Clinical trial NCT02218372
Conditions: Clostridium Difficile-associated Diarrhea (CDAD)
Keywords: Clostridium difficile-associated Diarrhea (CDAD) vancomycin Clostridium difficile infection fidaxomicin
Sponsor: Astellas Pharma Europe B.V.
Start date: 2015-01-09; Completion date: 2018-03-07
Enrollment: 148 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to investigate the clinical response to fidaxomicin oral suspension or tablets and vancomycin oral liquid or capsules in pediatric participants with Clostridium difficile-associated diarrhea (CDAD). It also investigated the recurrence/sustained clinical response to and safety of fidaxomicin and vancomycin, as well as acceptance of the fidaxomicin oral suspension formulation.

Detailed description:

Arms: arm 1: Participants from birth to \< 6 years of age received weight based doses of fidaxomicin oral suspension (32 mg/kg/day with a maximum dose of 400 mg/day divided in 2 doses) 2 times daily for 10 days. Participants aged ≥ 6 years to \< 18 years of age received a 200 mg fidaxomicin tablet 2 times daily for 10 days. arm 2: Participants from birth to \< 6 years of age received weight based doses of vancomycin oral liquid (40 mg/kg/day with a maximum dose of 500 mg/day divided in 4 doses) 4 times daily for 10 days. Participants aged ≥ 6 years to \< 18 years of age received a 125 mg vancomycin capsule 4 times daily for 10 days.
Interventions: intervention 1: Fidaxomicin oral suspension intervention 2: Fidaxomicin tablets intervention 3: Vancomycin oral liquid intervention 4: Vancomycin capsules
Intervention descriptions: intervention 1: Participants from birth to \< 6 years of age received weight based doses of fidaxomicin oral suspension (32 mg/kg/day with a maximum dose of 400 mg/day divided in 2 doses) 2 times daily for 10 days. intervention 2: Participants aged ≥ 6 years to \< 18 years of age received a 200 mg fidaxomicin tablet 2 times daily for 10 days. intervention 3: Participants from birth to \< 6 years of age received weight based doses of vancomycin oral liquid (40 mg/kg/day with a maximum dose of 500 mg/day divided in 4 doses) 4 times daily for 10 days. intervention 4: Participants aged ≥ 6 years to \< 18 years of age received a 125 mg vancomycin capsule 4 times daily for 10 days.

Protocol documents:
Prot_000.pdf: 
A Phase 3, Multicenter, Investigator-blind, Randomized, Parallel
Group Study to Investigate the Safety and Efficacy of 
Fidaxomicin Oral Suspension or Tablets Taken q12h, and 
Vancomycin Oral Liquid or Capsules Taken q6h, for 10 Days in 
Pediatric Subjects with Clostridium difficile-associated Diarrhea
The SUNSHINE Study
ISN/Protocol 2819-CL-0202
ClinicalTrials.gov Identifier: NCT02218372
Date of Protocol Version 3.0: 21 Jul 2015
Sponsor: Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
The Netherlands


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 1 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
A Phase 3, Multicenter, Investigator-blind, Randomized, Parallel 
Group Study to Investigate the Safety and Efficacy of Fidaxomicin 
Oral Suspension or Tablets Taken q12h, and Vancomycin Oral Liquid
or Capsules Taken q6h, for 10 Days in Pediatric Subjects with 
Clostridium difficile-associated Diarrhea
The SUNSHINE Study
ISN/Protocol 2819-CL-0202
Version 3.0
Incorporating Substantial Amendment 2 [See Attachment 1]
21 July 2015 
EudraCT 2013-000508-40
Sponsor: 
Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62
2333 BE Leiden
The Netherlands
Protocol History:
Version 1.0 [17Sep2013]
Version 1.1 Incorporating Non-Substantial Amendment 1 [05Jun2014] 
Version 2.0 Incorporating Substantial Amendment 1 [21Nov2014]
Investigator: 
Investigator information is on file at Astellas
--------------------------------------------------------------------------------------------------------------------------------------
This confidential document is the property of the Sponsor. No unpublished information contained in this 
document may be disclosed without prior written approval of the Sponsor.


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 2 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
Table of Contents
I.
SIGNATURES ······················································································ 8
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················11
List of Abbreviations·····················································································11
Definition of Key Study Terms ·········································································13
IV.
SYNOPSIS··························································································15
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································22
Flow Chart·································································································22
Table 1: Schedule of Assessments······································································23
1
INTRODUCTION·················································································26
1.1
Background ····················································································26
1.2
Non-clinical and Clinical Data ······························································31
1.2.1
Non-Clinical Data ·······································································31
1.2.2
Clinical Data ·············································································31
Table 2: Summary of Fidaxomicin Clinical Studies·················································31
1.2.2.1
Phase 1 Studies ··········································································33
1.2.2.2
Phase 2A Study··········································································34
1.2.2.3
Phase 3 Studies ··········································································35
1.2.2.4
Phase 2A Pediatric Study·······························································35
1.3
Summary of Key Safety Information for Study Drugs ···································36
1.3.1
Fidaxomicin··············································································36
1.3.2
Vancomycin··············································································36
1.4
Risk-Benefit Assessment·····································································36
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································38
2.1
Study Objectives ··············································································38
2.1.1
Primary ···················································································38
2.1.2
Secondary ················································································38
2.2
Study Design and Dose Rationale···························································38
2.2.1
Study Design·············································································38
2.2.2
Dose Rationale···········································································40
2.3
Endpoints·······················································································40


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 3 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
2.3.1
Primary Endpoint········································································40
2.3.2
Secondary Endpoints····································································41
2.3.3
Exploratory Endpoints ··································································42
3
STUDY POPULATION··········································································43
3.1
Selection of Study Population ·······························································43
3.2
Inclusion Criteria··············································································43
3.3
Exclusion Criteria ·············································································44
4
TREATMENT(S)··················································································44
4.1
Identification of Investigational Product(s) ················································44
4.1.1
Test Drug(s)··············································································44
4.1.2
Comparative Drug(s)····································································45
4.2
Packaging and Labeling ······································································45
4.3
Study Drug Handling ·········································································46
4.4
Blinding ························································································46
4.4.1
Unblinding for Subject Safety Reasons···············································47
4.4.2
Blinding Method·········································································47
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································47
4.4.4
Breaking the Treatment Code for Emergency ·······································47
4.4.5
Breaking the Treatment Code by the Sponsor ·······································47
4.5
Assignment and Allocation ··································································48
5
TREATMENTS AND EVALUATION························································48
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················48
5.1.1
Dose/Dose Regimen and Administration Period ····································48
Table 3A:  Weight-based Dosing Instruction of the Fidaxomicin Oral Suspension··············48
Table 3B: Weight-based Dosing Instruction of the Vancomycin Oral Liquid ····················48
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································49
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································49
5.1.3.1
Prohibited Medication and Restricted Medication ··································49
5.1.4
Treatment Compliance··································································50
5.2
Demographics and Baseline Characteristics ···············································50
5.2.1
Demographics············································································50
5.2.2
Medical History··········································································50


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 4 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············50
5.2.4
Rotavirus ·················································································51
5.3
Efficacy Assessment··········································································51
5.4
Safety Assessment ············································································52
5.4.1
Vital Signs················································································52
5.4.2
Adverse Events ··········································································52
5.4.2.1
Adverse Events of Possible Hepatic Origin ··········································52
5.4.3
Laboratory Assessments································································52
Table 4
Clinical Laboratory Tests to be Performed·················································53
5.4.4
Physical Examination···································································54
5.4.5
Electrocardiogram (ECG) ······························································54
5.4.6
CDAD Signs and Symptoms···························································54
5.5
Adverse Events and Other Safety Aspects ·················································54
5.5.1
Definition of Adverse Events (AEs) ··················································55
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································55
5.5.3
Criteria for Causal Relationship to the Study Drug ·································57
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························57
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································57
5.5.6
Follow-up of Adverse Events··························································58
5.5.7
Monitoring of Common Serious Adverse Events ···································59
5.5.8
Procedure in Case of Pregnancy·······················································59
5.5.9
Emergency Procedures and Management of Overdose ·····························59
5.5.10
Supply of New Information Affecting the Conduct of the Study··················60
5.6
Test Drug Concentration ·····································································60
5.7
Other Measurements, Assessments or Methods ···········································61
5.7.1
Stool Samples for Toxigenic C.difficile and Microbiological Testing ············61
5.7.2
Palatability Testing······································································61
5.8
Total Amount of Blood·······································································62
Table 5: Examples of the total amount of blood collected per subject during the course of 
the study························································································62
6
DISCONTINUATION············································································62
6.1
Discontinuation of Individual Subject(s)···················································62
6.2
Discontinuation of the Site···································································63
6.3
Discontinuation of the Study·································································63


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 5 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
7
STATISTICAL METHODOLOGY ···························································63
7.1
Sample Size····················································································64
7.2
Analysis Sets···················································································64
7.2.1
Full Analysis Set (FAS) ································································64
7.2.2
Safety Analysis Set (SAF)······························································64
7.2.3
Pharmacokinetic Analysis Set (PKAS) ···············································65
7.2.4
Intent to Treat Analysis Set (ITT) ·····················································65
7.3
Demographics and Other Baseline Characteristics········································65
7.4
Analysis of Efficacy ··········································································65
7.4.1
Analysis of Primary Endpoint ·························································65
7.4.1.1
Primary Analysis ········································································65
7.4.1.2
Subgroup Analysis ······································································65
7.4.2
Analysis of Secondary Endpoints ·····················································66
7.4.2.1
Other Analyses - Palatability···························································66
7.5
Analysis of Safety·············································································66
7.5.1
Adverse Events ··········································································66
7.5.2
Laboratory Assessments································································67
7.5.3
Vital Signs················································································67
7.5.4
ECGs······················································································67
7.6
Analysis of Pharmacokinetics ·······························································67
7.6.1
Test Drug Concentration ·······························································67
7.7
Analysis of Pharmacodynamics ·····························································67
7.8
Protocol Deviations and Other Analyses···················································67
7.8.1
Protocol Deviations ·····································································67
7.8.2
Medical History··········································································68
7.8.3
Previous and Concomitant Medication ···············································68
7.8.4
Diagnosis of the Target Disease ·······················································68
7.8.5
Analysis of Exploratory Endpoints····················································68
7.8.5.1
···································································68
7.8.6
Treatment Compliance··································································68
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················68
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········68
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················69
8.1
Procedure for Clinical Study Quality Control ·············································69


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 6 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
8.1.1
Data Collection ··········································································69
8.1.2
Specification of Source Documents···················································70
8.1.3
Clinical Study Monitoring······························································70
8.1.4
Direct Access to Source Data/Documents············································70
8.1.5
Data Management ·······································································71
8.1.6
Protocol Deviations ·····································································71
8.1.7
End of Trial in All Participating Countries···········································72
8.2
Ethics and Protection of Subject Confidentiality··········································72
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ···························································72
8.2.2
Ethical Conduct of the Study···························································72
8.2.3
Informed Consent of Subjects ·························································72
8.2.3.1
Subject Information and Consent······················································72
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information···································73
8.2.4
Subject Confidentiality ·································································73
8.3
Administrative Matters ·······································································74
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····74
8.3.2
Documents and Records Related to the Clinical Study ·····························74
8.3.3
Protocol Amendment and/or Revision················································74
8.3.4
Insurance of Subjects and Others······················································75
8.3.5
Signatory Investigator for Clinical Study Report····································75
9
QUALITY ASSURANCE········································································75
10
STUDY ORGANIZATION······································································75
10.1
Data and Safety Monitoring Board (DSMB) ··············································75
10.2
Other Study Organization ····································································76
11
REFERENCES ····················································································77
12
APPENDICES ·····················································································80
12.1
List of Excluded Concomitant Medications················································80
12.2
Liver Safety Monitoring and Assessment ··················································81
12.3
Common Serious Adverse Events···························································84
13
ATTACHMENTS ·················································································85
13.1
Attachment 1:  Substantial Amendment 2··················································85
13.2
Attachment 2:  Substantial Amendment 1 [21Nov2014]·································92


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ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
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14
SPONSOR’S SIGNATURES·································································· 116


Sponsor: APEB
ISN/Protocol 2819-CL-0202
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I.
SIGNATURES
1.  
SPONSOR’S SIGNATURES
Required signatures (e.g. Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in Section 14, Sponsor’s Signatures; e-signatures (when applicable) are located at 
the end of this document.


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2.  INVESTIGATOR’S SIGNATURE
A Phase 3, Multicenter, Investigator-blind, Randomized, Parallel Group Study to 
Investigate the Safety and Efficacy of Fidaxomicin Oral Suspension or Tablets 
Taken q12h, and Vancomycin Oral Liquid or Capsules Taken q6h, for 10 Days 
in Pediatric Subjects with Clostridium difficile-associated Diarrhea
ISN/Protocol 2819-CL-0202 / Version 3.0
Incorporating Substantial Amendment 2 / 21 July 2015
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with ICH GCP guidelines and applicable 
local regulations. I will also ensure that sub-investigator(s) and other relevant members of my staff 
have access to copies of this protocol and the ICH GCP guidelines to enable them to work in 
accordance with the provisions of these documents.
Principal Investigator:
Signature:
Printed Name:
Date (DD Mmm YYYY)
Address:




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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase (GPT)
APEB
Astellas Pharma Europe BV
ATC
Anatomical Therapeutic Chemical
AST
Aspartate Aminotransferase (GOT)
AUC
Area under the curve
BI
Epidemic hypervirulent C. difficile strain
CA
Competent Authorities 
CDAD
Clostridium Difficile Associated Diarrhea
CDI
Clostridium Difficile Infection
CIOMS
Council for International Organizations of Medical Sciences
Cmax
Maximum concentration
CRO
Contract Research Organization
DILI
Drug-induced Liver Injury
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eCTD
Electronic Common Technical Document
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOS
End of Study 
EOT
End of Treatment 
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practices
GGT
Gamma glutamyltransferase
GRAS
Generally Recognized as Safe
HIPAA
The Health Insurance Portability and Accountability Act of 1996
ICD
International Classification of Disease
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IMPD
Investigational Medicinal Product Dossier
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology


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Abbreviations
Description of abbreviations
ITT
Intent To Treat
ISN
International Study Number
IUD
Intrauterine device
IUS
Intrauterine system
KID
Kid’s Inpatient Database
LA-CRF
Liver Abnormality Case Report Form
LFT
Liver Function Tests
LLOQ
Lower Limit of Quantification
LS
Least Squares
MAA
Marketing Authorization Application
MedDRA
Medical Dictionary for Regulatory Activities
NAP1
North American Pulsed 1
NDA
New Drug Application
NASH
Non-alcoholic steatohepatitis
NHDS
National Hospital Discharge Survey
OP-1118
Main metabolite of Fidaxomicin
OTC
over-the-counter
PCR
Polymerase Chain Reaction
PHIS
Pediatric Health Information System
PHI
Protected Health Information
PK
Pharmacokinetics
PKAS
Pharmacokinetics Analysis Set
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total Bilirubin
TC
Telephone call
TEAE
Treatment Emergent Adverse Event
TLF
Tables, Listings, Figures
TMF
Trial Master File
TTROD 
Time to resolution of diarrhea
UBM
Unformed Bowel Movement
ULN
Upper Limit of Normal
US
United States
WBC
White Blood Cell
WHODRL
World Health Organization Drug Reference List


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Definition of Key Study Terms
Terms
Definition of terms
Baseline
Observed values/findings which are regarded observed starting point for 
comparison. 
Clinical response for 
subjects aged from 
birth to < 2 years 
Absence of watery diarrhea for 2 consecutive days during treatment and 
subjects remain well until the time of study drug discontinuation (initial 
clinical response). 
In addition, subjects should not require further CDAD therapy within 2 days 
after completion of study drug (confirmed clinical response). Resolution of 
diarrhea is assessed during interviews of the subject/parent/legal guardian 
supplemented by a review of the subject’s personal records for the day (if 
hospitalized), and the presence of watery diarrhea.
Clinical response for 
subjects aged ≥ 2 
years to < 18 years
Improvement in the number and character of bowel movements as 
determined by < 3 unformed bowel movements (UBMs) per day for 2 
consecutive days during treatment and subjects remain well until the time of 
study drug discontinuation (initial clinical response). 
In addition, subjects should not require further CDAD therapy 2 days after 
completion of study drug (confirmed clinical response). Resolution of 
diarrhea is assessed during interviews of the subject/parent/legal guardian, 
supplemented by a review of the subject’s personal records for the day (if 
hospitalized), and the number of UBMs.
Enroll
To register or enter into a clinical trial. NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject. 
End of Study
The end of the study is defined as the date of the last subject’s last visit/TC. 
Intervention
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study. (e.g., health-
related quality of life, efficacy, safety, pharmacoeconomics).
Investigational period
Period of time where major interests of protocol objectives  are observed, and 
where the test drug or comparative drug is given to a subject, and continues 
until the last assessment after completing administration of the test drug or 
comparative drug.
Post investigational 
period
Period of time after the last assessment of the protocol. Follow-up
observations for sustained adverse events and/or survival are done in this 
period.
Randomization
The process of assigning trial subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias.
Recurrence for 
subjects aged from 
birth to < 2 years
The re-establishment of watery diarrhea after confirmed clinical response to 
an extent that is greater than that noted on the last day of study drug with 
positive direct or indirect testing for the presence of toxigenic C.difficile in 
stool and that, in the investigator's opinion, would require retreatment with 
CDAD anti-infective therapy.
Recurrence for 
subjects aged ≥ 2 
The re-establishment of diarrhea after confirmed clinical response to an 
extent (as measured by the frequency of UBMs) that is greater than that 
noted on the last day of study drug with positive direct or indirect testing for 


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Terms
Definition of terms
years < 18 year
the presence of toxigenic C.difficile in stool and that, in the investigator's 
opinion, would require retreatment with CDAD anti-infective therapy.
Screening
A process of active consideration of potential subjects for enrollment in a 
trial.
Screen failure
Potential subject who was not randomized and did not receive any study drug
Screening period
Period of time before entering the investigational period, usually from the 
time of signing consent until just before the test drug or comparative drug  is 
given to a subject.
Start of study
The start of the study is defined as the date that the first Informed Consent 
Form (ICF) is signed. 
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Sustained clinical 
response
Confirmed clinical response (EOT + 2 days) without CDAD recurrence until 
the time of assessment during the Follow-up period.
Time to recurrence 
The time (days) from confirmed clinical response until the onset of 
recurrence as defined above.
Time to resolution of 
diarrhea (TTROD) 
for subjects aged 
from birth < 2 years 
The time elapsing (in hours rounded up from minutes > 30) from the start of 
treatment (time of first dose of study medication) to resolution of diarrhea 
(time of last episode of watery diarrhea the day prior to the first of 
2 consecutive days without watery diarrhea that was sustained through EOT).
Time to resolution of 
diarrhea (TTROD) 
for subjects aged ≥ 2 
years to < 18 years 
The time elapsing (in hours rounded up from minutes > 30) from the start of 
treatment (time of first dose of study medication) to resolution of diarrhea 
(time of the last UBM the day prior to the first of 2 consecutive days of <
3 UBMs that are sustained through EOT). 
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
21 July 2015 / Version 3.0
Sponsor: Astellas Pharma Europe BV (APEB)
Protocol Number: 2819-CL-0202
Name of Study Drug: Fidaxomicin
Phase of Development: 3
Title of Study:  
A Phase 3, Multicenter, Investigator-blind, Randomized, Parallel Group Study to Investigate the 
Safety and Efficacy of Fidaxomicin Oral Suspension or Tablets Taken q12h, and Vancomycin Oral 
Liquid or Capsules Taken q6h, for 10 Days in Pediatric Subjects with Clostridium difficile-
associated Diarrhea
Planned Study Period: 
From 3Q 2014 to 2Q 2017
Study Objective(s): 
The primary objective of this study is to investigate the clinical response to fidaxomicin oral 
suspension or tablets and vancomycin oral liquid or capsules of pediatric subjects with Clostridium 
difficile-associated diarrhea (CDAD) from birth to < 18 years of age.
Planned Total Number of Study Centers and Location(s):  
Approximately 65-80 centers in North America and Europe.
Study Population:  
Male and female subjects from birth to < 18 years of age, diagnosed with CDAD confirmed by a 
positive C. difficile toxin test in stool or positive detection of toxigenic C. difficile in stool.
Number of Subjects to be Enrolled:  
144 subjects from birth to < 18 years of age will be enrolled with at least 24 subjects in each of the 
following age categories: birth to < 24 months, ≥2 years to < 6 years, ≥6 years to < 12 years, and 
≥12 years to < 18 years (the remaining 48 subjects can be enrolled in any of the age groups).
Study Design Overview:  
This multicenter, investigator-blind, randomized parallel group study will investigate the safety 
and efficacy of a 10-day course of fidaxomicin oral suspension or tablets and a 10-day course of 
vancomycin oral liquid or capsules in subjects from birth to < 18 years of age with confirmed 
CDAD. Note that in the United States of America subjects can only be included if aged ≥ 6 months 
to < 18 years.
One hundred forty four subjects, stratified by age at enrollment (birth to < 24 months, ≥2 years to 
< 6 years, ≥6 years to < 12 years, and ≥12 years to < 18 years) will be enrolled. A minimum of 24 
subjects will be enrolled into each age group.
Subjects must meet all inclusion criteria, no exclusion criteria, and have been diagnosed with 
CDAD. 
Subjects will be randomized to either fidaxomicin or vancomycin in a 2:1 ratio, stratified by age 
group.
Subjects from birth to < 6 years of age will be randomized to receive weight based doses of either 
fidaxomicin oral suspension (32 mg/kg/day with a maximum dose of 400 mg/day, divided in 
2 doses) 2 times daily for 10 days, or vancomycin oral liquid (40 mg/kg/day with a maximum dose 
of 500 mg/day divided in 4 doses) 4 times daily for 10 days.


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Study Design Overview continued:  
Subjects aged ≥6 years to < 18 years of age will be randomized to receive a 200 mg fidaxomicin 
tablet 2 times daily for 10 days, or a 125 mg vancomycin capsule 4 times daily for 10 days. If a 
subject aged ≥6 years to <18 years is unable to swallow tablets or capsules, the investigator can 
decide to give fidaxomicin oral suspension, at a dose of 400 mg/day, or vancomycin oral liquid at a
dose of 500 mg/day.
Plasma and stool samples will be analyzed for fidaxomicin and its main metabolite OP-1118 
concentrations. For subjects receiving fidaxomicin, two blood samples will be taken on any day 
between Day 5 and 10 inclusive. Every effort should be made to take these samples in conjunction 
with routine blood samples being taken for standard of care. However, one sample should be 
collected within 30 minutes pre-dose and another between 1 to 5 hours post-dose. The two samples 
do not have to be collected on the same day. For all subjects a stool sample will be taken between 
Day 5 and 10 inclusive, within 24 hours of a dose.
At End of Treatment (EOT), subjects will be evaluated for initial clinical response (see Definition 
of Key Study Terms section) and two days thereafter for confirmed clinical response. Clinical 
responses will be based on the investigator’s assessment of clinical parameters, most importantly 
resolution of diarrhea and the need for further treatment for CDAD. 
Subjects without initial clinical response at EOT will enter the Follow-up period for safety (adverse 
events) and will be contacted (visit or telephone call [TC]) at EOS (EOT+30 days).
Subjects without confirmed clinical response at EOT + 2 days will continue in the Follow-up 
period for safety (adverse events) and will be contacted (visit or TC) at EOS.
Subjects who have a confirmed clinical response will be followed for recurrence and sustained 
clinical response (see Definition of Key Study Terms section) throughout the Follow-up period, 
with weekly visits or TCs. At the end of the 30 day Follow-up period the EOS TC / visit will take 
place.
If diarrhea recurs during the Follow-up period an Unscheduled visit will take place for reassess-
ment of CDAD recurrence. If recurrence is confirmed, subjects will continue in the Follow-up 
period for safety (adverse events) and will be contacted (visit or TC) at the EOS.
In case of discontinuation of study drug before completion of the full 10-day treatment course, the 
subject should complete the EOT visit as soon as possible after the last drug administration. If at 
this visit, subject has an initial clinical response, the subject will continue in the Follow-up period
for safety and efficacy unless consent has been withdrawn.
CDAD status will be assessed by interviews with the subject/parent/legal guardian (or hospital staff 
e.g. when hospitalized). These interviews will be conducted in the morning, daily during the 
treatment period through the End of Treatment and at EOT+2; thereafter weekly at 9, 16 and 23 
days after the EOT, and at End of Study (EOS) EOT + 30 days, following a standardized 
questionnaire. These interviews may be conducted by telephone (e.g. when not hospitalized). 
Palatability will be assessed  for all subjects receiving fidaxomicin oral suspension and vancomycin 
oral liquid.
Site and Sponsor staff involved in dispensing, administering or collecting the study drug will be 
unblinded as well as the subject and parents/legal guardians. They will be instructed not to discuss 
the study drug with the blinded staff.
A Data and Safety Monitoring Board (DSMB) will be established for this study.  


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Inclusion/Exclusion Criteria:  
Inclusion:
Subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written 
Informed Consent/ assent ( if applicable) and privacy language as per national regulations 
(e.g., HIPAA Authorization for U.S. sites) must be obtained from the subject or legally 
authorized representative prior to any study-related procedures (including withdrawal of 
prohibited medication, if applicable).
2.
Male and female subjects aged from birth to < 18 years.  Note that in the United States of 
America subjects can only be included if aged ≥6 months to < 18 years.
3.
Subject is diagnosed with CDAD according to local diagnostic criteria. As a minimum there 
must be positive detection, within 72 hours prior to randomization, of either toxin A and/or 
toxin B in stool or positive detection of toxigenic C. difficile in stool and:
a. Subject from birth to < 2 years: watery diarrhea in the 24 hours prior to screening.
b. Subject ≥2 years to < 18 years: > 3 unformed bowel movements in the 24 hours prior to 
screening.
4.
For subjects < 5 years: Negative rotavirus test.
5.
Female subject of childbearing potential:
a. must have a negative urine pregnancy test at Screening, and
b. must abstain from sexual activity for the duration of the study, or
c. must use two forms of birth control* (at least one of which must be a barrier method) 
starting at Screening and throughout the study period and for 28 days after the final 
study drug administration.
6.
Female subject must not be breastfeeding at Screening or during the study period, and for 28 
days after the final study drug administration. 
7.
Female subject must not donate ova starting at Screening and throughout the study period, and 
for 28 days after the final study drug administration. 
8.
Subject agrees not to participate in another interventional study while in the study (with the 
exception of studies as described in exclusion criteria 6).
Waivers to the inclusion criteria will NOT be allowed.
*Acceptable forms of birth control include:

Established use of oral, injected or implanted hormonal methods of contraception.

Placement of an intrauterine device (IUD) or intrauterine system (IUS).

Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository.
Exclusion:  
Subject will be excluded from participation if any of the following apply:
1.
Concurrent use of metronidazole, oral vancomycin or any other antibiotic treatments for 
CDAD. If the investigator feels the clinical imperative is to begin treatment before knowing 
the laboratory result for toxigenic C. difficile, up to four doses but no more than 24 hours of 
treatment with metronidazole, oral vancomycin or any other effective treatment for CDAD are 
allowed. 


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2.
Subject has pseudomembranous colitis, fulminant colitis, toxic megacolon or ileus.
3.
Subject has a history of inflammatory bowel disease (e.g., ulcerative colitis or Crohn’s disease
etc.).
4.
Subject has diarrhea caused by an agent other than C. difficile (e.g. infections, infestations, 
drugs etc.). 
5.
Subject has known hypersensitivity to fidaxomicin, vancomycin or their excipients or to 
teicoplanin.
6.
Subject has received an investigational therapy within 28 days, prior to Screening, with the 
exception of studies with primary treatment for cancer without novel Investigational Medicinal 
Product (IMP) and which do not affect the assessment of diarrhea.
7.
Subject has a condition which, in the investigator’s opinion, makes the subject unsuitable for 
study participation.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Product(s):
Fidaxomicin oral suspension and fidaxomicin 200 mg tablets
Dose(s):  
From birth to < 6 years of age: fidaxomicin oral suspension, 32 mg/kg/day with a maximum daily 
dose of 400 mg, divided in 2 doses per day.
Ages ≥6 years to < 18 years: fidaxomicin 200 mg tablet, two times daily.
If a subject aged ≥6 years to < 18 years is unable to swallow tablets, fidaxomicin oral suspension 
at a dose of 200 mg, two times daily can be given.
Mode of Administration:
Oral
Comparative Drug(s):
Vancomycin oral liquid and vancomycin 125 mg capsules.
Dose(s):
From birth to < 6 years of age: vancomycin oral liquid 40 mg/kg/day with a maximum daily dose 
of 500 mg, divided in 4 doses per day.
Ages ≥6 years to < 18 years: vancomycin 125 mg capsule, four times daily.
If a subject aged ≥6 years to <18 years is unable to swallow capsules, vancomycin oral liquid at a
dose of 125 mg, four times daily can be given.
Mode of Administration:
Oral
Rescue Therapy:
Standard of care
Concomitant Medication Restrictions or Requirements:   
No other antibacterial drugs potentially useful in the treatment of CDAD (e.g., metronidazole, oral 
vancomycin, oral bacitracin, fusidic acid, rifaximin, nitazoxanide) or fecal transplantation should
be given during the trial unless they are specifically given because of a primary treatment failure 
or suspected CDAD recurrence after initial clinical response. 


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Drugs to control diarrhea (e.g., loperamide) should also be withheld during the study period.
Whenever possible, drugs which could affect peristalsis should be avoided. Subjects receiving 
opioids for pain prior to enrollment may continue to receive the same opioid and dose during the 
treatment phase if required. 
Duration of Treatment:  
10 days
Definitions:
Clinical response for subjects aged from birth to < 2 years is defined as: Absence of watery 
diarrhea for 2 consecutive days during treatment and subjects remain well until the time of study 
drug discontinuation (initial clinical response). In addition, subjects should not require further 
CDAD therapy within 2 days after completion of study drug (confirmed clinical response). 
Resolution of diarrhea is assessed during interviews of the subject/parent/legal guardian 
supplemented by a review of the subject’s personal records for the day (if hospitalized), and the 
presence of watery diarrhea.
Clinical response for subjects aged ≥ 2 years to < 18 years is defined as:  Improvement in the 
number and character of bowel movements as determined by < 3 unformed bowel movements 
(UBMs) per day for 2 consecutive days during treatment and subjects remain well until the time of 
study drug discontinuation (initial clinical response). In addition, subjects should not require further 
CDAD therapy 2 days after completion of study drug (confirmed clinical response). Resolution of 
diarrhea is assessed during interviews of the subject/parent/legal guardian, supplemented by a 
review of the subject’s personal records for the day (if hospitalized), and the number of UBMs.
Time to resolution of diarrhea (TTROD) for subjects aged from birth to < 2 years is defined as:  
the time elapsing (in hours rounded up from minutes > 30) from the start of treatment (time of first 
dose of study medication) to resolution of diarrhea (time of last episode of watery diarrhea the day 
prior to the first of 2 consecutive days without watery diarrhea that was sustained through EOT).
Time to resolution of diarrhea (TTROD) for subjects aged ≥ 2 years to < 18 years is defined 
as:  the time elapsing (in hours rounded up from minutes > 30) from the start of treatment (time of 
first dose of study medication) to resolution of diarrhea (time of the last UBM the day prior to the 
first of 2 consecutive days of < 3 UBMs that are sustained through EOT).
Recurrence for subjects aged from birth to < 2 years is defined as: the re-establishment of watery 
diarrhea after confirmed clinical response to an extent that is greater than that noted on the last day 
of study drug with the demonstration of a positive direct or indirect testing for the presence of 
toxigenic C.difficile in stool and that, in the investigator's opinion, would require retreatment with 
CDAD anti-infective therapy.
Recurrence for subjects aged ≥ 2 years < 18 years is defined as: the re-establishment of diarrhea 
after confirmed clinical response to an extent (as measured by the frequency of passed unformed 
stools) that is greater than that noted on the last day of study drug with the demonstration of a 
positive direct or indirect testing for the presence of toxigenic C.difficile in stool and that, in the 
investigator's opinion, would require retreatment with CDAD anti-infective therapy.
Time to recurrence is defined as: the time (days) from confirmed clinical response until the onset 
of recurrence as defined above.
Sustained clinical response is defined as: Confirmed clinical response (EOT + 2 days) without 
CDAD recurrence until the time of assessment during the Follow-up period.




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Efficacy
Efficacy data will be summarized for the Full Analysis Set (FAS), defined as all subjects who were 
randomized and received at least one dose of the study drug. In general, all summaries will be 
provided by treatment arm and age group.
The proportion of subjects with confirmed clinical response (primary efficacy endpoint) at EOT+2 
days will be summarized  within each treatment arm by age group along with exact 95% 
confidence intervals (CIs). In addition, 95% CIs will be presented for the adjusted difference in 
confirmed clinical response between  treatment arms, where adjusted difference will be calculated 
using stratified CMH (Cochran-Mantel-Haenszel) method using age group as the stratified variable.
The secondary efficacy endpoints recurrence of CDAD and sustained clinical response (at 16 days 
after EOT and at EOS) will be summarized in the same manner as the primary efficacy endpoint.
For the endpoints TTROD and time to recurrence of CDAD, Kaplan-Meier survival functions will 
be generated and graphically displayed (with 95% CIs) by treatment arm. Quartile estimates 
for the time to event and corresponding 95% CIs will be computed for each treatment arm. 
Other analyses may be done as deemed appropriate.
Drug Concentration Measurement  
Descriptive statistics will be provided for plasma concentrations of fidaxomicin and its main 
metabolite OP-1118 by time point (pre-dose and 1 to 5 hours post-dose) and for the fecal 
concentration of fidaxomicin and OP-1118 , overall and by age group (only for subjects treated 
with fidaxomicin).
Pharmacodynamics  
Not applicable.
Safety
All safety parameters will be summarized descriptively for the whole safety population. Summaries 
will be grouped by treatment; further stratification by age group might be done where deemed 
appropriate.
Interim Analyses 
Not applicable.


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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart
Study Schematic Diagram 
Start and End of Study
The start of the study is defined as the date that the first Informed Consent Form (ICF) is signed. 
The end of the study is defined as the date of the last subject’s last visit (End of Study). 
In case of premature withdrawal or failure during the treatment period, the subject should complete the 
End of Treatment (EOT) visit and End of Study (for safety information).
In case of recurrence of diarrhea during the Follow-up period and for any other reason that in the opinion 
of the investigator requires a clinic visit, the subject should complete an Unscheduled visit for 
reassessment of CDAD.


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Table 1: Schedule of Assessments
Study Period
Screening 
period
Treatment perioda
Follow up period
End of Study 
TC/Visit 
(EOS)k
Unscheduled 
Visitl
Screening
Daily Assessment
End of 
Treatment 
(EOT)f,g
Confirmation 
Clinical Response 
TC/Visith
Follow-up 
TCi
Day
-2  to 1
1b
2-4
5-10
10
EOT+2
EOT +9, 16 & 
23
EOT+30
Window
+2
+2
+2
+2
Assessments
Subject information & informed consent
X
Demographics
X
Height and Weight
X
Medical History
X
CDAD History
X
Investigator Evaluation of Signs & Symptoms 
of CDAD
X
X
Inclusion/Exclusion Criteria Check
X
Randomization
X
Study Drug Dosing
X
X
X
Study Drug Compliance Check
X
Previous and Concomitant Medication
X
X
X
X
X
X
X
X
X
CDAD Status (Subject/parent/legal guardian 
interview)e
X
X
X
X
X
X
X
Drug Concentration Blood  Samplesn
X
Drug Concentration Stool Sampleo
X
Stool Sample for Toxigenic C.difficile and 
possible microbiology testing
Xm
Xr
Xj
Fecal Rotavirus Testingt
X
Palatabilityp
X
X
Table continued on next page


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Study Period
Screening 
period
Treatment perioda
Follow up period
End of Study 
TC/Visit 
(EOS)k
Unscheduled 
Visitl
Screening
Daily Assessment
End of 
Treatment 
(EOT)f,g
Confirmation 
Clinical Response 
TC/Visith
Follow-up 
TCi
Day
-2  to 1
1b
2-4
5-10
10
EOT+2
EOT +9, 16 & 
23
EOT+30
Window
+2
+2
+2
+2
Safety
Hematology, Biochemistry and Urinalysiss
X
X
O
Pregnancy Testc
X
X
O
Physical Examination
X
X
O
Vital Signsd
X
X
O
ECGq
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Efficacy
Clinical Response 
X
X
Recurrence j
X
X
Xj
X = required, O=optional
a)
Subjects may be treated on an inpatient/outpatient/ or combined basis at the discretion of the investigator. 
b)
After all screening procedures are completed and the subject is eligible, the subject will be randomized and study drug will be administered. This is the start of the Treatment 
Period (i.e., Day 1)
c)
At Screening, at the End of Treatment (EOT) visit and at the Unscheduled visit (if deemed necessary by the investigator) a pregnancy test locally in urine (dipstick) will only be 
performed in women of childbearing potential. 
d)
Includes blood pressure, pulse, and body temperature.
e)
CDAD status will be assessed by interviews with the subject/parent/legal guardian (or hospital staff e.g. when hospitalized). These interviews will be conducted in the morning, 
daily during the treatment period through End of Treatment and at EOT+2; thereafter weekly at 9, 16 and 23 days after the EOT, and at End of Study (EOS) EOT + 30 days, 
following a standardized questionnaire. These interviews may be conducted by telephone (e.g. when not hospitalized).
f)
Subjects who discontinue study drug prematurely should complete the EOT visit as soon as possible after the final dose. 
Footnotes continued on next page


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g)
At EOT, the clinical response will be assessed. All subjects will continue in the Follow-up period. 
Subjects that have no clinical response will only be contacted at EOT +30 days for safety (adverse events).
h)
Two days after EOT, a telephone contact with the subject/parent/legal guardian or a visit (if the subject is still in the hospital) will take place for all subjects with an initial clinical 
response at EOT to confirm the clinical response. All subjects will continue in the 30-day Follow-up period. Subjects without a confirmed clinical response will only be contacted 
at EOT +30 days for safety (adverse events).
i)
At 9, 16 and 23 days after EOT, for subjects who had confirmed clinical response; the subject/parent/legal guardian will be contacted by phone. 
j)
For subjects with a recurrence of diarrhea during the Follow-up period, an Unscheduled visit is mandatory, including a stool sample. The stool sample will be split in two aliquots 
one for detection of toxigenic C.difficile at site and one for the reference lab (for possible microbiological and biochemistry testing), for reassessment of CDAD (as per protocol 
criteria). Subjects with recurrence of CDAD will after the Unscheduled visit continue in the Follow-up period and will only be contacted at EOT +30 days for safety (adverse 
events).
k)
30 days after  EOT, the EOS TC/visit will take place. For subjects that had a confirmed clinical response at EOT +2 days and did not experience a recurrence during the Follow-up 
period, all assessments will be done, including sustained clinical response assessment. For all other subjects a telephone call (TC) will be done for safety (adverse events).
l)
Unscheduled visits could take place throughout the study period, if deemed necessary by the investigator. Only those assessments that are relevant according to the investigators 
opinion should be performed. However, evaluation of adverse events (AE) and concomitant medication is mandatory. 
m) Stool sample will be split in two aliquots, one for the detection of toxigenic C. difficile at study site and one for the reference laboratory (for possible microbiological and 
biochemistry testing). Alternatively, a test for toxigenic C. difficile done as standard of care, including pre-consent samples, provided the sample was obtained within 72 hours 
prior to randomization, may be used to assess eligibility and a different sample sent to the reference laboratory.
n)
For subjects receiving fidaxomicin, two blood samples will be taken on any day between Day 5 and 10 inclusive. Every effort should be made to take these samples in conjunction 
with routine blood samples being taken for standard of care. However one sample should be collected within 30 minutes pre-dose and another between 1 to 5 hours post-dose. The 
two samples do not have to be collected on the same day. 
o)
For all subjects a stool sample will be taken between Day 5 and 10 inclusive, within 24 hours of a dose.
p)
For subjects receiving fidaxomicin oral suspension or vancomycin oral liquid palatability assessment will be performed on Day 1 and Day 7 
(± 1 day).
q)
Two ECGs will be performed. One at screening prior to the first dose of study drug and another 1 to 5 hours post-dose (the morning or evening dose for the fidaxomicin arm, or the 
first or the third dose of the day for the vancomycin arm) on any day between days 5 and 10 inclusive, but not within 30 minutes after venipuncture. 
For the ECG at screening, an ECG that is performed before consent is acceptable, provided that it was recorded after the onset of CDAD and within 3 days prior to randomization. 
r)
At the EOT visit a stool sample will be split in two aliquots, one for direct or indirect testing for presence of toxigenic C.difficile at study site and one for the reference laboratory 
(for possible microbiological and biochemistry testing). 
s)
For hematology, biochemistry and urinalysis at Screening, results that were obtained per standard of care before consent (historical sample) are acceptable, provided that the 
sampling was done after the onset of CDAD and within 3 days prior to randomization. For the hematology, biochemistry and urinalysis at EOT visit, results that were obtained as 
part of standard of care between Day 8 and Day 10 (inclusive) (standard of care sample) are acceptable. The most recent results should be used for eCRF completion. The 
historical or standard of care sample may not include all parameters as described in Table 4, section 5.4.3  A historical/standard of care samples without parameter(s) indicated 
with * in the table is acceptable.
t)
For subjects < 5 years only, a rotavirus test is required. A pre-consent standard of care result may be used (historical sample), provided the sample was taken after the onset of 
diarrhea and within 3 days prior to randomization.


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1
INTRODUCTION
1.1
Background
Fidaxomicin is a macrolide (18-membered macrocycle) antibacterial drug produced by 
Dactylosporangium aurantiacum, and has a highly potent yet narrow-spectrum bactericidal 
activity against Clostridium difficile. Fidaxomicin was approved by the Food and Drug
Administration (FDA) in May 2011 for the United States (US) and in December 2011 by the 
European Committee for the European Union (EU) for the treatment of C. difficile infection 
(CDI) also known as C. difficile-associated diarrhea (CDAD) in adults, and is now being 
developed for use in pediatric patients with the same condition. 
CDAD is the most common cause of nosocomial diarrhea in developed countries. The 
disease accounts for approximately 20% of cases of antibiotic-associated diarrhea, and for the 
majority of cases of antibiotic-associated pseudomembranous colitis [Blanckaert et al, 2008; 
Calfee 2008; Monaghan et al, 2008; Mylonakis et al, 2001]. Although typically associated 
with hospitals and long-term care facilities, CDAD may also be acquired in the community.  
While not nearly as common as hospital-acquired CDAD, community-acquired CDAD is 
afflicting otherwise healthy people with no recent history of hospital admission or antibiotic 
use [Monaghan et al, 2008; Bartlett, 2006; Kuijper et al, 2006; Mylonakis et al, 2001]. One 
study reported that approximately 50% of patients with CDAD who visited a general 
practitioner in 2006 acquired the disease outside of a healthcare setting [Weil et al, 2007]
C. difficile is a spore-forming, anaerobic, gram-positive bacillus. CDAD is caused by an 
overgrowth of C. difficile in the colon often resulting from antibiotic use that disrupts the 
beneficial microflora found in the gut, allowing C. difficile to proliferate. The rising 
incidence of CDAD has been attributed to the frequent prescription of broad-spectrum
antibiotics to hospitalized patients, the increasing incidence of virulent strains (such as the 
North American PFGE pulse-field gel electrophoresis type 1 [NAP1]/restriction endo-
nuclease analysis type BI (Epidemic hypervirulent C. difficile strain)/Polymerase Chain 
Reaction ribotype 027 or NAP1/BI/027),[Kuijper et al, 2006; Kuijper et al, 2008] or less 
commonly to cancer chemotherapy [Fekety, 1997]. Antibiotics commonly linked to CDAD 
include ampicillin, amoxicillin, clindamycin, fluoroquinolones, and cephalosporins,
[Wistrom et al, 2001; Fekety, 1997] but almost all antibiotics can induce CDAD.  Once 
overgrown, C.difficile produces harmful toxins that can cause a variety of complications, 
including pseudomembranous colitis, toxic megacolon, perforations of the colon, and sepsis, 
and can cause or contribute to death in up to 14.4% of cases [Loo et al, 2005]. Recent reports 
mostly in adults suggest that CDAD is evolving into a more severe disease. Outbreaks of 
CDAD with increased morbidity and mortality have been described in North America and in 
the EU [Ackermann et al, 2004]. These outbreaks were associated with the emergence and 
dissemination of a hypervirulent strain characterized as toxinotype III, NAP1/BI/027. The 
NAP1/BI/027 strain has been reported in the US, Canada, and Northern Europe [Blanckaert 
et al, 2008; Calfee 2008; Kuijper et al, 2006]. This strain is thought to be responsible for 
increasing morbidity and mortality. It contains an 18-base pair tcdC deletion, and has been 
shown in vitro to produce 16 to 23 times more toxins A and B than other strains [Monaghan 


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et al, 2008; Credito & Appelbaum, 2004].To date, hypervirulent strains of C. difficile have 
been identified in the US, Canada, Japan, and many other countries, and are of increasing 
concern [Kuijper et al, 2008].
CDAD has long been considered a disease of adults and not a clinical problem in children
[McFarland et al, 2000; Larson et al, 1982]. It is unclear whether typical CDAD occurs in 
children under 2 years of age. Even in older children, CDAD is associated with variable 
diarrheal symptoms, with some reports stating that CDAD rarely causes severe diarrhea in 
children [Vernacchio et al, 2006; Spivack et al, 2003]. However, other studies have shown 
the presence of C. difficile in a significant number of older children presenting with diarrhea; 
27.3% of hospitalized children with diarrhea had a positive C. difficile test in a study in the 
US [Kader et al, 1998].
Recently, the disease has been recognized to be increasing in children and younger adults with a 
significant proportion of these cases exhibiting the onset of symptoms in the community [DuPont 
et al, 2008; Benson et al, 2007]. These observations along with the emergence of a more virulent 
and possibly more transmissible strain (NAP1/BI/027) prompted the initiation of population-
based surveillance systems for CDAD. The preliminary data now emerging from these 
surveillance systems, as well as data from hospital discharge records confirm that prevalence of 
CDAD in pediatric populations is much lower than in adults, but is steadily increasing. The most 
recent data indicate that the incidence/prevalence of CDAD in children in the US has likely 
reached a rate of approximately 20,000 cases annually [Kuijper et al, 2008].
The most recent data on population-based surveillance of CDAD in children in the US were 
reported by Kast and colleagues at the recent 2010 International Conference on Emerging 
Infectious Diseases [Kast et al, 2010]. 
The investigators reported the incidence of CDAD in 2009 from 2 distinct catchment areas:  
five metropolitan counties in Colorado and four rural counties in Minnesota. The analysis 
captured both healthcare facility-onset disease and community-onset disease. The overall 
incidence of CDAD in individuals aged 1-17 years was similar between the two areas. In the 
urban centers in Colorado, the rate was 16 per 100,000, whereas in the rural counties, the rate 
was 21 per 100,000. Adjusting for the regional differences in CDAD prevalence described by 
Elixhauser and Jhung [Elixhauser & Jhung, 2011], the rates in each surveillance area closely 
approximate to 20 per 100,000.a  The inclusion of both rural and metropolitan populations 
and the similarity of the results across populations support the generalizability of the data to 
the general US pediatric population. Thus, using current US census data for individuals under 
18 years of age (i.e., 74,548,215 persons aged under 5 years through 17 years) yields a 
national incidence of approximately 15,000 cases per year based on both the rural and 
metropolitan data.
                                                
a When regional CDAD rates (all ages combined) were evaluated, the rate in the Midwest (including Minnesota) 
was slightly higher than the overall national rate (83 versus 79.3 per 100,000; 5% higher) whereas the rate in the 
West (including Colorado) was somewhat lower than the national rate (62 versus 79.3 per 100,000; 20% lower).  
Adjusting the rate of 21 per 100,000 from Minnesota by 5% results in a rate of 20 per 100,000.  Adjusting the 
rate of 16 per 100,000 from Colorado upward by 20% also results in a rate of 20 per 100,000.


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Lower national CDAD rates were obtained by McDonald and colleagues based on data on 
discharges from short-stay hospitals from a period approximately 10 years prior to that 
covered by Kast and colleagues [Kast et al, 2010; McDonald, 2006]. In the McDonald study, 
diagnoses of intestinal infection due to Clostridium difficile (ICD-9 code 8.45) between 1996 
and 2003 from the National Hospital Discharge Survey (NHDS) database were used to 
estimate national rates. The NHDS consists of diagnosis and demographic data collected from 
a national probability sample of patient discharge records from approximately 500 hospitals. 
An algorithm (SUDAAN™) was used to estimate national rates. Although this study included 
adults as well as children, rates were analyzed by age groups. The point estimate rate for 
patients <15 years was 9/100,000 (95% CI 5-9 per 100,000). Using US census data on 
individuals <15 years (61,882,854 persons aged under 5 years through 14 yearsb), the point 
estimate of the national rate in the years between 1993 and 2003 is 5,570 cases/year.
The increase in the incidence of pediatric CDAD between time periods covered by the 
McDonald and Kast studies is supported by an analysis of pediatric hospitalization data by 
Zilberberg [ Zilberberg, 2009]. Using the Kid’s Inpatient Database (KID) and the NHDS 
database, the incidence of CDAD diagnoses between 1997 and 2006 was evaluated. The KID 
database represents 3,789 hospitals from 38 states and the NHDS database covers discharges 
from about 5000 non institutional, nonfederal, short-stay hospitals in the US. The most recent 
data from this study (2006 data) indicated that the rate of CDAD among hospitalized children 
in the US was 12.8 per 10,000 hospitalizations based on KID data and 14.03 per 
10,000 hospitalizations based on the NHDS database.
The actual number of cases calculated by Zilverberg does not deviate greatly from the 
national estimates calculated in the McDonald study [McDonald et al, 2006] using data from 
1996 to 2003.
Relatively recent multi-hospital rates of CDAD in pediatric populations were also reported by 
Kim [Kim et al, 2008]. This study examined the rate of CDAD at 22 free-standing children’s 
hospitals from major metropolitan areas in the US from 2001 to 2006 using data from the 
Pediatric Health Information System (PHIS) database. During the study period, investigators 
identified a total of 4,895 pediatric patients with CDAD at the children’s hospitals.  Based on 
this data they report rates of 4.4 cases per 10,000 patient days in 2001 and 6.5 cases per 
10,000 patient days in 2006. The annual incidence density per 1,000 admissions was 2.6 in 
2001 and 4.0 in 2006. Insufficient data are available on the denominator used in this study to 
estimate the annual number of cases nationwide based on these findings. The same study 
showed a mortality rate of 3.8% in children with CDAD.
Although community-onset disease is an impetus for the development of population-based 
surveillance, it is likely that hospital discharge data capture the majority of this segment of 
the CDAD population because community-onset disease is most typically diagnosed in 
conjunction with a visit to the hospital emergency room. The extent to which re-infection 
accounts for potential double-counting is unknown.
                                                
b US census distribution. < 5 years: 21,299,656; 5 to 9 years: 20,609,634; 10 to 14 years: 19,973,564.


