Conditions: Clostridium Difficile Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 148
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to evaluate the pharmacokinetics (PK), safety, and tolerability of bezlotoxumab (MK-6072) in children aged 1 to \<18 years of age with a confirmed diagnosis of Clostridium difficile infection (CDI) who are receiving antibacterial drug treatment. The primary hypothesis is that the area under the concentration-time curve from 0 to infinity (AUC0-inf) of bezlotoxumab after treatment of pediatric participants with bezlotoxumab is similar when compared to the AUC0-inf of bezlotoxumab after treatment of adults with bezlotoxumab.

Detailed description:
Historical adult pharmacokinetic data is from NCT01241552 and NCT01513239.

Arms:
arm 1: Participants receive 10 mg of bezlotoxumab per kg body weight via a single 60-minute (±10 minutes) intravenous (IV) infusion on Day 1. Additionally, participants receive background antibacterial drug treatment (ABD) for 10-21 days per institutional guidelines, at the investigator's discretion. Dose may then be changed based on results from initial 12 participants. arm 2: Participants receive placebo for bezlotoxumab consisting of either 0.9% sodium chloride or 5% dextrose via a single 60-minute (±10 minutes) IV infusion on Day 1. Additionally, participants receive background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.

Interventions: intervention 1: Bezlotoxumab intervention 2: Placebo intervention 3: Antibacterial drug treatment (ABD)
Intervention descriptions: intervention 1: A single intravenous (IV) infusion of 10 mg of bezlotoxumab per kg body weight. Dose may then be changed based on results from initial 12 participants. intervention 2: A single IV infusion of placebo for bezlotoxumab consisting of either 0.9% sodium chloride or 5% dextrose. intervention 3: ABD will be administered for 10-21 days including the duration of ABD prior to the screening visit, during the screening period, and after the infusion of study treatment, per institutional guidelines, at the investigator's discretion. ABD is defined as the receipt of oral metronidazole, oral vancomycin, intravenous (IV) metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03182907 
Document Date: 
07-Feb-2019
A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of a 
Single Infusion of Bezlotoxumab (MK-6072, Human Monoclonal 
Antibody to C. difficile Toxin B) in Children Aged 1 to <18 Years 
Receiving Antibacterial Drug Treatment for C. difficile Infection 
(MODIFY III)


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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate 
the Safety, Tolerability, Pharmacokinetics, and Efficacy of a Single Infusion of 
Bezlotoxumab (MK-6072, Human Monoclonal Antibody to C. difficile Toxin B) in Children 
Aged 1 to <18 Years Receiving Antibacterial Drug Treatment for C. difficile Infection 
(MODIFY III)
Protocol Number: 001-01
Compound Number: MK-6072
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER:   12,823
EudraCT NUMBER: 2017-000070-11
Approval Date: 07 February 2019
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment -01
Overall Rationale for the Amendment:
The main reason for this protocol amendment is to modify the enrollment strategy, as described in the Summary of Changes Table, 
with the aim of shortening the overall enrollment timelines.
Based on population pharmacokinetic (PK) considerations, the Sponsor considers it unlikely that a dose modification will be needed 
within an age cohort, and therefore the initially planned pause in enrollment after 12 participants have a complete set of PK samples in 
Panel A of an age cohort has been removed. Patients will continue to be enrolled in Panel A until the PK analysis is completed, and 
the dose has been confirmed, enrollment in Panel B of the age cohort will commence.  Furthermore, the Sponsor considers it unlikely 
that PK data from Panel A of Age Cohort 1 (12 to <18 years of age) will result in a modification of the planned dose (10 mg/kg) for 
Age Cohort 2 (1 to <12 years of age), and therefore enrollment in Panel A of Age Cohort 2 will commence after the first 12 
participants in Panel A of Age Cohort 1 have completed all study visits.  There is no change in the 2 planned evaluations of safety data 
to be conducted by the Data Monitoring Committee (DMC) after the first 12 participants in Age Cohort 1 complete the study and after 
the first 12 participants in Age Cohort 2 complete the study.
Additional changes have been made as well, as outlined in the Summary of Changes table.
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Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
5.1.2 – Enrollment Strategy
5.2 – Number of 
Participants
5.5.1 – Starting Dose for 
This Trial
7.1 – Treatments 
Administered
7.2 – Dose Modification 
(Escalation/Titration/Other)
7.5.1 – Dose Preparation
10.1 – Statistical Analysis 
Plan Summary
10.5.3 – Efficacy 
Population
The enrollment strategy has been 
modified as follows:

Enrollment into Age Cohort 2 will be 
initiated after 12 participants in Age 
Cohort 1 Panel A have completed all 
study visits. The initial dose for Age 
Cohort 2 will be 10 mg/kg.

Enrollment into Panel A of each age 
cohort will not be paused during the 
time PK assessments in each age
cohort are conducted.
This change will shorten the overall enrollment period by 
removing the enrollment pauses that were initially planned
for the PK evaluation and the DMC safety review.  Blinded 
safety information from the trial is reviewed by the 
Sponsor on an ongoing basis to identify any unexpected 
safety findings; therefore, safety oversight will not be 
impacted. An evaluation of safety data from the first 12
participants in each age cohort who complete the study will 
still be conducted by the DMC as planned in the original 
version of the protocol.
Based on the adult population PK studies, neither intrinsic 
factors (including age) nor extrinsic factors affect the 
efficacy or safety of bezlotoxumab. The weight-based dose 
(10 mg/kg) adequately controls for differences in 
bezlotoxumab pharmacokinetics related to body weight.  
An evaluation of PK data from approximately 12
participants in each age cohort who provide all 
protocol-required serum samples for PK analysis will still 
be performed to determine if dose modifications are 
needed for that age cohort. Enrollment into Panel A will 
continue while this evaluation is performed, as it is 
unlikely that the doses will need to be modified in the older 
age cohort based on the age range, mechanism of action, 
PK properties, and/or the established exposure-response 
relationships. Moreover, it is unlikely that data from 12 to 
<18-year-old adolescents will inform dosing information in 
the younger age cohort.  Thus, there is no need to wait for 
the PK evaluation in the older cohort before initiating 
enrollment in the younger cohort.  
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Section # and Name
Description of Change
Brief Rationale
6.1 – Inclusion Criteria
Appendix 5 –
Contraceptive Guidance 
and Pregnancy Testing

Added language to clarify that 
contraception methods classified as 
“acceptable” (ie, with a failure rate of 
>1% per year when used consistently 
and correctly) are sufficient for use 
in this study.

This change was made to ensure it is clear that 
agreement to use a highly effective method of 
contraception is not required to participate in this 
study.

Added language in Table 14 to 
specify that acceptable contraceptive 
methods include progestogen-only
oral hormonal contraception, where 
inhibition of ovulation is not the 
primary mode of action.

This change was made to allow for the use of 
progestogen-only oral hormonal contraception, where 
inhibition of ovulation is not the primary mode of 
action, as an acceptable contraceptive method, in 
accordance with Clinical Trial Facilitation Group 
(CTFG) guidelines.

Deleted the sentence in the Note in 
the Table 14 footnotes that stated, 
“Use should be consistent with local 
regulations regarding the use of 
contraceptive methods for 
participants of clinical studies.”

Note was deleted to remove potential ambiguity about 
the choice of study-permitted contraceptive measures.

Corrected footnote “a” in Table 14 as 
follows: “Typical use failure rates are 
lower higher than perfect-use failure 
rates…”

This change was made to correct a typo.

Deleted footnote “b” from Table 14, 
which stated, “If hormonal 
contraception efficacy is potentially 
decreased due to interaction with 
study treatment, condoms must be 
used in addition to the hormonal 
contraception during the treatment 

This footnote does not apply to this study treatment, as 
there is no known or expected interaction between 
bezlotoxumab and hormonal contraception.
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Section # and Name
Description of Change
Brief Rationale
period and for at least 12 weeks after 
the last dose of study treatment.”

Deleted footnote “c” from Table 14, 
which stated, “If locally required, in 
accordance with Clinical Trial 
Facilitation Group (CTFG) 
guidelines, acceptable hormonal 
contraceptives are limited to those 
which inhibit ovulation.”

This footnote does not apply to this study treatment.
6.2 – Exclusion Criteria
Added exclusion of potential participants 
with a known hypersensitivity to any 
ingredients of bezlotoxumab.
This revision was implemented for consistency with the 
prescribing information in some markets that 
contraindicate the use of bezlotoxumab in patients with 
known hypersensitivity to any of the ingredients.
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Section # and Name
Description of Change
Brief Rationale
6.2 – Exclusion Criteria
7.7 – Concomitant Therapy
Removed intravenous immune globulin 
(IVIG) as an excluded prior and 
concomitant treatment.
IVIG was originally excluded because this treatment 
contains a broad spectrum of antibodies and therefore has 
the theoretical potential to impact efficacy outcomes. 
However, efficacy is not the primary objective of this 
study, and participants who have received or may receive 
IVIG may still benefit from receiving bezlotoxumab.
Excluding patients who have received IVIG but would 
otherwise be eligible decreases the pool of potential 
participants because some types of pediatric patients who 
have CDI receive IVIG due to their underlying condition. 
There are no anticipated safety concerns with the use of 
bezlotoxumab in participants who have received or will 
concomitantly receive IVIG.
A supportive analysis of efficacy outcomes in an Efficacy 
Evaluable population has been added in this amendment; 
this population will exclude, among others, participants 
who receive IVIG.
6.2 – Exclusion Criteria
Clarified that surgery for CDI exclusion 
criterion is specific to surgery for the 
current CDI episode
Clarified so that participants who had surgery in the past 
for a prior episode of CDI are not excluded.
10.1 – Statistical Analysis 
Plan Summary
10.5.3 – Efficacy 
Population
Added an Efficacy Evaluable population.
Added such that supportive analyses of efficacy endpoints 
can be conducted in a subset of participants who do not 
have any important protocol deviations that may impact 
efficacy results (specific deviations will be determined 
prior to final unblinding of the database) or require any 
prior or concomitant treatment with IVIG.
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Section # and Name
Description of Change
Brief Rationale
9 – Study Assessments and 
Procedures
Updated approximate total blood volume 
to be drawn over the 12 weeks of the trial 
from 21.5 mL to 29 mL.
Corrected to align with increased volume required for PK 
blood samples. The need for increased volume was 
identified after finalizing the original protocol and before 
enrolling the first participant in the trial. The maximum 
blood volume collected from each participant should be 
based on weight and should generally not exceed 1% of 
total blood volume on any 1 day or 3% of total blood 
volume (2.4 mL blood per kg of body weight) during a 
given 4-week trial period, unless appropriate justification is 
documented by the investigator.
9.3.5 – Disease-Related 
Events and/or Disease-
Related Outcomes Not 
Qualifying as AEs or SAEs
Specified that Clostridium difficile
infection (CDI) recurrence is not 
considered a reportable safety event 
unless it meets one or more SAE criteria.
CDI recurrence is being monitored as an efficacy endpoint 
and therefore does not also need to be reported as a 
nonserious AE.
9.3.7 – Events of Clinical 
Interest (ECI)
Specified that the ECI definition
regarding AST, ALT, and bilirubin 
elevations is limited to postbaseline 
abnormalities that were not present at 
baseline or are clinically significantly 
worse than they were at baseline (as 
determined by the investigator).
Revised because participants with hepatic impairment are 
allowed to enroll in the trial, so it is important to clarify 
that baseline AST or ALT elevations will not be 
considered ECIs unless they clinically significantly worsen 
at a postbaseline time point.
2 – Schedule of Activities
Added weight measurement to screening 
visit.
Added to ensure adequate drug supply at site for future 
randomization and treatment.
6.1 – Inclusion Criteria
9.2.2 – Daily Diary 
Specified that watery diarrhea 
corresponds to Bristol Stool Scale types 
6 or 7.
Revised for clarity.
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Section # and Name
Description of Change
Brief Rationale
7.6.1 – Compliance With 
Antibacterial Drug 
Treatment for CDI
Clarified that any interruptions (ie, not 
just those >1 calendar day) in the 
prescribed antibacterial drug treatment 
plan require documentation on the eCRF.
Revised for clarity.
9.1.11 – Calibration of 
Equipment
Revised text and removed list of critical 
equipment.
Textual revisions were applied to clarify investigator 
responsibility for calibration and maintenance of study 
equipment.
9.2.1.1 – Assessment of 
Disease Severity
Revised definition of hypoalbuminemia 
from <20 mg to <2 g/dL. 
Revision made to correct an inaccuracy.
12.2 – Appendix 2: Clinical 
Laboratory Tests
Removed % reticulocytes and 
phosphorous from the list of laboratory 
parameters.
These parameters are not needed for assessment of 
bezlotoxumab safety and tolerability or for assessment of 
CDI.
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Table of Contents
PROTOCOL AMENDMENT SUMMARY OF CHANGES.............................................. 3
1.
Synopsis...................................................................................................................... 20
2.
Schedule of Activities (SoA)..................................................................................... 24
3.
Introduction............................................................................................................... 27
Study Rationale..................................................................................................... 27
Background ........................................................................................................... 27
Pharmaceutical and Therapeutic Background .................................................... 27
Pre-clinical and Clinical Trials ........................................................................... 29
Ongoing Clinical Trials....................................................................................... 29
Information on Other Trial-Related Therapy...................................................... 29
Benefit/Risk Assessment....................................................................................... 30
4.
Objectives/Hypotheses and Endpoints.................................................................... 31
5.
Study Design.............................................................................................................. 33
Overall Design....................................................................................................... 33
Trial Diagram...................................................................................................... 36
Enrollment Strategy ............................................................................................ 36
Number of Participants........................................................................................ 38
Beginning and End of Study Definition.............................................................. 39
Clinical Criteria for Early Trial Termination...................................................... 39
Scientific Rationale for Study Design.................................................................. 39
Rationale for Endpoints ...................................................................................... 39
Pharmacokinetic Endpoints ......................................................................... 39
Safety Endpoints.......................................................................................... 39
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Efficacy Endpoints....................................................................................... 40
Planned Exploratory Biomarker Research................................................... 40
Planned Genetic Analysis ............................................................................ 40
Future Biomedical Research........................................................................ 41
Rationale for The Use of Comparator/Placebo................................................... 41
Justification for Dose............................................................................................ 41
Starting Dose for This Trial ................................................................................ 41
Maximum Dose/Exposure for This Trial............................................................ 42
Rationale for Dose Interval and Trial Design ..................................................... 42
6.
Study Population....................................................................................................... 42
Inclusion Criteria.................................................................................................. 43
Exclusion Criteria................................................................................................. 44
Lifestyle Restrictions ............................................................................................ 45
Meals and Dietary Restrictions........................................................................... 45
Caffeine, Alcohol, and Tobacco ......................................................................... 46
Activity ............................................................................................................... 46
Screen Failures...................................................................................................... 46
Participant Replacement Strategy ...................................................................... 46
7.
Treatments................................................................................................................. 46
Treatments Administered .................................................................................... 46
Antibacterial Drug Treatment for CDI ............................................................... 47
Dose Modification (Escalation/Titration/Other)................................................ 49
Method of Treatment Assignment....................................................................... 50
Stratification........................................................................................................ 51
Blinding.................................................................................................................. 51
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Preparation/Handling/Storage/Accountability .................................................. 51
Dose Preparation................................................................................................. 51
Handling, Storage and Accountability................................................................ 52
Treatment Compliance......................................................................................... 52
Compliance With Antibacterial Drug Treatment for CDI .................................. 52
Concomitant Therapy........................................................................................... 53
Rescue Medications & Supportive Care............................................................. 54
Treatment After the End of the Study................................................................ 54
Clinical Supplies Disclosure................................................................................. 54
8.
Discontinuation/Withdrawal Criteria..................................................................... 55
Discontinuation of Study Treatment................................................................... 55
Withdrawal from the Study................................................................................. 55
Lost to Follow Up.................................................................................................. 56
9.
Study Assessments and Procedures......................................................................... 56
Administrative and General Procedures ............................................................ 57
Informed Consent/Assent.................................................................................... 57
General Informed Consent/Assent............................................................... 57
Consent/Assent and Collection of Specimens for Future Biomedical 
Research....................................................................................................... 58
Inclusion/Exclusion Criteria ............................................................................... 58
Participant Identification Card............................................................................ 58
Medical History .................................................................................................. 58
Prior and Concomitant Medications Review ...................................................... 59
Prior Medications......................................................................................... 59
Concomitant Medications............................................................................ 59
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Assignment of Screening Number...................................................................... 59
Assignment of Treatment/Randomization Number............................................ 60
Treatment Administration................................................................................... 60
Timing of Dose Administration................................................................... 60
Withdrawal/Discontinuation............................................................................... 60
Withdrawal From Future Biomedical Research .......................................... 61
Participant Blinding/Unblinding......................................................................... 61
Calibration of Equipment.................................................................................... 62
Efficacy Assessments ............................................................................................ 62
Details of Baseline and Recurrent CDI Episodes ............................................... 62
Assessment of Disease Severity................................................................... 63
Daily Diary.......................................................................................................... 63
Phone/Visit Contact ............................................................................................ 64
Stool Sample Collection and Assessments ......................................................... 65
Gastrointestinal Panel .................................................................................. 65
Investigator Assessment of Clinical Outcomes .................................................. 66
Investigator Assessment of Clinical Response ............................................ 66
Investigator Assessment of a New Episode of Diarrhea During the 
12-Week Follow-Up Period......................................................................... 67
Adverse Events, Serious Adverse Events and Other Reportable Safety 
Events..................................................................................................................... 68
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information.................................................................................... 68
Method of Detecting AE and SAE...................................................................... 71
Follow-up of AE, SAE and Other Reportable Safety Event Information........... 71
Regulatory Reporting Requirements for SAE .................................................... 71
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Disease-Related Events and/or Disease-Related Outcomes Not Qualifying 
as AEs or SAEs................................................................................................... 71
Pregnancy and Exposure During Breastfeeding ................................................. 72
Events of Clinical Interest (ECI)......................................................................... 72
Infusion-Related Reactions.......................................................................... 72
Treatment of Overdose......................................................................................... 73
Safety...................................................................................................................... 74
Physical Examinations........................................................................................ 74
Vital Signs........................................................................................................... 74
Clinical Safety Laboratory Assessments............................................................. 75
Pharmacokinetics.................................................................................................. 75
Blood Collection for Bezlotoxumab (MK-6072) in Serum ................................ 75
Pharmacodynamics............................................................................................... 76
Future Biomedical Research Sample Collection................................................ 76
Biomarkers ............................................................................................................ 76
Planned Genetic Analysis Sample Collection..................................................... 76
Immunogenicity Assessments............................................................................. 76
Visit Requirements ............................................................................................... 77
Screening............................................................................................................. 77
Treatment Period................................................................................................. 77
Unscheduled Visits ............................................................................................. 77
Discontinued Participants Continuing to be Monitored in the Study ................. 77
Post-Study........................................................................................................... 77
10.
Statistical Analysis Plan ........................................................................................... 78
Statistical Analysis Plan Summary ..................................................................... 78
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Responsibility for Analyses/In-House Blinding ................................................. 80
Hypotheses/Estimation ......................................................................................... 81
Analysis Endpoints ............................................................................................... 81
Pharmacokinetics Endpoints............................................................................... 81
Safety Endpoints ................................................................................................. 81
Efficacy Endpoints.............................................................................................. 81
Analysis Populations............................................................................................. 84
Pharmacokinetic Population ............................................................................... 84
Safety Population................................................................................................ 84
Efficacy Population............................................................................................. 84
Statistical Methods................................................................................................ 85
Statistical Methods for Pharmacokinetics Analyses ........................................... 85
Statistical Methods for Safety Analyses ............................................................. 86
Statistical Methods for Efficacy Analyses .......................................................... 87
Statistical Methods for Immunogenicity Analyses ............................................. 88
Demographic and Baseline Characteristics ........................................................ 88
Interim Analyses ................................................................................................... 88
Multiplicity ............................................................................................................ 89
Sample Size and Power Calculations .................................................................. 89
Sample Size and Power for Pharmacokinetic Analyses...................................... 89
Sample Size and Power for Efficacy Analyses................................................... 89
Sample Size and Power for Safety Analyses ...................................................... 90
Subgroup Analyses ............................................................................................... 91
Compliance (Medication Adherence).................................................................. 91
Extent of Exposure................................................................................................ 91
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11.
References.................................................................................................................. 92
12.
Appendices................................................................................................................. 99
Appendix 1: Abbreviations and Trademarks .................................................... 99
Appendix 2: Clinical Laboratory Tests ............................................................ 101
Appendix 3: Study Governance Considerations.............................................. 103
Merck Code of Conduct for Clinical Trials.................................................................. 103
Financial Disclosure........................................................................................................ 106
Data Protection ............................................................................................................... 106
Confidentiality of Data................................................................................................... 106
Confidentiality of Participant Records......................................................................... 107
Confidentiality of IRB/IEC Information ...................................................................... 107
Committees Structure..................................................................................................... 107
Scientific Advisory Committee ...................................................................................... 107
Executive Oversight Committee.................................................................................... 107
Data Monitoring Committee.......................................................................................... 107
Publication Policy ........................................................................................................... 108
Compliance with Trial Registration and Results Posting Requirements .................. 108
Compliance with Law, Audit and Debarment ............................................................. 108
Data Quality Assurance.................................................................................................. 109
Source Documents........................................................................................................... 110
Study and Site Closure ................................................................................................... 110
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................. 111
Definition of AE .............................................................................................................. 111
Definition of SAE ............................................................................................................ 112
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Additional Events reported............................................................................................ 113
Recording AE and SAE.................................................................................................. 114
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor........... 117
Appendix 5: Contraceptive Guidance and Pregnancy Testing ...................... 119
Contraception Requirements......................................................................................... 119
Pregnancy Testing........................................................................................................... 121
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research........................................................................................... 121
Appendix 7: C. Difficile Diagnostic Test Method Requirements ................... 126
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LIST OF TABLES
    
