eri o us a dv ers e e v e nts ( S A Es) ar e t h os e e v e nts 
v ers e Ev e nts p a g e of 
t h e ( e) C R F, a n d will b e list e d. 
1 6. 1. 3.  
D E RI V A TI O N  
A dv ers e Ev e nt 
I nt e nsit y gr a d e 
P ar a m et er 
a
 
1 6. 2.  S A F E T Y L A B O R A T O R Y E V AL U A TI O N S  
L a b or at ory r es ults will b e i ncl u d e d i n t h e r e p orti n g of t his st u dy f or H e m at ol o g y, Bi oc h e mistry a n d 
Uri n al ysis. A list of l a b or at or y ass ess m e nts t o b e i ncl u d e d i n t h e o ut p uts is i ncl u d e d i n A p p e n dix 4 of 
t h e pr ot oc ol, T a bl e 2 3. 
F or e ac h gr o u p a n d f or e ac h h a e m at ol o g y, bi oc h e mistr y, a n d uri n al ysis p ar a m et er: 
P P D
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or 
i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


  
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Page 32 of 34 
 
The percentage of subjects having hematology, biochemistry, and urinalysis results below or 
above the local laboratory normal ranges will be tabulated by timepoint 
 
The maximum grading from Screening up to Visit 5 (Day 61)/ Visit 7 (Day 390) for subjects 
receiving 2 doses/Visit 11 (Day 670) for subjects receiving a third dose will be tabulated. 
 
Frequency of Grade 3/4 laboratory toxicities will be summarized for subjects with COVID-19 
infection. 
 
Individual profiles for each hematology and biochemistry parameter will be plotted by 
treatment group for which FDA grading scale is defined.  
16.2.1. 
GRADING FOR LABORATORY DATA 
Grades will be based on local laboratory normal ranges and derived from Food and Drug 
Administration [FDA] Guidance to Industry Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials  [refer to Table 8 in protocol]). Those 
laboratory parameters not included in the FDA grading scale will not be graded). 
16.3. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
 
Resting systolic and diastolic blood Pressure (mmHg)  
 
Resting heart rate (bpm) 
 
 
The following summaries will be provided for vital signs data: 
 
Actual and change from baseline 
16.4. COVID-19 
Data collected on the COVID-19 Corona virus infection assessment page from the eCRF will be 
presented in a listing. 
17. DATA NOT SUMMARIZED OR PRESENTED 
The other variables not summarized or presented are: 
 
Cross-neutralization data generated post dose 2 and post dose 3 
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Comments 
These variables will not be summarized or presented, but will be available in the clinical study 
database, SDTM and/or ADaM datasets. 
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18. REFERENCES  
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of binomial. 
Biometrika. 1934;26:404-413 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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