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The etiology in children is the same as in adults with one major difference: children, 
particularly those < 2 years of age, frequently harbor C. difficile while being clinically 
asymptomatic. In addition, unlike in adults and older children with CDAD, the exclusion of 
other causes of diarrhea is not as conclusive in neonates and young babies < 6 months because 
children often have underlying gastrointestinal or immunologic diseases and children are more 
susceptible to infection by viral diarrhea agents, for example rotavirus, many of which cannot 
be cultured at all or only in sophisticated research labs.  
Several studies have been carried out to determine the culture rates in feces of C. difficile in 
children with and without diarrhea, with these studies showing variable culture rates and no 
apparent association between a positive culture and clinical diagnosis. In newborn infants in 
particular (i.e., < 1 month old), the occurrence of positive cultures varied widely, from 4% in 
Sweden, 11% in France, 25% in the Netherlands, 31% in the US, 67% in Belgium, and 71% 
in the UK [Penders et al, 2006; Enad et al, 1997; Collignon et al, 1993; Delmee et al, 1988;
Al-Jumaili et al, 1984; Holst et al, 1981]. It should be noted that these results were seen in all 
newborns, with no direct correlation to the presence of diarrhea.
A 1989 study demonstrated that C. difficile-positive cultures were obtained at a similar 
frequency from infants of less than 1 year of age both with and without diarrhea (32.5% 
compared to 27.9%, difference not significant, p=0.44) [Karsch et al, 1989]. Similarly, 
Vernacchio and colleagues demonstrated that 3.5% of healthy children (aged 6 to 36 months) 
had positive C. difficile cultures, whereas the proportion of children with positive C. difficile
cultures plus diarrhea was only 1.9% (p=0.12) [Vernacchio et al, 2006]. In a Finnish study, 
the prevalence of positive cultures was compared between hospitalized children with diarrhea 
(21.1%) to any hospitalized children (32.7%) [Vesikari et al, 1984]. In this study newborns 
and infants were included (i.e., patients of 0 to 2 years).
Taken together, it is clear that young children of all age groups frequently harbor C. difficile
and tolerate the presence of C. difficile, but can be clinically asymptomatic and not develop 
CDAD. The presence of intestinal colonization with C. difficile does not necessarily correlate 
with diarrhea in this age group.
As a possible scientific rationale for the differences in colonization and incidence of CDAD
seen in young children compared to adults, it has been suggested that neonates and infants do 
not respond to clostridial toxins in the same way as adults do [Tullus et al, 1989]. Though the 
mechanism for this difference is unclear, hypotheses include the inability of immature 
receptors to bind or respond to the toxins, transference of protective maternal antibodies, and 
the inability of the infant’s immune system to mount an effective immune response.
Patients are currently treated by discontinuation of the offending medication, as well as 
supportive therapy, but antimicrobial therapy is required if these measures fail to control the 
infection (Kelly, 1994; Fekety, 1997). The two most commonly utilized specific therapies are 
vancomycin and metronidazole, the latter being used off-label. 
Vancomycin is recommended for first-line treatment of CDAD in severe cases, but not in mild 
to moderate cases, which represent the majority of CDAD patients (Bauer, 2009). Increasing 


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use of vancomycin has caused some concern as it is the only antibiotic active against some 
serious life-threatening, multi-drug resistant bacteria [Hospital Infection Control Practices 
Advisory Committee (HICPAC), 1995; Watanabe, 1997]. 
Metronidazole is the recommended treatment for patients with mild to moderate disease 
experiencing a first episode of CDI [American Society of Health-System Pharmacists 
(ASHP), 1998; Bauer, 2009]. Metronidazole is effective in these subgroups of patients, and 
can be used either orally or intravenously. However, it is near-fully absorbed in the absence of 
diarrhea, and oral absorption is associated with significant adverse effects including nausea, 
neuropathy, leukopenia, seizures, and a toxic reaction to alcohol [Kelly, 1994; Fekety, 1984, 
Fekety, 1997]. 
Furthermore, its use is discouraged in young children and pregnant women [Yassin, 2001]. 
Finally, several reports have shown a lower clinical response rate in severe cases when 
treated with metronidazole treatment compared to vancomycin [Zar, 2007; Louie, 2007]. The 
current recommendations for CDAD treatment in The Medical Letter and Up-To-Date, and 
endorsed by the recent guidelines of the European Society of Clinical Microbiology and 
Infectious Diseases (ESCMID) [Bauer, 2009] and the Society for Healthcare Epidemiology 
of America and the Infectious Disease Society of America (SHEA-IDSA) [Cohen, 2010] 
state that vancomycin, but not metronidazole, should be used to treat severe cases of CDAD. 
Although current CDI treatment options are effective in treating the acute symptoms, none of 
the available treatments is without significant problems. In the case of vancomycin, these 
problems include high recurrence rate, high risk of acquiring resistant organisms, especially 
VRE. Therapy with metronidazole presents the following problems high recurrence rate, 
higher rate of failures in severe cases compared to vancomycin, frequent adverse effects.
A major shortcoming of currently available antimicrobial treatments for CDI is the typical 
recurrence rate of approximately 20% to 50% [Kyne, 1999; Kyne, 2001; Aslam, 2005; Louie, 
2007; Louie, 2006; Musher, 2006]. A new agent that effectively treats CDI and markedly 
reduces recurrence would be a significant therapeutic advance. 
Fidaxomicin tablets are approved for use in the US and other countries to treat adult subjects 
with CDAD. Also due to the need for a liquid formulation for pediatric patients, an oral 
suspension formulation of fidaxomicin has been developed. 
Data from the recent pediatric PK study with fidaxomicin tablets and oral suspension suggest 
a pharmacokinetic profile that is generally similar to that observed in adults. The safety 
observations were consistent with both the underlying conditions of the subjects and with 
data from prior studies in the adult CDAD population, and suggest that fidaxomicin is well 
tolerated in this population. Fidaxomicin showed strong efficacy in treating the initial 
disease, but higher recurrence percentage than observed in prior adult studies. The pharmaco-
kinetic, safety, and efficacy results observed in this study support the continuation of 
pediatric development of fidaxomicin. 


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1.2
Non-clinical and Clinical Data
1.2.1
Non-Clinical Data
The pharmacology, toxicology and pharmacokinetics of fidaxomicin have been studied in 
different animal species and in in vitro studies, and have demonstrated the safety of 
fidaxomicin for human use. 
Juvenile nonclinical studies have been conducted to study the effect of fidaxomicin on the 
growth and development of major organ systems in order to allow clinical studies to be 
performed in pediatric patients with CDAD, ranging from birth to 18 years. The 4-week oral 
repeated-dose toxicity study in juvenile Beagle dogs showed no target organ for toxicity and 
fidaxomicin was well tolerated in dogs from Post Natal Day 4, which is the age equivalent a 
newborn child, onwards. Furthermore, no adverse effects were seen on development of any 
organ system evaluated after 28 days of dosing up to 200 mg/kg/day fidaxomicin. Although 
GI tracts were considered to be the most susceptible organ due to the expected high local 
concentrations of fidaxomicin, no histological changes were observed in the GI tract of 
juvenile animals. Fidaxomicin was shown to have the same safety profile in young animals as 
in adult animals. There are no indications for target organs or differences in sensitivity. In 
summary, long term dosing of fidaxomicin up to 200 mg/kg/day does not show adverse 
effects on any of the developing organ systems in juvenile animals and does not indicate any 
safety concern for pediatric patients from birth and older.
Full details can be found in the current version of the Investigator’s Brochure (IB) version 9.3.
1.2.2
Clinical Data
The safety and efficacy of fidaxomicin have been evaluated in 8 phase 1 studies in healthy 
adult subjects, a phase 2A study conducted in adults with CDAD, 2 phase 3 studies
conducted in adults with CDAD and a recent phase 2A study conducted in children with 
CDAD. All studies have been completed and the data have been analyzed. Full details can be 
found in the current version of the IB addendum 1 version 9.3. A summary of the studies is 
provided in Table 2
Table 2:
Summary of Fidaxomicin Clinical Studies
Study 
Number
Title
Duration and 
Dose of 
Fidaxomicin
Comparator
Number of 
Subjects 
Treated
OPT-80-005
Phase 1
A single center, open-label, randomized, 
two-period, cross-over study to 
determine the pharmacokinetics and the 
effect of food on the bioavailability of 
OPT-80 in healthy subjects and the 
pharmacokinetics of a lead-in single arm 
of 200 mg OPT-80 in healthy subjects
Single dose: 
200 mg or 
400 mg
None
34
OPT-80 1A-
SD
Phase 1
A phase 1A, single dose-escalating 
safety study of OPT-80 in healthy 
volunteers 
Single dose: 
100 mg, 200 mg, 
300 mg, 450 mg
Placebo
16
Table continued on next page


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Study 
Number
Title
Duration and 
Dose of 
Fidaxomicin
Comparator
Number of 
Subjects 
Treated
OPT-80 1B-
MD
Phase 1
A phase 1B, multiple dose-escalating 
safety study of OPT-80 in healthy 
volunteers 
10 days: 150 mg, 
300 mg, 450 mg
Placebo
24
OPT-80-007
Phase 1
A phase 1, open-label, two-period, 
randomized crossover study to evaluate 
the effect of a single dose of 
cyclosporine on the single-dose 
pharmacokinetic profile of fidaxomicin 
(OPT-80) in healthy male subjects 
Single dose:
200 mg
Fidaxomicin 
200 mg with 
Cyclosporine 
(Neoral®) 200 
mg
14
OPT-80-008
Phase 1
A phase 1, open-label, monosequence 
crossover study to evaluate the effect of 
steady-state fidaxomicin (OPT-80) 
tablets on the single-dose 
pharmacokinetic profile of digoxin in 
healthy subjects 
11 days: 400 mg 
(200 mg q12h)
Digoxin 0.5 mg, 
with or without 
fidaxomicin
14
OPT-80-009
Phase 1
A phase 1, open-label, monosequence 
crossover study to evaluate the potential 
for cytochrome P450-mediated drug 
interactions with fidaxomicin (OPT-80) 
in healthy male subjects 
7 days: 400 mg 
(200 mg q12h)
Warfarin 10 mg;
Omeprazole 
40 mg;
Midazolam 5 mg; 
with or without 
fidaxomicin
24
2819-CL-2003 
Phase 1 
A Phase 1, Open-label, Randomized, 
Two-way Crossover Study to Evaluate 
the Effect of Multiple Doses of 
Fidaxomicin on the Single Dose 
Pharmacokinetics of Rosuvastatin in 
Healthy Male Subjects 
5 days: 400 mg 
(200 mg q12h) 
10 mg 
rosuvastatin, with 
or without 
fidaxomicin 
26 
2819-CL-3001 
Phase 1 
A Phase 1, Randomized, Double-Blind, 
Placebo-Controlled, Dose Escalation 
Study to Assess the Safety, Tolerability 
and Pharmacokinetics of Single and 
Multiple Ascending Doses of 
Fidaxomicin in Healthy Male Japanese 
and Caucasian Subjects 
100 mg or 200 mg 
given as a single 
dose with 5 day 
washout, then 
twice daily for 9 
days with a final 
dose on the 10th 
day 
Placebo 
36 
OPT-80
Phase 2A 
An open-label, dose ranging, randomized 
clinical evaluation of OPT-80 in patients 
with Clostridium difficile-associated 
diarrhea (CDAD) 
10 days: 100 mg, 
200 mg, 400 mg
(each as split 
dose, q12h)
None
48
101.1.C.003
Phase 3
A multi-national, multicenter, double-
blind, randomized, parallel group study 
to compare the safety and efficacy of 
200 mg PAR-101 taken Q12h with 
125 mg vancomycin taken Q6h for ten 
days in subjects with Clostridium 
difficile-associated diarrhea 
10 days: 400 mg
(200 mg q12h)
Vancomycin
500 mg
(125 mg q6h)
623
101.1.C.004
Phase 3
A multi-national, multicenter, double-
blind, randomized, parallel group study 
to compare the safety and efficacy of 
200 mg PAR-101 taken Q12h with 
125 mg vancomycin taken Q6h for ten 
10 days:
400 mg
(200 mg q12h)
Vancomycin
500 mg
(125 mg q6h)
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Study 
Number
Title
Duration and 
Dose of 
Fidaxomicin
Comparator
Number of 
Subjects 
Treated
days in subjects with Clostridium 
difficile-associated diarrhea 
OPT-80-206
Phase 2A in 
pediatrics
A Phase 2A, Multi-Center, Open-Label, 
Uncontrolled Study to Determine the 
Safety, Tolerability, and 
Pharmacokinetics of fidaxomicin Oral 
Suspension or Tablets in Pediatric 
Subjects With Clostridium difficile-
associated Diarrhea (CDAD)
10 days: 
Fidaxomicin oral 
suspension, 32 
mg/kg/day with a 
maximum dose of 
400 mg/day, 
divided in 2 doses 
(ages 6 months–5 
years 11 months) 
every 12 hours. 
Fidaxomicin 200 
mg tablets, PO. 
(ages 6 years–17 
years 11 months) 
every 12 hours.
None
38
1.2.2.1 Phase 1 Studies
In two ascending dose studies (Studies OPT-80 1A-SD and OPT-80 1B-MD), following single 
oral doses of 100 to 450 mg and multiple oral doses of 150 to 450 mg of fidaxomicin to healthy 
adult volunteers, plasma levels of fidaxomicin were near the lower limit of quantification 
[LLOQ]=5 ng/mL, showing a dose-proportional increase over the dose range studied. Plasma 
elimination half-lives ranged from 0.94 to 2.77 hours. In contrast, normalized to the 150 mg 
dose, fecal concentrations of fidaxomicin reached a mean of 916.0 μg/g (range 138.4 to 1768.9 
μg/g) after 10 days of dosing. The high fecal concentrations and low systemic level are 
consistent with the therapeutic properties of fidaxomicin, which is indicated for local, 
bactericidal effects in the gastrointestinal tract. Overall, fidaxomicin was well tolerated by all 
subjects at doses up to 450 mg. The adverse events (AEs) were comparable between active and 
placebo over the dose range studied. There were no clinically significant abnormalities or drug-
related changes in serum chemistry, hematology, and urinalysis throughout the study period. 
There were no clinically significant abnormalities in hemodynamic or electrocardiographic 
data collected throughout the study.
Fidaxomicin and its main metabolite, OP-1118, showed maximum plasma concentration (Cmax) 
values that were 21.5% and 33.4% lower, respectively, in the fed versus the fasted states, while 
extents of exposure (AUC0-t) were equivalent (Study OPT-80-005). The frequency, types and 
severities of AEs following the administration of either 200 or 400 mg fidaxomicin indicated 
that it was generally well tolerated under both fasted and fed conditions. 
In a study comparing the pharmacokinetics of 200 mg fidaxomicin in Japanese and Caucasian 
healthy male adults (Study 2819-CL-3001), Cmax of fidaxomicin and OP-1118 was higher in the 
Japanese group by 70% and 62%, respectively, while AUC0-last was increased by 28% and 31% 
respectively, following a single dose (and similar results were observed after repeated 
administration). As these increases are within the range of exposures observed following dosing 


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with fidaxomicin (200 mg) in clinical studies, and these exposure levels were demonstrated to be 
safe, the increases are not considered clinically significant. Coadministration of the P-
glycoprotein inhibitor cyclosporine with fidaxomicin (Study OPT-80-007) increased the least 
squares (LS) mean Cmax of fidaxomicin and main metabolite OP-1118 by approximately 
4-fold and 10-fold, respectively, compared to fidaxomicin alone. AUC0-t for fidaxomicin and 
OP-1118 were also increased by cyclosporine, but to a lesser extent (approximately 2-fold and 
4-fold, respectively). Despite these increases in systemic exposure with cyclosporine, plasma 
fidaxomicin concentrations remained low (< 27 ng/mL) and the drug was safe and well 
tolerated. Therefore, the increases in fidaxomicin concentrations that may occur during 
concomitant treatment with cyclosporine are unlikely to be clinically meaningful as systemic 
exposure is not relevant to the safety or efficacy of fidaxomicin which is used for CDAD, 
infections that are confined to the gastrointestinal (GI) tract.
In study OPT-80-008, subjects received a single oral dose of 0.5 mg digoxin tablets on Days
1 and 13. All subjects also received oral fidaxomicin tablets (200 mg, q12h) on Days 8 to 18.  
When digoxin was administered 1 hour after a dose of 200 mg fidaxomicin, the LS mean 
Cmax and AUC0-∞values for digoxin were increased by approximately 14% and 12%, 
respectively, on Day 13 as compared to Day 1. Other pharmacokinetic parameters were 
generally similar between Days 1 and 13. These data suggested that 200 mg fidaxomicin 
q12h had little or no effect on the pharmacokinetics of digoxin.
When a probe cocktail of R- and S-warfarin, omeprazole, and midazolam was administered 
as a single dose with steady-state 200 mg fidaxomicin (Study OPT-80-009), no statistically 
significant drug-drug interactions (DDI) were observed between fidaxomicin and warfarin 
isomers, omeprazole and its metabolite 5-hydroxyomeprazole, or with midazolam.
Following coadministration of rosuvastatin with fidaxomicin (Study 2819-CL-2003), a 
substrate for transporters BCRP, MRP2, and OATP2B1, with fidaxomicin (200 mg twice 
daily) in healthy volunteers, the rosuvastatin Cmax increased by 17% and AUC0-∞ by 9.7%. 
This effect of fidaxomicin on rosuvastatin exposure is not considered clinically relevant and 
no dose adjustment is necessary.
1.2.2.2 Phase 2A Study
In the phase 2A study, fidaxomicin administered to subjects with CDAD twice daily for 
10 days at total daily doses of 100, 200 and 400 mg showed dose-dependent relief of CDAD 
symptoms by the end of therapy. Almost 90% of subjects receiving 400 mg/day (200 mg q12h) 
showed total relief of symptoms at the end of treatment. There were no treatment-emergent 
adverse events (TEAE) that were considered to be drug-related. An analysis of time-to-
resolution of diarrhea provided additional evidence that higher doses were more efficacious 
than lower doses.
At the dose of 200 mg q12h (400 mg/day), observable plasma fidaxomicin concentrations 
from Day 1 and Day 10 ranged from 5.32 to 84.9 ng/mL, while stool concentrations averaged 
over 1,400 μg/g. At the same dose, stool concentrations of fidaxomicin were approximately


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2-3 fold higher than OP-1118, the active metabolite, but plasma levels of OP-1118 remained 
well below the μg/mL range (maximum value 402 ng/mL).
Microbiological evaluation of the stool samples from this study alongside stools from 
vancomycin-treated subjects showed that by comparison with vancomycin treated subjects, 
subjects treated with fidaxomicin had: (i) undiminished fecal titers of Bacteroides fragilis and 
other major phylogenetic groups; (ii) lower post-treatment C. difficile spore counts; (iii) less 
frequent post-therapy expression of toxin.
1.2.2.3 Phase 3 Studies
Two randomized, double-blind, parallel group, multicenter phase 3 studies Studies 101.1.C.003 
and 101.1.C.004) were conducted to compare the safety and efficacy of 400 mg/day 
fidaxomicin (taken orally as 200 mg tablet q12h) with 500 mg/day vancomycin capsule (taken 
orally as 125 mg q6h) for 10 days in subjects with CDAD. Comparing fidaxomicin to 
vancomycin, clinical response rates at the EOT were similar (Study 101.1.C.003: 92.2% versus 
89.6%; Study 101.1.C.004: 91.7% versus 90.6%, fidaxomicin versus vancomycin, per protocol 
population). Fidaxomicin was superior to vancomycin for sustained clinical response at 30 
days follow-up (Study 101.1.C.003: 74.4% versus 64.2%, p=0.007; Study 101.1.C.004: 76.7% 
versus 63.3%, p=0.001, Full Analysis Set (FAS) population). Recurrence rates were 
significantly lower with fidaxomicin compared to vancomycin (Study 101.1.C.003: 15.7% 
versus 25.1%, p=0.008; Study 101.1.C.004: 12.6% versus 27.0%, p<0.001, FAS population). 
In pooled results, fidaxomicin was well-tolerated with a safety profile similar to that of 
vancomycin. Only 5.9% of subjects treated with fidaxomicin withdrew from trials due to 
AEs. The primary cause leading to discontinuation was vomiting, occurring at an incidence 
of 0.5% in both fidaxomicin and vancomycin treatment groups.
1.2.2.4 Phase 2A Pediatric Study
A single arm phase 2A study (OPT-80-206) in subjects with CDAD aged 6 months to 17 
years and 11 months to assess the safety, tolerability and pharmacokinetics of fidaxomicin 
tablets and suspension was conducted. Subjects below 6 years of age received weight-based 
doses of fidaxomicin oral suspension (32 mg/kg/day with a maximum dose of 400 mg/day, 
divided into two doses) every 12 hours for 10 days. Subjects 6 years–17 years 11 months 
received 200 mg fidaxomicin tablets every 12 hours for 10 days.
Clinical response rates were high overall, with 92.1% of subjects experiencing a clinical cure. 
Recurrence rates were 28.6% overall, and higher than observed in prior adult studies. This is 
likely reflective of high number of pediatric patients enrolling with prior episodes of CDAD, 
which is a strong risk factor for further recurrence [McFarland, 1999]. 
This study was conducted in children with underlying CDAD, and frequently severe 
underlying diseases such as neoplasms (24%). Overall, the safety observations were consistent 
with both the underlying conditions of the subjects and with data from prior studies in the adult 
CDAD population, and suggest that fidaxomicin is well tolerated in this population. 


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Fecal concentrations were in excess of the MIC90 of the organism in all age groups. There 
was a trend toward higher fecal concentrations of fidaxomicin in the lowest age group.
Higher fecal concentrations in the lowest age group or in individuals in other age groups are 
not related to AEs.
As observed previously in adults, plasma concentrations were generally in the low ng/mL 
range, with a mean fidaxomicin concentration across the age strata that ranged from 9.8 
ng/mL to 15.2 ng/mL, at 3-5 hours post-dose. As in adults, metabolite concentrations in the 
plasma were typically higher than parent concentrations, though still in the ng/mL range, 
with mean values from 28.5 ng/mL to 122 ng/mL across the age strata. There appeared to be 
no age-related trends in systemic exposures.
The observed plasma levels were not found to be above the levels observed in the main 
juvenile dog oral toxicity study (2819-TX-0004).
For further study results details reference is made to the Investigator’s Brochure addendum 1 
version 9.3.
1.3
Summary of Key Safety Information for Study Drugs
1.3.1
Fidaxomicin
The safety of fidaxomicin has been evaluated in 8 phase 1 studies in healthy adult subjects, one
phase 2A dose-finding study conducted in adults with CDAD, 2 phase 3 studies conducted in 
adults with CDAD in which oral vancomycin was a comparator and one recent phase 2A 
pediatric study. In addition, there is post-marketing pharmacovigilance data. The full safety 
information of fidaxomicin is described in the Investigator’s Brochure (IB) version 9.3. 
1.3.2
Vancomycin
The safety profile of oral vancomycin has been established through extensive post-marketing 
experience and clinical studies. For safety information of vancomycin reference is made to 
the SmPC vancomycin capsules.
1.4
Risk-Benefit Assessment
CDAD in adults is associated with significant mortality and morbidity, particularly in those 
infected with highly virulent strains. Loo showed that deaths attributable to CDAD occurred 
in 6.9% of patients [Loo et al, 2005], while all cause mortality in the fidaxomicin phase 3 
studies was 5.3% to 7.6%. In an observational study the mortality in children with CDAD 
was 3.8% [Kim et al, 2008]. The risks of any treatment should therefore be assessed in the 
context of the seriousness of the underlying condition. The currently recommended 
treatments, metranidazole and vancomycin, have limitations such as disruption of intestinal 
flora, cross resistance with other agents and a high rate of recurrence. Fidaxomicin has low 
systemic absorption and a narrow spectrum of antimicrobial activity and therefore represents 
a potentially useful treatment for CDAD in children.


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Non-clinical safety pharmacology, repeat dose toxicity, genotoxicity and reproductive 
toxicity studies of fidaxomicin did not identify any hazard for humans.
Although systemic bioavailability is low in humans (Cmax 9.88 ng/mL after a 200 mg dose), 
the elderly and those with CDAD appear to have higher exposure, as do patients with hepatic 
impairment.
Common AEs observed in the adult phase 3 studies were nausea, vomiting, and constipation. 
Uncommon AEs were rash, pruritis, decreased appetite, dizziness, headache, dysgeusia, 
abdominal distension, flatulence, dry mouth and alanine aminotransferase increased (SmPC 
Dificlir). Acute hypersensitivity reactions have been reported during post marketing such as 
rash, pruritis, angioedema and dyspnea. [reference IB version 9.3]. 
In the phase 2 and 3 studies in adults, the deaths were mainly due to respiratory disorders, 
sepsis and malignancy, and all were considered unrelated or unlikely to be related to 
fidaxomicin or vancomycin.  
Given the limited experience with fidaxomicin to date, lack of efficacy should also be 
considered a possibility. However, the results of phase 3 studies in adults showed that one of 
the standard treatments for CDAD, vancomycin, was comparable in terms of clinical 
response and safety and may be associated with higher rates of recurrence compared with 
fidaxomicin treatment.
The results of the phase 2A pediatric study (age: > 6 months - < 18 years: see section 1.2) 
showed a safety profile consistent with that seen in adults, with gastrointestinal disorders and 
infections/infestations the commonest AEs.  Six subjects developed AEs considered related 
to study drug none of which were serious. These were tachycardia, constipation, diarrhea, 
nausea, vomiting, increased body temperature, urticaria, and elevated liver enzymes. There 
were no safety signals detected by analysis of vital signs, ECG or laboratory data.  
Fidaxomicin has not been used in children < 6 months. A 4-week oral repeated-dose toxicity 
study in juvenile beagle dogs showed no target organ for toxicity after 28 days of dosing up 
to 200 mg/kg/day fidaxomicin from Post Natal Day 4 (see section 1.2.1), which is the age 
equivalent to a newborn child.
Fidaxomicin is the first representative in the novel antibacterial class of macrocycles. The 
current safety data-base consists of a total of 798 patients with mild to moderately severe 
CDI treated up to 10 days. Based on post-marketing experience since July 2011, the safety 
profile of fidaxomicin has slightly changed relative to that seen in the Phase III studies. Some 
patients with hypersensitivity reactions reported a history of allergy to macrolides. 
Fidaxomicin should be used with caution in patients with a known macrolides allergy (SmPC 
Dificlir). The available data suggest that fidaxomicin will have an acceptable benefit-risk 
balance in the treatment of CDAD in children.


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2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary
The primary objective of this study is to investigate the clinical response to fidaxomicin oral 
suspension or tablets and vancomycin oral liquid or capsules of pediatric subjects with 
Clostridium difficile-associated diarrhea (CDAD) from birth to < 18 years of age.
2.1.2
Secondary
The secondary objectives of this study are to investigate the recurrence/sustained clinical 
response to and safety of fidaxomicin and vancomycin in pediatric subjects with Clostridium 
difficile-associated diarrhea (CDAD) from birth to < 18 years of age, as well as palatability 
(acceptance) of the fidaxomicin oral suspension formulation. 
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a multicenter, investigator-blind, randomized parallel group study to investigate the 
safety and efficacy of a 10-day course of fidaxomicin oral suspension or tablets and a 10-day 
course of vancomycin oral liquid or capsules in subjects from birth to < 18 years of age with 
confirmed CDAD. Note that in the United States of America subjects can only be included if 
aged ≥ 6 months to < 18 years.
In order to reduce differential assessment of safety and efficacy outcomes, typically a double-
blind study would be preferred. However, due to nature of the active treatment and the 
comparator (e.g. formulation differences, dosing regimen differences), double blinding of the 
study drug for this pediatric study population is not feasible, given dosing constraints. 
Therefore the study will be investigator-blinded only.
The study will be conducted in North America and Europe across ~65 to 80 sites. A target of 
one hundred forty four subjects, stratified by age at enrollment (from birth to < 24 months, 
≥ 2 years to < 6 years, ≥ 6 years to < 12 years, and ≥ 12 years to < 18 years) will be enrolled. 
A minimum of 24 subjects will be enrolled into each age group. 
Subjects will be randomized to either fidaxomicin or vancomycin arm in a 2:1 ratio, stratified 
by age group.
CDAD status will be assessed by interviews with the subject/parent/legal guardian (or hospital 
staff e.g. when hospitalized). These interviews will be conducted in the morning, daily during 
the treatment period through the End of Treatment and at EOT+2; thereafter weekly at 9, 16 
and 23 days after the EOT, and at End of Study (EOS) EOT + 30 days, following a 
standardized questionnaire. These interviews may be conducted by telephone (e.g. when not 
hospitalized). During the interviews a standardized questionnaire will be used to collect the 
following information, number, date and time of the last episode of watery diarrhea or 
unformed bowel movements since the last contact and if the subject has been hospitalized. The 


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subjects/parent/ legal guardian/hospital staff will receive a leaflet with instructions what 
information is to note.
Subjects who discontinue study drug prematurely should complete the EOT visit as soon as 
possible after the final dose. 
At EOT, the initial clinical response will be assessed. All subjects will continue in the 
Follow-up period. Subjects that have no initial clinical response will only be contacted at 
EOS for safety (adverse events).
Two days after EOT, a telephone contact with the subject/parent/legal guardian or a visit (if 
the subject is still in the hospital) will take place for all subjects with an initial clinical 
response at EOT to confirm the clinical response. All subjects will continue in the 30-day 
Follow-up period. Subjects without a confirmed clinical response will only be contacted at 
EOS for safety (adverse events).
At 9, 16 and 23 days after EOT, for subjects who had confirmed clinical response; the 
subject/parent/legal guardian will be contacted by phone. 
For subjects with a recurrence of diarrhea during the Follow-up period, an Unscheduled visit as 
soon as possible is mandatory, including a stool sample. The stool sample will be split in two 
aliquots one for detection of toxigenic C.difficile at site and one for the reference lab (for 
possible microbiological and biochemistry testing), for reassessment of CDAD (as per protocol 
criteria). Subjects with recurrence of CDAD will after the Unscheduled visit, continue in the 
Follow-up period and will only be contacted at EOS for safety (adverse events).
Thirty days after EOT, the EOS TC/visit will take place. For subjects that had a confirmed 
clinical response at EOT +2 days and did not experience a recurrence during the Follow-up 
period, all assessments will be done, including sustained clinical response assessment. For all 
other subjects a telephone call (TC) will be done for recording of safety information (adverse 
events).
Unscheduled visits could take place throughout the study period, if deemed necessary by the 
investigator. Only those assessments that are relevant according to the investigators opinion 
should be performed. However, evaluation of adverse events (AE) and concomitant 
medication is mandatory. (For subjects with a recurrence of diarrhea during the Follow-up 
period, a stool sample for reassessment of CDAD, see above.)
For subjects receiving fidaxomicin, plasma and stool samples will be analyzed fidaxomicin 
and its main metabolite OP-1118 concentrations. Palatability will be assessed for all subjects 
receiving fidaxomicin oral suspension or vancomycin oral liquid.
A Data and Safety Monitoring Board (DSMB) will be established for this study.  