Table 1
Number of Participants, Assuming Dose Modification is Not Required........38
Table 2
Prohibited Prior and Concomitant Treatments and Procedures at Time of 
Screening Visit and During Screening Period.................................................45
Table 3
Study Treatment(s)..........................................................................................47
Table 4
Antibacterial Drug Treatment for Baseline Episode of CDI...........................49
Table 5
Prohibited Concomitant Treatments and Procedures During the Trial  (Day 1 
through Day 85 ± 5 days)................................................................................53
Table 6
Pathogens Detected by Gastrointestinal Panel ................................................66
Table 7
Investigator Assessment of Initial Clinical Response.....................................67
Table 8
Investigator Assessment of New Episode of Diarrhea....................................68
Table 9
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events ................................................................................70
Table 10 Analysis Strategy for Safety Parameters.........................................................87
Table 11 Variability Around Various Possible Treatment Differences .........................90
Table 12 Protocol-Required Safety Laboratory Assessments......................................101
Table 13 Directed Hematology and Chemistry Parameters (Unscheduled Visit 1).....102
Table 14 Contraceptive Methods..................................................................................120
Table 15 Permitted Commercial Enzyme Immunoassay Tests for Detecting Presence of 
Clostridium difficile Toxin in Stool...............................................................126
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LIST OF FIGURES
          
Figure 1
Diagram of Trial Design ..............................................................................36
Figure 2
Enrollment Strategy .....................................................................................37
Figure 3
Bezlotoxumab Dose Modification ...............................................................50
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1. Synopsis
Protocol Title:  
A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of a Single Infusion of Bezlotoxumab (MK-
6072, Human Monoclonal Antibody to C. difficile Toxin B) in Children Aged 1 to <18 
Years Receiving Antibacterial Drug Treatment for C. difficile Infection (MODIFY III)
Short Title: 
Bezlotoxumab (MK-6072) versus placebo in children with CDI: MODIFY III
Objectives/Hypotheses and Endpoints:
The following objectives and endpoints will be evaluated in pediatric participants aged 1 
year to <18 years who are receiving antibacterial drug treatment for Clostridium difficile
infection (CDI):
Objective/Hypothesis
Endpoint
Primary
1) Objective: To characterize bezlotoxumab 
pharmacokinetics (PK) in 2 age cohorts 
(Age Cohort 1: 12 to <18 years; Age 
Cohort 2: 1 to <12 years) of pediatric 
participants to support dose selection in 
this population.

Hypothesis: The area under the 
concentration-time curve from 0 to 
infinity (AUC0-inf) of bezlotoxumab after 
treatment of 2 age cohorts of pediatric 
participants (Age Cohort 1: 12 to <18 
years; Age Cohort 2: 1 to <12 years)
with a single infusion of bezlotoxumab is 
similar when compared to the AUC0-inf of 
bezlotoxumab after treatment of adult 
participants with a single infusion of 
10 mg/kg bezlotoxumab, a dose 
demonstrated to be safe and efficacious 
in adults. That is, the true geometric 
mean ratios (GMRs, pediatric 
participants/adults) for AUC0-inf of 
bezlotoxumab are contained in the 
clinical comparability bounds of (0.6, 
1.6) in each of the age cohorts.

The AUC0-inf will be determined for 
each age cohort from bezlotoxumab 
serum concentration data.
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2) Objective: To evaluate the safety and 
tolerability of a single infusion of 
bezlotoxumab as compared with a single 
infusion of placebo through 12 weeks 
following infusion.

Proportion of participants 
experiencing adverse events (AEs)

Proportion of participants 
discontinuing study medication due to 
AEs
Secondary
3) Objective: To estimate the proportion of 
participants who have a CDI recurrence
within 12 weeks following administration 
of a single infusion of bezlotoxumab or 
placebo.

Proportion of participants who have a 
CDI recurrence within 12 weeks of 
study medication infusion. CDI 
recurrence is assessed by the 
investigator using the criteria defined 
in Section 9.2.5.2.
4) Objective: To estimate the proportion of 
participants with sustained clinical 
response over a period of 12 weeks in 
participants who received a single 
infusion of bezlotoxumab or placebo.

Proportion of participants with 
sustained clinical response over a 
period of 12 weeks. Sustained clinical 
response is defined as initial clinical 
response of the baseline CDI episode 
(assessed by the investigator using the 
criteria defined in Section 9.2.5.1) 
AND no CDI recurrence (Section 
9.2.5.2) through Week 12.
5) Objective: To estimate efficacy (CDI 
recurrence and sustained clinical 
response) in the subset of participants at 
high risk of CDI recurrence within 
12 weeks following administration of a 
single infusion of bezlotoxumab or 
placebo.

Proportion of participants who have a 
CDI recurrence and proportion of 
participants who achieve sustained 
clinical response within 12 weeks of 
study medication infusion in the 
subset of participants at high risk of 
CDI recurrence. High risk is defined 
as meeting 1 or more of the following 
criteria at or before randomization:
o
Was immunocompromised (as 
defined in Section 9.1.4)
o
Had one or more episodes of CDI 
at any point prior to the baseline 
episode
o
Had a baseline CDI episode that 
met criteria for severe CDI (as 
defined in Section 9.2.1.1)
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o
Had C. difficile ribotype 027 
isolated from a stool sample 
collected during the baseline CDI 
episode 
o
Had received treatment with 1 or 
more systemic antibacterials
known to increase the risk of CDI
(during treatment of the baseline 
CDI episode). Systemic 
antibacterial agents are defined in 
Section 7.7.
6) Objective: To assess the incidence of 
infusion-related reactions in participants 
who received a single infusion of 
bezlotoxumab or placebo.

Proportion of participants 
experiencing 1 or more infusion-
related reactions within 24 hours 
following the start of the infusion. 
The definition of infusion-related
reactions can be found in Section 
9.3.7.1.
7) Objective: To assess the potential for 
bezlotoxumab to induce immunogenicity 
within 12 weeks following administration 
of a single infusion of bezlotoxumab.