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2.2.2
Dose Rationale
Subjects aged ≥ 6 years to < 18 years will be randomized to receive either 400 mg daily dose 
of fidaxomicin or 500 mg daily dose of vancomycin and subjects from birth to < 6 years of 
age will be randomized to receive weight based doses of either fidaxomicin oral suspension 
or vancomycin oral liquid.
Vancomycin will be given at a dose of 40 mg/kg/day up to a maximum of 500 mg/day, either 
as an oral liquid (Vancomycin Hospira powder for oral solution and for solution for infusion, 
Hospira SpA, Italian SmPC), or oral capsules. This dose of vancomycin is considered 
standard for children (SmPC vancomycin capsules). Please refer to section 5.1.1 Table 3B 
weight based dosing instruction of the vancomycin oral liquid.
The standard total daily dose of vancomycin in adults is 500 mg/day, while that for 
fidaxomicin is 20% lower at 400 mg/day. Neither drug undergoes appreciable systemic 
absorption when administered orally, both are considered effective and have an acceptable 
risk/benefit balance.
The total daily dose of fidaxomicin for children in the current study was therefore chosen to 
be 20% lower than the standard dose of vancomycin as follows:
Fidaxomicin will be given at a dose of 32 mg/kg/day up to a maximum of 400 mg/day, either 
as an oral suspension, or oral tablets. Please refer to section 5.1.1 Table 3A weight based 
dosing instruction of the fidaxomicin oral suspension. 
Both treatments will be given for 10 days, a duration demonstrated to result in an acceptable 
cure rate of 85.7% to 88.2% in the adult phase 3 studies.
The results of the Phase 2A pediatric study (OPT-80-206) suggest a pharmacokinetic profile 
that is generally similar to that observed in adults, with low ng/mL concentrations of 
fidaxomicin and its metabolite observed in the plasma, while concentrations in the feces are 
in the μg/g range, well above the MIC90 of the target organism. Overall, the safety 
observations were consistent with both the underlying conditions of the subjects and with 
data from prior studies in the adult CDAD population, and suggest that fidaxomicin is well 
tolerated in this population. The pharmacokinetic, safety, and efficacy results observed in this 
study support the continuation of pediatric development of fidaxomicin with the same dose.
2.3
Endpoints 
2.3.1
Primary Endpoint
Efficacy 
Confirmed clinical response based on the assessment by the investigator (at EOT+2 
days).


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Definitions
Clinical response for subjects aged from birth to < 2 years is defined as: 
Absence of watery diarrhea for 2 consecutive days during treatment and subjects remain well 
until the time of study drug discontinuation (initial clinical response). In addition, subjects 
should not require further CDAD therapy within 2 days after completion of study drug 
(confirmed clinical response). Resolution of diarrhea is assessed during interviews of the 
subject/parent/ legal guardian supplemented by a review of the subject’s personal records for 
the day (if hospitalized), and the presence of watery diarrhea.
Clinical response for subjects aged ≥ 2 years to < 18 years is defined as:  Improvement in 
the number and character of bowel movements as determined by < 3 unformed bowel 
movements (UBMs) per day for 2 consecutive days during treatment and subjects remain 
well until the time of study drug discontinuation (initial clinical response). In addition, 
subjects should not require further CDAD therapy 2 days after completion of study drug 
(confirmed clinical response). Resolution of diarrhea is assessed during interviews of the 
subject/parent/legal guardian, supplemented by a review of the subject’s personal records for 
the day (if hospitalized), and the number of UBMs.
2.3.2
Secondary Endpoints 
Efficacy

Sustained clinical response at the EOS (EOT +30 days)

Sustained clinical response 14 days after Confirmation Clinical Response (EOT +16
days)

Time to resolution of diarrhea (TTROD) 

Recurrence of CDAD during or at the end of the Follow-up period.

Time to recurrence during or at the end of the Follow-up period.
Definitions:
Sustained clinical response is defined as: Confirmed clinical response (EOT + 2 days) 
without CDAD recurrence until the time of assessment during the Follow-up period.
Time to resolution of diarrhea (TTROD) for subjects aged from birth to < 2 years is 
defined as:  the time elapsing (in hours rounded up from minutes > 30) from the start of 
treatment (time of first dose of study medication) to resolution of diarrhea (time of last 
episode of watery diarrhea the day prior to the first of 2 consecutive days without watery 
diarrhea that was sustained through EOT).
Time to resolution of diarrhea (TTROD) for subjects aged ≥ 2 years to < 18 years is 
defined as:  the time elapsing (in hours rounded up from minutes > 30) from the start of 
treatment (time of first dose of study medication) to resolution of diarrhea (time of the last 
UBM the day prior to the first of 2 consecutive days of < 3 UBMs that are sustained through 
EOT).


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Recurrence for subjects aged from birth to < 2 years is defined as: the re-establishment of 
watery diarrhea after confirmed clinical response to an extent that is greater than that noted 
on the last day of study drug with the demonstration of a positive direct or indirect testing for 
the presence of toxigenic C.difficile in stool and that, in the investigator's opinion, would 
require retreatment with CDAD anti-infective therapy.
Recurrence for subjects aged ≥ 2 years < 18 years is defined as: the re-establishment of 
diarrhea to an extent (as measured by the frequency of passed unformed stools) that is greater 
than that noted on the last day of study drug after confirmed clinical response with the 
demonstration of a positive direct or indirect testing for the presence of toxigenic C.difficile 
in stool and that, in the investigator's opinion, would require retreatment with CDAD anti-
infective therapy.
Time to recurrence is defined as: the time (days) from confirmed clinical response until the 
onset of recurrence as defined above.
Safety 

AEs

Vital signs: systolic and diastolic blood pressure, pulse rate and body temperature

Laboratory tests: hematology, biochemistry, urinalysis 

Electrocardiogram (ECG) assessment
Drug concentration

Plasma concentrations of fidaxomicin and its main metabolite (OP-1118) within 
30 minutes pre-dose and 1 to 5 hours post-dose taken on any day between Day 5 and 10
inclusive. 

Fecal concentration of fidaxomicin and its main metabolite (OP-1118) within 24 hours of 
a dose taken between Day 5 and 10 inclusive.
Palatability

Acceptance of formulation at first administration of study drug and at Day 7 (± 1 day) in 
all subjects receiving fidaxomicin oral suspension and vancomycin oral liquid.
2.3.3
Exploratory Endpoints
 
 
 
 
 
 
 


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3
STUDY POPULATION
3.1
Selection of Study Population 
Male and female subjects from birth to < 18 years of age, diagnosed with CDAD confirmed by 
a positive C. difficile toxin test in stool or positive detection of toxigenic C. difficile in stool.
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written 
Informed Consent/assent (if applicable) and privacy language as per national regulations 
(e.g., HIPAA Authorization for US sites) must be obtained from the subject or legally 
authorized representative prior to any study-related procedures (including withdrawal of 
prohibited medication, if applicable).
2. Male and female subjects aged from birth to < 18 years. Note that in the United States of 
America subjects can only be included if aged ≥6 months to < 18 years.
3.
Subject is diagnosed with CDAD according to local diagnostic criteria. As a minimum 
there must be positive detection, within 72 hours prior to randomization, of either toxin A 
and/or toxin B in stool or positive detection of toxigenic C. difficile in stool and:
a.
Subject from birth to < 2 years: watery diarrhea in the 24 hours prior to screening.
b. Subject ≥ 2 years to < 18 years: > 3 unformed bowel movements in the 24 hours 
prior to screening.
4. For subjects < 5 years: Negative rotavirus test.
5. Female subject of childbearing potential:
a.
must have a negative urine pregnancy test at Screening, and
b. must abstain from sexual activity for the duration of the study, or
c.
must use two forms of birth control* (at least one of which must be a barrier 
method) starting at Screening and throughout the study period and for 28 days after 
the final study drug administration.
6. Female subject must not be breastfeeding at Screening or during the study period, and for 
28 days after the final study drug administration. 
7. Female subject must not donate ova starting at Screening and throughout the study period, 
and for 28 days after the final study drug administration. 
8. Subject agrees not to participate in another interventional study while in the study (with the 
exception of studies as described in exclusion criteria 6).
*Acceptable forms of birth control include:
Established use of oral, injected or implanted hormonal methods of contraception.
Placement of an intrauterine device (IUD) or intrauterine system (IUS).
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.


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Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1. Concurrent use of metronidazole, oral vancomycin or any other antibiotic treatments for 
CDAD. If the investigator feels the clinical imperative to begin treatment before knowing 
the laboratory result for toxigenic C.difficile, up to four doses but no more than 24 hours of 
treatment with metronidazole, oral vancomycin or any other effective treatment for CDAD 
are allowed. 
2. Subject has pseudomembranous colitis, fulminant colitis, toxic megacolon or ileus.
3. Subject has a history of inflammatory bowel disease (e.g., ulcerative colitis or Crohn’s 
disease etc.).
4. Subject has diarrhea caused by an agent other than C. difficile (e.g., infections, infestations, 
drugs etc.). 
5. Subject has known hypersensitivity to fidaxomicin, vancomycin or their excipients or to 
teicoplanin.
6. Subject has received an investigational therapy within 28 days, prior to Screening, with the 
exception of studies with primary treatment for cancer without novel Investigational 
Medicinal Product (IMP) and which do not affect the assessment of diarrhea.
7. Subject has a condition which, in the investigator’s opinion, makes the subject unsuitable
for study participation.
Waivers to the exclusion criteria will NOT be allowed.
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Test Drug(s)
Fidaxomicin granules for oral suspension is supplied as granules in a bottle. A separate box 
will be provided with ancillaries for preparation of the oral suspension. A pharmacy manual 
will be provided for the preparation of the fidaxomicin suspension. The prepared bottle is for 
multiple dosing and sufficient for 10 day treatment.
The fidaxomicin oral suspension contains fidaxomicin, microcrystalline cellulose, sodium 
starch glycolate, xanthan gum, anhydrous citric acid, sodium citrate, sodium benzoate, 
sucralose and mixed berry flavor*. All excipients are Generally Recognized as Safe (GRAS)
listed.
Administration via nasogastric tube is acceptable and specific material characteristics for 
specific tubes should be with the information in the pharmacy manual.


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If a patient leaves the hospital, instructions will be provided to caregivers on how to store and 
administer the suspension in a patient information card. The suspension will always be made 
by or under responsibility of the pharmacy or qualified designee (if allowed as per the local 
regulations) of the investigational site.
* All flavor ingredients contained in this product are approved for use by the FDA or in a 
reliable published industry list. All the flavoring ingredients contained in the above 
mentioned product are listed in Annex I - (EU) No 872/2012 (list of flavouring substances) 
- to Regulation (EC) No 1334/2008 adopted on October 1, 2012 and that will apply starting 
22 April 2013 and are composed of Art. 3.2.D. Flavouring preparations. It also contains 
modified food starch (E1520), propylene glycol (E1450) and triacetine. The product was 
not derived from a genetically modified source material.
Fidaxomicin tablets are commercially available as Dificlir 200 mg film-coated tablets (SmPC 
Dificlir). Each tablet contains 200 mg of fidaxomicin.
4.1.2
Comparative Drug(s) 
Vancomycin oral liquid is supplied as powder for oral liquid. A separate box will be provided 
with ancillaries for preparation of the oral liquid. 
Sweet syrups may be added to the liquid to improve the taste of the oral administration. 
[Vancomycin Hospira powder for oral solution and for solution for infusion, Hospira SpA, 
Italian SmPC]. SyrSpend will be provided to be used as sweet syrup for the vancomycin oral 
liquid. A pharmacy manual will be provided for the preparation of the vancomycin oral 
liquid. 
Administration via nasogastric tube is described in the pharmacy manual.
If a subject leaves the hospital, instructions will be provided to caregivers on how to store 
and administer the liquid in a patient information card. The liquid will always made by or 
under responsibility of the pharmacy or qualified designee (if allowed as per the local 
regulations) of the investigational site.
Vancomycin capsules are provided as commercially available 125 mg vancomycin capsules 
containing 125mg vancomycin (SmPC of vancomycin capsules) . 
4.2
Packaging and Labeling
All medication used in this study will be prepared, packaged, and labeled under the
responsibility of qualified staff at Astellas Pharma Europe B.V.(APEB) or Sponsor’s designee 
in accordance with APEB or Sponsor’s designee Standard Operating Procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, and applicable local 
laws/regulations.
Each patient kit and medicinal parts will bear a label conforming to regulatory guidelines, 
GMP and local laws and regulations which identifies the contents as investigational drug.


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A qualified person of APEB or Sponsor’s designee will perform the final release of the 
medication according to Directive 2003/94/EC annex 13.
4.3
Study Drug Handling 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the Sponsor are received by the investigator/or designee and

that such deliveries are recorded,

that study drug is handled and stored according to labeled storage conditions,

that study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and

that any unused study drug is returned to the Sponsor.
As this is an investigator blind study, site and Sponsor staff involved in dispensing, 
administering or collecting the study drug will be unblinded. 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/or designee. Study drug accountability throughout the study must be documented 
and reconciled. The following guidelines are therefore pertinent:

The investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol.

The investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these test drugs.

A study drug inventory will be maintained by the investigator or designee. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which subject.

At the conclusion or termination of this study, the investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned medication. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility.

The site must return study drug to the Sponsor or designee at the end of the study or 
upon expiration.
4.4
Blinding
This is an investigator-blind study. Subjects will be randomized to receive fidaxomicin or 
vancomycin in an investigator-blind fashion such that the investigator, Sponsor’s or 
designee’s study management team, and clinical staff will not know which agent is being 
administered. However, site and Sponsor or designee staff involved in dispensing, 
administering or collecting the study products and drug concentration blood sampling will be 
unblinded, as well as subjects and the parents/legal guardians. In case of questions, subjects 
and parents/legal guardians can discuss with the unblinded staff. Subjects, parents/legal 


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guardians and unblinded staff will be instructed not to discuss the treatment (appearance, 
frequency of dosing, times of individual doses, palatability etc) and drug concentration blood 
sampling with the blinded staff. Blinded staff will be instructed not to discuss the study 
treatment with unblinded staff, subjects and parents/legal guardians.
Given the complexity of maintaining the blind because of the charactaristics of the study 
medication and the pediatric population, accidental unblinding is a risk. Every effort will be 
taken to maintain the blind. In the event of accidental unblinding of blinded site, CRO or 
sponsor staff, this will be documented. Accidental unblinding is not a reason to discontinue 
study drug, even if the unblinding occurs before the start of treatment. Subjects should not be 
re-randomized for any reason, even if accidental unblinding occurs. Further details will be 
described in the blinding instructions.
4.4.1
Unblinding for Subject Safety Reasons
Unblinding of the study drug should only be considered for subject safety or when critical 
therapeutic decisions are contingent upon knowing the blinded study drug assignment. Any 
unblinding by the investigational staff must be reported immediately to the Sponsor and must 
include an explanation of why the treatment allocation was disclosed. If possible, the Sponsor
should be contacted prior to unblinding of the study drug.
4.4.2
Blinding Method
The medication will be provided in a blinded outer carton to prevent accidental unblinding by 
the investigator. The content of the provided medication will be unblinded hence medication 
will only be prepared and handled by unblinded care givers and site staff.
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code
Breaking
The randomization list and study drug blind will be maintained by the Interactive Response 
Technology (IRT) system.
The DSMB will be provided access to the treatment assignment for periodic review of the 
data as documented in the DSMB Charter.
4.4.4
Breaking the Treatment Code for Emergency
The treatment code for each randomized subject will be provided by the IRT in the event of a
medical emergency requiring knowledge of the treatment assigned to the subject. The time,
date, subject number and reason for obtaining any of these codes, and therefore breaking the
blind, must be documented in the study file. They must only be requested by the investigator 
or other persons designated as sub-investigators. 
4.4.5
Breaking the Treatment Code by the Sponsor
The Sponsor may break the treatment code for subjects who experience a Suspected 
Unexpected Serious Adverse Reaction (SUSAR), in order to determine if the individual case 
or a group of cases requires expedited regulatory reporting. Individual Emergency Codes will 


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be provided to the limited staff that is responsible to break the codes for all SUSAR cases for 
reporting purposes.
4.5
Assignment and Allocation
Randomization will be performed via IRT. Prior to the first study drug administration, the 
unblinded site staff will contact the IRT system in order to determine the randomly assigned 
treatment. Specific procedures for randomization through the IRT are contained in the Study 
Procedures Manual.
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug(s) and Other 
Medication(s)
5.1.1
Dose/Dose Regimen and Administration Period
At the end of Screening, eligible subjects will be randomized to the fidaxomicin or vancomycin 
treatment arm. The subject will take the study drug for 10 days. 
Subjects randomized to the fidaxomicin treatment arm, from birth to < 6 years of age will be 
administered fidaxomicin oral suspension, 32 mg/kg/day with a maximum dose of 
400 mg/day, divided in 2 doses/day for 10 days (see Table 3A below) and subjects aged ≥6 
years to < 18 years will receive a fidaxomicin 200 mg tablet, 2 times daily, for 10 days. 
Table 3A:  Weight-based Dosing Instruction of the Fidaxomicin Oral Suspension 
Weight band of 
patient
Dose in mg/day (twice 
daily dosing)
mg/dose 
Volume of fidaxomicin oral 
suspension to administer
≤ 3.9 kg
80 mg
40 mg
1.0 mL
4.0-6.9 kg
160 mg
80 mg
2.0 mL
7.0-8.9 kg
240 mg
120 mg
3.0 mL
9.0-12.4 kg
320 mg
160 mg
4.0 mL
≥ 12.5 kg
400 mg
200 mg
5.0 mL
Subjects randomized to the vancomycin treatment arm, from birth to < 6 years of age will be 
administered a vancomycin oral liquid 40 mg/kg/day with a maximum dose of 500 mg/day, 
divided in 4 doses/day, for 10 days (see Table 3B below) and subjects aged ≥6 years to < 18 
years will be administered a vancomycin 125 mg capsule, 4 times daily, for 10 days.
Table 3B: Weight-based Dosing Instruction of the Vancomycin Oral Liquid 
Weight band of 
patient
Dose in mg/day 
(four times daily dosing)
mg/dose 
Volume of vancomycin oral 
liquid to administer
≤ 3.9 kg
100 mg
25 mg
1.0 ml
4.0-6.9 kg
200 mg
50 mg
2.0 ml
7.0-8.9 kg
300 mg
75 mg
3.0 ml
9.0-12.4 kg
400 mg
100 mg
4.0 ml
≥ 12.5 kg
500 mg
125 mg
5.0 ml


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For subjects aged ≥6 years to < 18 years prior to randomization the ability for the subject to 
swallow tablets or capsules needs to be determined. If a subject aged ≥ 6 years to < 18 years 
cannot swallow tablets or capsules, fidaxomicin oral suspension or vancomycin oral liquid
can be given as per the subject’s treatment allocation. During the treatment period, a change 
of formulation for a subject is not allowed.
Subjects and parents/legal guardians/unblinded study staff will be instructed not to discuss 
the treatment (appearance, frequency of dosing, palatability, times of individual doses etc.) 
with the blinded study staff.
5.1.2
Increase or Reduction in Dose of the Study Drug(s)
Increases and reductions of study drug are not permitted because the aim of the study is to 
investigate fixed weight based dose of fidaxomicin and vancomycin.  
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy)
Previous medication (medication history) taken within a month prior to screening will be 
entered in the Electronic Case Report Form (eCRF).  Any treatments of relevance to CDAD, 
either as treatments for CDAD or causative agents such as antibiotics or anti-cancer therapies 
used within 3 months prior to screening should be recorded in the eCRF.  The most recent 
use of fidaxomicin or any macrolide antibiotic should be recorded in the eCRF, regardless of 
how long ago it was taken.
Concomitant medication includes relevant therapies prescribed by the study doctor, other 
doctors and over the counter drugs taken from Day 1 until the EOS (EOT + 30 days) and 
should be recorded in the eCRF.
Medication history and concomitant treatment consists of drug and non-drug therapies, 
prescribed and over-the-counter (OTC) and all alternative medicines. This also includes 
drugs used on a chronic and as-needed basis. Subjects will be instructed not to start any new
medication during the screening period through EOS, both prescribed and OTC, without prior 
consultation of the investigator wherever possible.
5.1.3.1 Prohibited Medication and Restricted Medication
No other antibacterial agents potentially useful in the treatment of CDAD (e.g., 
metronidazole, oral vancomycin, oral bacitracin, fusidic acid, rifaximin, nitazoxanide) or 
fecal transplantation should be given during the study unless they are specifically given 
because of a primary treatment failure or suspected CDAD recurrence after initial clinical 
response. 
It is preferred that prior to randomization, no pretreatment for CDAD is given. However, if 
the investigator feels there is a clinical imperative to begin treatment before knowing the 
laboratory result of direct or indirect testing for presence of toxigenic C.difficile, up to four 
doses but no more than 24 hours of treatment with metronidazole, oral vancomycin or any 
other effective treatment for CDAD are allowed.


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Drugs to control diarrhea (e.g., loperamide) should also be withheld during the study period. 
Whenever possible, drugs which could affect peristalsis should be avoided. Subjects 
receiving opioids for pain prior to enrollment may continue to receive the same opioid and 
dose during the treatment phase if required. 
See Appendix 12.1 Excluded Concomitant Medications for additional details on prohibited 
medications and medications permitted with restrictions.
Co-administration of potent P-glycoprotein inhibitors such as cyclosporine, ketoconazole, 
erythromycin, clarithromycin, verapamil, dronedarone and amiodarone is not recommended, 
but these medications are not prohibited.
5.1.4
Treatment Compliance
Study subjects and/or legal guardian (as applicable) should be counseled on the need to meet 
100% treatment compliance. The unblinded investigator or designee should ensure that 
subjects meet this goal. The quantity of study drug dispensed will be counted or measured 
and recorded in the eCRF at EOT. 
Treatment compliance will be based on the weight of the oral liquid/oral suspension used or 
count of tablets/capsules used during the treatment period (whatever applies), which will be 
recorded in the eCRF. Subjects will be regarded as compliant if the calculated amount of 
oral liquid/oral suspension used or of tablets/capsules used (as applicable) is between 80%
and 120% (inclusive) of the expected amount for the number of days on treatment. 
Site and Sponsor staff involved in dispensing, administering or collecting the study drug will 
be unblinded. 
The study drug will not be dispensed to any persons not enrolled in the study.
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
The subject’s age, gender, race and ethnicity (if permitted), height and weight will be 
recorded at screening visit.
5.2.2
Medical History
Medical history (other than for CDAD) for each subject will be obtained at Screening.
Relevant past and present conditions, as well as prior surgical procedures will be recorded in 
the eCRF.
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease 
A detailed diarrhea history for each subject will be obtained during Screening. This includes 
start and stop date, antibiotic treatment, and all CDAD episodes that occurred in the last three 
months prior to screening. Additionally start date and signs and symptoms of the current 
CDAD episode will be collected, including number of UBMs/presence of watery diarrhea 
within 24 hours prior to enrollment. The following risk factors will be collected in the eCRF: 
Antibiotics/ Cancer/ Other, if applicable.


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5.2.4
Rotavirus
For subjects < 5 years only, a rotavirus test is required at Screening. A pre-consent standard 
of care result (historical sample) may be used, provided the sample was taken after the onset 
of diarrhea and within 3 days prior to randomization.
5.3
Efficacy Assessment
The following efficacy variables will be assessed:

Confirmed clinical response based on the assessment by the investigator (at EOT+2 days).

Sustained clinical response at the End of Study (EOT +30 days).

Sustained clinical response 14 days after Confirmation Clinical Response (EOT +16 days).

Time to resolution of diarrhea (TTROD).

Recurrence of CDAD during or at the end of the Follow-up period.

Time to recurrence of CDAD during or at the end of the Follow-up period.
Definitions are described in sections 2.3.1 and 2.3.2
During the treatment period (until EOT) the subject/parent/legal guardian (or hospital staff e.g. 
when hospitalized) will be contacted daily in the morning for interviews. These interviews will 
also take place at EOT+2; thereafter weekly at 9, 16 and 23 days after the EOT, and at End of 
Study (EOS) EOT + 30 days. These interviews may be conducted by telephone (e.g. when not 
hospitalized). During the interviews a standardized questionnaire will be used to collect the 
following information, number, date and time of the last episode of watery diarrhea or unformed 
bowel movements since the last contact and if the subject has been hospitalized. The 
subjects/parent/legal guardian/hospital staff will receive a leaflet with instructions what 
information is to note.
Resolution of diarrhea is to be assessed by the investigator based on these interviews, 
supplemented by review of the subject’s personal records for the day (if subject is 
hospitalized), and the number of UBMs/presence of watery diarrhea (as applicable).
The assessment of initial clinical response will take place at EOT; 2 days thereafter the 
assessment of confirmed clinical response will be done.
Sustained clinical response and recurrence will only be assessed in subjects having confirmed 
clinical response at EOT +2 days. For this, the subject/parent/legal guardian will be contacted 
weekly after EOT (at EOT + 9, +16 and +23 days) until recurrence or the EOS TC/visit (EOT 
+ 30 days), whichever comes first. (If an Unscheduled visit occurs, recurrence will be 
assessed). The subject/parent/legal guardian will be instructed to note the date in the event of 
recurrence. The assessment of recurrence will be done by the investigator.


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5.4
Safety Assessment
5.4.1
Vital Signs
Systolic and diastolic blood pressure, pulse rate and body temperature will be measured as 
indicated in the Schedule of Assessments.  
Wherever possible, for blood pressure and pulse rate measurements the same arm should be 
used throughout the study, and with the subject in the same position (sitting or supine). The 
size of the sphygmomanometer cuff should be age appropriate and not change throughout the 
study.
Whenever possible, the route and device used to measure body temperature should remain 
unchanged throughout the study.
5.4.2
Adverse Events
See Section 5.5 Adverse Events and Other Safety Aspects for information regarding adverse 
event collection and data handling.
5.4.2.1 Adverse Events of Possible Hepatic Origin
See Appendix 12.2 Liver Safety Monitoring and Assessment for detailed information on liver 
abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study and 
receiving study drug is accompanied by increases in liver function testing (LFT) e.g., AST, 
ALT, bilirubin, etc. or is suspected to be due to hepatic dysfunction.
5.4.3
Laboratory Assessments
Routine safety laboratory assessments will be performed at the Screening and End of 
Treatment visit by the local laboratory and recorded in the eCRF. Additional laboratory 
testing may be carried out by the investigator if deemed necessary.
In Table 4 the laboratory tests that will be performed during the conduct of the study are 
listed. See the Schedule of Assessments for study visit collection dates. It is not required that 
the subjects are fasting prior to blood sampling for these assessments. Please refer to 
Appendix 12.2 for additional Drug Induced Liver Injury (DILI) laboratory testing 
requirements and timing.
For the hematology, biochemistry and urinalysis at Screening, results that were obtained as 
part of standard of care before consent (“historical sample”) are acceptable, provided that the 
sampling was done after the onset of CDAD and within 3 days prior to randomization. For 
the hematology, biochemistry and urinalysis at EOT visit, results that were obtained as part 
of standard of care between Day 8 and Day 10 (inclusive) (“standard of care sample”) are 
acceptable. The most recent results should be used for eCRF completion. If such results are 
not available, samples should be taken for the purpose of the study. The historical or standard 
of care sample may not include all parameters as described in Table 4  A historical/standard 
of care samples without parameter(s) indicated with * in the table is acceptable.


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Every effort will be made to reduce anxiety and discomfort due to blood tests. A topical 
anesthetic will be offered to minimize discomfort associated with venipuncture.
During Screening, at the EOT visit and at the Unscheduled visit (if deemed necessary by the 
investigator) the pregnancy test will be done locally in urine (dipstick). 
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/sub-investigator who is a qualified physician.
Any changes in laboratory values are to be evaluated by the investigator. Clinically relevant 
changes will be recorded as AEs in the eCRF (see Section 5.5.1).
Table 4
Clinical Laboratory Tests to be Performed
Assessment Time Point
Panel
Parameter
Screening
End of Treatment 
Unscheduled visit, as 
applicable
Hematology
Hemoglobin
Hematocrit
Red Blood Cell (RBC)
WBC
Neutrophils
Segmented neutrophils*
Band neutrophils*
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Screening
End of Treatment
Unscheduled visit, as 
applicable
Biochemistry
Sodium*
Potassium
Calcium
Chloride*
Glucose*
Creatinine
CRP*
Alkaline phosphatase
AST
ALT
GGT*
Total bilirubin
Direct bilirubin*
Total protein*
Albumin
Screening
End of Treatment
Unscheduled visit, as 
applicable
Urinalysis 
Protein*
Glucose*
pH*
Blood*
Beta hCG (females of child-bearing potential 
only)
* A historical / standard of care samples (see above) without parameter(s) indicated with * is acceptable. 


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5.4.4
Physical Examination
The subject’s physical state will be examined and recorded at Screening, End of Treatment
and if deemed necessary by the investigator at an Unscheduled visit. This includes 
examination of main body systems. The date of the physical examination only will be 
recorded in the eCRF. Any clinically relevant adverse change will be recorded as an AE in 
the eCRF (see section 5.5.1).
5.4.5
Electrocardiogram (ECG)
Two 12 lead ECGs will be performed: one at Screening prior to the first dose of study drug 
and another 1 to 5 hours post-dose (the morning or evening dose for the fidaxomicin arm, or 
the first or the third dose of the day for the vancomycin arm) on any day between Days 5 and 
10 inclusive, but not within 30 minutes after venipuncture. 
For the ECG at Screening, an ECG that is performed as a part of standard of care before 
consent is acceptable, provided that it was recorded after the onset of CDAD and within 
3 days prior to randomization.
Wherever possible, ECGs will be taken with the subject in the supine position, after the 
subject has been lying quietly for 5 minutes. 
ECGs will be recorded at a speed of 25 mm/sec and all leads have to include at least 
4 complexes. The original ECG traces will include the subject number, date and visit number 
and must be kept with the source documents. If the ECG traces are printed on thermal paper, 
a photocopy must be made and kept with the source documents.
Original ECGs will be collected for central ECG reading and returned to site if requested.
Central ECG read data will be transferred electronically to the sponsor.
Any clinically significant adverse changes on the ECG will be reported as AEs in the eCRF 
(see section 5.5.1).
5.4.6
CDAD Signs and Symptoms
CDAD signs and symptoms (highest body temperature in the 3 days prior to first dose, 
highest white blood cell in the 3 days prior to first dose, abdominal discomfort, abdominal 
tenderness) will be recorded at Screening. Abdominal discomfort and abdominal tenderness 
will be recorded at End of Treatment. Any clinically relevant adverse change will be 
recorded as an AE in the eCRF (see section 5.5.1).
5.5
Adverse Events and Other Safety Aspects
The reference safety information for fidaxomicin to be used for this study is the IB. The 
reference safety information for vancomycin to be used for this study is the SmPC vancomycin 
capsules.


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5.5.1
Definition of Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets one of the 
following criteria:

Induces clinical signs or symptoms.

Requires active intervention.

Requires interruption or discontinuation of study drug.

The abnormality or investigational value is clinically significant in the opinion of the 
investigator.
All subjects will remain in the study until EOS for safety assessment. All AEs occurring 
between signing informed consent and EOS TC/visit should be recorded.
The specified AEs / findings of interest for this study are shown below and may require more 
extensive collection of information which will be collected in targeted questionnaires: 

Development of microbial resistance to fidaxomicin

Hypersensitivity to fidaxomicin

GI hemorrhage

Decreases in WBC, neutrophil and lymphocyte counts 

Hepatic laboratory value abnormalities

Renal laboratory value abnormalities

QT-interval prolongation 

Lack of efficacy / lack of effect / treatment failure
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE. In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the (e)CRF accordingly.
In addition, if any of these events meet the criteria for a Serious Adverse Event (SAE), the 
SAE reporting requirements in section 5.5.5 will apply.
5.5.2
Definition of Serious Adverse Events (SAEs)
An adverse event is considered “serious” if, in the view of either the investigator or Sponsor, 
it results in any of the following outcomes:

Results in death

Is life threatening (an adverse event is considered “life-threatening” if, in the view of 
either the investigator or Sponsor, its occurrence places the subject at immediate risk of 


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death. It does not include an adverse event that, had it occurred in a more severe form, 
might have caused death)

Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions

Results in congenital anomaly, or birth defect

Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 

Other medically important events
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
should also usually be considered serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.
Special situation events relevant to the medicinal products administered to the subject as part 
of the study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:

Overdose of the medicinal product(s)

Suspected abuse/misuse of the medicinal product(s)

Inadvertent or accidental exposure to the medicinal product(s)

Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion)

Drug-drug interaction

Lack of efficacy
All special situations listed above should be especially monitored and reported on a SAE 
form, even if considered non-serious and regardless whether or not an (S)AE occurred. The 
above special situation will not be captured on the AE form in the eCRF, instead they will be 
captured in the dosing and accountability forms within the eCRF. 
As fidaxomicin is orally administered, for this study, there is no risk of occupational 
exposure and risk of transmission of infectious agents is limited, therefore the Sponsor do not 
expect these events to be reported.
The Sponsor has a list of events that they classify as “always serious” events.  If an adverse 
event is reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested.  
If a subject becomes pregnant during treatment, this should be reported as if it were an SAE. 
Refer to section 5.5.8 Procedure in Case of Pregnancy.


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5.5.3
Criteria for Causal Relationship to the Study Drug
Adverse events that fall under either "Possible" or "Probable" should be defined as "adverse 
events whose relationship to the study drugs could not be ruled out".
Causal relationship
to the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a 
temporal  relationship to drug administration which makes a causal 
relationship improbable, and/or in  which other drugs, chemicals or 
underlying disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or 
unclear.
Probable
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to 
be attributed to concurrent disease or  other drugs or chemicals, and 
which follows a clinically reasonable response on re-
administration (rechallenge) or withdrawal (dechallenge).
5.5.4
Criteria for Defining the Severity of an Adverse Event
The following standard with 3 grades is to be used to measure the severity of AEs, including 
abnormal clinical laboratory values:

Mild: 
No disruption of normal daily activities

Moderate:  Affect normal daily activities

Severe: 
Inability to perform daily activities
5.5.5
Reporting of Serious Adverse Events (SAEs)
In the case of a serious adverse event (SAE), the investigator must contact the delegated CRO 
by telephone or fax immediately (within 24 hours of awareness).
The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the delegated CRO by fax immediately 
(within 24 hours of awareness). If the faxing of an SAE Worksheet is not possible or is not 
possible within 24 hours, the local drug safety contact should be informed by phone.
The SAE Worksheet should be sent to the delegated CRO: 
(Toll-free fax numbers will be provided for each country; the country-specific fax number 


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can be found on the SAE Worksheet fax cover sheet)
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Expert or his/her designee (see Section II Contact Details of Key 
Sponsor’s Personnel). 
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification.
Full details of the SAE should be recorded on the medical records and on the eCRF. The 
investigator must ensure that information on the SAE Worksheet is reconciled with the 
information on the AE pages within the eCRF. 
The following minimum information is required:

ISN/Study number  2819-CL-0202,

Subject number, sex and age,

The date of report,

A description of the SAE (event, seriousness of the event), and

Causal relationship to the study drug.
The Sponsor or Sponsor's designee will submit expedited safety reports (i.e. CIOMS, IND 
Safety Reports) to the regulatory agencies (i.e. EMA, FDA) as necessary, and will inform the 
investigators of such regulatory reports. Investigators must submit safety reports as required 
by their local Institutional Review Board (IRB)/Independent Ethics Committee (IEC) within 
timelines set by regional regulations (i.e. EU, (e)CTD, FDA). Documentation of the 
submission to and receipt by the IRB/IEC of expedited safety reports should be retained by 
the site.
The delegated CRO will notify all investigators responsible for ongoing clinical studies with 
the study drug of all SAEs which require submission per local requirements to IRB/IEC.
The investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor.
You may contact the Sponsor's Medical Monitor/Expert for any other problem related to the 
safety, welfare, or rights of the subject.
For Suspected Unexpected Serious Adverse Reactions (SUSARs) from a blinded trial, 
unblinded CIOMS-I reports will be submitted to the authorities and central IRB/IEC where 
required.
5.5.6
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized. 
If during AE follow-up, the adverse event progresses to an "SAE", or if a subject experiences 
a new SAE, the investigator must immediately report the information to the Sponsor. 


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Please refer to Appendix 12.2 Liver Safety Monitoring and Assessment for detailed 
instructions on DILI.
5.5.7
Monitoring of Common Serious Adverse Events
For this protocol, there are no SAEs that are exempted from expedited safety reporting.
5.5.8
Procedure in Case of Pregnancy
If a female subject or partner of a male subject becomes pregnant during the treatment period 
or Follow-up period, the investigator should report the information to the delegated CRO as 
if it is an SAE. The expected date of delivery or expected date of the end of the pregnancy, 
last menstruation, estimated conception date, pregnancy result and neonatal data etc., should 
be included in this information.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the investigator should respond in accordance with the report procedure 
for SAEs. Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below.

"Spontaneous abortion" includes miscarriage, abortion and missed abortion

Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug

If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator

In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth

Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination.
If during the conduct of a clinical trial, a male subject makes his partner pregnant, the 
subject should report the pregnancy to the investigator. The investigator will report the 
pregnancy to the Sponsor/delegated CRO as an SAE.
5.5.9
Emergency Procedures and Management of Overdose
Fidaxomicin: In the event of suspected overdose, the subject should receive supportive care 
and monitoring. The Medical Monitor/Expert should be contacted as applicable.
Vancomycin: In the event of suspected overdose, guidance in the local product labeling is to 
be followed at the investigator’s discretion. The Medical Monitor/Expert should be contacted 
as applicable.


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5.5.10
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study 
properly, the Sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed. 
5.6
Test Drug Concentration
Plasma and stool samples will be analyzed for fidaxomicin and its main metabolite OP-1118
concentrations. 
For subjects receiving fidaxomicin, two blood samples will be taken on any day between 
Day 5 and 10 inclusive. Every effort should be made to take these samples in conjunction 
with routine blood samples being taken for standard of care. However, one sample should be 
collected within 30 minutes pre-dose and another between 1 to 5 hours post-dose. The two 
samples do not have to be collected on the same day. 
Blood samples will be collected via an intravenous cannula or by direct venipuncture. Whole 
blood will be collected at each sampling time point into an appropriately labeled blood 
collection tube. A 1 mL blood tube containing EDTA as anticoagulant will be collected. 
Plasma will be prepared and stored in pre labeled polypropylene vials at nominal -70 C, 
according to procedures specified in the laboratory operations manual.
For all the subjects, one stool sample will be taken on any day between Day 5 and 10 
inclusive, within 24 hours of a dose for drug concentration analysis. 
Stool samples will be collected in containers provided by the central laboratory according to 
the instructions provided in the laboratory operations manual.
Information on the pre-printed sample tube labels should contain at a minimum:

Study number 2819-CL-0202

Subject number

“Plasma” or “feces” 

Unique sample number

Protocol Day and time
All samples for a subject will be stored and shipped as a package for that subject as organized by 
the central laboratory. Samples will be shipped under appropriate dry-ice conditions by a courier 
to the central laboratory and analyzed under responsibility of Astellas Bioanalysis-Europe
section of Astellas in Europe for subsequent determination of fidaxomicin and OP-1118 
concentrations. Bioanalysis of fidaxomicin and OP-1118 in plasma and faeces will be performed 
using validated liquid chromatography with tandem mass spectrometry (LC MS/MS) methods.
Further details will be specified in the laboratory operations manual.
The actual date and time of each blood and stool sample collection will be recorded in the 
eCRF, as well as if the stool sample is taken from the diaper.


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5.7
Other Measurements, Assessments or Methods
5.7.1
Stool Samples for Toxigenic C.difficile and Microbiological Testing
Stool samples will be obtained at Screening, at the End of Treatment visit and in case of 
recurrence at the Unscheduled visit. Stool samples will be split into two aliquots; one for 
local (direct or indirect) testing for presence of toxigenic C.difficile at the study site and one 
for microbiological testing at the reference laboratory. 
For assessment of inclusion criteria for Screening, a routinely performed local rapid test that 
was taken after the onset of CDAD and within 72 hours prior to randomization is acceptable.
This sample may be a pre-consent sample taken as standard of care. In this situation an
additional stool sample (for possible microbiological and biochemistry testing) for the
reference laboratory needs to be taken as part of Screening, even if on antibiotic treatment. 
Microbiological testing will be performed on stool samples collected pre-treatment and post-
treatment and in case of recurrence. Results from relevant microbiological and biochemical 
assays may be used for an exploratory evaluation of efficacy or to further increase knowledge 
on the investigational product.
Stool samples for microbiology testing at the reference laboratory will be frozen at -70 C and 
stored at the site until sent batch-wise to a central laboratory for further characterization. Stool 
samples will be analyzed in order to confirm the presence of toxigenic C. difficile and where 
sufficient sample allows, also confirm the presence of toxin in the stool sample. C. difficile will 
be cultured from all confirmed positive samples and additional tests may be carried out on 
these isolates including, but not limited to PCR ribotyping and antimicrobial susceptibility 
profile evaluation. The samples will be stored for no longer than 5 years after the completion of 
the study. A decision on the exact analyses to be performed will be taken at a later stage and 
may be dependent on the results of the toxin tests or ribotyping. Assessments will be limited to 
any microbiological marker present in the stool sample or its derived culture.
Results from the central laboratory will not be returned to the investigator.
Details for processing and shipping the stool samples will be described in the laboratory 
manual, to be provided before the start of the study.
5.7.2
Palatability Testing
Palatability will be assessed for all subjects receiving fidaxomicin oral suspension and 
vancomycin oral liquid (i.e. subjects from birth to ≤ 6 years of age and subjects > 6 years 
unable to swallow tablets) on Day 1 and on Day 7 (±1 day) by means of a five point rating 
scale by unblinded staff if hospitalized, and by the subject/parents/legal guardian when at 
home. 
Details will be provided in the palatability assessment instructions.
In case the drug product is rejected without actual oral administration the response cannot be 
rated. This will be recorded in the eCRF.


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5.8
Total Amount of Blood
The following blood volume limits for sampling are recommended (although are not evidence-
based). If an investigator decides to deviate from these, this should be justified. Per individual, 
the trial-related blood loss (including any losses in the manoeuvre) should not exceed 3% of 
the total blood volume during a period of four weeks and should not exceed 1% at any single 
time. In the rare case of simultaneous trials, the recommendation of 3% remains the maximum. 
The total volume of blood is estimated at 80 to 90 mL/kg body weight; 3% is 2.4 mL blood per 
kg body weight. (Ethical Considerations for Clinical Trials on Medicinal Products Conducted 
with the Paediatric Population, European Medicines Agency, 2008).
Examples of the total amount of blood collected per subject during the course of the study are
shown in Table 5. 
Table 5:
Examples of the total amount of blood collected per subject during 
the course of the study
Assessment
Volume of 
Blood per 
Sample 
[mL]
Volume of 
Blood per 
Sample
Pediatric 
tubes [mL]
Number of 
Assessments
Total 
Volume of 
Blood (mL)
Total 
Volume 
of Blood 
using 
pediatric 
tubes (mL)
Drug concentration 
measurement
1
1
2
2
2
Safety Laboratory
Hematology
(Sample volumes are 
estimated)
2.7
1*
2
5.4
2
Biochemistry
5
1*
2
10
2
Total Maximum Amount per Subject
17.4
6
* Example only
Age appropriate pediatric sampling tubes should be used, in order to comply with the guidelines 
of maximum blood volume above. 
An historical or standard of care sample may be acceptable (see section 5.4.3).
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who was enrolled in the study and for whom study treatment is 
permanently discontinued prematurely for any reason.  
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it.


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If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 
attempt to provide follow-up until the condition stabilizes or no longer is clinically 
significant. 
Examples for Discontinuation Criteria for Individual Subjects:

Adverse event(s)

Lack of efficacy 

Subject lost to follow up

Protocol deviation
A clear and concise reason for discontinuation should be recorded in the eCRF. 
In case of discontinuation of study drug before completion of the full 10-day treatment 
course, the subject should complete the EOT visit as soon as possible after the last drug 
administration. If at this visit, subject has an initial clinical response, the subject will continue 
in the Follow-up period for safety and efficacy unless consent has been withdrawn. 
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor.
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of Astellas. A 
Statistical Analysis Plan (SAP) will be written to provide details of the statistical analysis 
along with specifications for tables, listings and figures (TLFs) to be produced. The SAP will 
be finalized before the database soft lock at the latest. 
Prior to database lock, a Final Data Review and TLFs Meeting will be held to allow a review 
of the clinical study data and to verify the data that will be used for analysis set classification. 
If required, consequences for the statistical analysis will be discussed. A meeting to 
determine analysis set classifications may also be held prior to database lock.
Any deviation from the SAP will be described and justified in the Clinical Study Report.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.


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In general, data summaries will be presented within each treatment arm, by age group (and 
overall) and time point (as applicable), using the following classifications:
Treatment arm:
fidaxomicin or vancomycin
Age group:
from birth to < 24 months
≥2 years to < 6 years
≥6 years to < 12 years
≥12 years to < 18 years
and overall
7.1
Sample Size
One hundred forty four eligible subjects will be enrolled and randomized to either fidaxomicin 
or vancomycin in a 2:1 ratio (96 randomized to fidaxomicin and 48 to vancomycin), stratified 
by age at enrollment (from birth to < 24 months, ≥ 2 years to < 6 years, ≥ 6 years to < 12 years, 
and ≥ 12 years to < 18 years). At least 24 subjects will be enrolled into each age group (i.e., a 
minimum of 16 randomized to fidaxomicin and 8 to vancomycin).
The sample size for this study was agreed on with the Pediatric Development Committee as 
part of the Pediatric Investigational Plan (EMEA, 2012), and is based on clinical and 
practical considerations as the prevalence of the target disease in the study population is low.
7.2
Analysis Sets
The following analysis sets, defined in the following subsections, will be used in the analysis 
and reporting of this study:

Full Analysis Set (FAS).

Safety Analysis Set (SAF).

Pharmacokinetic Analysis Set (PKAS).

Intent to Treat (ITT)
Detailed criteria for the analysis sets will be laid out in the SAP and the Classification 
Specifications. The allocation of subjects to analysis sets will be determined prior to database 
hard-lock.
7.2.1
Full Analysis Set (FAS)
The FAS will consist of all subjects who were randomized and who received at least one dose 
of study medication (treatment allocation as randomized). In the FAS, subjects will be 
allocated to the treatment arm corresponding to the study medication that were randomized to 
(treatment allocation as randomized).  The FAS will be used for primary and secondary 
efficacy analyses, as well as selected demographic and baseline characteristics.
7.2.2
Safety Analysis Set (SAF)
The SAF will consist of all subjects who were randomized and who received at least one 
administration of study medication. In the SAF, a subject will be allocated to the treatment 


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arm corresponding to the study medication that was first administered, even if it differs from 
the treatment arm the subject was randomized to.
7.2.3
Pharmacokinetic Analysis Set (PKAS)
The PKAS will consist of all subjects randomized to fidaxomicin, having received at least 
one dose of fidaxomicin and having at least one valid measurement of plasma concentration 
or fecal concentration of fidaxomicin or its main metabolite OP-1118.
7.2.4
Intent to Treat Analysis Set (ITT)
The intent-to-treat (ITT) set consists of all randomized subjects, irrespective of a subject 
having received a study drug (fidaxomicin or vancomycin) or not. In the ITT, subjects will be 
allocated to the treatment arm corresponding to the study medication that were randomized to
(treatment allocation as randomized). The ITT will be used for efficacy analyses, as well as 
selected demographic and baseline characteristics when necessary. 
7.3
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized for the FAS, stratified 
by treatment arm (and overall) and age group. Gender, race and other categorical baseline 
characteristics will be summarized using frequency tables. Continuous variables, such as age, 
height and weight, will be summarized using descriptive statistics. Data will be listed as 
appropriate.
7.4
Analysis of Efficacy 
The definitions for the terms confirmed clinical response, recurrence and sustained clinical 
response used in this section are given in section 2.3
7.4.1
Analysis of Primary Endpoint 
The primary endpoint will be the assessment of confirmed clinical response assessed by the 
investigator at EOT+2. A missing assessment of the primary endpoint will be imputed
according to the rules and methods in section 7.10
7.4.1.1 Primary Analysis
The analysis of the primary efficacy endpoint, confirmed clinical response (see definition in 
section 2.3.1) at EOT+2 days will be conducted for the FAS.
The proportion of subjects with confirmed clinical response at EOT+2 days will be 
summarized within each treatment arm by age group along with exact 95% confidence 
intervals (CIs). In addition, 95% CIs will be presented for the adjusted difference in confirmed 
clinical response between treatment arms, where adjusted difference will be calculated using 
stratified CMH (Cochran-Mantel-Haenszel) method using age group as the stratified variable.
7.4.1.2 Subgroup Analysis
In general, efficacy data will be summarized by treatment group and age group using the 
classifications given in section 7


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The proportion of subjects with confirmed clinical response at EOT+2 days and the 
associated exact 95% CIs will further be provided by treatment arm within age group. Further 
subgroup analyses, if deemed appropriate, will be described in the SAP.
7.4.2
Analysis of Secondary Endpoints 
In general, summaries for the secondary efficacy endpoints will be provided for the FAS 
population overall and by age group. Definition of secondary efficacy endpoints can be found 
in section 2.3.2
For the secondary efficacy variables,

Sustained clinical response 14 days after Confirmation Clinical Response (EOT +16 days)

Sustained clinical response at the EOS (EOT +30 days)
the response rates and their difference between the two treatments will be calculated along 
with corresponding 95% CIs in the same manner as for the primary efficacy endpoint.
For the variable,

Recurrence of CDAD
the incidence rate of recurrence in subjects with confirmed clinical response at EOT+2 days 
and the difference in incidence rates between treatments will be calculated along with 95% 
CIs in the same manner as for the primary efficacy endpoint.
For the variables,

Time (hours) to resolution of diarrhea, measured from first dose of study medication,

Time (days) to recurrence of CDAD (only for subjects with confirmed clinical response) 
descriptive statistics by treatment arm will be provided and the survival functions in both 
treatment arms will be estimated using the Kaplan-Meier method and displayed graphically 
(with 95% CIs). Quartile estimates for the time to event and corresponding two-sided 95% 
CIs will be computed for both treatment arms. For these two time-to-event variables, no 
further stratification by age group is intended but may be done if deemed appropriate.
7.4.2.1 Other Analyses - Palatability
Results from the assessments of palatability in subjects receiving fidaxomicin oral suspension 
on Day 1 and on Day 7 (±1 day) will be summarized by means of a frequency table, stratified 
by treatment arm, age group and study day.
7.5
Analysis of Safety
Safety data will be summarized in a descriptive manner for the SAF, generally grouped by 
treatment arm. Stratification by age group might be done where deemed appropriate.
7.5.1
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). An 
AE starting or a condition existing pre-treatment that worsens after first study drug intake 


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will be considered as treatment emergent AE (TEAE). The number and percentage of TEAEs, 
SAEs, TEAEs leading to discontinuation, and TEAEs related to study drug will be 
summarized by system organ class, preferred term and treatment arm. The number and 
percentage of TEAEs by severity will also be summarized. All AEs will be listed.
Further details will be provided in the SAP.
7.5.2
Laboratory Assessments 
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline by treatment arm and time point. Shifts relative to normal 
ranges from baseline to each time point during treatment period in lab tests will also be 
tabulated. Laboratory data will be displayed in listings.
7.5.3
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
(change only for blood pressure and pulse rate) by treatment arm and time point (visit). Vital 
signs data will be displayed in listings.
7.5.4
ECGs
The 12-lead ECG results (from the central readings) will be summarized by treatment arm
and time point (visit).
7.6
Analysis of Pharmacokinetics
7.6.1
Test Drug Concentration
Descriptive statistics (incl. numbers of values below level of quantification) will be provided 
for plasma concentrations of fidaxomicin and its main metabolite OP-1118 by time point 
(pre-dose and 1 to 5 hours post dose [the morning or evening dose]) and for the fecal 
concentration of fidaxomicin and OP-1118 (assessed on Day 5 or after).
These summaries will be provided for the PKAS (only for treatment arm fidaxomicin), 
overall and by age group and once by formulation with nesting of the two strata being done 
when deemed reasonable.
7.7
Analysis of Pharmacodynamics
Not applicable.
7.8
Protocol Deviations and Other Analyses  
7.8.1
Protocol Deviations
Protocol deviations as defined in Section 8.1.6 Protocol Deviations will be summarized for 
all randomized subjects by treatment arm and total as well as by site. A data listing will be 
provided by site and subject.  
The protocol deviation criteria will be uniquely identified in the summary table and listing. 