Proportion of participants with 
treatment-emergent positive 
antibodies to bezlotoxumab in serum 
through 12 weeks following a single 
dose of bezlotoxumab.
Overall Design:
Trial Phase
Phase 3
Clinical Indication
Prevention of recurrent CDI
Population
Male and female participants aged 1 year to <18 years 
with CDI will be enrolled in this trial.
Trial Type
Interventional
Type of design
Randomized (3:1 bezlotoxumab:placebo), placebo-
controlled, parallel-group, multi-site, double-blind trial
stratified by age cohort (Age Cohort 1: 12 to <18 years; 
Age Cohort 2: 1 to <12 years) and with sequential 
enrollment starting with Age Cohort 1 
Type of control
Placebo control
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Trial Blinding
Double-blind
Estimated duration 
of trial
The Sponsor estimates that the trial will require 
approximately 36 months from the time the first 
participant signs the informed consent/assent until the 
last participant’s last study-related phone call or visit.
Number of Participants:
Approximately 192 (144 bezlotoxumab, 48 placebo) participants will be enrolled.
A list of abbreviations used in this document can be found in Appendix 1.
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2. Schedule of Activities (SoA)
Trial Period:
Screening
Treatmenta
Post-Treatmenta
Visit Number/Title
1 Screening
2
EOTb
3
4
5
6
Unscheduled 1c
Unscheduled 2d
Scheduled Day/Week 
and Window:
Variablee
Day 1
~48 hours after 
last dose of 
antibacterial 
drug treatment
Day 10
(±3 days)
Week 4
(Day 29 
±3 days)
Week 8
(Day 57 
±5 days)
Week 12
(Day 85
±5 days)
Day 1 to 
Week 12 
(Day 85 
±5 days)
Day 1 to 
Week 12 
(Day 85 
±5 days)
Administrative Procedures
Informed Consent/Assent
X
Informed Consent/Assent for 
Future Biomedical Research
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
X
Prior/Concomitant Medication 
Reviewf
Xg
X
X
X
X
X
X
X
X
Randomization
Xh
Bezlotoxumab/Placebo Infusion
X
Efficacy Procedures
Collect Stool Sample(s)i
Xj
Xk
Investigator Assessment of 
Clinical Outcome
Xl
Xm
Xm
Xm
Xm
Xm
Participant or Participant’s 
Parent or Caregiver Complete 
Daily Diary
Phone/Visit Contactn
Safety Procedures
Full Physical Examination
Xo
Xo,p
X
Directed Physical Examinationq
X
X
X
X
X
Height
X
Weight
X
Xp
Vital Signsr
X
Xs
X
X
X
X
X
X
Urine Pregnancy Test
Xt
Xt
Hematology and Chemistry
Xp,u
Xv
Xv
Xw
Xv
AE/SAE Review
X
X
X
X
X
X
X
X
X
Infusion-Related Reaction 
Monitoring
Xx
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Trial Period:
Screening
Treatmenta
Post-Treatmenta
Visit Number/Title
1 Screening
2
EOTb
3
4
5
6
Unscheduled 1c
Unscheduled 2d
Scheduled Day/Week 
and Window:
Variablee
Day 1
~48 hours after 
last dose of 
antibacterial 
drug treatment
Day 10
(±3 days)
Week 4
(Day 29 
±3 days)
Week 8
(Day 57 
±5 days)
Week 12
(Day 85
±5 days)
Day 1 to 
Week 12 
(Day 85 
±5 days)
Day 1 to 
Week 12 
(Day 85 
±5 days)
Pharmacokinetics/Pharmacodynamics/Future Biomedical Research/Biomarkers
Blood for Anti-Drug Antibody 
Levels and Neutralizing 
Antibody for Bezlotoxumabi
X
X
X
Blood Sample for Bezlotoxumab 
Serum Concentration Assay for 
Pharmacokineticsi
Xy
X
X
X
X
Blood for Genetic Analysisz
X
Abbreviations: AE = adverse event; CDI = Clostridium difficile infection; DNA = deoxyribonucleic acid; EOT = end of treatment with antibacterial drug for baseline episode of 
CDI; FBR = future biomedical research; SAE = serious adverse event; UBM = unformed bowel movement.
a. Timing of each trial period and of all visits except the EOT Visit is relative to the infusion of study medication (bezlotoxumab or placebo) on Day 1. Timing of the EOT Visit is 
relative to the end of antibacterial drug treatment for the baseline episode of CDI.
b. The EOT assessment can be conducted in person or via telephone.
c. Unscheduled Visit 1 to be conducted if the participant experiences watery diarrhea (if the child is using diapers or other fecal collection device) or 3 or more UBMs within a 
24-hour period after completion of antibacterial drug treatment for the baseline episode of CDI. The unscheduled visit should preferably occur within 2 days of the onset of 
diarrhea or UBMs.
d. Unscheduled Visit 2 to be conducted for any reason other than the onset of a new diarrhea episode (eg, AE assessment, premature withdrawal from the trial, if warranted).
e. Screening period can start as early as the first day of antibacterial drug treatment for the baseline episode of CDI and can extend as long as the last day of antibacterial drug 
treatment for the baseline episode of CDI.
f. For breast-fed participants, the mothers’ prior and concomitant medications should also be recorded.
g. Prior medication use should be recorded for the 28 days prior to the onset of the baseline episode of CDI. Treatment(s) given for the most recent prior episode of CDI should be 
recorded even if the treatment ended more than 28 days prior to the onset of the baseline episode of CDI.
h. Screening and randomization may occur on the same day, as long as all trial entry criteria have been met. Randomization and study infusion must occur while the participant is 
receiving antibacterial drug treatment for the baseline episode of CDI. Study infusion is to be given on the day of randomization or as close as possible to the date on which the 
participant is randomized.
i. Leftover main study stool and serum will be stored for FBR if the participant consents to FBR.
j. Before screening, a stool sample must have tested positive by the local laboratory for toxigenic C. difficile. During screening, a new stool sample may need to be collected for 
study-specific testing. A new sample is not needed if aliquots of the same stool sample that was used for the pre-screening diagnosis are available. If the pre-screening diagnosis 
was based on a method that does not test for the presence of C. difficile toxin, a new test will need to be performed at the local laboratory prior to randomization to confirm the 
diagnosis. A list of acceptable tests is described in Appendix 7. An aliquot of the pre-screening stool sample or a sample obtained during screening will also be sent to the central 
laboratory.
k. After completion of antibacterial drug treatment for the baseline episode of CDI, if the participant experiences watery diarrhea (if the child is using diapers or other fecal 
collection device) or 3 or more UBMs within a 24-hour period, a stool sample is to be collected and aliquots sent to both a local laboratory and the central laboratory (see 
Section 9.2.4).
l. The investigator will assess whether the participant has achieved initial clinical response (as defined in Section 9.2.5.1) approximately 48 hours after the last dose of antibacterial 
drug treatment for the baseline episode of CDI. This assessment can be performed via telephone contact or in person.
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m. After completion of antibacterial drug treatment for the baseline episode of CDI, if the participant experiences watery diarrhea (if the child is using diapers or other fecal 
collection device) or 3 or more UBMs within a 24-hour period, a clinical assessment will be performed to determine whether the criteria are met for a diarrhea recurrence or a 
CDI recurrence (as defined in Section 9.2.5.2).
n. Trial personnel will contact the participant or the participant’s parent or caregiver at least 3 times per week during antibacterial drug treatment for the baseline episode of CDI
for assessment of antibacterial drug treatment compliance. Trial personnel will also contact the participant or the participant’s parent or caregiver approximately 24 hours after 
the end of the infusion to assess for infusion-related reactions. Trial personnel will contact the participant or the parent or caregiver twice weekly after the EOT Visit through 
Week 12 to ensure that the daily diary is maintained by the participant or the parent or caregiver. The information communicated by the participant or the parent or caregiver
during the contact is to be recorded in the source documents.
o. If a full physical examination was previously performed as part of routine clinical management within 72 hours of screening or Day 1, those results can be used for the 
corresponding visit and a new physical examination for the trial is not required.
p. Must be collected before the start of study infusion.
q. Targeted to the participant’s illness and complaints.
r. Heart rate, blood pressure, respiratory rate, body temperature, and, on Day 1 only, pulse oximetry.
s. To be collected within 30 minutes before the start of the infusion, 30 (±10) minutes into the infusion, and 30 (±10) minutes after the end of the infusion.
t. Required before study infusion for female participants for child-bearing potential (defined in Appendix 5). If results are positive, the participant should be excluded from trial 
participation.
u. If the site has hematology and serum chemistry results for the participant from a blood sample that was collected as part of non-trial-related, routine clinical management up to 
72 hours pre-infusion, these results can be used in lieu of collecting a new sample on Day 1.
v. Laboratory assessments at discretion of investigator per presenting symptoms.
w. Directed hematology and directed chemistry parameters will be assessed at this visit (Appendix 2).
x. Monitoring for approximately 24 hours after the end of the study infusion (Section 9.3.7.1). This monitoring should include at least 1 hour of in-clinic monitoring.
y. A sample should be collected 2 hours (±15 minutes) after the end of the infusion.
z. This sample should be collected for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at the site if there 
is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, leftover 
extracted DNA will be stored for FBR if the participant signs the FBR consent. If the planned genetic analysis is not approved, but FBR is approved and consent is given, this 
sample will be collected for the purpose of FBR.
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3. Introduction
Study Rationale 
This trial is intended to determine a dosing recommendation for bezlotoxumab in the 
pediatric population and will evaluate bezlotoxumab pharmacokinetics (PK), safety, 
tolerability, and efficacy in children with Clostridium difficile infection (CDI). The proposed 
trial will randomize children aged 1 to <18 years of age with a confirmed diagnosis of CDI
who are receiving antibacterial drug treatment for CDI. Infants less than 1 year of age will 
not be evaluated due to challenges with accurate CDI diagnoses; during the first year of life, 
up to 70% of children have detectable levels of C. difficile in their stool yet are 
asymptomatic, and there is no evidence of an epidemiologic association between colonization
and disease during this timeframe [Bryant, K. 2009].
The primary objectives of this trial are to evaluate the PK, safety, and tolerability of 
bezlotoxumab, and secondary objectives are to estimate the rates of CDI recurrence and 
sustained clinical response through 12 weeks following a single-dose infusion in participants 
with CDI aged 1 year to <18 years. 
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on bezlotoxumab.
Pharmaceutical and Therapeutic Background
C. difficile is an anaerobic, spore-forming gram-positive bacillus that produces toxin A and 
toxin B [Voth, D. E. and Ballard, J. D. 2005] [Warny, Michel, et al 2005]. CDI occurs when 
toxigenic strains of C. difficile, either endogenous to the colon or exogenously acquired, 
flourish after disruption of the normal bacterial colonic flora – typically following exposure 
to antibiotics that alter the endogenous micro-ecology of the gut – and thus lead to clinically 
significant disease. The laboratory diagnosis of CDI requires the demonstration of toxigenic 
C. difficile or its toxins in stool. A number of different tests are used, including enzyme-
linked immunoassays (EIAs) for toxins A and B; cell culture cytotoxicity assay; anaerobic 
culture followed by toxin detection; nucleic acid amplification tests using polymerase chain 
reaction (PCR), which detects the gene for toxin B; and EIA for the C. difficile common 
antigen glutamate dehydrogenase, which is typically followed by either a toxin test or a PCR 
test [Crobach, M. J., et al 2016]. 
CDI represents an important medical and health care burden. The incidence, severity, rate of 
complications (eg, ileus, toxic megacolon), and mortality of CDI in adults have increased 
dramatically in the US, Canada, and Europe over the last 10-15 years [Goorhuis, Abraham, et 
al 2008] [Gravel, Denise, et al 2009] [Loo, Vivian G., et al 2005] [Loo, Vivian G., et al 2006] 
[McDonald, L. Clifford, et al 2005] [Pepin, Jacques, et al 2005]. Similarly, CDI incidence 
rates in pediatric patients have increased over time [Kim, Jason, et al 2008] [Zilberberg, M. 
D., et al 2010]. Based on the most recent estimates from the Centers for Disease Control and 
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Prevention for 2011, the incidence of CDI in pediatric patients was 24.2/100,000 population 
whereas the incidence in those >65 years of age was 627.7/100,000 [Lessa, F. C., et al 2015]. 
The increased incidence in adult and pediatric patients is attributable in part to the emergence 
of the NAP1/BI/027 epidemic/hypervirulent strain [Kim, Jason, et al 2008] [Freeman, J., et al 
2010]. 
The risk factors for CDI in pediatric patients appear similar to those for adults (eg, antibiotic 
use, multiple antibiotics use, and longer duration of hospital stay). In pediatric patients, CDI 
is also strongly associated with additional factors, namely malignancy, inflammatory bowel 
disease (IBD), and immune suppression [Pant, Chaitanya, et al 2013] [Hojsak, I., et al 2012] 
[Banaszkiewicz, Aleksandra, et al 2012] [Enoch, D. A., et al 2011]. The CDI risk appears to 
be highest in pediatric patients with malignancy [Enoch, D. A., et al 2011] [de Blank, P., et al 
2013] [Price, Victoria, et al 2013] [Tai, E., et al 2011]. A case control study identified 
additional risk factors for pediatric CDI that include solid organ transplant, presence of 
gastrostomy or jejunostomy tube, receipt of fluoroquinolones, and lack of prior 
hospitalization; however, the last of these may be a result of control subjects who were 
hospitalized [Sandora, T. J., et al 2011]. In children, the majority of cases of CDI are 
community-onset or community-acquired [McFarland, L. V., et al 2016] [Lo Vecchio, A., et 
al 2016].
Symptoms of pediatric CDI include fever, profuse diarrhea, abdominal tenderness, 
abdominal distension, leukocytosis, volume depletion, electrolyte imbalance, and 
occasionally, pseudomembranous colitis. Most cases of pediatric CDI are typically mild in 
severity and self-limiting in nature. However, moderate to severe CDI does occur in pediatric 
patients and accumulating evidence indicates that hospital-onset pediatric CDI is associated 
with increased risk of death, longer length of stay, and higher costs as compared to 
community-onset CDI in children [Sammons, Julia Shaklee, et al 2013].  
Treatment of pediatric patients with moderate to severe CDI typically involves 
discontinuation of predisposing antibiotics, supportive measures, and initiating antimicrobial 
therapy directed against C. difficile [Cooperstock, M. S., et al 2012]. Both metronidazole and 
oral vancomycin have been used as standard-of-care regimens to treat pediatric CDI 
[McFarland, L. V., et al 2016] [American Academy of Pediatrics 2015]. Fidaxomicin is a 
newer antibiotic, which received approval in 2011 in the US and other countries for treatment 
of CDI in adults; however, its safety and efficacy have not yet been established in pediatric 
patients.  
One of the key challenges in the clinical management of CDIs in adults and children is to 
reduce the incidence of recurrent CDI; such recurrences in pediatric patients have been 
treated with tapered/pulsed administration of oral vancomycin, vancomycin followed by 
rifaximin, intravenous (IV) immunoglobulin, and therapy with other microorganisms,
including fecal microbiota transplantation (FMT) [Kelly, Ciaran P. and LaMont, J. Thomas 
2008]. The available limited data for pediatric CDI recurrence rates ranges from 7.5% to 
38%, which is similar to that seen in adults [Lo Vecchio, A., et al 2016] [Kelsen, J. R., et al 
2011] [Mezoff, E., et al 2011]. 
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Bezlotoxumab (MK-6072) is a fully human monoclonal antibody (mAb) that binds to and 
neutralizes C. difficile toxin B. In Phase 3 trials in adults with CDI, bezlotoxumab
significantly reduced CDI recurrence compared to placebo [Wilcox, M. H., et al 2017]. 
Bezlotoxumab is currently approved for use in adults for the reduction (United States) or 
prevention (European Union) of CDI recurrence in patients who are receiving antibacterial 
drug treatment for CDI and are at a high risk for CDI recurrence. Aside from bezlotoxumab, 
no other therapeutic or prophylactic biological agents or drugs to prevent CDI recurrences 
have been licensed to date, and bezlotoxumab is not approved for use in pediatric 
populations. In the context of the worsening CDI epidemic, there remains an unmet medical 
need for therapies to prevent CDI recurrence in the pediatric population.
Bezlotoxumab does not have antimicrobial activity and does not take the place of antibiotic 
therapy for CDI. Moreover, bezlotoxumab does not impact the initial efficacy of the 
antibiotics that are used to treat CDI because it is administered after the toxins have already 
caused damage to the gut lining and after antibiotics have already significantly reduced the 
amount of toxin present in the colon. When administered concurrently with antibacterial drug 
treatments for CDI (metronidazole, oral vancomycin, or fidaxomicin in adults), 
bezlotoxumab prevents recurrent infections by providing passive immunity against C. 
difficile toxin B produced by the outgrowth of persistent or newly acquired spores, thereby 
preventing new or further damage to the gut epithelium.
In order to determine a dosing recommendation for the pediatric population, the current trial 
was designed to assess the safety, tolerability, and PK of bezlotoxumab, and to estimate the 
efficacy of bezlotoxumab in participants 1 to <18 years of age.
Pre-clinical and Clinical Trials
Details of pre-clinical studies are described in the bezlotoxumab IB.
Seven adult clinical trials of bezlotoxumab alone or in combination with MK-3415
(actoxumab, mAb directed against C. difficile toxin A) have been completed and are 
described in the bezlotoxumab IB. There are no completed pediatric clinical trials at this 
time.
Ongoing Clinical Trials
There are no other ongoing adult or pediatric clinical trials involving bezlotoxumab at the
time of approval of this protocol.
Information on Other Trial-Related Therapy
Participants will be receiving antibacterial drug treatment for CDI. Please see Section 7.1.1
for further details on antibacterial drug treatment (eg, doses and administration routes for 
metronidazole, oral vancomycin, or fidaxomicin) for this trial. The investigator should also
refer to the local label for information about these antibacterial drug treatments. Please see 
Section 7.7 for concomitant medication exclusions.
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Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical trials will directly benefit from treatment 
during participation. In general, bezlotoxumab has a favorable risk-benefit profile and fulfills 
a significant unmet medical need for therapies to prevent CDI recurrence.
Efficacy data from 2 adult Phase 3 trials demonstrate that a single infusion of bezlotoxumab 
(10 mg/kg) given in combination with antibacterial drug treatment for CDI is superior to 
placebo in prevention of CDI recurrence through a 12-week at-risk period for recurrence, 
addressing an unmet medical need. The low incidence of CDI recurrence in the 
bezlotoxumab group and the treatment difference in CDI recurrence between the 
bezlotoxumab and placebo groups were clinically meaningful and highly consistent in each 
of the Phase 3 trials. The trials included a substantial number of participants (76%) with 1 or 
more risk factors for CDI recurrence; bezlotoxumab consistently lowered CDI recurrence 
rates compared with placebo across subgroups at high risk for CDI recurrence. In addition, 
superior efficacy of bezlotoxumab compared with placebo was demonstrated for the
secondary endpoint of sustained cure in the integrated Phase 3 data. In an exploratory 
analysis of a subset of participants evaluated for up to 12 months following infusion of the 
trial medication, no bezlotoxumab-treated participants who had achieved sustained cure at 
the end of the 12-week main trial experienced a CDI recurrence in the subsequent 9 months, 
thereby providing evidence that the efficacy of bezlotoxumab observed in the main trial was
due to prevention of CDI recurrence rather than a delay in onset of a recurrent episode.
In the Phase 3 program, the safety analysis was conducted using integrated data, in which 
786 participants received bezlotoxumab, 777 participants received actoxumab + 
bezlotoxumab, and 781 participants received placebo. The totality of the safety data show 
that bezlotoxumab, when given with antibacterial drug treatment for CDI, does not increase 
the risks associated with administration of antibacterial drug treatment for CDI alone.
Bezlotoxumab has a very low potential for immunogenicity, and bezlotoxumab 
administration did not result in the development of treatment-emergent anti-drug antibodies 
in the Phase 2 and 3 trials; it is therefore unlikely that anti-drug antibodies will compromise 
efficacy of the product.
The Sponsor considers that 10 mg/kg of bezlotoxumab is an appropriate starting dosage to 
provide the proper benefit:risk ratio evaluation in this trial based on the efficacy and safety 
profiles of bezlotoxumab as demonstrated in the Phase 3 trials for adults with CDI. As 
described elsewhere in the protocol (Section 5.1), provisions are in place to perform PK 
assessments of the 10 mg/kg dose of bezlotoxumab in Panel A of both age cohorts in the 
trial.
Additional details regarding specific benefits and risks for participants participating in this 
clinical trial may be found in the accompanying IB and informed consent documents.
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4. Objectives/Hypotheses and Endpoints
The following objectives and endpoints will be evaluated in pediatric participants aged 1 year 
to <18 years who are receiving antibacterial drug treatment for CDI:
Objective/Hypothesis
Endpoint
Primary
1) Objective: To characterize 
bezlotoxumab PK in 2 age cohorts (Age 
Cohort 1: 12 to <18 years; Age Cohort 
2: 1 to <12 years) of pediatric 
participants to support dose selection in 
this population.

Hypothesis: The area under the 
concentration-time curve from 0 to 
infinity (AUC0-inf) of bezlotoxumab after 
treatment of 2 age cohorts of pediatric 
participants (Age Cohort 1: 12 to <18 
years; Age Cohort 2: 1 to <12 years) 
with a single infusion of bezlotoxumab
is similar when compared to the AUC0-
inf of bezlotoxumab after treatment of 
adult participants with a single infusion 
of 10 mg/kg bezlotoxumab, a dose 
demonstrated to be safe and efficacious 
in adults. That is, the true geometric 
mean ratios (GMRs, pediatric 
participants/adults) for AUC0-inf of 
bezlotoxumab are contained in the 
clinical comparability bounds of (0.6, 
1.6) in each of the age cohorts.

The AUC0-inf will be determined for 
each age cohort from bezlotoxumab 
serum concentration data.
2) Objective: To evaluate the safety and 
tolerability of a single infusion of 
bezlotoxumab as compared with a single 
infusion of placebo through 12 weeks 
following infusion.

Proportion of participants experiencing 
adverse events (AEs)

Proportion of participants discontinuing 
study medication due to AEs
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Objective/Hypothesis
Endpoint
Secondary
3) Objective: To estimate the proportion of 
participants who have a CDI recurrence
within 12 weeks following 
administration of a single infusion of 
bezlotoxumab or placebo.

Proportion of participants who have a
CDI recurrence within 12 weeks of 
study medication infusion. CDI 
recurrence is assessed by the 
investigator using the criteria defined in 
Section 9.2.5.2.
4) Objective: To estimate the proportion of 
participants with sustained clinical 
response over a period of 12 weeks in 
participants who received a single 
infusion of bezlotoxumab or placebo.

Proportion of participants with sustained 
clinical response over a period of 
12 weeks. Sustained clinical response is 
defined as initial clinical response of the 
baseline CDI episode (assessed by the 
investigator using the criteria defined in 
Section 9.2.5.1) AND no CDI 
recurrence (Section 9.2.5.2) through 
Week 12.
5) Objective:  To estimate efficacy (CDI 
recurrence and sustained clinical 
response) in the subset of participants at 
high risk of CDI recurrence within 12 
weeks following administration of a 
single infusion of bezlotoxumab or 
placebo.

Proportion of participants who have a 
CDI recurrence and proportion of 
participants who achieve sustained 
clinical response within 12 weeks of 
study medication infusion in the subset 
of participants at high risk of CDI 
recurrence. High risk is defined as
meeting 1 or more of the following 
criteria at or before randomization:
o Was immunocompromised (as defined 
in Section 9.1.4)
o Had one or more episodes of CDI at 
any point prior to the baseline episode
o Had a baseline CDI episode that met 
criteria for severe CDI (as defined in 
Section 9.2.1.1)
o Had C. difficile ribotype 027 isolated 
from a stool sample collected during 
the baseline CDI episode 
o Had received treatment with 1 or more 
systemic antibacterials known to 
increase the risk of CDI (during 
treatment of the baseline CDI 
episode). Systemic antibacterial 
agents are defined in Section 7.7.
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Objective/Hypothesis
Endpoint
6) Objective: To assess the incidence of 
infusion-related reactions in participants 
who received a single infusion of 
bezlotoxumab or placebo.

Proportion of participants experiencing 
1 or more infusion-related reactions 
within 24 hours following the start of 
the infusion. The definition of 
infusion-related reactions can be found 
in Section 9.3.7.1.
7) Objective: To assess the potential for
bezlotoxumab to induce immunogenicity 
within 12 weeks following 
administration of a single infusion of 
bezlotoxumab.

Proportion of participants with
treatment-emergent positive antibodies 
to bezlotoxumab in serum through 
12 weeks following a single dose of 
bezlotoxumab.
Tertiary/Exploratory
8) Objective: To estimate the proportion of 
participants who have a diarrhea 
recurrence within 12 weeks following 
administration of a single infusion of 
bezlotoxumab or placebo.

Proportion of participants who have a 
diarrhea recurrence within 12 weeks of 
study medication infusion. Diarrhea 
recurrence is assessed by the 
investigator as defined in 
Section 9.2.5.2.
9) Objective: To explore the relationship 
between genetic variation and response 
to the treatment(s) administered and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected 
in this trial.
5. Study Design
Overall Design 
This is a Phase 3, randomized, placebo-controlled, parallel-group, multi-site, double-blind 
trial evaluating the PK, safety, tolerability, and efficacy of a single infusion of bezlotoxumab 
in pediatric participants from 1 to <18 years of age receiving antibacterial drug treatment for 
CDI.
Participants will be enrolled into 1 of the following 2 age cohorts:

Age Cohort 1: 12 to <18 years of age

Age Cohort 2: 1 to <12 years of age
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Enrollment into the trial will begin with Age Cohort 1, and Age Cohort 2 will commence 
later; the timing for enrollment into each age cohort is described in Section 5.1.2.
At screening, eligible participants must have suspected or confirmed CDI, as described in 
Section 6.1, and be receiving or planning to receive a 10- to 21-day course of antibacterial 
drug treatment for CDI (Section 7.1.1). 
Prior to randomization, participants’ diagnosis of CDI must be confirmed by a positive stool 
test for C. difficile toxin (see Appendix 7 for assay requirements). Once the CDI diagnosis 
has been confirmed, participants will be randomly assigned to a treatment group in a 3:1 ratio
(bezlotoxumab:placebo) and will receive a single IV infusion of either bezlotoxumab or 
placebo (Day 1). Note that the participant must still be receiving antibacterial drug treatment 
for CDI on the day of randomization/study infusion. Throughout the protocol, timing of 
assessments expressed as study day and study week is relative to receipt of study infusion, 
which is Day 1.
After receiving the study infusion, participants will be followed for 12 weeks (ie, 85 ± 
5 days) for collection of blood samples for PK and immunogenicity assessments and 
monitoring of safety and tolerability parameters (clinical and laboratory AEs, vital sign
measurements, physical examinations) and signs and symptoms (including clinical laboratory 
assessments, watery diarrhea or unformed bowel movements [UBMs], abdominal discomfort, 
and body temperature) to assess efficacy outcomes (including initial clinical response, 
diarrhea recurrence, and CDI recurrence) (Figure 1).
Each day throughout the 12-week follow-up period, participants or the participants’ parents 
or caregivers will record in a paper diary whether the participant had watery diarrhea or 
UBMs in the previous 24 hours. If the participant has at least a single episode of watery 
diarrhea or UBMs, the participant or the participants’ parents or caregivers will record the 
number of episodes, the participant’s worst abdominal discomfort score, and the presence or 
absence of a fever (and the highest body temperature if a fever is present) during the previous 
24 hours. The diary will be used as a tool for the investigator to use when performing 
efficacy outcome assessments and will be maintained as a source document. Daily diary 
entries will not be entered into the electronic data collection (EDC) system, with the 
exception of the specific information noted in Section 9.2.5.2.
Trial personnel will contact the participant or the participant’s parent or caregiver at the 
following time points during the study:

Approximately 24 hours after the end of the infusion to assess for infusion-related 
reactions. 

At least 3 times per week during antibacterial drug treatment for the baseline episode 
of CDI for assessment of antibacterial drug treatment compliance.
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
Twice weekly after the End of Treatment (EOT) Visit through Week 12 to ensure that 
the daily diary is maintained by the participant or the parent or caregiver and to 
remind them to collect a stool sample if the participant experiences watery diarrhea 
(if the child is using diapers or other fecal collection device) or 3 or more UBMs 
within a 24-hour period.
The information communicated by the participant or the parent or caregiver during the 
contact is to be recorded in the source documents.
Initial clinical response will be assessed by the investigator approximately 48 hours after the 
last dose of antibacterial drug treatment for the baseline episode of CDI (EOT Visit), as 
described in Section 9.2.5.1. 
Diarrhea recurrence and CDI recurrence will be assessed by the investigator as described in 
Section 9.2.5.2 at each scheduled visit that occurs after the EOT Visit and at any unscheduled 
visits due to diarrhea. The investigator will review the diary to assess whether the 
protocol-specified criteria for diarrhea recurrence were met. If the criteria for diarrhea 
recurrence were met, a stool sample will be tested for C. difficile toxin, and the investigator 
will record whether the criteria for a CDI recurrence have been met.
Sustained clinical response will be derived from the investigator assessment of initial clinical 
response and CDI recurrence, as described in Section 10.4.3.
An independent data monitoring committee (DMC) will be appointed and will review the 
safety and tolerability data. There will be 2 planned reviews by the DMC, as described in 
Section 5.1.2, with additional information provided in Appendix 3.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 – Study Assessments and Procedures.
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Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Diagram of Trial Design
Enrollment Strategy
Each age cohort will be enrolled in 2 panels (Panel A and Panel B), as shown in Figure 2. 
Enrollment will start with Age Cohort 1 participants. Enrollment into Age Cohort 2 Panel A 
will commence after approximately 12 participants in Age Cohort 1 Panel A complete all 
study visits. 
The starting dose of bezlotoxumab for both age cohorts in Panel A will be 10 mg/kg body 
weight, which is the dose that has been shown to be effective in reducing recurrent CDI in 
adults. 
When approximately 12 participants from Panel A of each age cohort have complete PK 
data, their PK data will be evaluated to determine whether dose modification is warranted for 
subsequent participants in the respective age cohort.
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The PK evaluation will determine the following:

If the criterion described in Section 7.2 is met, then participants enrolled subsequent 
to the PK evaluation will continue to receive the same dose (10 mg/kg) used in 
Panel A.

If the criterion described in Section 7.2 is not met, the bezlotoxumab dose will be 
modified as needed (see Section 7.2), and participants enrolled subsequent to the PK 
evaluation will receive the modified bezlotoxumab dose.
Enrollment into Panel A of each age cohort will continue until the PK assessment is complete 
for that age cohort, at which point enrollment into Panel B of that age cohort will begin.
Safety and tolerability data will be reviewed by a DMC (Appendix 3) as follows:

Data from Age Cohort 1 Panel A after 12 participants in this panel have completed 
all study visits through 12 weeks.

Data from Age Cohort 2 Panel A after 12 participants in this panel have completed 
all study visits through 12 weeks, plus data from all Age Cohort 1 participants 
enrolled at that point in time.
Figure 2
Enrollment Strategy
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Number of Participants
In Panel A, for which the purpose is to determine the dose for each age cohort, a minimum of 
24 participants across both age cohorts will be enrolled (Age Cohort 1 Panel A: 12 
participants [9 bezlotoxumab, 3 placebo]; Age Cohort 2 Panel A: 12 participants 
[9 bezlotoxumab, 3 placebo]). 
The trial will continue until trial enrollment has reached a total of 192 participants who 
received the final age-appropriate dose (Table 1). If the dose needs to be modified for either 
age cohort, then additional participants will be enrolled in Panel B in order to achieve a total 
of 192 participants who received the final age-appropriate dose.
There is no requirement to enroll an equal number of subjects across the 2 age cohorts.
However, a minimum of 24 participants will be required to be enrolled in each age cohort at 
the final age-appropriate dose as follows:

Age Cohort 1: 24 participants (18 bezlotoxumab at the final age-appropriate dose, 
6 placebo); 

Age Cohort 2: 24 participants (18 bezlotoxumab at the final age-appropriate dose, 6 
placebo), with a minimum of 12 participants (9 bezlotoxumab, 3 placebo) aged 1 to 
<6 years of age, and a minimum of 12 participants (9 bezlotoxumab, 3 placebo) aged 
6 to <12 years of age.
If a dose modification is needed, the number of participants may be adjusted in order to 
ensure 192 participants receive the final age-appropriate dose.
Table 1
Number of Participants, Assuming Dose Modification is Not Required
Panel A
Panel B
Total 
Number of 
Participants
Total 
Number of 
Participants 
Who 
Receive
Final Age-
Appropriate 
Dose
Age 
Cohort 
1
Age 
Cohort 
2
Minimum 
in Age 
Cohort 1
Minimum in 
Age Cohort 
2
Total 
Across 
Both 
Age 
Cohorts
1 to 
<6 
years
6 to 
<12
years
Number of 
Participants
at Final Age-
Appropriate 
Dose
≥12
≥12
24
12
12
168
192
192
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Beginning and End of Study Definition
The overall trial begins when the first participant signs the informed consent/assent form.  
The overall trial ends when the last participant completes the last study-related phone-call or 
visit, withdraws from the trial or is lost to follow-up (i.e. the participant is unable to be 
contacted by the investigator).
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. If the extent (incidence and/or severity) of emerging effects/clinical endpoints is such that 
the risk/benefit ratio to the trial population as a whole is unacceptable.
2. At the recommendation of the DMC based on their evaluation of the ongoing study safety 
data and the resultant risk/benefit assessment.
3. Further recruitment in the trial or at (a) particular trial site(s) may be stopped due to 
insufficient compliance with the protocol, Good Clinical Practice (GCP) and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
Scientific Rationale for Study Design
Rationale for Endpoints
Pharmacokinetic Endpoints
The AUC0-inf of bezlotoxumab will be evaluated following a single IV dose from samples 
collected at time points through 12 weeks after the infusion, as specified in Section 2 –
Schedule of Activities (SoA). Based on the shape of the concentration-time profile in adults 
and experience with this sampling scheme in the Phase 3 trials, the chosen sampling time 
points are anticipated to provide sufficient data for estimation of AUC0-inf. In addition, 
maximum concentration (Cmax), time of maximum concentration (Tmax), terminal half-life, 
volume (Vdss), and clearance (Cl) will be evaluated for bezlotoxumab. These endpoints will 
be assessed for Panels A and B.
Safety Endpoints
The safety and tolerability of bezlotoxumab will be primarily assessed by clinical and 
laboratory AEs.
Bezlotoxumab is a mAb, and mAbs have been associated with acute hypersensitivity 
reactions, referred to hereafter as infusion-related reactions. Although these types of 
reactions were not observed in participants who received bezlotoxumab alone or in 
combination with actoxumab in the adult Phase 3 trials, it is important to continue to evaluate 
the potential for infusion-related reactions in a pediatric population because it is difficult to 
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detect potentially serious but low-frequency toxic effects. Therefore, the potential for
bezlotoxumab to cause infusion-related reactions will be evaluated in the current trial 
(Section 9.3.7.1). 
Efficacy Endpoints
The efficacy endpoints in this trial include the proportion of participants who have a CDI 
recurrence and the proportion of participants who achieve sustained clinical response within 
12 weeks (Day 85 ± 5 days) of a single infusion of bezlotoxumab or placebo. CDI recurrence 
is assessed by the investigator as defined in Section 9.2.5.2, and sustained clinical response is 
derived from the investigator’s assessment of initial clinical response and CDI recurrence, as 
defined in Section 10.4.3.
In the adult Phase 3 trials of bezlotoxumab, a follow-up period of 12 weeks for CDI 
recurrence was sufficient to allow for robust demonstration of the efficacy of bezlotoxumab.  
In these trials, 71% of all recurrences occurred by Week 4 while 29% of recurrences occurred 
in Weeks 5 through 12. In a subset of participants followed for 12 months, recurrences were 
rarely observed. Therefore, a minimum of a 12-week follow-up period is necessary to allow 
for robust assessment of efficacy, but a longer period is not warranted. A 12-week follow-up 
period will be used in this pediatric trial.
Planned Exploratory Biomarker Research
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, and 
severity and progression of disease. Variable response to therapy may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. Therefore, where local regulations and IRB/IEC allow, a sample will be 
collected for DNA analysis from consenting participants.
DNA samples will be used for research related to the study treatment(s), the disease under 
study and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to the disease under study, related diseases and study drug(s). Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome [or analysis of the entire genome] (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data. 
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
     
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Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
Future Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time.  The 
details of this Future Biomedical Research sub-trial are presented in Appendix 6 –
Collection and Management of Specimens for Future Biomedical Research.
Rationale for The Use of Comparator/Placebo
A placebo control treatment of either 0.9% sodium chloride or 5% dextrose will be included 
in the trial. These are the approved diluents for the preparation of the bezlotoxumab infusion 
solution. 
Importantly, all participants (regardless of treatment group assignment) enrolled in this trial 
will receive antibacterial drug treatment for CDI (Section 7.1.1) concurrent with 
administration of trial infusion. Placebo participants will therefore be receiving current 
medically acceptable treatment for CDI. Use of a placebo allows for estimation of efficacy of 
bezlotoxumab and a comparison for safety assessments.
Justification for Dose
Starting Dose for This Trial
The initial dose of the single, IV infusion of bezlotoxumab to be administered to Panel A of 
each age cohort is 10 mg/kg body weight. This dose demonstrated superior efficacy in 
prevention of CDI recurrence in the adult Phase 3 trials conducted among adults aged >18 
years. This dose was also generally safe and well tolerated in adults. 
Bezlotoxumab is catabolized through protein degradation processes; thus, metabolism does 
not contribute to its clearance and it is not eliminated by renal or biliary excretion. 
Consequently, the clearance of bezlotoxumab is not expected to be different in children 
compared with adults, except based on weight, which is accounted for by weight-based 
dosing. Hence, the 10 mg/kg dose is anticipated to be appropriate for children and to provide 
serum exposures similar to those observed in adults. However, the dose may be modified for 
Panel B of each age cohort based on PK evaluations performed during this trial (Section 7.2).
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Maximum Dose/Exposure for This Trial
The maximum dose and exposure of bezlotoxumab during the trial will not exceed a single, 
20 mg/kg IV dose of bezlotoxumab and the exposure associated with this dose previously 
observed in adults. As described in the bezlotoxumab IB, the maximum known tolerated dose 
in humans is 20 mg/kg. Based on PK data from children obtained in the initial panels and age 
cohorts in this trial, the starting dose may be increased to achieve serum exposures similar to 
those observed in adults receiving 10 mg/kg (Section 7.2).
Rationale for Dose Interval and Trial Design
The dose and trial design are similar to those for the Phase 3 bezlotoxumab clinical trials in 
adults, MK-3415A Protocol 001 and 002 trials, in which the safety and efficacy of 
bezlotoxumab was demonstrated, as summarized in the bezlotoxumab IB.
The key trial design differences between the current pediatric trial and the Phase 3 adult trials 
are as follows:

Randomization is being stratified on the basis of age cohort instead of being stratified
based on antibacterial drug treatment for CDI or hospitalization status, 

Allowed duration of antibacterial drug treatment for the baseline CDI episode has 
been increased to 21 days to increase the proportion of participants who achieve 
initial clinical response and are assessable for the CDI recurrence endpoint, 

Characterization of diarrhea recurrence (as defined in Section 9.2.5.2) has been 
changed, 

The laboratory diagnostic criteria for CDI at study entry and for CDI recurrences has
been changed to require a test that detects toxin in the stool, and

Clinical outcomes will be assessed by the investigator. To be consistent with study 
inclusion criteria, an outcome of CDI recurrence will require that treatment be given.
6. Study Population
Male and female participants between the ages of 1 and <18 years with CDI will be enrolled 
in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. At the time of screening, participant 
a.
has suspected or confirmed CDI, as evidenced by the following:
had a change in normal bowel habits for 2 or more calendar days with 
either watery diarrhea (for participants using diapers or other type of 
fecal collection device, Bristol Stool Scale types 6 or 7) or at least 6
UBMs (eg, takes shape of container, or Bristol Stool Scale types 5, 6, 
or 7) within a 48-hour period, and
produced a stool sample that has tested positive for toxigenic C. 
difficile according to local diagnostic criteria.
b. is receiving or is planning to receive a 10- to 21-day course of antibacterial 
drug treatment for CDI, which is defined as oral vancomycin, oral 
metronidazole, or oral fidaxomicin. Additionally, IV metronidazole may be 
given concurrently with oral vancomycin or oral fidaxomicin (see 
Section 7.1.1 for further details).
2. At the time of randomization/study infusion, participant:
a.
has a diagnosis of CDI confirmed by a diagnostic assay which detects the 
presence of C. difficile toxin in stool (see Appendix 7 for additional 
information regarding C. difficile assay requirements), and
b. is still receiving antibacterial drug treatment for CDI.
Demographics
3. Participant is of either sex and of any race, and ≥1 year to <18 years of age at the time 
of randomization.
Female participants:
4. A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR 
b.) A WOCBP who agrees to use any contraceptive method listed in Table 14 in 
Appendix 5 (including those classified as “acceptable”) from Day 1 through at least 
12 weeks after the single infusion of study treatment.
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Informed Consent/Assent
5. The participant (or legally acceptable representative [LAR] if applicable) provides 
written informed consent/assent for the trial.  The participant or LAR may also 
provide consent/assent for Future Biomedical Research (FBR).  However, the 
participant may participate in the main trial without participating in FBR.
Adherence to Study Procedures
6. Participant must be able to adhere to the study visit schedules.
7. Participant and/or parent or caregiver must be able to read, understand, and complete 
the daily diary (Section 9.2.2).
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Participant has an uncontrolled chronic diarrheal illness such as, but not limited to,
Crohn’s disease, ulcerative colitis, or with a condition such that their normal 24-hour 
bowel movement habit is 3 or more UBMs. Participants with a history of IBD who 
are controlled (ie, had no recent active diarrhea/UBMs prior to current CDI episode) 
may be enrolled if in the opinion of the investigator, the symptoms are more likely 
due to CDI than a flare of the IBD.
2. Has a known hypersensitivity to bezlotoxumab, its active substance and/or any of its 
excipients (refer to the Investigator’s Brochure for a list of excipients).
Prior/Concomitant Therapy
3. Participant for whom, at the time of randomization, the planned course of
antibacterial drug treatment for CDI is longer than 21 days.
4. Participant has received any treatment or procedure listed in Table 2 within the 
indicated exclusion window.
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Table 2
Prohibited Prior and Concomitant Treatments and Procedures at Time of 
Screening Visit and During Screening Period
Treatment/Procedure
Exclude if Given in the Window Indicated
Treatments
Rifaximin 
Within 14 days prior to receipt of study infusion
Nitazoxanide 
Within 14 days prior to receipt of study infusion
Procedures
Surgery for episode of CDI
under treatment at time of 
randomization
Any time prior to screening or during screening
period
Prior/Concurrent Clinical Study Experience
5. Participant has previously participated in this trial, has previously received 
bezlotoxumab, has received an experimental mAb against C. difficile toxin B, or has 
received a vaccine directed against C. difficile or its toxins.
6. Participant has received an investigational trial agent within the previous 30 days, or 
is currently participating in or scheduled to participate in any other clinical trial with 
an investigational agent during the 12-week trial period.
Other Exclusions
7. Participant is not expected to survive for 72 hours.
8. Participant has any other condition that, in the opinion of the investigator, would 
jeopardize the safety or rights of the participant, would make it unlikely for the 
participant to complete the trial, or would confound the results of the trial.
9.
Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Lifestyle Restrictions
Participant should not donate blood and/or blood products within 3 months following the trial 
medication infusion.
No other lifestyle restrictions are required in this trial.
Meals and Dietary Restrictions
There are no dietary restrictions for participants in this trial.
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Caffeine, Alcohol, and Tobacco
There are no restrictions of caffeine, alcohol, or tobacco for participants in this trial.
Activity
There are no activity restrictions for participants in this trial.
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the entry guidelines.
Participant Replacement Strategy
In general, a participant who discontinues from trial treatment or withdraws from the trial 
will not be replaced. However, if a Panel A participant discontinues from the trial prior to the 
last PK blood sampling or had incomplete PK sampling and the collected PK data were 
determined to be insufficient to allow PK assessments, a replacement participant may be 
enrolled to replace the original participant. The replacement participant will receive the same 
treatment that the original participant was randomized to receive.
7. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment and replacement participants as required.  When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
supplies.  Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Treatments Administered
The study treatment(s) to be used in this trial are outlined below in Table 3.    
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Table 3
Study Treatment(s)
Study Treatment Name:
Bezlotoxumab (MK-6072)
Placebo
Dosage Formulation:
Sterile solution for IV 
infusion in 0.9% sodium 
chloride or 5% dextrose 
0.9% sodium chloride or 
5% dextrose 
Unit Dose Strength(s):
25 mg/mL
Not applicable
Dosage Level(s):
10 mg/kg
Starting dose for Panel A of 
each age cohort. Dose 
modification may be made 
for Panel B of each age 
cohort (Section 7.2).
Not applicable
Route of Administration:
IV infusion
IV infusion
Sourcing:
Sponsor
Trial site
All supplies indicated in Table 3 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. The trial site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to section 9.1.8 for details regarding administration of the study treatment.
Bezlotoxumab or placebo (0.9% sodium chloride or 5% dextrose) is to be administered as a 
single IV infusion using a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron 
in-line or add-on filter over approximately 60 (±10) minutes.
Antibacterial Drug Treatment for CDI
Participants enrolled in this study should be prescribed an antibacterial drug treatment
regimen for CDI by the treating physician; acceptable treatments are oral vancomycin, oral 
metronidazole, or oral fidaxomicin. Additionally, IV metronidazole may be given 
concurrently with oral vancomycin or oral fidaxomicin.
Antibacterial drug treatment for CDI should be prescribed for a minimum duration of 10 
days and a maximum duration of 21 days, including the duration of antibacterial drug 
treatment prior to the screening visit, during the screening period, and after the infusion of 
study treatment. If antibacterial drug treatment is switched, participants should still be 
prescribed a minimum of 10 days and a maximum of 21 days of total antibacterial drug 
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treatment for CDI (eg, if oral metronidazole is given as the primary agent initially, but then 
switched to oral vancomycin, the total antibacterial drug treatment duration with both 
therapies administered sequentially should total no more than 21 days). 
Participants receiving IV metronidazole concurrently with oral vancomycin or oral 
fidaxomicin may be switched to the respective oral treatment alone when clinically 
warranted. 
The first through the last day of each antibacterial drug treatment for CDI will be recorded in 
source documents and via the appropriate electronic case report form (eCRF). Also, all 
changes in antibacterial drug treatment (including changes in dosages) should be recorded.
Permitted antibacterial agents, routes, and dosages for the baseline episode of CDI are 
specified in Table 4. The choice of agent, dosing regimen, and treatment duration can be per 
institutional guidelines; however, any regimen not in accordance with those specified in 
Table 4 must be discussed with the Sponsor’s Clinical Director; if this discussion does not 
result in the use of a protocol-specified regimen, then a valid clinical reason for deviating 
from the protocol-specified regimen must be documented.
The choice of agents, dosages, and treatment durations to treat a CDI recurrence during the 
12-week follow-up period is at the discretion of the investigator; see Section 7.7 for 
additional details.
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Table 4
Antibacterial Drug Treatment for Baseline Episode of CDI
Study Treatment 
Name:
Metronidazole
Vancomycin
Fidaxomicin
Dosage Level(s):
30 mg/kg body 
weight per day 
given as 3 or 4 
divided doses, or 
1.2 g to 1.5 g per 
day given as 3 or 
4 divided doses. 
Total daily dose 
not to exceed 
1.5 g per day.a
40 mg/kg body 
weight per day 
given as 3 or 4 
divided doses, or 
500 mg to 2 g per 
day given as 3 or 
4 divided doses. 
Total daily dose 
not to exceed 2 g 
per day.a
For participants 
≤12.5 kg: 32 mg/kg
body weight per day 
given as 2 divided 
dosesb
For participants 
>12.5 kg: 400 mg 
per day given as 2 
divided dosesb
Route of 
Administration:
Oralc
or
IV infusiond
Oralc,e
Oralc
Sourcing:
Trial site
Trial site
Trial site
a. Sources: [American Academy of Pediatrics 2015] [Schutze, G. E. and Willoughby, R. E. 2013] [Cohen, S. H., 
et al 2010]; UpToDate [Internet].
b. Source: Optimer Pharmaceuticals LLC. In: ClinicalTrials.gov [Internet]. Safety, tolerability, and 
pharmacokinetics of fidaxomicin in pediatric subjects with Clostridium difficile-associated diarrhea (CDAD).
Bethesda (MD): National Library of Medicine (US). 2000- [cited date 2017 Apr 05]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT01591863?term=fidaxomicin&rank=7 NLM Identifier: 
NCT01591863.
c. May be administered via gastrostomy tube. 
d. IV metronidazole may be administered concurrently with oral vancomycin or oral fidaxomicin.
e. May not be administered intravenously for CDI treatment.
Dose Modification (Escalation/Titration/Other)
As indicated in Section 7.1, the starting dose of bezlotoxumab for Panel A of each age cohort 
will be 10 mg/kg. As described in Section 5.1.2, data from approximately 12 participants in 
Panel A of each age cohort who have complete PK data will be reviewed and evaluated 
against the following criterion:

Bezlotoxumab exposure in the relevant panel and age cohort is similar to that observed 
in adults, as determined by a 90% CI for the pediatric/adult AUC0-inf comparison 
within the clinical comparability bounds of (0.6, 1.6). These bounds have been 
established based on the clinical experience in the Phase 3 trials as reflecting the range 
of relative change in AUC0-inf that is expected to be clinically comparable to a 
10 mg/kg dose in adult participants with respect to safety and efficacy. Differences in 
ratios of bezlotoxumab exposures that fall within this range are not considered 
clinically meaningful and do not warrant dose modification. It is important to note that 
the upper bound of 1.6 for bezlotoxumab reflects the limit of current clinical exposure.
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As shown in Figure 3, if this criterion is met, then participants in Panel B of that age cohort
will commence without dose modification. Alternatively, if this criterion is not met, then the 
dose will be modified to either a higher or a lower dose for participants enrolled subsequent 
to the PK evaluation based on results of modeling and simulation analyses (see Section 
10.6.1).
Figure 3
Bezlotoxumab Dose Modification
Method of Treatment Assignment 
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).  There are 2 study treatment arms.  
Participants will be assigned randomly in a 3:1 ratio to bezlotoxumab or placebo, 
respectively.
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. Participant’s age at the time of randomization:
a.
Age Cohort 1 (12 to <18 years of age)
b.
Age Cohort 2 (1 to <12 years of age).
Blinding 
A double-blinding technique will be used.  Bezlotoxumab and placebo will be prepared 
and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified trial site 
personnel. The participant and the investigator who is involved in the study treatment 
administration or clinical evaluation of the participants are unaware of the group 
assignments.
See Section 9.1.10 for a description of the method of unblinding a participant during the trial, 
should such action be warranted.
Preparation/Handling/Storage/Accountability
Dose Preparation
The quantity of bezlotoxumab administered is based on the participant’s actual body weight. 
The initial dose will be 10 mg/kg bezlotoxumab for participants in Panel A of each age 
cohort, and potential dose modifications are described in Section 7.2.
The required dose of bezlotoxumab will be diluted directly in 0.9% sodium chloride or 5% 
dextrose to comprise a total infusion volume such that the final concentration is between the 
range of 1 mg/mL and 10 mg/mL. For the preparation of placebo infusions, a weight-
appropriate volume of 0.9% sodium chloride or 5% dextrose solution will be given as an IV 
infusion. Additional details will be provided in the Operational Manual. 
In order to maintain the blind, the unblinded pharmacist (or qualified study site personnel 
designated to prepare the IV supplies) will be responsible solely for the preparation of the IV 
study therapy. He/She will not be involved in evaluating participants for efficacy or safety. 
Due to a slight difference in appearance of the bezlotoxumab diluted solution compared with 
0.9% sodium chloride and 5% dextrose, an opaque sleeve will be placed over the infusion 
bag or syringe to maintain the blind.
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The product does not contain preservative. The diluted solution of bezlotoxumab may be 
stored either at room temperature for up to 16 hours or under refrigeration at 2°C to 8°C 
(36°F to 46°F) for up to 24 hours. If refrigerated, allow the diluted solution to come to room 
temperature prior to use. These time limits include storage of the infusion solution through 
the duration of infusion. Do not freeze the diluted solution.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate.  Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
For all participants, the blinded trial staff will be responsible for administration of trial 
medication, which will be recorded in the participant’s eCRF.
Compliance With Antibacterial Drug Treatment for CDI
From the signing of the ICF through the last scheduled day of antibacterial drug treatment for 
the baseline episode of CDI, the study personnel will have contact by phone or in person with 
the participant or the participant’s parent or caregiver to obtain the compliance with the 
antibacterial drug treatment for CDI at least 3 times per week. If the antibacterial drug 
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treatment is being administered in an inpatient or other institutional settings in which 
medication administration records are routinely kept, then study personnel will transfer the 
administration records from the participant’s chart into the corresponding telephone contact 
source document worksheet of the participant for the purposes of this trial.
Any interruptions from the prescribed antibacterial drug treatment plan require 
documentation on the eCRF.
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the timeperiods specified by this protocol for that medication or vaccination, unless 
administered to treat a CDI recurrence, as noted below.   The investigator should discuss any 
intended use of these medications as prophylactic or pre-emptive therapy or use for another 
indication (e.g., metronidazole for intra-abdominal infection) with the Sponsor Clinical 
Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  
The medications in Table 5 are prohibited during the timeframes specified in the table, unless
administered to treat a CDI recurrence (as defined in Section 9.2.5.2), or if the participant is 
considered a clinical failure (as defined in Section 9.2.5.1).
Table 5
Prohibited Concomitant Treatments and Procedures During the Trial (Day 1 
through Day 85 ± 5 days)
Prohibited Timing of Treatment or Procedure
Treatment/Procedure
From study infusion through 
12-week trial period
Cholestimide (>24-hour regimen)
Cholestyramine (>24-hour regimen)
Experimental monoclonal antibody 
against C. difficile toxin B or vaccine 
directed against C. difficile
Fecal microbiota transplantation 
(FMT)b
Nitazoxanide
Rifaximin
Saccharomyces boulardii (probiotic)
Teicoplanin (oral or rectal)a
Tigecyclineb
Any other treatments not currently 
specified in the protocol that have 
been shown to decrease CDI 
recurrence
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Prohibited Timing of Treatment or Procedure
Treatment/Procedure
From end of antibacterial drug treatment for the 
baseline CDI episode through 12 week trial 
period
Fidaxomicina
Metronidazoleb
Vancomycin (oral or rectal)a
a. Discuss prophylactic or pre-emptive use for CDI with Sponsor Clinical Director.
b. Discuss prophylactic or pre-emptive use for CDI or use for another indication (eg, intra-abdominal 
infection) with Sponsor Clinical Director.
Medications given to decrease gastrointestinal peristalsis, such as loperamide (ImodiumTM) 
or diphenoxylate hydrochloride/atropine sulfate (LomotilTM), are prohibited as treatments for 
CDI recurrences throughout the 12-week trial period.
The use of investigational study agents during the 12-week trial period is prohibited.
The use of systemic antibacterial agents, defined as an antibiotic given via a route that results 
in therapeutic concentrations in the systemic circulation, is permitted before and after 
randomization.
Refer to Section 9.1.5 for recording of relevant prior and concomitant medications in the 
eCRF.
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
This trial is blinded but supplies are provided open label; therefore, an unblinded pharmacist 
or qualified trial site personnel will be used to blind supplies.  Study treatment identity 
(name, strength or potency) is included in the label text; random code/disclosure envelopes or 
lists are not provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind participants and to unmask study treatment identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 9.1.10). In the 
event that the emergency unblinding call center is not available for a given site in this trial, 
the central electronic treatment allocation/randomization system (IVRS/IWRS) should be 
used in order to unblind participants and to unmask study treatment identity.  The Sponsor 
will not provide random code/disclosure envelopes or lists with the clinical supplies.
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See Section 9.1.10, Participant Blinding/Unblinding, for a description of the method of 
unblinding a participant during the trial, should such action be warranted.
8. Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the single infusion (ie, participants who 
receive a partial dose) will still continue to participate in the study as specified in Section 2 -
SoA and Section 9.1.9 – Withdrawal/Discontinuation.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9 – Withdrawal/Discontinuation.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.
For participants who are discontinued from study treatment but continue to be monitored in 
the trial, all visits and procedures, as outlined in the trial flowchart, should be completed.
Participants may be allowed to begin study treatment again if deemed medically appropriate; 
that is, if there is an interruption in the 1-hour infusion for any reason, the infusion can be re-
started if medically acceptable.
Withdrawal from the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
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Specific details regarding procedures to be performed at the time of withdrawal from the 
study including the procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant, as well as 
specific details regarding withdrawal from Future Biomedical Research are outlined in 
Section 9.1.9 – Withdrawal/Discontinuation.
Lost to Follow Up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
o
The site must attempt to contact the participant and reschedule the missed visit..  If 
the participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
o
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (e.g. phone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These
contact attempts should be documented in the participant’s medical record.
o
Note:  A participant is not considered lost to follow up until the last scheduled visit 
for the individual participant.  The amount of missing data for the participant will be 
managed via the pre-specified data handling and analysis guidelines
9. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
All study-related medical decisions must be made by an investigator who is a 
qualified physician.
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
The approximate total blood volume to be drawn over the 12 weeks of the trial is 29 mL. The 
maximum volume of blood drawn on any 1 day is 7 mL; this is within approximately 1% of 
total blood volume (0.8 mL blood per kg of body weight) for the majority of eligible subjects 
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in this study (ie, starting with 1-year-old girls in the 50th percentile of growth according to 
World Health Organization growth charts).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. The maximum blood volume collected from each participant should be based on 
weight and should generally not exceed 1% of total blood volume on any 1 day or 3% of total 
blood volume (2.4 mL blood per kg of body weight) during a given 4-week trial period, 
unless appropriate justification is documented by the investigator [EMEA/CPMP 2008] 
[Food and Drug Administration (CDER) 2014].
Administrative and General Procedures
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent, and assent if applicable, from each potential participant or each 
participant’s legally acceptable representative prior to participating in a clinical trial or 
Future Biomedical Research. If there are changes to the participant’s status during the trial 
(eg, health or age of majority requirements), the investigator or medically qualified designee 
must ensure the appropriate consent/assent is in place.
General Informed Consent/Assent
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the trial.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form and any written information provided to the participant must receive the 
IRB/IEC’s approval/favorable opinion in advance of use.  The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
trial.  The communication of this information will be provided and documented via a revised 
consent/assent form or addendum to the original consent/assent form that captures the 
participant’s dated signature or by the participant’s legally acceptable representative’s dated 
signature.
Specifics about a trial and the trial population will be added to the consent/assent form 
template at the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements. The assent, as applicable will adhere to IRB/ERC requirements, 
applicable laws and regulations and Sponsor requirements. 
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Consent/Assent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the Future Biomedical Research 
consent/assent to the participant, answer all of his/her questions, and obtain written informed 
consent/assent before performing any procedure related to the Future Biomedical Research 
sub-trial.  A copy of the informed consent/assent will be given to the participant.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the trial.
Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research trial. The card will contain trial site contact information (including 
direct telephone numbers) to be utilized in the event of an emergency. The investigator or 
qualified designee will provide the participant with a Participant Identification Card 
immediately after the participant provides written informed consent/assent. At the time of 
treatment allocation/randomization, site personnel will add the treatment/randomization 
number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. In addition to 
the evaluation of a participant’s medical history in terms of trial eligibility, all medical 
conditions since birth will be documented on the appropriate eCRF. 
The number of prior episodes of CDI will be documented separately on the appropriate 
eCRF, along with additional relevant information, including timing and treatment(s) given
for the most recent prior episode.
Whether or not each participant is immunocompromised will be assessed by the investigator 
and will be based on the participants’ status at or before randomization. Compromised 
immunity is defined as meeting 1 or more of the following criteria:

Active hematological malignancy (including, but not limited to, leukemia, lymphoma, 
multiple myeloma)

Receiving cytotoxic chemotherapy (or received within the 28 days prior to onset of
the baseline CDI episode) for an active malignancy 
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
Receiving immunosuppressive therapy following hematopoietic stem cell transplant 
or a solid organ transplant

Asplenia

Neutropenia (≤500 counts/mm3) 

Congenital or acquired immunodeficiency disorder

Receiving other medications known to suppress the immune system (including, but 
not limited to, antineoplastic and immunomodulating agents, immunosuppressive 
dose of systemic corticosteroids of at least 7 days’ duration) or received within the 28 
days prior to onset of the baseline CDI episode.
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant
from 28 days prior to the onset of the baseline episode of CDI through signing of informed 
consent. This will include but is not limited to all antibacterial medications, anti-diarrheal 
medications, treatments for dehydration (including fluids), and any therapies given and 
procedures performed for treatment of CDI (eg, colectomy, endoscopy, FMT). For breast-fed 
participants, the mothers’ prior medications should also be recorded.
Treatment(s) given for the most recent prior episode of CDI should be recorded even if the 
treatment ended more than 28 days prior to the onset of the baseline episode of CDI.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant
at any point from the signing of informed consent through Week 12 (85 ± 5 days). This will 
include but is not limited to all antibacterial medications, anti-diarrheal medications, 
treatments for dehydration (including fluids), any therapies given and procedures performed 
for treatment of CDI (eg, colectomy, endoscopy, FMT), and any medications used to treat 
AEs. For breast-fed participants, the mothers’ concomitant medications should also be 
recorded.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.  Each participant
will be assigned only one screening number.  Screening numbers must not be re-used for 
different participants.
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Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 9.10.1. 
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
Blinded trial staff will be responsible for administration of trial medication.
Study treatment is to be given on the day of treatment allocation/randomization or as close as 
possible to the date on which the participant is allocated/assigned.
Timing of Dose Administration
Bezlotoxumab or placebo will be administered as a single IV infusion over approximately 
60 (±10) minutes on the day of randomization (Day 1) or as close as possible to the date of 
randomization. All participants must still be receiving antibacterial drug treatment for CDI 
on the day of the infusion (that is, participants will receive their last antibacterial dose on the 
day of study infusion or after).
It is important to record the details of the infusion, including start and stop times and date as 
well as any interruptions, on the appropriate eCRF. If a participant does not receive the entire 
infusion, the volume administered and reason the infusion was stopped must be recorded. 
Withdrawal/Discontinuation
Participants who discontinue study treatment prior to completion of the single infusion (ie, 
participants who receive a partial dose) should be encouraged to continue to be followed for 
all remaining study visits.
When a participant discontinues/withdraws from participation in the trial, all applicable 
activities scheduled for the Unscheduled Visit 2 in the Schedule of Assessments should be 
performed at the time of discontinuation.  Any adverse events which are present at the time 
of discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 9.3 - Adverse Events.
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Withdrawal From Future Biomedical Research
A Participant’s consent for Future Biomedical Research may be withdrawn by the participant 
or the participant’s legally acceptable representative (as appropriate) and have their 
specimens and all derivatives destroyed.  A participant’s consent may be withdrawn at any 
time by contacting the principal investigator for the main trial.  If medical records for the 
main trial are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@merck.com).  Subsequently, the participant's 
consent for Future Biomedical Research will be withdrawn.  A letter will be sent from the 
Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal.  Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results.  
No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the drug used by a participant and/or the dosage 
administered he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding. As requested by the investigator or medically qualified 
designee, the emergency unblinding call center will provide the information to him/her 
promptly and report unblinding to the Sponsor. Prior to contacting the emergency unblinding 
call center to request unblinding of a participant’s treatment assignment, the investigator who 
is a qualified physician should make reasonable attempts to enter the intensity of the AEs
observed, the relation to study drug, the reason thereof, etc., in the medical chart. If it is not 
possible to record this assessment in the chart prior to the unblinding, the unblinding should 
not be delayed.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or non-study treating physician should continue to be monitored in the 
trial.
Additionally, the investigator or medically qualified designee must go into the IVRS system 
and perform the unblind in the IVRS system to update drug disposition.  In the event that the 
emergency unblinding call center is not available for a given site in this trial, IVRS/IWRS 
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should be used for emergency unblinding in the event that this is required for participant
safety.
Study treatment identification information is to be unmasked ONLY if necessary for the 
welfare of the participant.  Every effort should be made not to unblind the participant unless 
necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Once an emergency unblinding has 
taken place, the principal investigator, site personnel, and Sponsor personnel may be 
unblinded so that the appropriate follow-up medical care can be provided to the participant.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Efficacy Assessments 
Details of Baseline and Recurrent CDI Episodes
Details of the baseline episode of CDI and any recurrent episodes with an onset during the 
12-week follow-up period should be documented separately in the source documents and on 
the appropriate eCRFs (including documentation of the local stool test for toxigenic C.
difficile, as per Appendix 7). The investigator site personnel will also need to record on the 
appropriate eCRF the onset date and the highest number of UBMs in a 24-hour period for the 
baseline and recurrent CDI episodes.
Additionally, the following information of relevance to the baseline and each recurrent CDI 
episode will be collected on the appropriate eCRF: 

Presence of pseudomembranous colitis;

Presence of bloody diarrhea;

Highest body temperature;

Highest white blood cell count;

Lowest serum albumin concentration;

Highest serum creatinine concentration;
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
Signs and symptoms consistent with dehydration;