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The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment.   
Further details will be provided in the SAP.
7.8.2
Medical History
Medical history will be summarized coded using MedDRA and summarized by system organ 
class and preferred term.
7.8.3
Previous and Concomitant Medication
Previous and concomitant medication will be coded using World Health Organization Drug 
Reference List (WHODRL) and Anatomical Therapeutic Chemical (ATC) classification 
system and will be summarized by ATC 2nd and 4th levels.
7.8.4
Diagnosis of the Target Disease
Appropriate descriptive summaries will be provided for the data collected in context of 
diagnosis of the target disease. Details will be provided in the SAP.
7.8.5
Analysis of Exploratory Endpoints 
7.8.5.1
 
7.8.6
Treatment Compliance
Treatment compliance rates and number (%) of subjects who were treatment compliant (as 
defined in section 5.1.4 will be summarized by treatment arm and age group.
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned. If required for regulatory submissions, interim 
analyses may be carried out (e.g. to present the results of some age strata while recruitment is 
ongoing in other strata). If so, details of the analysis and for preserving the blind will be 
included in the analysis plan.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Every effort should be made to follow-up subjects and to obtain data – especially on the 
important endpoints of confirmed clinical response (EOT+2) and recurrence/sustained 
clinical response (to EOS). 


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The following imputation of missing information for the assessment of clinical response and 
recurrence/sustained response is foreseen (taking into consideration applicable visit 
windows):

Missing information for efficacy variables of confirmed clinical response and sustained 
clinical response will be estimated using the multiply imputation procedure which will
replace each missing value with a set of plausible values as predictions from logistic 
regression based on bowel movement data, and previous CDAD experience. Each
multiply imputed data set will then be analyzed and the methodology combines the 
results from all datasets to give a single final analysis that takes into account the 
uncertainty of the imputed values.
Sensitivity analyses for efficacy endpoints  will be described in the SAP. 
As a general principle, no imputation of other missing data will be done (e.g. labs, vital signs, 
ECGs, etc). Exceptions are the start and stop dates of AEs and concomitant medication. The 
imputed dates will be used to allocate the concomitant medication and AEs to a study period, 
in order to determining whether an AE is/is not treatment emergent. Listings of the AEs and 
concomitant medications will present the actual partial dates; imputed dates will not be shown.
Visit windows for the assessments planned after the EOT are defined in the Schedule of 
Assessments.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or designee will enter data collected using an Electronic Data Capture 
(EDC) system. All data on each subject generated according to the protocol must be recorded 
continuously in an eCRF designed according to the protocol. The investigator or site 
designee is responsible to ensure that all data in the eCRFs and queries are accurate and 
complete and that all entries are verifiable with source documents. These documents should 
be appropriately maintained by the site.
For data that can potentially unblind staff (e.g., drug dispensing, drug intake, drug returned, 
palatability, drug concentration blood samples) a separate database will be set up, only 
accessible for unblinded site staff and the unblinded monitor.
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
Laboratory tests are performed at local laboratory. The data will be entered in the eCRF.
The ECGs are done locally at site and all original ECG traces are to be shipped to central 
ECG reader for central ECG reading. Central ECG read data will be transferred electronically 
to the Sponsor.


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For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF.
Palatability scale will be completed by the subject/parent/legal guardian on paper. Unblinded 
site staff should review the scale data while the subject/parent legal guardian is at the site. 
The unblinded site staff will enter the subject questionnaire data directly into the EDC 
system. 
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The following information should be included in the source medical records:

Demographic data (age, sex, race, ethnicity (if permitted), height and body weight)

Inclusion and exclusion criteria details

Participation in study and original signed and dated informed consent forms 

Visit dates

Medical history and physical examination details

Key efficacy and safety data, if applicable (as specified in the protocol)

AEs and concomitant medication 

Results of relevant examinations (e.g., ECG charts, X-ray films etc.)

Laboratory printouts (if applicable)

Reason for premature discontinuation (if applicable)

Randomization number (if applicable) 

Dispensing and return of study drug details
Source documents related to the study drug or treatment allocation will be stored in a 
separate binder, only accessible for unblinded study staff.
8.1.3
Clinical Study Monitoring
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The Sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures.  
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
(refer to section 8.1.2 "Specification of Source Documents") when they are requested by the 


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Sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access.
8.1.5
Data Management
Data Management will be coordinated by the Global Data Science department of the Sponsor 
in accordance with the SOPs for data management. All study specific processes and 
definitions will be documented by Data Management. eCRF completion will be described in 
the eCRF instructions. Coding of medical terms and medications will be performed using 
MedDRA and World Health Organization (WHO) Drug Dictionary respectively.
8.1.6
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.  
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who: 

Entered into the study even though they did not satisfy entry criteria. 

Developed withdrawal criteria during the study and not withdrawn

Received wrong treatment or incorrect dose. 

Received excluded concomitant treatment. 
When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the Sponsor is notified. The Sponsor will follow-up with the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and / 
or efficacy of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor 
immediately.
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File (TMF).  
NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable. 


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8.1.7
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the Last Subject’s Last visit.
8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigator’s Brochure, the informed consent and all other forms of subject information 
related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IEC/IRB.  The IEC/IRB will review the ethical, scientific and 
medical appropriateness of the study before it is conducted.  IEC/IRB approval of the 
protocol, informed consent and subject information and/or advertising, as relevant, will be 
obtained prior to the authorization of drug shipment to a study site.
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site.  The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet reporting criteria, as dictated by local regulations, will 
be reported to both responsible Ethics Committees and Regulatory Agencies, as required.
During the conduct of the study, the investigator should promptly provide written reports 
(e.g., ICH Expedited Reports, and any additional reports required by local regulations) to the 
IEC/IRB of any changes that affect the conduct of the study and/or increase the risk to 
subjects. Written documentation of the submission to the IEC/IRB should also be provided to 
Sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding one year. The 
investigator shall make an accurate and adequate final report to the IRB/IEC within one year 
after last subject out (LSO) or termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian(s) or legal representative(s), and answer all questions regarding this study.  
For this pediatric study next to Information Sheets and Consent Forms, Assent forms for subjects 
(according to applicable local regulations) will be prepared. Prior to any study-related screening 
procedures being performed on the subject, the informed consent statement will be reviewed 


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and signed and dated by the subject or his/her guardian(s) or legal representative(s), the 
person who administered the informed consent and any other signatories according to local 
requirements. A copy of the signed informed consent/assent form will be given to the subject 
or his/her guardian(s) / legal representative(s) and the original will be placed in the subject’s 
medical record. An entry must also be made in the subject’s dated source documents to 
confirm that informed consent was obtained prior to any study-related procedures and that 
the subject / his/her guardian(s) / legal representative(s) received a signed copy.
The signed consent/assent forms will be retained by the investigator and made available (for 
review only) to the study monitor and auditor regulatory authorities and other applicable 
individuals upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent
and Revision of the Written Information
The investigator or his/her representative will immediately inform the subject/his/her 
guardian(s)/legal representative(s) orally whenever new information becomes available that 
may be relevant to the subject’s consent or may influence the subject’s/his/her guardian(s)/ 
legal representative(s) willingness to continue to participate in the study (e.g., report of 
serious drug adverse drug reaction). The communication must be documented in the subject’s 
medical records and must document whether the subject/his/her guardian(s)/legal 
representative(s) is willing to remain in the study or not.
The investigator must update their ICF/assent and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the subject/ 
his/her guardian(s)/legal representative(s) on all updated ICFs throughout their participation 
in the study. The investigator or his/her designee must re-consent subjects with the updated 
ICF/assent even if relevant information was provided orally. The investigator or his/her 
representative who obtained the written informed consent and the subject/his/her guardian(s)/
legal representative(s) should sign and date the informed consent form. A copy of the signed 
informed consent/assent form will be given to the subject/his/her guardian(s)/legal 
representative(s) and the original will be placed in the subject’s medical record. An entry 
must be made in the subject’s records documenting the re-consent process.
8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
Sponsor. However, the Sponsor requires the investigator to permit the Sponsor, Sponsor's 


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representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The Sponsor will ensure that the use and disclosure of protected health information (PHI) 
obtained during a research study complies with the federal and/or regional legislation related 
to the privacy and protection of personal information (i.e. HIPAA).
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the Sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 
of the study only. It is understood by the investigator that the Sponsor will use the 
information obtained during the clinical study in connection with the development of the 
drug and therefore may disclose it as required to other clinical investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the Sponsor with all data 
obtained during the study.
Publication of the study results is discussed in the Clinical Study Agreement.
8.3.2
Documents and Records Related to the Clinical Study
The investigator will archive all study data (e.g., Subject Identification Code List, source 
data, eCRFs, and Investigator's File) and relevant correspondence. These documents are to be 
kept on file for the appropriate term determined by local regulation (for US sites, two years 
after approval of the NDA or discontinuation of the IND). The Sponsor will notify the 
site/investigator if the NDA/MAA is approved or if the IND/IMPD is discontinued. The 
investigator agrees to obtain the Sponsor's agreement prior to disposal, moving, or 
transferring of any study-related records. The Sponsor will archive and retain all documents 
pertaining to the study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. All data will be entered on the eCRFs supplied 
for each subject. 
The documents of the DSMB shall be retained by the Sponsor.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments. 
Depending on the nature of the amendment, IRB/IEC, Competent Authority (CA) approval or 
notification may be required. The changes will become effective only after the approval of 
the Sponsor, the investigator, the regulatory authority, and the IRB/IEC (if applicable).


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Amendments to this protocol must be signed by the Sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations.
If there are changes to the Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor.  An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor.
8.3.4
Insurance of Subjects and Others 
The Sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the certificate 
of insurance, the policy number and the sum insured are provided in the Investigator's File. 
8.3.5
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the
representative for the Coordinating Investigator(s) or the Principal Investigator(s). The 
representative for the Coordinating Investigator (s) or the Principal Investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating investigators by the Sponsor prior to database lock.
9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.
10
STUDY ORGANIZATION 
10.1
Data and Safety Monitoring Board (DSMB) 
A DSMB will be set up for this study in order to monitor on periodic basis the safety of the 
study subjects. The board for this study will consist of members independent of the Sponsor 
and the conduct of the study. The board will advise the Sponsor on safety aspects of the study 
and based on this information, continuation of the trial. The procedures and scope of the
board are defined in a separate document, the DSMB Charter.


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10.2
Other Study Organization
Not applicable.


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11
REFERENCES 
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difficile. Antimicrob Agents Chemother. 2004;48(6):2280-2282.
Al-Jumaili IJ, Shibley M, Lishman AH, Record CO. Incidence and origin of Clostridium difficile in 
neonates. J Clin Microbiol. 1984;19(1):77-78.
ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of 
Clostridium difficile-associated disease. Am J Health Syst Pharm. 1998;55(13):1407-1411.
Aslam S, Hamill RJ, Musher DM. Treatment of Clostridium difficile-associated disease: old 
therapies and new strategies. Lancet Infect Dis. 2005;5(9):549-57.
Bartlett JG. Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. 
Ann Intern Med. 2006;145(10):758-764.
Bauer MP, Kuijper EJ, van Dissel JT. European Society of Clinical Microbiology and Infectious 
Diseases. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): 
treatment guidance document for Clostridium difficile infection (CDI). Clin Microbiol 
Infect. 2009;15(12):1067-1079.
Benson L, Song X, Campos J, Singh N. Changing epidemiology of Clostridium difficile-associated 
disease in children. Infect Control Hosp Epidemiol. 2007;28(11):1233-1235.
Blanckaert K, Coignard B, Grandbastien B, Astagneau P, Barbut F. Update on Clostridium difficile
infections. Rev Med Interne. 2008;29(3):209-214.
Calfee DP. Clostridium difficile: a reemerging pathogen. Geriatrics. 2008;63(9):10-21.
Cohen SH, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile
Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America 
(SHEA) and the Infectious Disease Society of America (IDSA). Infect Control Hosp 
Epidemiol. 2010;31(5):431-55.
Collignon A, Ticchi L, Depitre C, Gaudelus J, Delmee M, Corthier G. Heterogeneity of Clostridium 
difficile isolates from infants. Eur J Pediatr. 1993;152(4):319-322.
Credito KL, Appelbaum PC. Activity of OPT-80, a novel macrocycle, compared with those of eight 
other agents against selected anaerobic species. Antimicrob Agents Chemother. 
2004;48(11):4430-4434.
Delmee M, Verellen G, Avesani V, Francois G. Clostridium difficile in neonates: serogrouping and 
epidemiology. Eur J Pediatr. 1988;147(1):36-40.
DuPont HL, Garey K, Caeiro JP, Jiang ZD. New advances in Clostridium difficile infection: changing 
epidemiology, diagnosis, treatment and control. Curr Opin Infect Dis. 2008;21(5):500-507.
Elixhauser A, Jhung M.- Clostridium difficile-associated disease in US hospitals, 1993-2005. HCUP 
Statistical Brief #50. April 2008. Agency for Healthcare Research and Quality, Rockville, MD. 
http://www.hcup-us.ahrq.gov/reports/statbriefs/sb50.pdf. Accessed 16 August 2011.
EMEA-000636-PIP01-09-M01; December 2012
Enad D, Meislich D, Brodsky NL, Hurt H. Is Clostridium difficile a pathogen in the newborn 
intensive care unit? A prospective evaluation. J Perinatol. 1997;17(5):355-359.


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Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea 
and colitis. American College of Gastroenterology, Practice Parameters Committee. Am J 
Gastroenterol. 1997;92(5):739-750.
Fekety R, Silva J, Buggy B, Deery HG. Treatment of antibiotic-associated colitis with 
vancomycin. J Antimicrob Chemother. 1984;14(Suppl D):97-102.
HICPAC Recommendations for preventing the spread of vancomycin resistance: 
recommendations of the Hospital Infection Control Practices Advisory Committee 
(HICPAC). Am J Infect Control. 1995;23(2):87-94.
Holst E, Helin I, Mardh PA. Recovery of Clostridium difficile from children. Scand J Infect Dis. 
1981;13(1):41-45.
Karsch W, Strelau E, Grahlow WD, Fischer E, Schulz R. Occurrence and significance of Clostridium 
difficile in faecal specimens of hospitalized children. Zentralbl Bakteriol Mikrobiol Hyg A. 
1989;270(3):441-448.
Kast KR, Holzbauer SM, Cronquist AB, Lynfield R, Smith K, Lessa FC. Population-based 
surveillance for Clostridium difficile infections, Colorado and Minnesota, 2009. International 
Conference on Emerging Infectious Diseases Atlanta, Georgia; 2010.
Kelly CP, Pothoulakis C, LaMont, JT. Clostridium difficile colitis. N Engl J Med. 
1994;330(4):257-262.
Kyne L, Merry C, O'Connell B, et al. Factors associated with prolonged symptoms and severe 
disease due to Clostridium difficile. Age Ageing. 1999;28(2):107-113.
Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and 
protection against recurrent Clostridium difficile diarrhoea. Lancet. 2001;357:189-193.
Kim J, Smathers SA, Prasad P, Leckerman KH, Coffin S, Zaoutis T. Epidemiological features of 
Clostridium difficile-associated disease among inpatients at children's hospitals in the United 
States, 2001-2006. Pediatrics. 2008;122(6):1266-1270.
Kuijper EJ, Barbut F, Brazier JS, et al. Update of Clostridium difficile infection due to PCR ribotype 
027 in Europe, 2008. Euro Surveill. 2008;13(31).
Kuijper EJ, Coignard B, Tull P. Emergence of Clostridium difficile-associated disease in North 
America and Europe. Clin Microbiol Infect. 2006;12:2-18.
Larson HE, Barclay FE, Honour P, Hill ID. Epidemiology of Clostridium difficile in infants. J Infect 
Dis. 1982;146(6):727-733.
Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of 
Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med. 
2005;353(23):2442-2449.
Louie TJ, Peppe J, Watt CK, et al. Tolevamer, a novel nonantibiotic polymer, compared with 
vancomycin in the treatment of mild to moderately severe Clostridium difficile– associated 
diarrhea. Clin Infect Dis. 2006;43(4):411-420.
Louie T, Gerson M, Grimard D, et al. Results of a Phase III trial comparing tolevamer, 
vancomycin and metronidazole in patients with Clostridium difficile-associated diarrhea 
(CDAD). Poster 3826, ICAAC 2007.
McDonald LC, Owings M, Jernigan DB. Clostridium difficile infection in patients discharged from 
US short-stay hospitals, 1996-2003. Emerg Infect Dis. 2006;12(3):409-415.


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McFarland LV, Brandmarker SA, Guandalini S. Pediatric Clostridium difficile: a phantom menace or 
clinical reality? J Pediatr Gastroenterol Nutr. 2000;31(3):220-231.
McFarland LV, Surawicz CM, Rubin M, Fekety R, Elmer GW, Greenberg RN. Recurrent 
Clostridium difficile disease: epidemiology and clinical characteristics. Infect Control Hosp 
Epidemiol. 1999 Jan;20(1):43-50.
Monaghan T, Boswell T, Mahida YR. Recent advances in Clostridium difficile-associated disease. 
Gut. 2008;57(6):850-860.
Musher DM, Logan N, Hamill RJ. Nitazoxanide for the treatment of Clostridium difficile colitis. 
Clin Infect Dis. 2006;43(4):421-7.
Mylonakis E, Ryan ET, Calderwood SB. Clostridium difficile--associated diarrhea: A review. Arch 
Intern Med. 2001;161(4):525-533.
Penders J, Thijs C, Vink C, et al. Factors influencing the composition of the intestinal microbiota in 
early infancy. Pediatrics. 2006;118(2):511-521.
Spivack JG, Eppes SC, Klein JD. Clostridium difficile-associated diarrhea in a pediatric hospital. Clin 
Pediatr (Phila). 2003;42(4):347-352.
Tullus K, Aronsson B, Marcus S, Mollby R. Intestinal colonization with Clostridium difficile in 
infants up to 18 months of age. Eur J Clin Microbiol Infect Dis. 1989;8(5):390-393.
Vernacchio L, Vezina RM, Mitchell AA, Lesko SM, Plaut AG, Acheson DW. Diarrhea in American 
infants and young children in the community setting: incidence, clinical presentation and 
microbiology. Pediatr Infect Dis J. 2006;25(1):2-7.
Vesikari T, Isolauri E, Maki M, Gronroos P. Clostridium difficile in young children. Association with 
antibiotic usage. Acta Paediatr Scand. 1984;73(1):86-91.
Weil HP Fischer-Brügge U, Harmanus C, Mattner F, Gastmeier P, Kuijper EJ. High incidence of 
Clostridium difficile associated diarrhea with a community onset in a hyperendemic region in 
Germany; 17th European Congress of Clinical Microbiology and Infectious Diseases. Munich, 
Germany; 2007; 1732-213.
Wistrom J, Norrby SR, Myhre EB, et al. Frequency of antibiotic-associated diarrhoea in 2462 
antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother. 
2001;47(1):43-50.
Yassin SF, Young-Fadok TM, Zein NN,Pardi S. Clostridium difficile-associated diarrhea and 
colitis. Mayo Clin Proc. 2001;76(7):725-30.
Zar FA, Bakkanagari SR, Moorthi KM,Davis MB. A comparison of vancomycin and 
metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by 
disease severity. Clin Infect Dis. 2007;45(3):302-7.
Zilberberg MD. Clostridium difficile-related hospitalizations among US adults, 2006. Emerg Infect 
Dis. 2009;15(1):122-124.


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12
APPENDICES
12.1
List of Excluded Concomitant Medications
Part A
Prohibited Medications 
Use of these medications is prohibited during the entire study, unless they are specifically 
given because of a primary treatment failure or suspected CDAD recurrence after initial 
clinical response. 
This list is not exhaustive. In case of doubt, the investigator should contact the local study 
monitor. 
CDAD treatment 
Oral vancomycin
Metronidazole
Oral bacitracin
Fusidic acid
Rifaximin
Nitazoxanide
Linezolid
Rifampicin
Fecal transplantation
Part B
Medications Permitted With Restrictions 
The use of these medications is to be avoided between Screening and End of Study. They are 
permitted provided the subject has been taking this medication on a long-term basis on the 
same dose and will continue with the same dose during the study. 
Subjects receiving opioids for pain prior to enrollment may continue to receive the same 
opioid and dose during the treatment phase if required. 
This list is not exhaustive. In case of doubt, the investigator should contact the local study 
monitor. 
Drugs to that could affect peristalsis
Loperamide
Codeine
Morphine
Pethidine
Fentanyl
Methadone
Tramadol
Other opioids


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12.2
Liver Safety Monitoring and Assessment
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN, or bilirubin > 2 × ULN, should undergo detailed 
testing for liver enzymes (including at least ALT, AST, ALP, and Total Bilirubin [TBL]). 
Testing should be repeated within 48-72 hours of notification of the test results. Subjects 
should be asked if they have any symptoms suggestive of hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3× ULN 
Or
> 2× ULN
Severe*
> 3× ULN
and
> 2× ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8× ULN
●
ALT or AST > 5× ULN for more than 2 weeks  
●
ALT or AST > 3× ULN and INR > 1.5 (If INR testing is applicable/evaluated).
●
ALT or AST > 3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site should complete the Liver Abnormality Case Report 
Form (LA-CRF) that has been developed globally and can be activated for any study or an 
appropriate document. Subjects with confirmed abnormal liver function testing should be 
followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another etiology, 
may be considered an important medical event and may be reported as a Serious Adverse 
Event (SAE).  The Sponsor should be contacted and informed of all subjects for whom severe 
hepatic liver function abnormalities possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:


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●
Obtain a more detailed history of symptoms and prior or concurrent diseases.  Symptoms 
and new onset-diseases should be recorded as ‘adverse events’ on the AE page of the
(e)CRF. Illnesses and conditions such as hypotensive events, and decompensated cardiac 
disease that may lead to secondary liver abnormalities should be noted. Non-alcoholic 
steatohepatitis (NASH) is seen in obese hyperlipoproteinemic, and/or diabetic patients 
and may be associated with fluctuating aminotransferase levels.   The investigator should 
ensure that the medical history form captures any illness that pre-dates study enrollment 
that may be relevant in assessing hepatic function. 
●
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets.  Medications, including dose, should be entered on the concomitant 
medication page of the (e)CRF.  Information on alcohol, other substance use, and diet 
should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history,  other testing may be appropriate including: 
○
acute viral hepatitis (A,B, C, D, E or other infectious agents) 
○
ultrasound or other imaging to assess biliary tract disease
○
other laboratory tests including INR, direct bilirubin
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFT’s, such as viral hepatitis, pre-existing or 
acute liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study. The investigator may determine that it is not in the subject’s best 
interest to continue study enrollment. Discontinuation of treatment should be considered if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks 
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia ( > 5%). 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests is 
not possible, drug should be discontinued.
*Hy’s Law Definition-Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10–50% mortality (or 
transplant).” The two “requirements” for Hy’s Law are: 1) Evidence that a drug can cause 
hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 3 
times the upper limit of normal (“2 x ULN elevations are too common in treated and untreated 
patients to be discriminating”). 2) Cases of increased bilirubin (at least 2 x ULN) with 
concurrent transaminase elevations at least 3x ULN and no evidence of intra- or extra-hepatic 


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bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome. [Temple R. Hy's 
law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006 Apr;15(4):241-3.]
Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009. 


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12.3
Common Serious Adverse Events
For this protocol, there are no SAEs that are exempted from expedited safety reporting.


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13
ATTACHMENTS
13.1
Attachment 1:  Substantial Amendment 2
I.
The purpose of this amendment is:
Substantial Changes
1. Update Inclusion Criteria
DESCRIPTION OF CHANGE:
Inclusion Criteria #2 has been amended to specify that in the United States of America 
subjects can only be included if aged ≥6 months to < 18 years.
RATIONALE:
Following the submission of Substantial Amendment 1 protocol version 2.0, dated 21 
November 2014, related to the widening of the inclusion criteria to open the study for 
inclusion of children from birth onwards, the FDA raised concerns regarding the inclusion of 
children younger than 6 months. The FDA is concerned that the extension of enrollment to 
children younger than 6 months of age will result in inclusion of subjects who are colonized 
rather than infected with C. difficile. 
Because the FDA has granted a waiver for the development of fidaxomicin for children from 
birth to 6 months due to the concern around diagnosis in this age group, subjects from birth 
to less than 6 months cannot be included in the 2819-CL-0202 US study sites. 
Non-Substantial Changes
1. Update Safety Reporting
DESCRIPTION OF CHANGE:
Removal of safety reporting to delegated CRO for North American sites. 
RATIONALE:
Unify the safety reporting process for European and North American sites by using the same 
delegated CRO.  
2. Update Contact Details of Key Sponsor Personnel
DESCRIPTION OF CHANGE:
Update contact details for the clinical research contact.
RATIONALE:
Study manager has been replaced.


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3. Update Planned Study Period
DESCRIPTION OF CHANGE:
Planned study period is extended.
RATIONALE:
Planned study period has been extended based on expected recruitment rate.
4. Update Study Design
DESCRIPTION OF CHANGE:
1) Revision is made to investigate subjects from birth instead of ≥ 6 months, with the 
exception of the USA. 
2) Revision is made to subjects aged ≥ 6 years instead from birth to receive fidaxomicin 
tablets.
RATIONALE:
1)
Subjects from birth to < 18 years of will be investigated, with the exception of the USA. 
2)
Only subjects aged ≥ 6 years to < 18 years will be randomized to receive fidaxomicin 
tablets. Error was identified and corrected.  
5. Update Concomitant Treatments
DESCRIPTION OF CHANGE:
To include the most recent use of fidaxomicin or any macrolide antibiotic to be recorded in 
the eCRF. 
RATIONALE:
Previous exposure to fidaxomicin or any macrolide antibiotic is considered important 
information in the event of hypersensitivity to fidaxomicin during the study, irrespective of 
how long ago the prior exposure occurred. 
6. Update Discontinuation of Individual Subject(s)
DESCRIPTION OF CHANGE:
Protocol violation is revised to protocol deviation.
RATIONALE:
Update language to align with current process for protocol deviation. 
7.
Include instructional text related to reporting certain events as adverse events (AEs) based 
on local requirements.
DESCRIPTION OF CHANGE:


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Include statement related to reporting certain events as AEs based on local requirements in 
Section 5.5.1, Definition of an Adverse Event (AE).
RATIONALE:
Based on local requirements, certain events that occur during a subject’s participation in the 
clinical trial may be reported as adverse events or expedited as serious adverse events. 
Investigators will be responsible for reporting these events as required in the eCRFs as 
applicable.  
8. Include other minor administrative-type corrections
DESCRIPTION OF CHANGE:
Corrections of mis-spellings, format, etc. through-out the protocol.
RATIONALE:
For accuracy throughout the protocol.
II.
Amendment Summary of Changes: Substantial
IV Synopsis and 3 Study Population
Inclusion/Exclusion Criteria, Inclusion & 3.2 Inclusion Criteria
WAS:
2.
Male and female subjects aged from birth to < 18 years.
IS AMENDED TO:
2.
Male and female subjects aged from birth to < 18 years. Note that in the United States 
of America subjects can only be included if aged ≥ 6 months to < 18 years. 
IV Synopsis
Study Design Overview 
WAS:
This multicenter, investigator-blind, randomized parallel group study will investigate the 
safety and efficacy of a 10-day course of fidaxomicin oral suspension or tablets and a 10-day 
course of vancomycin oral liquid or capsules in subjects aged ≥ 6 months to < 18 years with 
confirmed CDAD. 
IS AMENDED TO:
This multicenter, investigator-blind, randomized parallel group study will investigate the 
safety and efficacy of a 10-day course of fidaxomicin oral suspension or tablets and a 10-day 
course of vancomycin oral liquid or capsules in subjects from birth aged ≥ 6 months to < 18 
years of age with confirmed CDAD. Note that in the United States of America subjects 
can only be included if aged ≥ 6 months to < 18 years.


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Study Design Overview
WAS:
Subjects from birth to < 18 years of age will be randomized to receive a 200 mg fidaxomicin 
tablet 2 times daily  for 10 days, or a 125 mg vancomycin capsule 4 times daily for 10 days. 
If a subject aged ≥ 6 years to <18 years is unable to swallow tablets or capsules, the 
investigator can decide to give fidaxomicin oral suspension, at a dose of 400 mg/day, or 
vancomycin oral liquid at a dose of  500 mg/day.
IS AMENDED TO:
Subjects aged ≥ 6 years from birth to < 18 years will be randomized to receive a 200 mg 
fidaxomicin tablet 2 times daily  for 10 days, or a 125 mg vancomycin capsule 4 times daily 
for 10 days. If a subject aged ≥ 6 years to <18 years is unable to swallow tablets or capsules, 
the investigator can decide to give fidaxomicin oral suspension, at a dose of 400 mg/day, or 
vancomycin oral liquid at a dose of  500 mg/day.
2.2 Study Design and Dose Rationale
2.2.1 Study Design
ADDED:
This is a multicenter, investigator-blind, randomized parallel group study to investigate the 
safety and efficacy of a 10-day course of fidaxomicin oral suspension or tablets and a 10-day 
course of vancomycin oral liquid or capsules in subjects from birth to < 18 years of age with 
confirmed CDAD. Note that in the United States of America subjects can only be 
included if aged ≥ 6 months to < 18 years.
IIb  Amendment Summary of Changes: Non-Substantial
II. CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL
CRO Contact for Reporting of Serious Adverse Events (SAEs)
DELETED:
Please send the SAE Worksheet to:
European sites: 
(Toll-free fax numbers will be provided for each country; the country-specific fax number 
can be found on the SAE Worksheet fax cover sheet)
North American sites: 






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6  DISCONTINUATION
6.1 Discontinuation of Individual Subjects(s)
WAS:

Protocol violation
IS AMENDED TO:

Protocol violationdeviation


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13.2
Attachment 2:  Substantial Amendment 1 [21Nov2014]
I.
The purpose of this amendment is:
To describe substantial change to the study population following the EMA decision 
(P/0264/2014) dated 03 Oct 2014 on the acceptance of a modification of the agreed Paediatric 
Investigational Plan (PIP) for fidaxomicin to open the study for subjects from birth onwards.
To include non-substantial changes (e.g., administrative changes, clarifications, additions). 
This amendment is considered substantial. The non-substantial changes however, will be 
implemented once submitted. 
Substantial Changes
1. Update of Age Ranges to Include Subjects from birth onwards
DESCRIPTION OF CHANGE:
Throughout the protocol, the age ranges ‘< 6 months of age’ are changed to ‘from birth’.
RATIONALE:
The age ranges are updated following the EMA decision (P/0264/2014) dated 03 Oct 2014 on 
the acceptance of a modification of the agreed Paediatric Investigational Plan (PIP) for 
fidaxomicin.
The non-substantial changes mentioned below do not meet any of the criteria for a substantial 
amendment, as they have no impact on the safety, or physical or mental integrity of the 
clinical trial participants or the scientific value of the study.
Non-Substantial Changes
2. Update Contact Details of Key Sponsor Personnel
DESCRIPTION OF CHANGE:
1) CRO contact for reporting of Serious Adverse Events was updated
2) Updated contact details of Clinical Research Contact
RATIONALE:
1) Information is updated to reflect the SAE reporting process in European and North 
American sites
2) New study manager was added to the study team
3. Update List of Abbreviations
DESCRIPTION OF CHANGE:
1) Removed abbreviation for Astellas Bioanalysis-Europe
2) Added abbreviation for Intent To Treat 


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RATIONALE:
1) Abbreviation for Astellas Bioanalysis-Europe is no longer used
2) Statistical methodology section has been updated
4. Update Definition of Key Study Terms
DESCRIPTION OF CHANGE:
TC is added to End of Study definition
RATIONALE:
Addition is made to align with Table 1 Schedule of Assessments
5. Update Study Objectives
DESCRIPTION OF CHANGE:
The term palatability is added 
RATIONALE:
Palatability is added for clarification and consistency
6. Update Study Design / Planned Total Number of Study Centers and Location(s)  
DESCRIPTION OF CHANGE:
Number of study sites is updated to ~65 to 80 sites
RATIONALE:
Number of study sites is updated according to the current situation
7. Update Secondary Endpoints
DESCRIPTION OF CHANGE:
1) Palatability is moved from exploratory endpoint to secondary endpoint
2)
 
RATIONALE:
1) Palatability is moved from exploratory endpoint to secondary endpoint, to align with 
protocol study objectives and protocol consistency. 
2)
8. Update Statistical Methodology 
DESCRIPTION OF CHANGE:
1) Intent to Treat (ITT) added to the analysis sets


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2) Full Analysis Set (FAS) text updated 
3) Added wording to Analysis of Primary Endpoint
4) Method changed to exact
5) The primary analysis method is modified
6) Subgroup Analysis is modified
7) Additional Efficacy Analyses is added
8) Palatability is removed from the Analysis of Exploratory Endpoints and added to the 
Analysis of Secondary Endpoints
9) Interim Analysis section is updated
10) Handling of missing data has been updated
RATIONALE:
1) Intent to Treat (ITT) is added to analysis sets, as recommended by the FDA
2) Full Analysis Set (FAS) text updated for clarification
3) Wording added for clarification
4) Method changed to exact to be more accurate
5) The primary analysis method is modified to take into account the stratification to ensure 
statistical correctness and clarification. 
6) Subgroup Analysis is modified to ensure statistical correctness and clarification
7) Additional Efficacy Analyses is added to include and explain ITT analysis
8) Palatability is removed from the Analysis of Exploratory Endpoints and added to the 
Analysis of Secondary Endpoints, to align with protocol study objectives and protocol 
consistency
9) Interim Analysis section is updated to allow interim reporting according to regulatory 
requirements, as it may be necessary to report data for some age groups earlier than 
others
10) The imputation of missing values has changed to make better use of available data. It 
uses multiple imputation to make better estimates of the differences between the 
treatments and the associated variability. Additional changes to the text have been made 
for clarification
9. Update Schedule of Assessments
DESCRIPTION OF CHANGE:
Table 1 - Schedule of Assessments ‘Follow-up visit’ has been changed to ‘Follow-up TC’
RATIONALE:
Change is made for clarification that this is normally a phone call instead of a visit 


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10. Update Timeframe for Positive Detection of CDAD
DESCRIPTION OF CHANGE:
Timeframe of a positive detection of CDAD is changed from within 48 hours to within 72 
hours prior to randomization
RATIONALE:
The time frame is aligned with the Inclusion criteria of the protocol
11. Update on Concomitant Treatments / Prohibited Medication
DESCRIPTION OF CHANGE:
1) Text on the coadministration of PgP inhibitor is added
2) Section title has been changed to Prohibited Medication and Restricted Medication, and 
Restricted therapies has been changed to medications permitted with restrictions
RATIONALE:
1) Addition is made to align protocol with the fidaxomicin SmPC
2) Change is made to cover section content and align with Appendix 12.1
12. Update Risk-Benefit Assessment
DESCRIPTION OF CHANGE:
1) Addition made to include text on children < 6 months 
2) Text added on hypersensitivity reactions
RATIONALE:
1) Addition is made to make reference to the included age range from birth to < 6 months 
2) Addition is made to align protocol with the fidaxomicin SmPC
13. Dose Regimen
DESCRIPTION OF CHANGE:
Weight based dosing instruction of the fidaxomicin oral suspension and the vancomycin oral 
liquid have been added
RATIONALE:
Weight band dosing is included in the protocol to further clarify weight based dosing based 
on pragmatic ranges related to comparable safe adult dosages


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15. Update Comparative Drug(s)
DESCRIPTION OF CHANGE:
Vancomycin oral solution has been changed to Vancomycin oral liquid
RATIONALE:
Change is made for consistency throughout protocol
16. Update Laboratory Assessments
DESCRIPTION OF CHANGE:
1) Table number has been updated
2) Asterisk has been removed from creatinine
3) Asterisk has been removed from Albumin
RATIONALE:
1) Table number has been updated as new tables were inserted
2) Creatinine is to be measured as Clinical Laboratory test as reporting of Renal laboratory 
value abnormalities is requested by PRAC assessment of PSUR4  with DLP 26-Nov-2013
3) Change is made to better characterize the severity of the CDAD at baseline
17. Definition of Adverse Events (AEs) / Definition of Serious Adverse Events (SAEs)
DESCRIPTION OF CHANGE:
1) The specified AEs of interest have been updated
2) Lack of efficacy has been added to the special situation events
RATIONALE:
1) Additions are made to align with PBEBR5 of JUL2014, PRAC assessment of PSUR4 
with DLP 26-Nov-2013, and for clarification. 
2) Lack of efficacy has been added to the special situation events as Lack of efficacy is 
related to the potential risk of Development of resistance to fidaxomicin and narratives 
have been requested by PRAC on PSUR4 assessment. 




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IS AMENDED TO:
Clinical response for subjects aged from birth ≥ 6 months to < 2 years
WAS: 
Recurrence for subjects aged ≥ 6 months to < 2 years
IS AMENDED TO:
Recurrence for subjects aged from birth ≥ 6 months to < 2 years
WAS: 
Time to resolution of diarrhea (TTROD) for subjects aged ≥ 6 months to < 2 years
IS AMENDED TO:
Time to resolution of diarrhea (TTROD) for subjects aged from birth ≥ 6 months to < 2 
years
Update Definition of Key Study Terms
Page 12 Definition of Key Study Terms
ADDED:
The end of the study is defined as the date of the last subject’s last visit/TC.
Update Study Objectives
Page 14 Synopsis, Page 38 2.1.1 Study Objectives - Primary
WAS:
The primary objective of this study is to investigate the clinical response to fidaxomicin oral 
suspension or tablets and vancomycin oral liquid or capsules of pediatric subjects with 
Clostridium difficile-associated diarrhea (CDAD) aged ≥ 6 months to < 18 years.
IS AMENDED TO:
The primary objective of this study is to investigate the clinical response to fidaxomicin oral 
suspension or tablets and vancomycin oral liquid or capsules of pediatric subjects with 
Clostridium difficile-associated diarrhea (CDAD) aged from birth≥ 6 months to < 18 years 
of age.
Page 38 2.1.2 Study Objectives - Secondary
WAS:
The secondary objectives of this study are to investigate the recurrence/sustained clinical 
response to and safety of fidaxomicin and vancomycin in pediatric subjects with Clostridium 
difficile-associated diarrhea (CDAD)  aged ≥ 6 months to < 18 years, as well as acceptance 
of the fidaxomicin oral suspension formulation.
IS AMENDED TO:


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The secondary objectives of this study are to investigate the recurrence/sustained clinical 
response to and safety of fidaxomicin and vancomycin in pediatric subjects with Clostridium 
difficile-associated diarrhea (CDAD)  aged from birth≥ 6 months to < 18 years of age, as 
well as palatability (acceptance) of the fidaxomicin oral suspension formulation.
Update Study Population
Page 14 Synopsis, Page 43 3.1 Selection of Study Population
WAS:
Male and female subjects aged ≥ 6 months to < 18 years, diagnosed with CDAD confirmed 
by a positive C. difficile toxin test in stool or positive detection of toxigenic C. difficile in 
stool.
IS AMENDED TO:
Male and female subjects aged from birth≥ 6 months to < 18 years of age, diagnosed with 
CDAD confirmed by a positive C. difficile toxin test in stool or positive detection of 
toxigenic C. difficile in stool.
Update Subjects to be Enrolled
Page 14 Synopsis
WAS:
144 subjects aged ≥ 6 months to < 18 years will be enrolled with at least 24 subjects in each 
of the following age categories: ≥ 6 months to < 24 months, ≥ 2 years to < 6 years, ≥ 6 years 
to < 12 years, and ≥ 12 years to < 18 years (the remaining 48 subjects can be enrolled in any 
of the age groups).
IS AMENDED TO:
144 subjects aged from birth≥ 6 months to < 18 years of age will be enrolled with at least 
24 subjects in each of the following age categories: ≥ 6 monthsbirth to < 24 months, ≥ 2 
years to < 6 years, ≥ 6 years to < 12 years, and ≥ 12 years to < 18 years (the remaining 48 
subjects can be enrolled in any of the age groups).
Update Study Design
Page 14 Synopsis
WAS:
One hundred forty four subjects, stratified by age at enrollment (≥ 6 months to < 24 months, 
≥ 2 years to < 6 years, ≥ 6 years to < 12 years, and ≥ 12 years to < 18 years) will be enrolled.
Subjects aged ≥ 6 months to < 6 years will be randomized to receive weight based doses of 
either fidaxomicin oral suspension (32 mg/kg/day with a maximum dose of 400 mg/day, 
divided in 2 doses) 2 times daily for 10 days, or vancomycin oral liquid (40 mg/kg/day with 
a maximum dose of 500 mg/day divided in 4 doses) 4 times daily for 10 days.
Subjects aged ≥ 6 years to < 18 years will be randomized to receive a 200 mg fidaxomicin 
tablet 2 times daily  for 10 days, or a 125 mg vancomycin capsule 4 times daily for 10 days. 
If a subject aged ≥ 6 years to <18 years is unable to swallow tablets or capsules, the 


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investigator can decide to give fidaxomicin oral suspension, at a dose of 400 mg/day, or 
vancomycin oral liquid at a dose of  500 mg/day.
IS AMENDED TO:
One hundred forty four subjects, stratified by age at enrollment (birth≥ 6 months to < 24 
months, ≥ 2 years to < 6 years, ≥ 6 years to < 12 years, and ≥ 12 years to < 18 years) will be 
enrolled.
Subjects from birth aged ≥ 6 months to < 6 years of age will be randomized to receive 
weight based doses of either fidaxomicin oral suspension (32 mg/kg/day with a maximum 
dose of 400 mg/day, divided in 2 doses) 2 times daily for 10 days, or vancomycin oral liquid 
(40 mg/kg/day with a maximum dose of 500 mg/day divided in 4 doses) 4 times daily for 10 
days.
Subjects aged from birth ≥ 6 years to < 18 years of age will be randomized to receive a 200 
mg fidaxomicin tablet 2 times daily  for 10 days, or a 125 mg vancomycin capsule 4 times 
daily for 10 days. If a subject aged ≥ 6 years to <18 years is unable to swallow tablets or 
capsules, the investigator can decide to give fidaxomicin oral suspension, at a dose of 400 
mg/day, or vancomycin oral liquid at a dose of  500 mg/day.
Page 38, section 2.2.1
WAS:
This is a multicenter, investigator-blind, randomized parallel group study to investigate the 
safety and efficacy of a 10-day course of fidaxomicin oral suspension or tablets and a 10-day 
course of vancomycin oral liquid or capsules in subjects aged  ≥ 6 months and < 18 years 
with confirmed CDAD.
The study will be conducted in North America and Europe across ~50 to 70 sites. A target of 
one hundred forty four subjects, stratified by age at enrollment (≥ 6 months to < 24 months,
IS AMENDED TO:
This is a multicenter, investigator-blind, randomized parallel group study to investigate the 
safety and efficacy of a 10-day course of fidaxomicin oral suspension or tablets and a 10-day 
course of vancomycin oral liquid or capsules in subjects aged from birth to ≥ 6 months and 
< 18 years of age with confirmed CDAD.
The study will be conducted in North America and Europe across ~6550 to 8070 sites. A 
target of one hundred forty four subjects, stratified by age at enrollment (from birth≥ 6 
months to < 24 months,
Update Inclusion Criteria
Page 16 Synopsis, Page 43 3.2 Inclusion Criteria
WAS:
2.
Male and female subjects aged ≥ 6 months to < 18 years.
3.
Subject is diagnosed with CDAD according to local diagnostic criteria. As a minimum 
there must be positive detection, within 72 hours prior to randomization, of either toxin 
A and/or toxin B in stool or positive detection of toxigenic C. difficile in stool and:


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a. Subject ≥ 6 months to < 2 years: watery diarrhea in the 24 hours prior to screening.
IS AMENDED TO:
2.
Male and female subjects aged from birth≥ 6 months to < 18 years.
3.
Subject is diagnosed with CDAD according to local diagnostic criteria. As a minimum 
there must be positive detection, within 72 hours prior to randomization, of either toxin 
A and/or toxin B in stool or positive detection of toxigenic C. difficile in stool and:
a. Subject from birth≥ 6 months to < 2 years: watery diarrhea in the 24 hours prior to 
screening.
Update Dose Rationale / Dose Regimen
Page 17 Synopsis, Investigational Product(s)
WAS:
Dose(s):  
Ages ≥ 6 months to < 6 years: fidaxomicin oral suspension, 32 mg/kg/day with a maximum 
daily dose of 400 mg, divided in 2 doses per day.
IS AMENDED TO:
Dose(s):  
Ages From birth ≥ 6 months to < 6 years of age: fidaxomicin oral suspension, 32 mg/kg/day 
with a maximum daily dose of 400 mg, divided in 2 doses per day.
Page 17 Synopsis, Comparative Drug(s)
WAS:
Dose(s):  
Ages ≥ 6 months to < 6 years: vancomycin oral liquid 40 mg/kg/day with a maximum daily 
dose of 500 mg, divided in 4 doses per day.
IS AMENDED TO:
Dose(s):  
Ages From birth ≥ 6 months to < 6 years of age: vancomycin oral liquid 40 mg/kg/day 
with a maximum daily dose of 500 mg, divided in 4 doses per day.
Page 40, section 2.2.2
WAS:
Subjects aged ≥ 6 years to < 18 years will be randomized to receive either 400 mg daily dose 
of fidaxomicin or 500 mg daily dose of vancomycin and subjects aged ≥ 6 months to < 6 
years will be randomized to receive weight based doses of either fidaxomicin oral suspension 
or vancomycin oral liquid.
IS AMENDED TO:


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Subjects aged ≥ 6 years to < 18 years will be randomized to receive either 400 mg daily dose 
of fidaxomicin or 500 mg daily dose of vancomycin and subjects aged from birth≥ 6 months
to < 6 years of age will be randomized to receive weight based doses of either fidaxomicin 
oral suspension or vancomycin oral liquid.
Page 40, section 2.2.2
ADDED:
Please refer to 5.1.1 Table 3B weight based dosing instruction of the vancomycin oral 
liquid.
Page 40, section 2.2.2
ADDED:
Please refer to 5.1.1 Table 3A weight based dosing instruction of the fidaxomicin oral 
suspension.
Page 45, section 4.1.2
WAS:
Vancomycin oral liquid is supplied as powder for oral solution. A separate box will be 
provided with ancillaries for preparation of the oral solution. 
Sweet syrups may be added to the solution to improve the taste of the oral administration. 
[Vancomycin Hospira powder for oral solution and for solution for infusion, Hospira SpA, 
Italian SmPC]. SyrSpend will be provided to be used as sweet syrup for the vancomycin oral 
liquid. A pharmacy manual will be provided for the preparation of the vancomycin oral 
solution.
IS AMENDED TO:
Vancomycin oral liquid is supplied as powder for oral solutionliquid. A separate box will be 
provided with ancillaries for preparation of the oral solutionliquid. 
Sweet syrups may be added to the solution liquid to improve the taste of the oral 
administration. [Vancomycin Hospira powder for oral solution and for solution for infusion, 
Hospira SpA, Italian SmPC]. SyrSpend will be provided to be used as sweet syrup for the 
vancomycin oral liquid. A pharmacy manual will be provided for the preparation of the 
vancomycin oral solutionliquid.
Page 48, section 5.1.1
WAS:
Subjects randomized to the fidaxomicin treatment arm, aged ≥ 6 months to < 6 years will be 
administered fidaxomicin oral suspension, 32 mg/kg/day with a maximum dose of 400 
mg/day, divided in 2 doses/day for 10 days and subjects aged ≥ 6 years to < 18 years will 
receive a fidaxomicin 200 mg tablet, 2 times daily, for 10 days.


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IS AMENDED TO:
Subjects randomized to the fidaxomicin treatment arm, aged from birth≥6 months to < 6 
years of age will be administered fidaxomicin oral suspension, 32 mg/kg/day with a 
maximum dose of 400 mg/day, divided in 2 doses/day for 10 days (see Table 3A below) and 
subjects aged ≥ 6 years to < 18 years will receive a fidaxomicin 200 mg tablet, 2 times daily, 
for 10 days. 
Table 3A:  Weight-based Dosing Instruction of the Fidaxomicin Oral Suspension 
Weight band of 
patient
Dose in mg/day 
(twice daily dosing)
mg/dose 
Volume of 
fidaxomicin oral 
suspension to 
administer
≤ 3.9 kg
80 mg
40 mg
1.0 mL
4.0-6.9 kg
160 mg
80 mg
2.0 mL
7.0-8.9 kg
240 mg
120 mg
3.0 mL
9.0-12.4 kg
320 mg
160 mg
4.0 mL
≥ 12.5 kg
400 mg
200 mg
5.0 mL
Page 48, section 5.1.1
WAS:
Subjects randomized to the vancomycin treatment arm, aged ≥ 6 months to < 6 years will be 
administered a vancomycin oral liquid 40 mg/kg/day with a maximum dose of 500 mg/day, 
divided in 4 doses/day, for 10 days and subjects aged ≥ 6 years to < 18 years will be 
administered a vancomycin 125 mg capsule, 4 times daily, for 10 days.
IS AMENDED TO:
Subjects randomized to the vancomycin treatment arm, aged from birth≥ 6 months to < 6 
years of age will be administered a vancomycin oral liquid 40 mg/kg/day with a maximum 
dose of 500 mg/day, divided in 4 doses/day, for 10 days (see Table 3B below) and subjects 
aged ≥ 6 years to < 18 years will be administered a vancomycin 125 mg capsule, 4 times daily,
for 10 days.
Table 3B: Weight-based Dosing Instruction of the Vancomycin Oral Liquid 
Weight band of 
patient
Dose in mg/day 
(four times daily 
dosing)
mg/dose 
Volume of vancomycin 
oral liquid to 
administer
≤ 3.9 kg
100 mg
25 mg
1.0 ml
4.0-6.9 kg
200 mg
50 mg
2.0 ml
7.0-8.9 kg
300 mg
75 mg
3.0 ml
9.0-12.4 kg
400 mg
100 mg
4.0 ml
≥ 12.5 kg
500 mg
125 mg
5.0 ml




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Updated Efficacy
Page 20 Synopsis
WAS:
The proportion of subjects with confirmed clinical response (primary efficacy endpoint) at 
the confirmation of clinical response (EOT+2 days) will be summarized by  treatment arm 
and age group along with 95% confidence intervals (CIs). In addition, 95% CIs will be 
presented for the difference in confirmed clinical response between the two treatment arms. 
IS AMENDED TO:
The proportion of subjects with confirmed clinical response (primary efficacy endpoint) at 
the confirmation of clinical response (EOT+2 days) will be summarized by  within each
treatment arm and by age group along with exact 95% confidence intervals (CIs). In 
addition, 95% CIs will be presented for the adjusted difference in confirmed clinical 
response between the two treatment arms, where adjusted difference will be calculated 
using stratified CMH (Cochran-Mantel-Haenszel) method using age group as the 
stratified variable.
Page 65 section 7.4.1, 7.4.1.1, and 7.4.1.2
WAS:
7.4.1    Analysis of Primary Endpoint 
7.4.1.1 Primary Analysis
The analysis of the primary efficacy endpoint, confirmed clinical response (see definition in 
section 2.3.1) will be conducted for the FAS.
The proportion of subjects with confirmed clinical response at the confirmation of clinical 
response (EOT+2 days) will be summarized by treatment arm along with 95% confidence 
intervals (CIs) according to the Wilson method (without continuity correction). In addition, 
95% CIs (according to the Newcombe-Wilson method without continuity correction) will be 
presented for the difference in clinical response between treatment arms. 
7.4.1.2 Subgroup Analysis
In general, efficacy data will be summarized by treatment group and age group using the 
classifications given in section 7.
The proportion of subjects with confirmed clinical response and the associated 95% CIs will 
further be provided by treatment arm within age group. Further subgroup analyses, if deemed 
appropriate, might be done and will be described in the SAP.
IS AMENDED TO:
7.4.1
Analysis of Primary Endpoint 
7.4.1The primary endpoint will be the assessment of confirmed clinical response 
assessed by the investigator at EOT+2.  A missing assessment of the primary endpoint 
will be imputed according to the rules and methods in section 7.10.
7.4.1.1 Primary Analysis


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The analysis of the primary efficacy endpoint, confirmed clinical response (see definition in 
section 2.3.1) at EOT+2 days will be conducted for the FAS.
The proportion of subjects with confirmed clinical response at the confirmation of clinical 
response (EOT+2 days) will be summarized by within each treatment arm by age group
along with exact 95% confidence intervals (CIs) according to the Wilson method (without 
continuity correction). In addition, 95% CIs (according to the Newcombe Wilson method 
without continuity correction) will be presented for the adjusted difference in confirmed
clinical response between treatment arms, where adjusted difference will be calculated 
using stratified CMH (Cochran-Mantel-Haenszel) method using age group as the 
stratified variable.
7.4.1.2 Subgroup Analysis
In general, efficacy data will be summarized by treatment group and age group using the 
classifications given in section 7.
The proportion of subjects with confirmed clinical response at EOT+2 days and the 
associated exact 95% CIs will further be provided by treatment arm within age group. 
Further subgroup analyses, if deemed appropriate, might be done and will be described in the 
SAP.
Update Schedule of Assessments
Page 22, 23 Table 1 Schedule of Assessments
WAS:
Follow-up Visit
IS AMENDED TO:
Follow-up Visit TCi
Page 24 Footnote m
WAS:
m) Stool sample will be split in two aliquots, one for the detection of toxigenic C. difficile at 
study site and one for the reference laboratory (for possible microbiological and 
biochemistry testing). Alternatively, a test for toxigenic C. difficile done as standard of care, 
including pre-consent samples, provided the sample was obtained within 48 hours prior to 
randomization, may be used to assess eligibility and a different sample sent to the reference 
laboratory.
IS AMENDED TO:
m) Stool sample will be split in two aliquots, one for the detection of toxigenic C. difficile at 
study site and one for the reference laboratory (for possible microbiological and 
biochemistry testing). Alternatively, a test for toxigenic C. difficile done as standard of care, 
including pre-consent samples, provided the sample was obtained within 48 72 hours prior 
to randomization, may be used to assess eligibility and a different sample sent to the 
reference laboratory.