Whether the participant had signs and symptoms consistent with toxic megacolon, 
bowel perforation, or ileus.
Assessment of Disease Severity
The baseline episode of CDI and any recurrent episodes with an onset during the 12-week 
follow-up period will be characterized by severity (mild to moderate versus severe) and
severe-complicated course.
Severity will be assessed by the investigator. Participants who meet at least one of the 
following criteria during the CDI episode will be characterized as having severe CDI [van 
Dorp, S. M., et al 2017]:

the presence of bloody diarrhea; and/or 

pseudomembranous colitis; and/or

diarrhea accompanied by dehydration (as judged by the treating physician); and/or

hypoalbuminemia (<2 g/dL); and/or

fever (≥38.0°C) with leukocytosis (>15.0 × 109/L). 
Participants will be characterized as having severe-complicated CDI if they meet at least one 
of the following criteria associated with the CDI episode within 30 days after diagnosis of the 
episode [Na, X., et al 2015], as assessed by the investigator:

Intensive care unit admission

Death

Toxic megacolon

Colectomy 
Daily Diary
The participant or the participant’s parent or caregiver will complete a daily diary to record 
the following information from randomization/study infusion through Week 12 (85 ± 5 
days): 

Whether the participant had watery diarrhea (for participants using diapers or other 
type of fecal collection device, Bristol Stool Scale types 6 or 7) or any UBMs (takes 
shape of container, or Bristol Stool Scale type 5, 6, or 7) in the previous 24-hour 
period. 
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
On any day when the participant has diarrhea, the following will be recorded:
o
Presence of watery diarrhea (if child uses diapers or other type of fecal 
collection device) or number of UBMs;
o
Intensity of abdominal discomfort; and
o
Elevations in body temperature.
It is recommended to complete the diary nightly (at approximately the same time each day).
If all or a portion of the daily diary is lost or misplaced, the participant or the participant’s 
parent or caregiver should contact study personnel to obtain a replacement.  
At the end of the trial, the daily diary will be maintained as a source document. The data 
recorded on the diary will not be entered into the EDC system, with the exception of the 
specific information noted in Section 9.2.5.2.
Phone/Visit Contact 
Trial personnel will contact the participant or the participant’s parent or caregiver at least 
3 times per week during antibacterial drug treatment for the baseline episode of CDI for 
assessment of antibacterial drug treatment compliance. 
Trial personnel will also contact the participant or the participant’s parent or caregiver either 
by phone or in person approximately 24 hours after the end of the infusion to assess for 
infusion-related reactions (see Section 9.3.7.1). 
Trial personnel will contact the participant or the parent or caregiver twice weekly from 
approximately 48 hours after the last dose of antibacterial drug treatment ( EOT) through 
Week 12 to ensure that the daily diary is maintained by the parent or caregiver. These phone 
calls will help to determine if the participant experienced watery diarrhea (for participants 
using diapers or other type of fecal collection device) or 3 or more UBMs within a 24-hour 
period, at which point a stool sample will be collected and an unscheduled study visit will be 
conducted to assess whether the criteria for a diarrhea recurrence or a CDI recurrence have 
been met (as defined in Section 9.2.5.2).
Study personnel do not need to contact the participant or the participant’s parent or caregiver
on weekends or holidays, unless the 24-hour infusion follow-up assessment for 
infusion-related reactions occurs on one of these days.
The information communicated by the participant or the parent or caregiver during the 
contact is to be recorded in the source documents. In addition, if any discrepancy is noted
between the information obtained via phone contact and the information provided in the daily 
diary, study personnel must discuss the discrepancy with the participant/caregiver, and the 
explanation/resolution must be documented.
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Stool Sample Collection and Assessments
Before screening, a stool sample collected during the episode of CDI being treated at the time 
of randomization must have tested positive by the local laboratory for toxigenic C. difficile; 
results of all C. difficile tests (positive of negative) performed for this episode are to be 
recorded in the eCRF. Positive results of any other tests performed at the local laboratory 
during this CDI episode to detect other pathogens in stool are to be recorded in the eCRF. 
During screening, a new stool sample may need to be collected for study-specific testing (see 
Appendix 7 for assay requirements). A new sample is not needed if aliquots of the same stool 
sample that was used for the pre-screening diagnosis are available. If the pre-screening 
diagnosis was based on a method that does not test for the presence of C. difficile toxin, a 
new test will need to be performed at the local laboratory prior to randomization to confirm 
the diagnosis. Results of the new test are to be recorded in the eCRF.
An aliquot of the pre-screening stool sample or a sample obtained during screening will also 
be sent to the central laboratory.
After completion of antibacterial drug treatment for the baseline episode of CDI, if the 
participant experiences watery diarrhea (if the child is using diapers or other fecal collection 
device) or 3 or more UBMs within a 24-hour period, a stool sample will be collected that 
same day, frozen, and brought to the unscheduled visit; if the criteria for a diarrhea 
recurrence are met (Section 9.2.5.2), the aliquots will be sent to both a local laboratory and 
the central laboratory for testing. The local laboratory will perform a C. difficile toxin test on 
stool samples (see Appendix 7 for assay requirements).
The central laboratory will perform the following tests on stool samples:

Anaerobic culture followed by toxin testing for C. difficile strains isolated

Toxigenic strain ribotyping

Antibacterial susceptibility testing (vancomycin, metronidazole, and fidaxomicin)

Panel for gastrointestinal pathogens (Section 9.2.4.1)
Stool samples will be collected at the time points indicated in Section 2 – SoA. Stool samples 
collected at sites will be stored at –70° C or below and shipped frozen to the central 
laboratory. Results of central laboratory tests are for data analysis purposes only and will not 
be available during the conduct of the study to inform patient care decisions.
Gastrointestinal Panel
The central laboratory will test frozen stool samples using FilmArray® gastrointestinal panel, 
manufactured by Biofire Diagnostics, Salt Lake City, UT, US. The FilmArray 
gastrointestinal panel is a sensitive and specific multiplex PCR-based assay capable of 
detecting 22 different pathogens directly from stool specimens (Table 6).
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Table 6
Pathogens Detected by Gastrointestinal Panel
Bacteria
Campylobacter (jejuni, coli and upsaliensis)
Clostridium difficile (toxin A/B)
Plesiomonas shigelloides
Salmonella
Yersinia enterocolitica
Vibrio (parahaemolyticus, vulnificus and cholerae)
Vibrio cholera
Diarrheagenic Escherichia coli/Shigella
Enteroaggregative E. coli (EAEC)
Enteropathogenic E. coli (EPEC)
Enterotoxigenic E. coli (ETEC) lt/st
Shiga-like toxin-producing E. coli (STEC) stx1/stx2
E. coli O157
Shigella/Enteroinvasive E. coli (EIEC)
Viruses
Adenovirus F 40/41 
Astrovirus 
Norovirus GI/GII 
Rotavirus A 
Sapovirus (I, II, IV and V)
Parasites 
Cryptosporidium 
Cyclospora cayetanensis 
Entamoeba histolytica 
Giardia lamblia
Sources: [Spina, A., et al 2015] [Buss, S. N., et al 2015] [Stockmann, C., et al 2015] [Murphy, C. N,, et al 2017]
Investigator Assessment of Clinical Outcomes
Investigator Assessment of Clinical Response
The investigator will assess clinical outcomes of the baseline episode of CDI approximately 
48 hours after the last dose of antibacterial drug treatment (EOT) for determination of initial 
clinical response (Table 7). This assessment can be performed via telephone contact or in 
person. The outcome of the investigator assessment will be recorded on the appropriate 
eCRF.
Randomized participants who are deemed clinical failures or have an indeterminate 
assessment will be medically managed as necessary and continue to be monitored during the 
trial unless they are discontinued or withdrawn from the trial for other reasons (Section 8).
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Table 7
Investigator Assessment of Initial Clinical Response 
Clinical Outcome
Response Definition
Initial Clinical Response 
Improvement in the number and character of bowel 
movements AND does not require further CDI therapy within 
2 days after completion of up to 21 days of antibacterial drug 
treatment for CDI.
Clinical Failure
Initial clinical response not achieved.
Indeterminate
Study data are not available for evaluation of clinical 
outcome for one of the following reasons:
a) Participant was withdrawn for any reason or died before 
sufficient data had been obtained to permit evaluation; OR
b) Extenuating circumstances (eg, a protocol violation) 
preclude classification as "initial clinical response" or 
"clinical failure."
Investigator Assessment of a New Episode of Diarrhea During the 12-Week 
Follow-Up Period
An investigator assessment will occur at each study visit after the EOT visit. In addition, an
unscheduled visit will be conducted if the participant experiences watery diarrhea (if the 
child is using diapers or other fecal collection device) or 3 or more UBMs within a 24-hour 
period, and an investigator assessment will determine whether the criteria for a diarrhea 
recurrence or a CDI recurrence have been met (Table 8). The unscheduled visit should 
preferably occur within 2 days of the onset of diarrhea or UBMs. The investigator assessment 
and information to support this assessment (eg, stool test result, treatments given, maximum 
number of UBMs, maximum temperature, maximum white blood cell count, maximum 
abdominal discomfort score) will be recorded on the appropriate eCRF.
Every effort will be made to ensure that all diarrhea recurrence episodes are assessed for CDI 
recurrence.
Sustained clinical response will be derived from the investigator assessment of initial clinical 
response and CDI recurrence, as described in Section 10.4.3.
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Table 8
Investigator Assessment of New Episode of Diarrhea
Diarrhea Recurrence
New episode of diarrhea after initial clinical response as 
defined by a change in normal bowel habits for 2 or more 
calendar days with either watery diarrhea (for participants 
using diapers or other type of fecal collection device) or at 
least 6 UBMs within a 48-hour period.
CDI Recurrence
Diarrhea recurrence (see above definition) associated with a 
positive test for the presence of C. difficile toxin in stool, and 
for which the participant, in the investigator's opinion, 
requires and receives antibacterial drug treatment for CDI.
Adverse Events, Serious Adverse Events and Other Reportable Safety Events
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the 
method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting AE, SAE and other reportable safety event reports can be 
found in Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AE, SAEs, and other reportable safety 
events for outcome according to Section 9.3.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
From the time of treatment allocation/randomization through 12 weeks following cessation 
of treatment, all AEs, SAEs and other reportable safety events must be reported by the 
investigator. 
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Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must 
promptly notify the sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 9.
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Table 9
Reporting Time Periods and Timeframes for Adverse Events and Other Reportable Safety Events
Type of Event
Reporting Time Period:
Consent to Randomization/ 
Allocation
Reporting Time Period:
Randomization/ Allocation 
through Protocol-Specified 
Follow-up Period
Reporting Time Period:
After the Protocol Specified 
Follow-up Period
Timeframe to Report 
Event and Follow-up 
Information to 
SPONSOR:
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- subject is receiving placebo 
run-in or other run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to outcome.)
Within 24 hours of 
learning of event
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- subject is receiving placebo 
run-in or other run-in treatment
Report all
Not required
Per data entry 
guidelines
Overdose
Report if:
- receiving placebo run-in or 
other run-in medication 
Report all
Not required
Within 5 days of 
learning of event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential DILI
- Require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and those 
not requiring regulatory 
reporting
Not required
Within 5 days of 
learning of event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 days of 
learning of event
Pregnancy/Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported – Follow to 
completion/termination; report 
outcome
Within 24 hours of 
learning of event
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Method of Detecting AE and SAE
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered AEs. Examples of this 
may include, but are not limited to, teething, typical crying in infants and children, and the 
onset of menses occurring at a physiologically appropriate time.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAE, pregnancy and exposure during 
breastfeeding, Events of Clinical interest (ECI), Cancer, and Overdose will be followed until 
resolution, stabilization, until the event is otherwise explained, or the participant is lost to 
follow-up (as defined in Section 8.3). In addition, the investigator will make every attempt to 
follow all non-serious AEs that occur in randomized participants for outcome.  Further 
information on follow-up procedures is given in Appendix 4.
Regulatory Reporting Requirements for SAE

Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, i.e., 
per ICH Topic E6 (R1) Guidelines for Good Clinical Practice.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs
or SAEs
A CDI recurrence is not considered a reportable event and will not be reported to the Sponsor 
as described in Section 9.3.1 unless it meets one or more SAE criteria.
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Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee) that occurs during the trial are reportable to the 
Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1. an elevated AST or ALT postbaseline lab value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase 
lab value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing in a participant 
with baseline values that did not meet these criteria, or if baseline values were 
elevated, there is a clinically significant worsening, as determined by the investigator.*
* Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology. The trial site 
guidance for assessment and follow up of these criteria can be found in the 
Investigator Trial File Binder (or equivalent).
2. infusion-related reactions (Section 9.3.7.1).
Infusion-Related Reactions
Anaphylaxis is likely when multiple organ systems are adversely affected following exposure 
to an allergen. A list of symptoms that may be present during anaphylaxis include flushing, 
apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in 
blood pressure, vomiting, diarrhea and abdominal cramps, wheezing, dyspnea due to 
laryngeal spasm, lower airway obstruction, pruritus, rashes (such as urticaria), or 
angioedema. A modification of the Sampson criteria [Sampson, H. A., et al 2006] will be 
used to identify potential anaphylaxis due to bezlotoxumab (infusion-related reactions).
Participants will be monitored during the infusion of study medication and asked to report 
onset of new symptoms through 24 hours following the end of the infusion; this monitoring 
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should include at least 1 hour of in-clinic monitoring. Events meeting any of the 3 criteria 
below will be assessed as potential infusion-related reactions and are to be reported to the 
Sponsor as an ECI.  Infusion-related reactions should be treated supportively, if clinically 
indicated.
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula) AND at least one of the following:

Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after onset of the study infusion (minutes 
to several hours):

Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)

Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia)

Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], 
syncope, incontinence)

Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced blood pressure after onset of the study infusion (minutes to several hours):

Low systolic blood pressure (age specific) 
o
1 to 10 years: less than (70 mm Hg + [2X age])
o
11 to 17 years: less than 90 mm Hg 

OR greater than 30% decrease in systolic blood pressure from participant’s 
baseline
Treatment of Overdose
In this trial, an overdose is any dose higher than the highest dose studied in man to date (ie,
>20 mg/kg body weight of bezlotoxumab).
No specific information is available on the treatment of overdose. 
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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
Safety 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations

A complete physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) as per institutional standard. 

A brief directed physical examination will be conducted by an investigator or 
medically qualified designee (consistent with local requirements) as per institutional 
standard and will be targeted to the participant’s illness and complaints.

Height and weight will also be measured and recorded.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.

Abnormal findings from complete and directed physical examinations will be 
recorded as AEs.
Vital Signs
Vital signs will be collected at the time points specified in the SoA and include heart rate, 
blood pressure, respiratory rate, body temperature, and, on Day 1 only, pulse oximetry.
Participants should be in a seated or semirecumbent position prior to having vital sign 
measurements obtained. For those participants who cannot sit up for any reason (eg, infants, 
intubated participants), vital sign measurements will be taken in a supine or semirecumbent 
position. When possible, oral temperatures should be taken, but if oral is not possible, 
tympanic, rectal, or axillary methods are acceptable.
     
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Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
●
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.
●
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
●
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 12 weeks after the last dose of study 
treatment, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator. 
All clinical safety laboratory assessments specified in Appendix 2 will be performed by local 
laboratories.
Directed Hematology and Chemistry Assessments
As specified in the SoA (Section 2), directed hematology and chemistry assessments will be 
conducted at specified time points. The parameters for these directed assessments are 
specified in Appendix 2.
Pharmacokinetics
Blood samples will be collected at the time points specified in Section 2 – SoA to measure 
the concentrations of bezlotoxumab for PK assessments. While every effort should be made 
to schedule visits with PK draws so that they occur within the window specified in Section 2, 
when this is not possible, the PK samples should still be collected even if out of the 
collection window, and this will not be considered a major protocol deviation.
Blood Collection for Bezlotoxumab (MK-6072) in Serum
Serum will be separated from blood samples and sent to a central laboratory for testing. 
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the operations/laboratory manual. 
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Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
Future Biomedical Research Sample Collection 
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover main study stool samples stored for future research

Leftover main study serum samples collected for anti-drug antibody levels and 
neutralizing antibody levels stored for future research

Leftover main study serum samples collected for bezlotoxumab serum concentration 
assay for PK stored for future research
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants in this 
study as specified in Section 2 – SoA:

Blood samples for planned genetic analysis (Section 9.9.1)

Blood samples for immunogenicity assessments (Section 9.9.2)
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the operations/laboratory manual.
Immunogenicity Assessments
The potential for bezlotoxumab to induce immunogenicity through 12 weeks in participants 
aged 1 to <18 years given a single dose will be evaluated as an exploratory endpoint in this 
trial by detecting treatment-emergent anti-drug and neutralizing antibodies to bezlotoxumab 
in serum at the time points specified in Section 2 – SoA.
Sample collection, storage, and shipment instructions for immunogenicity samples will be 
provided in the operations/laboratory manual.
     
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Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA). Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
Screening period can start as early as the first day of antibacterial drug treatment for the 
baseline episode of CDI and can extend as long as the last day of antibacterial drug treatment 
for the baseline episode of CDI. During this time, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Sections 6.1 and 6.2. 
Screening and randomization may occur on the same day, as long as all trial entry criteria 
have been met. The duration of the screening period cannot be longer than the antibacterial 
drug treatment regimen for the baseline episode of CDI, as the participant must still be 
receiving antibacterial drug treatment on the day of randomization/study infusion.
Screening procedures may be repeated after consultation with the Sponsor. If the subject is 
rescreened, screening procedures should be repeated, unless they fall within the window 
specified.
Treatment Period
The procedures before and after the trial infusion (ie, Day 1 and beyond until Week 12 [Day 
85 ± 5 days]) are described in Section 2 and in detail earlier in Section 9.
Unscheduled Visits
From completion of antibacterial drug treatment for the baseline episode of CDI through the 
end of the 12-week follow-up period, if the participant experiences watery diarrhea (for 
participants using diapers or other type of fecal collection device) or 3 or more UBMs in a 
24-hour period, an unscheduled visit must be conducted and the assessments specified in the 
“Unscheduled Visit 1” column in Section 2 – SoA will be performed to determine whether 
the criteria for a diarrhea recurrence or a CDI recurrence have been met (as defined in 
Section 9.2.5.2).
Unscheduled visits that are conducted for any other reason, including withdrawal from 
participation in the trial, should follow the assessments specified in the “Unscheduled Visit 
2” column in Section 2 – SoA.
Discontinued Participants Continuing to be Monitored in the Study
See Section 9.1.9.
Post-Study
No post-study follow-up is planned for this trial.
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10.
Statistical Analysis Plan
Statistical Analysis Plan Summary
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or secondary hypotheses, or the statistical methods related to those hypotheses, 
then the protocol will be amended (consistent with ICH Guideline E-9). Changes to 
exploratory or other non-confirmatory analyses made after the protocol has been finalized, 
but prior to unblinding/final database lock, will be documented in a supplemental SAP 
(sSAP) and referenced in the Clinical Study Report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR. Separate analysis plans (ie, separate 
documents from the sSAP) will be developed to detail other planned analyses (ie, those 
specific to the analysis of PK data, and future biomedical research).
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 10.2 - 10.12.
Study Design Overview
A Randomized, Double-Blind, Placebo-Controlled Clinical 
Trial to Evaluate the Safety, Tolerability, Pharmacokinetics 
and Efficacy of a Single Infusion of Bezlotoxumab (MK-
6072, Human Monoclonal Antibody to C. difficile Toxin 
B) in Children Aged 1 to <18 Years Receiving 
Antibacterial Drug Treatment for C. difficile Infection
Treatment Assignment
There are 2 study treatment arms.  Participants will be 
assigned randomly in a 3:1 ratio to bezlotoxumab or
placebo, respectively, and will be stratified into 2 age 
groups according to the participant’s age at the time of 
randomization (1 to <12 years of age or 12 to <18 years of 
age).
Analysis Populations
Pharmacokinetics: Per-Protocol (PP)
Safety: All Participants as Treated (APaT) 
Efficacy: modified Intent to Treat (mITT), Efficacy 
Evaluable (EE)
Primary Endpoint(s)
Pharmacokinetic: The AUC0-inf will be determined for 
each age cohort from bezlotoxumab serum concentration 
data.
Safety: Proportion of participants with any AE and 
proportion of participants with a discontinuation due to 
an AE through 12 weeks following infusion.
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Key Secondary Endpoints
Efficacy: 
1) Proportion of participants who have a CDI 
recurrence within 12 weeks of study medication 
infusion.
2) Proportion of participants with sustained clinical 
response over a period of 12 weeks.
3) Proportion of participants who have a CDI 
recurrence and proportion of participants who 
achieve sustained clinical response within 12 weeks 
of study medication infusion in the subset of 
participants at high risk for CDI recurrence.
Safety:
4) Proportion of participants experiencing 1 or more
infusion-related reactions within 24 hours following
the start of the infusion.
Immunogenicity:
5) Proportion of participants with treatment-emergent 
positive antibodies to bezlotoxumab in serum 
through 12 weeks following a single dose of 
bezlotoxumab.
Statistical Methods for 
Key Efficacy/
Pharmacokinetic Analyses
Pharmacokinetic: In each age cohort, a point estimate as 
well as its 90% confidence interval (CI) will be generated 
from an analysis of variance (ANOVA) model containing a 
factor for cohort (pediatric participants and adults) for the 
GMR (pediatric participants/adults) of bezlotoxumab
AUC0-inf. The 90% CI of the GMR will be compared 
against the pre-specified bounds (0.6, 1.6). If the 90% CI 
for the GMR falls within (0.6, 1.6), then it will be claimed 
that the AUC0-inf of bezlotoxumab in the pediatric age 
cohort is similar to adults.
Efficacy: Miettinen and Nurminen’s method for stratified 
data will be used to compare the proportion of participants 
with CDI recurrence and the proportion of participants who 
achieved sustained clinical response between the treatment 
groups (bezlotoxumab and placebo). The strata will be the 
participant's age category at time of trial entry (same as the 
stratification for the randomization). Similar methodology
will be used for sustained clinical response.
Statistical Methods for 
Key Safety Analyses
Miettinen and Nurminen’s method (not stratified) will be 
used for between group comparisons for all Tier 2 
endpoints.
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Immunogenicity
The Agresti & Coull method will be used to calculate the 
95% CI for the bezlotoxumab group for the proportion of 
participants with treatment-emergent positive antibodies to 
bezlotoxumab. 
Interim Analyses
An independent, unblinded DMC will be appointed and 
will review the safety and tolerability data. There will be 2
planned reviews by the DMC, which will occur during the 
pre-specified time points. There are no plans to conduct an
interim analysis of unblinded efficacy data in the study.
Multiplicity
No multiplicity adjustment is being made.
Sample Size and Power 
Pharmacokinetic: The estimated log-scale between-
subject standard deviation for AUC0-inf of bezlotoxumab
following single-dose IV administration of 10 mg/kg 
MK-3415A in adults was 0.402 based on data from two 
Phase 3 trials (MK-3415A P001 and MK-3415A P002). 
Assuming the same variability in pediatric participants, if 
the true GMR (pediatric participants/adults) is 1.00 for 
AUC0-inf of bezlotoxumab, then 9 pediatric participants
and 1400 adults provides at least 93.6% probability of 
observing the 90% CIs of AUC0-inf of bezlotoxumab to be 
contained within (0.6, 1.6).
Safety: The fundamental justification for the sample size 
is to complete the trial in a timely manner while still 
providing a sufficient number of participants with 
bezlotoxumab exposure in this population to assess the 
safety profile.
Efficacy: The study is not powered for the assessment of 
efficacy.
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR. The analyses and summaries described in 
10.6.1 are the responsibility of PPDM - Quantitative Pharmacology and Pharmacometrics of 
the SPONSOR and Early Clinical Development Statistics - Clinical Biostatistics of the 
SPONSOR.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete. 
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Separate functional unblinding for bioanalysis and PK will be conducted in support of PK
evaluations. A small team as specified in a separate unblinding memo will be unblinded for 
the purpose of preparing the PK analyses for Panel A. 
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an interactive voice 
response system (IVRS). 
Planned interim analyses are described in Section 10.7. Blinding to treatment assignment will 
be maintained at all investigational sites. The results of interim analyses will not be shared 
with the investigators prior to the completion of the study.
Treatment–level results will be provided by an internal, unblinded statistician (with no 
involvement in the conduct of the study) to the external DMC. Limited additional Sponsor
personnel may be unblinded to the treatment level results, if required, in order to act on the 
recommendations of the DMC. The extent to which individuals are unblinded with respect to 
results will be documented by the unblinded statistician.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 4.
Analysis Endpoints
Pharmacokinetics Endpoints
The primary PK endpoint of interest is AUC0-inf of bezlotoxumab following single-dose IV
administration of 10 mg/kg bezlotoxumab in pediatric participants. Other PK endpoints of 
interest are Cmax, Tmax, terminal half-life, Vdss, and Cl. 
Safety Endpoints
A description of safety measures is contained in Sections 9.3 and 9.5. The analysis of safety 
results will follow a tiered approach (see Section 10.6.2 for further detail).
Efficacy Endpoints
CDI Recurrence: 
The proportion of participants with CDI recurrence assessed through Week 12 (Day 85 ± 5 
days) will be evaluated as a secondary endpoint. The proportion of participants with CDI 
recurrence will be calculated as follows for each treatment group. The numerator will be the 
number of participants in the mITT population, as defined in Section 10.5.3, who have CDI 
recurrence (as assessed by the investigator as defined in Section 9.2.5.2) following initial 
clinical response.  CDI recurrence is defined as the development of diarrhea recurrence
associated with a positive test for the presence of C. difficile toxin in stool and for which the 
participant, in the investigator's opinion, requires and receives antibacterial drug treatment
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for CDI. The denominator will be the number of participants in the mITT population who 
achieve initial clinical response of the baseline episode. Every effort will be made to obtain 
CDI recurrence information for each randomized participant.
As a supportive approach, the proportion of participants with CDI recurrence will be 
evaluated in the mITT population. For this analysis, participants who do not achieve initial
clinical response of the baseline episode will be imputed as not having CDI recurrence.  The 
numerator will be the number of participants in the mITT population who have CDI 
recurrence following initial clinical response (as in the primary approach detailed above).  
The denominator will be the number of participants in the mITT population. 
As an additional analysis, the proportion of participants who have CDI recurrence in subsets
of participants at high risk of CDI recurrence (defined as those with one or more risk factors) 
will be assessed. The numerator will be the number of participants in the mITT population
who have CDI recurrence following initial clinical response among those at high risk for CDI 
recurrence. The denominator will be the number of participants in the mITT population who 
achieve initial clinical response of the baseline episode and are at high risk for CDI 
recurrence.
Participants at high risk for CDI recurrence are those who meet 1 or more of the following 
criteria at or before randomization: 

Was immunocompromised 

Prior history of CDI defined as one or more episodes of CDI at any point prior to the 
baseline episode

Had a baseline CDI episode that met criteria for severe CDI (as defined in Section 
9.2.1.1)

C. difficile ribotype 027 was isolated from a stool sample collected during the 
baseline CDI episode 

Had received treatment with 1 or more systemic antibacterials known to increase the 
risk of CDI (during treatment of the baseline CDI episode), including but not limited 
to clindamycin, fluoroquinolones, cephalosporins, aztreonam, penicillins, macrolides, 
and carbapenems. The list of specific antibacterials will be finalized prior to database 
lock.
As a sensitivity analysis, the proportion of participants who have a CDI recurrence will be 
calculated in the subset of participants at high risk for CDI recurrence (as defined above) or 
who received 1 or more systemic antibacterials during the 12-week follow-up period. 
As a supportive analysis, time to CDI recurrence will be assessed.  Time to CDI recurrence 
will be measured from the date of infusion.  For participants who discontinue prior to a CDI 
recurrence, time to CDI recurrence will be right censored at the date of discontinuation.  
Participants who complete the 12-week study period without documented CDI recurrence 
will be censored at the minimum of the date of study completion or 12 weeks.  Participants 
who fail to achieve initial clinical response will be excluded from this analysis.  
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Sustained Clinical Response: 
The proportion of participants with a sustained clinical response will be assessed as a 
secondary efficacy endpoint. Sustained clinical response is defined as a composite of initial 
clinical response of the baseline CDI episode AND no CDI recurrence through Week 12. 
The proportion of participants with sustained clinical response will be calculated as follows 
for each treatment group: The numerator will be the number of participants within the mITT
population who achieve sustained clinical response, and the denominator will be the number 
of participants in the mITT population.
As additional analyses, the proportion of participants who achieved sustained clinical 
response in subsets of participants at high risk of CDI recurrence (defined as those with one 
or more risk factors as above) will be assessed.  The numerator will be the number of 
participants in the mITT population who achieve sustained clinical response among those at 
high risk for CDI recurrence. The denominator will be the number of participants in the 
mITT population at high risk for CDI recurrence.
As a sensitivity analysis, the proportion of participants who achieved sustained clinical 
response will be calculated in the subset of participants at high risk for CDI recurrence (as 
defined above) or who received 1 or more systemic antibacterials during the 12-week 
follow-up period.
Initial Clinical Response of Baseline CDI Episode:
The proportion of participants with initial clinical response of the baseline CDI episode will 
be calculated as follows for each treatment group: The numerator will be the number of 
participants within the mITT population who achieve an initial clinical response, as 
determined by the investigator. The denominator will be the number of participants in the 
mITT population.
Diarrhea Recurrence:
The proportion of participants with diarrhea recurrence assessed through Week 12 (Day 85 ± 
5 days) will be assessed as an exploratory efficacy endpoint. The proportion of participants 
with diarrhea recurrence will be calculated as follows for each treatment group. The 
numerator will be the number of participants in the mITT population who develop diarrhea
recurrence (as assessed by the investigator as defined in Section 9.2.5.2). The denominator 
will be the number of participants in the mITT population who achieve initial clinical 
response of the baseline episode.
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Analysis Populations
Pharmacokinetic Population
The Per-Protocol (PP) population will be the subset of treated participants who complete PK 
sampling with at least 4 post-dose evaluable samples and comply with the protocol 
sufficiently to ensure that these data will be likely to exhibit the effects of treatment, 
according to the underlying scientific model. The non-compartmental PK analysis will be 
conducted for the PP population. 
Safety Population
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study. The APaT population consists of all randomized participants who receive 
infusion of study medication. Participants in Panel A (Cohort 1 and/or 2) will only be 
included in the APaT population if there is not a dose modification as described in Section 
5.1.2; if there is a dose modification in a particular cohort, participants in Panel A of that 
cohort will be summarized separately. Participants will be included in the treatment group 
corresponding to the study treatment they actually received for the analysis of safety data 
using the APaT population. For most participants, this will be the treatment group to which 
they are randomized.
At least 1 vital sign measurement obtained subsequent to at least one dose of study treatment 
is required for inclusion in the analysis of each specific parameter. To assess change from 
baseline, a baseline measurement is also required.
Efficacy Population
The mITT population will serve as basis for the efficacy analyses. The mITT population is a 
subset of all randomized participants with participants excluded for the following reasons:

Did not receive any amount of study medication

Did not have a positive local stool test for C. difficile toxin to confirm CDI diagnosis 
of the baseline episode

Was not taking a protocol-defined antibacterial drug treatment for CDI on the day of 
the infusion.
In addition, participants will only be included in the mITT population if they received the 
final age-appropriate dose; if there is a dose modification in a particular cohort, participants 
in that cohort will be summarized separately.
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A supportive analysis using the Efficacy Evaluable (EE) population will be performed for 
efficacy endpoints.  The EE population is a subset of the mITT population that excludes 
participants for the following reasons:

important deviations from the protocol that may affect the efficacy results

prior or concomitant usage of IV immune globulin (IVIG)
The final determination on protocol deviations, and thereby the composition of the EE
population, will be made prior to the final unblinding of the database and will be documented 
in a separate memo.
Details on the approach to handling missing efficacy data are provided in Sections 9.2.5.1 
and 10.4.3.
Statistical Methods
Statistical Methods for Pharmacokinetics Analyses
During the conduct of the trial, and to inform enrollment of additional participants, initial PK
evaluations will include all participants in Panel A who received the infusion of trial 
medication and who have sufficient data to calculate AUC0-inf. Data will be natural log 
transformed prior to model fitting. The AUC0-inf of bezlotoxumab following a single-dose IV 
administration in Panel A of each pediatric age cohort will be compared to the AUC0-inf of 
bezlotoxumab in adults using an analysis of variance (ANOVA) model. The adult PK 
dataset(s) to be used in this comparison will be based on that obtained from the participants 
in the 2 adult Phase 3 trials (MK-3415A P001 and MK-3415A P002). The ANOVA model 
will contain a factor accounting for group (pediatric participants and adults). Least-squares 
geometric mean (GM) (95% CI) of the AUC0-inf of bezlotoxumab in pediatric participants
will be calculated from the model. A point estimate as well as its 90% CI will also be 
generated from the model for the GMR (pediatric participants/adults) of bezlotoxumab
AUC0-inf. The 90% CI of the GMR will be compared against the pre-specified bounds (0.6, 
1.6). If the 90% CI for the GMR falls within (0.6, 1.6), then it will be claimed that the AUC0-
inf of bezlotoxumab in the pediatric age cohort is similar to adults. 
At the conclusion of this trial, PK data from all participants who received the trial medication 
and who have sufficient data to assess PK from both Panels A and B will be used to compile 
an overall bezlotoxumab PK profile in the pediatric population. 
Individual values will be listed for each PK parameter by treatment and age cohort, and the 
following (non-model-based) descriptive statistics will be provided: N (number of subjects 
with non-missing data), arithmetic mean, standard deviation, arithmetic  percent CV 
(calculated as 100 x standard deviation/arithmetic mean), median, minimum, maximum, GM, 
and geometric percent CV (calculated as 100 x sqrt( exp(s2) - 1), where s2 is the observed 
variance on the natural log-scale). Descriptive statistics will be provided by gender and race 
or other covariates of interest as well if needed. 
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Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and vital signs.
The analysis of safety results will follow a tiered approach (Table 10). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or AEs of special interest 
that are identified a priori constitute “Tier 1” safety endpoints that will be subject to 
inferential testing for statistical significance with p-values and 95% CIs provided for 
between-group comparisons. Other safety parameters will be considered Tier 2 or Tier 3. 
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for between-
group comparisons; only point estimates by treatment group are provided for Tier 3 safety 
parameters.
Adverse events (specific terms as well as system organ class terms) and predefined limits of 
change in laboratory and vital signs that are not pre-specified as Tier 1 endpoints will be 
classified as belonging to "Tier 2" or "Tier 3", based on the number of events observed. 
Membership in Tier 2 requires that at least 12 participants in the bezlotoxumab treatment 
group or 2 participants in the placebo treatment group exhibit the event; all other AEs and 
predefined limits of change will belong to Tier 3.
The threshold of at least 12 participants in the bezlotoxumab arm was chosen because the 
lower limit of 95% CI for the between-group difference (bezlotoxumab – placebo) in percent 
incidence would not exclude zero when the number of participants in bezlotoxumab was less 
than 12 and thus would add little to the interpretation of potentially meaningful differences. 
Similarly, the threshold of at least 2 participants in the placebo arm was chosen because the 
upper limit of 95% CI for the between-group difference (bezlotoxumab – placebo) in percent 
incidence would not exclude zero when the number of participants in placebo was less than 2 
and thus would add little to the interpretation of potentially meaningful differences. Because 
many 95% CIs may be provided without adjustment for multiplicity, the CIs should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in AEs.
Continuous measures such as changes from baseline in laboratory and vital signs parameters 
that are not pre-specified as Tier 1 endpoints will be considered Tier 3 safety parameters.  
Summary statistics for baseline, on-treatment, and change-from-baseline will be provided by 
treatment group in table format.
For this protocol, there are no Tier 1 events given the favorable safety profile demonstrated 
in the Phase 3 program.  The broad clinical and laboratory AE categories (through the 12 
week follow up period) consisting of the percentage of participants with any AE, a 
drug-related AE, a serious AE, a death, an AE which is both drug-related and serious, a
discontinuation due to an AE and specific AEs (meeting the thresholds described above) are 
considered Tier 2 endpoints. Infusion-related reactions, as previously defined in Section 
9.3.7.1, will also be considered Tier 2 endpoints. 95% CIs (Tier 2) will be provided for 
between-treatment differences in the percentage of participants with events; these analyses 
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will be performed using the Miettinen and Nurminen method (1985) [Miettinen, Olli and 
Nurminen, Markku 1985], an unconditional, asymptotic method.
For the analyses of safety, participants at the final dose selected for each cohort will be 
pooled across cohorts.  In addition, key summaries of safety will be provided separately by 
cohort. Limited summaries of safety will be provided in participants in Panel A if there is a 
dose modification.
Missing laboratory and vital sign measurements will be handled using the Data-As-Observed 
(DAO) approach.
Table 10
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpointa
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
None
X
X
X
Tier 2
Any AE
X
X
Any drug-related AE
X
X
Any serious AE
X
X
A death
X
X
Any serious and drug-related AE
X
X
Discontinuationb due to AE
X
X
Infusion-related reactionsc
X
X
Specific AEs or system organ classes (incidence ≥12 of 
participants in bezlotoxumab or ≥2 participants in 
placebo)
X
X
Tier 3
Specific AEs or system organ classes (incidence <12 of 
participants in bezlotoxumab and <2 participants in 
placebo)
X
Change from Baseline Results (Vital signs)
X
95% CIs will be based on the method of Miettinen and Nurminen [Miettinen, Olli and Nurminen, Markku 
1985].
a
Adverse Events references refer to both clinical and laboratory AEs.
b
Study medication withdrawn. 
c
Infusion-related reactions are defined in Section 9.3.7.1.
Note: X = results will be provided.
Statistical Methods for Efficacy Analyses
Miettinen and Nurminen’s method for stratified data will be used to compare the proportion 
of participants with CDI recurrence and the proportion of participants who achieve sustained 
clinical response between the treatment groups (bezlotoxumab and placebo). The strata will 
be the participant's age category at time of trial entry (same as the stratification for the 
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randomization). Cochran-Mantel-Haenszel weights will be used. The 95% CI for the 
differences in proportions will be presented along with nominal 2-sided p-values.  As there 
are no associated hypotheses to be tested, the p-values are not inferential and are only 
presented as an additional measure of the effect size.
For the proportion of participants who have CDI recurrence in subsets of participants at high 
risk of CDI recurrence, the bezlotoxumab vs. placebo difference (with a nominal 95% CI) 
will be estimated using Miettinen and Nurminen’s method without stratification.  Sustained 
clinical response in subset of participants at high risk of CDI recurrence will use the same 
methodology.
The nonparametric Kaplan-Meier method will be used to estimate the time to CDI recurrence 
distribution for each treatment group. Treatment differences in time to CDI recurrence will 
be assessed using the stratified log-rank test.
For the analyses of efficacy, participants at the final dose selected for each cohort will be 
pooled across cohorts.  In addition, key summaries of efficacy will be provided separately by 
cohort as described in Section 10.10. Limited summaries of efficacy will be provided in 
participants in Panel A if there is a dose modification.
Statistical Methods for Immunogenicity Analyses
The Agresti & Coull method will be used to calculate the 95% CI for the bezlotoxumab 
group for the proportion of participants with treatment-emergent positive antibodies to 
bezlotoxumab. 
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be 
displayed. Demographic variables (eg, age, sex, race), baseline characteristics, primary and 
secondary diagnoses, and prior and concomitant therapies will be summarized by treatment 
either by descriptive statistics or categorical tables.
Interim Analyses
Initial PK evaluations will be conducted as described in Section 10.6.1.
An independent, unblinded DMC will be appointed to review safety and tolerability data for 
Panel A of both Age Cohort 1 and Age Cohort 2, as described in Section 5.1.2, with 
additional information provided in Appendix 3. A description of the structure, function, and 
guidelines for decision-making by the DMC will be outlined in the DMC charter. There are 
no plans to conduct an interim analysis of unblinded efficacy data in the study. 
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Multiplicity
There are no multiplicity adjustments made.
Sample Size and Power Calculations
Sample Size and Power for Pharmacokinetic Analyses
The estimated log-scale between-subject standard deviation for AUC0-inf of bezlotoxumab
following single-dose IV administration of 10 mg/kg bezlotoxumab in adults was 0.402 
based on data from two Phase 3 trials (MK-3415A P001 and MK-3415A P002). 
Primary hypothesis: Assuming the same variability in pediatric participants, if the true GMR 
(pediatric participants/adults) is 1.00 for AUC0-inf of bezlotoxumab, then 9 pediatric 
participants and 1400 adults provides at least 93.6% probability of observing the 90% CIs of 
GMR (pediatric participants/adults) for AUC0-inf of bezlotoxumab to be contained within 
(0.6, 1.6). 
Precision estimates: 9 pediatric participants who receive bezlotoxumab in each age cohort
provides at least 69.7% probability that the 95% CI of the GM is within 60% and 140% of 
the GM estimates of AUC0-inf for bezlotoxumab. A minimum of 27 participants who receive 
bezlotoxumab in each age cohort provides at least 99.9% probability that the 95% CI is 
within 60% and 140% of the GM estimates of AUC0-inf for bezlotoxumab.
Sample Size and Power for Efficacy Analyses
This study will randomize approximately 144 participants into the bezlotoxumab group and 
48 into the placebo group at the final dose selected for each age cohort. The planned sample 
size for this study will have limited power to confirm superiority of bezlotoxumab over 
placebo.  Table 11 presents the treatment difference and 95% CI for various possible 
combinations of CDI recurrence event rates that could be observed in this study.  
Assumptions about the incidence of CDI recurrence among participants on bezlotoxumab are 
based on the pooled results from the Phase 3 clinical trials (PN001 and PN002) of a single 
infusion of this investigational product and expectations about the rates anticipated in this 
study population. In these studies, CDI recurrence was observed in 16.5% (129/781) of 
bezlotoxumab participants in the primary analysis population, while the recurrence rate 
among participants on placebo was 26.6% (206/773). Rates were slightly higher, in both 
treatment groups, in the subset of participants with initial clinical response: in this subset,
CDI recurrence was observed in 20.6% (129/625) of bezlotoxumab participants, while the 
recurrence rate among participants on placebo was 33.2% (206/621).
Similarly, there is also limited power for this study for sustained clinical response; the pooled 
response rates observed in the Phase 3 clinical trials (PN001 and PN002) were 63.5% 
(496/781) in bezlotoxumab participants, while the response rates among participants on 
placebo were 53.7% (415/773). 
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Table 11
Variability Around Various Possible Treatment Differences
Bezlotoxumab (n=144)
Placebo (n=48)
Difference (95% CI)
(Bezlotoxumab – Placebo)
8%  (11/144)
15% (7/48)
-7 (-20, 2)
12% (17/144)
19% (9/48)
-7 (-21, 4)
16% (23/144)
23% (11/48)
-7 (-22, 5)
20% (29/144)
27% (13/48)
-7 (-22, 6)
8%  (11/144)
17% (8/48)
-9 (-23, 1)
12% (17/144)
21% (10/48)
-9 (-23, 2)
16% (23/144)
25% (12/48)
-9 (-24, 3)
20% (29/144)
29% (14/48)
-9 (-24, 4)
8%  (11/144)
19% (9/48)
-11 (-25, -1)
12% (17/144)
23% (11/48)
-11 (-26, 0)
16% (23/144)
27% (13/48)
-11 (-26, 2)
20% (29/144)
31% (15/48)
-11 (-27, 2)
* Based on the Miettinen and Nurminen method (unstratified)
Sample Size and Power for Safety Analyses
The fundamental justification for the sample size is to complete the trial in a timely manner 
while still providing a sufficient number of participants with bezlotoxumab exposure in this 
population to assess the safety profile.  A 3:1 randomization was used to maximize the 
number of participants exposed to bezlotoxumab while still maintaining a control arm of 
reasonable size.
The probability of observing at least one serious adverse event in this study depends on the 
number of subjects treated and the underlying percentage of subjects with a serious adverse 
event in the study population. If the underlying incidence of a serious adverse event is 1% (1 
of every 100 subjects receiving bezlotoxumab), there is a 76% chance of observing at least 
one serious adverse event among 144 subjects in the bezlotoxumab group. If no serious 
adverse events are observed among the 144 subjects in bezlotoxumab group, this study will 
provide 95% confidence that the underlying percentage of subjects with a serious adverse 
event is ≤2.6% (<1 in every 38 subjects) in the bezlotoxumab group.
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Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the CDI 
recurrence and the sustained clinical response will be estimated within each category of each 
subgroup.  The following subgroups will be examined: 

Age cohort (1 to <12 years, 12 to <18 years)

Sex (female, male)

Race (white, non-white)

Antibiotic used for treatment of CDI episode ongoing at time of infusion 
(metronidazole, vancomycin, fidaxomicin)
The 95% CI will only be calculated if there are 10 or more participants in each treatment 
group.
As a secondary objective, the proportion of participants with CDI recurrence and the 
proportion of participants who achieved sustained clinical response in the subset of 
participants at high risk for CDI recurrence will be assessed as discussed in Section 10.4.3. 
Additionally, the proportion of participants who have a CDI recurrence and the proportion of 
participants who achieved sustained clinical response will be calculated in the subset of 
participants meeting the criteria for each risk factor. As above, the 95% CI will only be 
calculated if there are 10 or more participants in each treatment group.
Compliance (Medication Adherence)
Compliance assessments are not relevant for a single-dose infusion study.
Extent of Exposure
Assuming no change in dose following review of exposures in Panel A participants, all 
participants will receive the same dose (10 mg/kg).  Given this, the extent of exposure will be 
the same for all participants and no summary of this information will be provided.  If a dose 
change is required, the number of participants exposed at each dose level will be summarized 
using descriptive statistics.
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12. Appendices
Appendix 1: Abbreviations and Trademarks
Abbreviation
Description
AE
Adverse events
ALT 
Alanine aminotransferase
ANOVA
Analysis of variance
APaT
All Participants as Treated
AST
Aspartate aminotransferase
AUC0-inf
Area under the concentration-time curve from 0 to infinity
β hCG
β human chorionic gonadotropin 
BUN
Blood urea nitrogen
CDI
Clostridium difficile infection
CI
Confidence interval
Cl
Clearance
Cmax
Maximum concentration
CRF
Case report form
CSR
Clinical study report
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
ECI
Event of clinical interest
eCRF
Electronic case report form
EDC
Electronic data collection
EE
Efficacy Evaluable
EIAs
Enzyme-linked immunoassays
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EOT
End of treatment with antibacterial drug for baseline episode of 
CDI
FBR
Future biomedical research
FDAAA
Food and Drug Administration Amendments Act
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Abbreviation
Description
FMT
Fecal microbiota transplantation
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GM
Geometric mean
GMR
Geometric mean ratio
HRT
Hormonal replacement therapy
IB
Investigator’s Brochure
IBD
Inflammatory bowel disease
ICF
Informed consent form
ICH
International Council on Harmonisation
IEC
Independent ethics committee
IRB
Institutional review board
IV
Intravenous
IVIG
Intravenous immune globulin
IVRS/IWRS
Interactive voice response system/Integrated web response system
mAb
Monoclonal antibody
mITT
Modified intent to treat
LAR
Legally acceptable representative
PCR
Polymerase chain reaction
PK
Pharmacokinetic(s)
PP
Per-Protocol
RNA
Ribonucleic acid
SAC
Scientific Advisory Committee 
SAE
Serious adverse event
SoA
Schedule of Activities
sSAP
Supplemental statistical analysis plan
Tmax
Time of maximum concentration
UBM
Unformed bowel movements
Vdss
Volume
WOCBP
Woman of childbearing potential
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Appendix 2: Clinical Laboratory Tests 

The tests detailed in Table 12 will be performed by the local laboratory. Samples for 
these tests should be collected on Study Day 1, unless otherwise specified in the table.
If the tests were performed as part of routine patient care within 72 hours of the 
scheduled visit, there is no need to repeat the test.

The tests detailed in Table 13 will be performed by the local laboratory. Samples for 
these tests should be collected at Unscheduled Visit 1, at the time of a return of 
diarrhea.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 12
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
White blood cell count with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), red blood cell count, red blood cell 
indices (MCV, MCH), platelet count, hemoglobin, hematocrit
Chemistry
Alanine aminotransferase (ALT), albumin, alkaline phosphatase, 
aspartate aminotransferase (AST), bicarbonate, bilirubin (total, and 
direct bilirubin if total bilirubin is elevated above the upper limit of 
normal), blood urea nitrogen (BUN), calcium, chloride, creatinine, 
glucose (indicate if fasting or nonfasting on eCRF), potassium, sodium, 
total protein
Other 
Screening 
Tests
Urine β human chorionic gonadotropin (β hCG) pregnancy test (as 
needed for women of childbearing potential). Samples to be collected at 
screening and on Day 1. If results are positive, the participant should be 
excluded from trial participation.
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Table 13
Directed Hematology and Chemistry Parameters (Unscheduled Visit 1)
Directed Hematology
White blood cell count with differential 
(neutrophils, lymphocytes, monocytes, 
eosinophils, basophils)
Directed Chemistry
Albumin (serum), C-reactive protein,
creatinine (serum), lactate (plasma)
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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Appendix 3: Study Governance Considerations
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participant safety is the overriding concern 
in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (eg, contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
participant preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial 
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
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results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
III. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that 
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC
approval. For each site, the IRB/IEC and Merck will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance.  
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.  Participants are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent 
for participation.  Participants may withdraw from a Merck trial at any time, without any influence on their access to, 
or receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding participant confidentiality, to the greatest extent possible.  Unless required by 
law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential 
medical records that might identify the research participant by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll participants in its trials.  However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
Merck does not pay for participant referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/IEC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
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C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
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Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/IEC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
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Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the participant
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the participant will be identified by unique code 
only; full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this trial in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Committees Structure
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
Data Monitoring Committee (DMC) regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (eg, they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC  regarding steps to ensure both participant
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 10.7 - Interim 
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Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are 
participant to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
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Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in this appendix 
under the Merck Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the trial 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
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regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the trial documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or 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.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study 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 a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose without any associated clinical symptoms or abnormal laboratory 
results is reported using the terminology “accidental or intentional overdose without 
adverse effect.”
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●
Any new cancer or progression of existing cancer.
Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has 
not worsened.
●
Refer to section 9.3.5 for protocol specific exceptions.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
A SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation.  (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical 
condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.
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d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events reported
Additional Events which require reporting 
●
In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor.
●
Is a cancer;
●
Is associated with an overdose.
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Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) reported during the study and assign it to 1 of the 
following categories: 
●
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.  (for pediatric trials, 
awareness of symptoms, but easily tolerated)
●
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities. (for pediatric trials, definitely acting like something is wrong)
●
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe 
(for pediatric trials, extremely distressed or unable to do usual activities).
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Assessment of Causality
●
Did the Sponsor's product cause the adverse event?
●
The determination of the likelihood that the Sponsor's product caused the adverse 
event will be provided by an investigator who is a qualified physician.  The 
investigator’s signed/dated initials on the source document or worksheet that 
supports the causality noted on the AE form, ensures that a medically qualified 
assessment of causality was done.  This initialed document must be retained for 
the required regulatory time frame.  The criteria below are intended as reference 
guidelines to assist the investigator in assessing the likelihood of a relationship 
between the test product and the adverse event based upon the available 
information
●
The following components are to be used to assess the relationship between 
the Sponsor's product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more 
likely the Sponsor's product caused the adverse event:
●
Exposure:  Is there evidence that the participant was actually exposed to the 
Sponsor's product such as:  reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
●
Time Course:  Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor's product? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to trials with investigational 
medicinal product)?
●
Likely Cause:  Is the AE not reasonably explained by another etiology such 
as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
●
Dechallenge: Was the Sponsor's product discontinued or 
dose/exposure/frequency reduced?
●
If yes, did the AE resolve or improve?
●
If yes, this is a positive dechallenge. 
●
If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's 
product(s) is/are only used one time.)
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●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
trial?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death 
or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S 
PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product or drug class pharmacology or toxicology?
●
The assessment of relationship will be reported on the case report forms /worksheets 
by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product.  The temporal sequence 
of the AE onset relative to the administration of the Sponsor's product is 
reasonable.  The AE is more likely explained by the Sponsor's product than by 
another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product.  (Also 
entered for a participant with overdose without an associated AE.)
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●
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
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●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or 
secure e-mail of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
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Appendix 5: Contraceptive Guidance and Pregnancy Testing
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
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 hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use 
any one of the contraception methods described in Table 14 , including those classified as 
“acceptable” (ie, failure rate >1% per year when used consistently and correctly), during the 
protocol-defined time frame in Section 6.1.
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Table 14
Contraceptive Methods
Acceptable Contraceptive Methods 
Failure rate of >1% per year when used consistently and correctly.
●
Male or female condom with or without spermicide
●
Cervical cap, diaphragm or sponge with spermicide
●
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action
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 
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception 
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant  
●
Intrauterine hormone-releasing system (IUS)  
●
Intrauterine device (IUD)
●
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 WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
●
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 treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.) 
a) Typical use failure rates are higher than perfect-use failure rates (i.e. when used consistently and 
correctly). 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 9.8 – Future 
Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
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with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
trial visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the participants on the visit designated in 
the trial flow chart.  If delayed, present consent at next possible Participant Visit.  
Consent forms signed by the participant will be kept at the clinical trial site under 
secure storage for regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for Future Biomedical Research will be 
captured in the electronic Case Report Forms (eCRFs). Any specimens for which 
such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the participant is having blood drawn for other trial purposes.
4. Confidential Participant Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing participant
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
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To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant
identifiers and this unique code will be held at the trial site.  No personal identifiers will 
appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Participants may withdraw their consent for Future Biomedical Research and ask that 
their biospecimens not be used for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial. If 
medical records for the main trial are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for Future Biomedical Research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable.  
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research trial data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
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7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants.  Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the participant have been minimized. No 
additional risks to the participant have been identified as no additional specimens are 
being collected for FBR (ie, only leftover samples are being retained).
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The Sponsor has developed strict security, policies and procedures to address participant
data privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; http://www.ich.org/LOB/
media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
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Appendix 7: C. Difficile Diagnostic Test Method Requirements
A diagnosis of CDI is required prior to consent of the participant. A stool sample must have
tested positive for toxigenic C. difficile according to local diagnostic criteria prior to 
assigning the participant a screening number.
If the local diagnostic method(s) does not include an assay which detects the presence of C. 
difficile toxin in stool, a confirmatory test that detects C. difficile toxin in stool must be 
performed prior to randomization. The confirmatory test must not detect only toxin A (ie, it 
must also detect toxin B) and must be one of the following test types:
1. Cell culture cytotoxic assay, OR
2. Commercial stool assays, approved by the local regulatory agency, must detect the 
presence of C. difficile toxin, and the specificity of the assay must be ≥94% as stated 
in the manufacturers’ product insert 
The commercial tests shown in Table 15 are allowed per protocol. Use of other commercial 
tests not included in Table 15 must be discussed with the Sponsor.
Table 15
Permitted Commercial Enzyme Immunoassay Tests for Detecting Presence of 
Clostridium difficile Toxin in Stool
Type
Name of Test
Manufacturer
Well-type EIA toxins A/B
Clostridium difﬁcile Tox A/B II
TechLab (may also be 
distributed by Alere, Inc)
Premier toxins A/B
Meridian
Remel ProSpecT
Oxoid/Remel
Ridascreen toxins A/B
R-Biopharm
Membrane-type EIA toxins A/B
ImmunoCard toxins A/B
Meridian
Quik Chek Complete-Tox A/B
TechLab (may also be 
distributed by Alere, Inc)
Tox A/B Quik Chek
TechLab (may also be 
distributed by Alere, Inc)
Xpect
Oxoid/Remel
Automated EIA toxins A/B
Clostridium difﬁcile Tox A/B 
Certest
Biotec
Clostridium difficile Toxin A+ B
DRG
Diagnostics
GastroTect
Medical Chemical Corp
VIDAS CDAB
Biomerieux
Abbreviations: EIA = enzyme immunoassay.
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