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Page 61, Section 5.7.1
WAS:
For assessment of inclusion criteria for Screening, a routinely performed local rapid test that 
was taken after the onset of CDAD and within 48 hours prior to randomization is acceptable.
IS AMENDED TO:
For assessment of inclusion criteria for Screening, a routinely performed local rapid test that
was taken after the onset of CDAD and within 48 72 hours prior to randomization is
acceptable.
Page 25 Footnote s
WAS:
s) For hematology, biochemistry and urinalysis at Screening, results that were obtained per 
standard of care before consent (historical sample) are acceptable, provided that the sampling 
was done after the onset of CDAD and within 3 days prior to randomization. For the 
hematology, biochemistry and urinalysis at EOT visit, results that were obtained as part of 
standard of care between Day 8 and Day 10 (inclusive) (standard of care sample) are 
acceptable. The most recent results should be used for eCRF completion. The historical or 
standard of care sample may not include all parameters as described in table 3, section 5.4.3. 
A historical/standard of care samples without parameter(s) indicated with * in the table is 
acceptable.
IS AMENDED TO:
s) For hematology, biochemistry and urinalysis at Screening, results that were obtained per 
standard of care before consent (historical sample) are acceptable, provided that the sampling 
was done after the onset of CDAD and within 3 days prior to randomization. For the 
hematology, biochemistry and urinalysis at EOT visit, results that were obtained as part of 
standard of care between Day 8 and Day 10 (inclusive) (standard of care sample) are 
acceptable. The most recent results should be used for eCRF completion. The historical or 
standard of care sample may not include all parameters as described in table 43, section 
5.4.3. A historical/standard of care samples without parameter(s) indicated with * in the table 
is acceptable.
Update on Concomitant Treatments
Page 34, Section 1.2.2.1
WAS:
Coadministration of cyclosporine with fidaxomicin (Study OPT-80-007) increased the least 
squares (LS) mean Cmax of fidaxomicin and main metabolite OP-1118 by approximately 4 
fold and 10-fold, respectively, compared to fidaxomicin alone. AUC0-t for fidaxomicin and 
OP-1118 were also increased by cyclosporine, but to a lesser extent (approximately 2-fold 
and 4-fold, respectively).


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IS AMENDED TO:
Coadministration of the P-glycoprotein inhibitor cyclosporine with fidaxomicin (Study 
OPT-80-007) increased the least squares (LS) mean Cmax of fidaxomicin and main 
metabolite OP-1118 by approximately 4 fold and 10-fold, respectively, compared to 
fidaxomicin alone. AUC0-t for fidaxomicin and OP-1118 were also increased by 
cyclosporine, but to a lesser extent (approximately 2-fold and 4-fold, respectively).
Page 50, Section 5.1.3.1 Prohibited Medication and Restricted Medication
ADDED:
Co-administration of potent P-glycoprotein inhibitors such as cyclosporine, 
ketoconazole, erythromycin, clarithromycin, verapamil, dronedarone and amiodarone 
is not recommended, but these medications are not prohibited.
Update Risk Benefit Assessment
Page 37, Section 1.4
WAS:
The results of the phase 2A pediatric study (see section 1.2) showed a safety profile 
consistent with that seen in adults, with gastrointestinal disorders and infections/infestations 
the commonest AEs. Six subjects developed AEs considered related to study drug none of 
which were serious. These were tachycardia, constipation, diarrhea, nausea, vomiting, 
increased body temperature, urticaria, and elevated liver enzymes. There were no safety 
signals detected by analysis of vital signs, ECG or laboratory data.  
Fidaxomicin is the first representative in the novel antibacterial class of macrocycles. The 
current safety data-base consists of a total of 798 patients with mild to moderately severe 
CDI treated up to 10 days. Based on post-marketing experience since July 2011, the safety 
profile of fidaxomicin has slightly changed relative to that seen in the Phase III studies. 
IS AMENDED TO:
The results of the phase 2A pediatric study (age: > 6 months- <18 years: see section 1.2) 
showed a safety profile consistent with that seen in adults, with gastrointestinal disorders and 
infections/infestations the commonest AEs.  Six subjects developed AEs considered related 
to study drug none of which were serious. These were tachycardia, constipation, diarrhea, 
nausea, vomiting, increased body temperature, urticaria, and elevated liver enzymes.  There 
were no safety signals detected by analysis of vital signs, ECG or laboratory data.  
Fidaxomicin has not been used in children < 6 months. A 4-week oral repeated-dose 
toxicity study in juvenile beagle dogs showed no target organ for toxicity after 28 days 
of dosing up to 200 mg/kg/day fidaxomicin from Post Natal Day 4 (see section 1.2.1), 
which is the age equivalent to a newborn child.
Fidaxomicin is the first representative in the novel antibacterial class of macrocycles. The 
current safety data-base consists of a total of 798 patients with mild to moderately severe CDI 
treated up to 10 days. Based on post-marketing experience since July 2011, the safety profile 
of fidaxomicin has slightly changed relative to that seen in the Phase III studies. Some 
patients with hypersensitivity reactions reported a history of allergy to macrolides. 


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 109 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
Fidaxomicin should be used with caution in patients with a known macrolides allergy 
(SmPC Dificlir).
Update Prohibited Medication
Page 49, Section 5.1.3.1
WAS: 
5.1.3.1 Prohibited Medication
See Appendix 12.1 Excluded Concomitant Medications for additional details on prohibited 
medications and restricted therapies.
IS AMENDED TO:
5.1.3.1Prohibited Medication and Restricted Medication
See Appendix 12.1 Excluded Concomitant Medications for additional details on prohibited 
medications and medications permitted with restrictionsrestricted therapies.
Update Laboratory Assessments
Page 52, Section 5.4.3
WAS: 
In Table 3 the laboratory tests that will be performed during the conduct of the study are 
listed.
IS AMENDED TO:
In Table 34 the laboratory tests that will be performed during the conduct of the study are 
listed.
Page 53, Table 3, Screening EoT Unscheduled Visit
WAS: 
Creatinine*
IS AMENDED TO:
Creatinine*
Page 54, Section 5.4.3
WAS: 
Albumin*
IS AMENDED TO:
Albumin*
Update Definition of Adverse Events (AEs) / Definition of Serious Adverse Events 
(SAEs)


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 110 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
Page 55, Section 5.5.1
WAS: 
The specified AEs of interest for this study are shown below and will require more extensive 
collection of information which will be collected in targeted questionnaires: 

Development of microbial resistance to fidaxomicin

Hypersensitivity to fidaxomicin

GI hemorrhage

Decreases in WBC, neutrophil counts 

Hepatic laboratory value abnormalities 

QT-interval prolongation 
IS AMENDED TO:
The specified AEs / findings of interest for this study are shown below and will may require 
more extensive collection of information which will be collected in targeted questionnaires: 

Development of microbial resistance to fidaxomicin

Hypersensitivity to fidaxomicin

GI hemorrhage

Decreases in WBC, neutrophil and lymphocyte counts 

Hepatic laboratory value abnormalities 

Renal laboratory value abnormalities

QT-interval prolongation 

Lack of efficacy / lack of effect / treatment failure
Page 56, Section 5.5.2
WAS: 
Special situation events relevant to the medicinal products administered to the subject as part 
of the study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:

Overdose of the medicinal product(s)

Suspected abuse/misuse of the medicinal product(s)

Inadvertent or accidental exposure to the medicinal product(s)

Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion)

Drug-drug interaction
All special situations listed above should be especially monitored and reported on a SAE 
form, even if considered non-serious and regardless whether or not an (S)AE occurred. The 
above special situation will not be captured on the AE form in the eCRF, instead they will be 
captured in the dosing and accountability forms within the eCRF. 
Lack of efficacy will be recorded as part of the study endpoints and will be documented in the 
clinical study report. Lack of efficacy will not to be recorded/reported as an (S)AE in this 
study.


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 111 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
IS AMENDED TO:
Special situation events relevant to the medicinal products administered to the subject as part 
of the study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:

Overdose of the medicinal product(s)

Suspected abuse/misuse of the medicinal product(s)

Inadvertent or accidental exposure to the medicinal product(s)

Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion)

Drug-drug interaction

Lack of efficacy
All special situations listed above should be especially monitored and reported on a SAE 
form, even if considered non-serious and regardless whether or not an (S)AE occurred. The 
above special situation will not be captured on the AE form in the eCRF, instead they will be 
captured in the dosing and accountability forms within the eCRF. 
Lack of efficacy will be recorded as part of the study endpoints and will be documented in the 
clinical study report. Lack of efficacy will not to be recorded/reported as an (S)AE in this 
study.
Update Naming Astellas Bioanalysis-Europe
Page 60, Section 5.6
WAS: 
the Drug Discovery Research / Drug Metabolism Research Laboratory / BioAnalysis 
(DDR/DMRL/BA)
IS AMENDED TO:
Astellas Bioanalysis-Europe the Drug Discovery Research / Drug Metabolism Research 
Laboratory / BioAnalysis (DDR/DMRL/BA)
Update Palatability Testing
Page 61, Section 5.7.2
WAS: 
Palatability will be assessed for all subjects receiving fidaxomicin oral suspension and 
vancomycin oral liquid (i.e. subjects aged ≥ 6 months to ≤ 6 years 
IS AMENDED TO:
Palatability will be assessed for all subjects receiving fidaxomicin oral suspension and 
vancomycin oral liquid (i.e. subjects from agedbirth ≥ 6 months to ≤ 6 years of age


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 112 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
Update Total Amount of Blood
Page 62, Section 5.8
WAS: 
Examples of the total amount of blood collected per subject during the course of the study 
are shown in Table 4. 
Table 4: Examples of the total amount of blood collected per subject during the course of the 
study
IS AMENDED TO:
Examples of the total amount of blood collected per subject during the course of the study 
are shown in Table 5 4.
Table 4 5: Examples of the total amount of blood collected per subject during the course of 
the study
Update Statistical Methodology
Page 64, Section 7
WAS: 
In general, data summaries will be presented by treatment arm, by age group (and overall) 
and time point (as applicable), using the following classifications:
Treatment arm:
fidaxomicin or vancomycin
Age group:
≥ 6 months to < 24 months
≥ 2 years to < 6 years
≥ 6 years to < 12 years
≥ 12 years to < 18 years
and overall
IS AMENDED TO:
In general, data summaries will be presented by within each treatment arm, by age group 
(and overall) and time point (as applicable), using the following classifications:
Treatment arm:
fidaxomicin or vancomycin
Age group:
from birth≥ 6 months to < 24 months
≥ 2 years to < 6 years
≥ 6 years to < 12 years
≥ 12 years to < 18 years
and overall
Update Sample Size
Page 64, Section 7.1
WAS: 
One hundred forty four eligible subjects will be enrolled and randomized to either 
fidaxomicin or vancomycin in a 2:1 ratio (96 randomized to fidaxomicin and 48 to 
vancomycin), stratified by age at enrollment (≥ 6 months to < 24 months, ≥ 2 years to < 6 
years, ≥ 6 years to < 12 years, and ≥ 12 years to < 18 years).


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 113 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
IS AMENDED TO:
One hundred forty four eligible subjects will be enrolled and randomized to either 
fidaxomicin or vancomycin in a 2:1 ratio (96 randomized to fidaxomicin and 48 to 
vancomycin), stratified by age at enrollment (from birth≥ 6 months to < 24 months, ≥ 2 
years to < 6 years, ≥ 6 years to < 12 years, and ≥ 12 years to < 18 years).
Update Analysis Sets
Page 64, Section 7.2
WAS: 
The following analysis sets, defined in the following subsections, will be used in the analysis 
and reporting of this study:

Full Analysis Set (FAS).

Safety Analysis Set (SAF).

Pharmacokinetic Analysis Set (PKAS).
IS AMENDED TO:
The following analysis sets, defined in the following subsections, will be used in the analysis 
and reporting of this study:

Full Analysis Set (FAS).

Safety Analysis Set (SAF).

Pharmacokinetic Analysis Set (PKAS).

Intent to Treat (ITT)
Page 67, Section 7.2.4
ADDED: 
7.2.4
Intent to Treat Analysis Set (ITT)
The intent-to-treat (ITT) set consists of all randomized subjects, irrespective of a 
subject having received a study drug (fidaxomicin or vancomycin) or not. In the ITT, 
subjects will be allocated to the treatment arm corresponding to the study medication 
that were randomized to (treatment allocation as randomized). The ITT will be used 
for efficacy analyses, as well as selected demographic and baseline characteristics when 
necessary. 
Update Full Analysis Set
Page 66, Section 7.2.1
ADDED: 
In the FAS, subjects will be allocated to the treatment arm corresponding to the study 
medication that were randomized to (treatment allocation as randomized).  The FAS 
will be used for primary and secondary efficacy analyses, as well as selected 
demographic and baseline characteristics.


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 114 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
Update Analyses
Page 68, Section 7.4.2.1
ADDED: 
7.4.2.1 Other Analyses - Palatability
Results from the assessments of palatability in subjects receiving fidaxomicin oral 
suspension  on Day 1 and on Day 7 (±1 day) will be summarized by means of a 
frequency table, stratified by treatment arm, age group and study day.
Update Interim Analysis and Handling of Missing Data
Pages 68-69 Section 7.9, Interim Analysis (and Early Discontinuation of the Clinical Study )
and 7.10 Handling of Missing Data, Outliers, Visit Windows, and Other Information
WAS: 
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned. 
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information
The following imputation of completely missing information for the assessment of clinical 
response and recurrence is foreseen (taking into consideration applicable visit windows):

Missing information for confirmed clinical response will be classified as clinical failure 
(no response). 

Missing information for sustained clinical response 16 days after the EOT (at Day 26) 
will be classified as recurrence (= no sustained clinical response), unless data after Day 
26 is available that suggests/confirms that clinical response was sustained until Day 26.

Missing information for sustained clinical response 30 days after the EOT (at Day 40) 
will be classified as recurrence (= no sustained clinical response). 
Handling of other missing data related to efficacy endpoints will be detailed in the SAP, if 
deemed appropriate. Sensitivity analyses of efficacy results (with and without imputation) 
might be necessary and will be described in the SAP. 
As a general principle, no imputation of other missing data will be done.
IS AMENDED TO:
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned. If required for regulatory submissions, interim 
analyses may be carried out (e.g. to present the results of some age strata while 
recruitment is ongoing in other strata).  Is so, details of the analysis and for preserving 
the blind will be included in the analysis plan.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information
Every effort should be made to follow-up subjects and to obtain data – especially on the 
important endpoints of confirmed clinical response (EOT+2) and recurrence / sustained 
clinical response (to EOS). 
The following imputation of completely missing information for the assessment of clinical 
response and recurrence / sustained response is foreseen (taking into consideration 


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 115 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
applicable visit windows):

Missing information for efficacy variables of confirmed clinical response and sustained 
clinical response will be estimated using the multiply imputation procedure which 
will replace each missing value with a set of plausible values as predictions from 
logistic regression based on bowel movement data, and previous CDAD experience.  
Each multiply imputed data set will then be analyzed and the methodology 
combines the results from all datasets to give a single final analysis that takes into 
account the uncertainty of the imputed values. classified as clinical failure (no 
response).

Missing information for sustained clinical response 16 days after the EOT (at Day 26) 
will be classified as recurrence (= no sustained clinical response), unless data after Day 
26 is available that suggests/confirms that clinical response was sustained until Day 26.

Missing information for sustained clinical response 30 days after the EOT (at Day 40) 
will be classified as recurrence (= no sustained clinical response). 
Handling of other missing data related to efficacy endpoints will be detailed in the SAP, if 
deemed appropriate. Sensitivity analyses of for efficacy results endpoints (with and without 
imputation) might be necessary and will be described in the SAP.
As a general principle, no imputation of other missing data will be done (e.g. labs, vital 
signs, ECGs, etc).


Sponsor: APEB
ISN/Protocol 2819-CL-0202
EudraCT number 2013-000508-40
- CONFIDENTIAL -
21 Jul 2015
Astellas
Page 116 of 116
Version 3.0 Incorporating Substantial Amendments 1 & 2
[GPF V4.0]
14
SPONSOR’S SIGNATURES


 
S-1 
ELECTRONIC SIGNATURE PAGE 
Document Type :  
Document Control Number :  
Amendment Number :  
International Study Number :  
Departmental Study Number :  
Actual Version Number :  
Document Version :  
Nonclinical Initial SD Approved Date (UTC) :  
Date (UTC) 
Signed by 
Sign Off Meaning 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
*UTC: Coordinated Universal Time 
07/23/2015 19:11:54
Clinical Study Protocol
Study Manager Approval
Principal Reviewer Approval
07/23/2015 16:59:21
Reissue v3.0, 21Jul2015
Scientific Lead Approval
N/A
07/23/2015 16:35:02
N/A
MGC1500897
2819-CL-0202
2.0
N/A

SAP_001.pdf: 
A Phase 3, Multicenter, Investigator-blind, Randomized, 
Parallel Group Study to Investigate the Safety and 
Efficacy of Fidaxomicin Oral Suspension or Tablets Taken 
q12h, and Vancomycin Oral Liquid or Capsules Taken 
q6h, for 10 days in Pediatric Subjects with Clostridium 
difficile-associated Diarrhea
The SUNSHINE Study
ISN/Protocol 2819-CL-0202
ClinicalTrials.gov Identifier: NCT02218372
Date of Statistical Analysis Plan Final Version 3.0: 
20 Apr 2018
Sponsor: Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
The Netherlands


Sponsor: Astellas Pharma Europe B.V. (APEB)
SAP Final Version 3.0
ISN/Protocol 2819-CL-0202
20-April-2018
Astellas
Page 1 of 87
STATISTICAL ANALYSIS PLAN
Final Version 3.0, dated 20-Apr-2018
A Phase 3, Multicenter, Investigator-blind, Randomized, Parallel Group Study to Investigate 
the Safety and Efficacy of Fidaxomicin Oral Suspension or Tablets Taken q12h, and 
Vancomycin Oral Liquid or Capsules Taken q6h, for 10 Days in Pediatric Subjects with 
Clostridium difficile-associated Diarrhea.
The SUNSHINE Study
ISN: 2819-CL-0202
EudraCT number: 2013-000508-40 
Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62
2333 BE Leiden
The Netherlands 
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Europe B.V. (APEB)
SAP Final Version 3.0
ISN/Protocol 2819-CL-0202
20-April-2018
Astellas
Page 2 of 87
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 6
1
INTRODUCTION·················································································10
2
FLOW CHART AND VISIT SCHEDULE···················································10
3
STUDY OBJECTIVE(S) AND DESIGN······················································14
3.1
Study Objective(s) ············································································14
3.1.1
Primary Objective ·······································································14
3.1.2
Secondary Objective ····································································14
3.2
Study Design···················································································14
3.3
Randomization·················································································15
4
SAMPLE SIZE·····················································································15
5
ANALYSIS SETS ·················································································15
5.1
Full Analysis Set (FAS) ······································································16
5.2
Intent To Treat (ITT) ·········································································16
5.3
Safety Analysis Set (SAF) ···································································16
5.4
Pharmacokinetics Analysis Set (PKAS)····················································16
6
ANALYSIS VARIABLES ·······································································17
6.1
Efficacy Endpoints············································································17
6.1.1
Primary Efficacy Endpoint ·····························································17
6.1.2
Secondary Efficacy Endpoints·························································18
6.1.3
Exploratory Efficacy Endpoints ·······················································20
6.1.4
Other Efficacy Endpoints·······························································21
6.2
Safety Variables ···············································································21
6.2.1
Adverse Events ··········································································21
6.2.2
Laboratory Assessments································································22
6.2.3
Vital Signs················································································24
6.2.4
Electrocardiogram (ECG) ······························································24
6.2.5
Physical Examination···································································25
6.2.6
CDAD Signs and Symptoms···························································25
6.3
Drug Concentration Variables·······························································25
6.4
Other Variables················································································26
6.4.1
Demographic Data and Baseline Characteristics ····································26
6.4.2
Medical History··········································································26


Sponsor: Astellas Pharma Europe B.V. (APEB)
SAP Final Version 3.0
ISN/Protocol 2819-CL-0202
20-April-2018
Astellas
Page 3 of 87
6.4.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············26
6.4.4
Rotavirus ·················································································26
6.4.5
Duration of exposure····································································26
6.4.6
Treatment compliance ··································································26
6.4.7
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································27
6.4.8
Prohibited Medication ··································································28
7
STATISTICAL METHODOLOGY ···························································30
7.1
General Considerations·······································································30
7.1.1
Definitions················································································30
7.1.2
General Stratification Criteria··························································30
7.2
Study Population ··············································································31
7.2.1
Disposition of Patients··································································31
7.2.2
Protocol Deviations ·····································································32
7.2.3
Demographic and Other Baseline Characteristics ···································32
7.2.4
Previous and Concomitant Medications ··············································33
7.3
Study Drugs····················································································34
7.3.1
Exposure··················································································34
7.3.2
Treatment Compliance··································································34
7.4
Analysis of Efficacy ··········································································35
7.4.1
Analysis of Primary Endpoint ·························································35
7.4.2
Analysis of Secondary Endpoints ·····················································37
7.4.3
CDAD Signs and Symptoms Evaluation ·············································41
7.4.4
Analysis of Exploratory Endpoints····················································41
7.4.5
Analysis of Other Endpoints ···························································42
7.5
Analysis of Safety·············································································42
7.5.1
Adverse Events ··········································································42
7.5.2
Clinical Laboratory Evaluation ························································43
7.5.3
Vital Signs················································································45
7.5.4
Electrocardiograms (ECGs)····························································45
7.5.5
Pregnancies···············································································45
7.6
Analysis of Drug Concentration·····························································45
7.6.1
Estimation of Pharmacokinetic Parameters ··········································45
7.6.2
Statistical Analysis ······································································45
7.7
Analysis of PD·················································································46


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7.8
Subgroup Analyses············································································46
7.9
Other Analyses ················································································46
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················46
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········46
7.11.1
Missing Data ·············································································46
7.11.2
Outliers ···················································································54
7.11.3
Visit Windows ···········································································54
8
DOCUMENT REVISION HISTORY ·························································58
9
REFERENCES ····················································································62
10
APPENDICES ·····················································································63
10.1
Appendix 1: Logical Derivation, Multiple Imputation Rules: ···························63
10.2
Appendix 2: Multiple Imputation Programing Guidelines, General 
Considerations: ················································································66
10.3
Appendix 3: Pre-Specified Criteria for Adverse Events of Interest·····················68
10.4
Appendix 4: Laboratory results Normal ranges ···········································69
10.5
Appendix 5: Vital Signs Normal Ranges···················································77
10.6
Appendix 6: Treatment Compliance ························································78
10.7
Appendix 7: Changes from Planned Analysis ·············································85
10.8
Appendix 8: Key Contributors and Approvers ············································86


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List of In-Text-Tables
Table 1
Schedule of Assessments·····································································11
Table 2
Definition of Clinical Response at EOT and Confirmed Clinical Response at 
EOT+2 days····················································································17
Table 3
Definition of Time To Resolution Of Diarrhea (TTROD) ·······························18
Table 4
Definition of Recurrence ·····································································19
Table 5
Clinical Laboratory Tests to be Performed·················································24
Table 6
Comparative dosing scheme in mg per day ················································27
Table 7
Planned dose in mg for complete treatment (10 days)····································27
Table 8
Prohibited Medication ········································································29
Table 9
Age group categories ·········································································31
Table 10
Liver function tests and criteria······························································44
Table 11
Analysis Windows for Safety Assessments················································55
Table 12
Analysis Window for Efficacy Assessments···············································56
Table 13
Queries to be raised from Efficacy Data ···················································63
Table 14
Logical Derivation/ Multiple Imputation for CCR········································63
Table 15
Logical Derivation/Multiple Imputation for Recurrence ·································64
Table 16
Global Cure Derivation for EOS (EoT+30 days)··········································65
Table 17
Search strategies for Adverse Events of Interest ··········································68
Table 18
Common Normal ranges for Hematology and Biochemistry ····························69
Table 19
Common Normal ranges for Vital Signs ···················································77
Table 20
Comparative dosing scheme in mg per day ················································78
Table 21
Planned dose in mg for complete treatment (10 days)····································78
Table 22
Weight band dosing instruction of the fidaxomicin oral suspension····················80
Table 23
Weight band dosing instruction of the vancomycin oral liquid··························81


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Transaminase
ASCM
Analysis Set Classification Meeting 
AST
Aspartate Transaminase
ATC
Anatomical Therapeutic Chemical
BDRM
Blinded Data Review Meeting
BMI
Body Mass Index
BQL
Below Quantifiable Limit
CCR
Confirmed Clinical Response at EOT+2days
CDAD
Clostridium Difficile Associated Diarrhea
CDI
Clostridium Difficile Infection
CI
Confidence Intervals
CRF
Case Report Form
CM
Concomitant Medication
CMH
Cochran-Mantel-Haenszel
CS
Classification Specifications
CSR
Clinical Study Report
DBP
Diastolic Blood Pressure
DILI
Drug-induced Liver Injury
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EIA
Enzyme ImmunoAssay
eDISH
Evaluation of Drug-Induced Serious Hepatotoxicity
ELISA
Enzyme-Linked Immunosorbent Assay
EMEA
European Medicines Agency
EOS
End of Study (EOT+30days)
EOT
End of Treatment 
EU
Europe


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Abbreviations
Description of abbreviations
FAS
Full Analysis Set
FID
Fidaxomicin
FSI
First Subject In
GC
Global Cure at EOT+9days, EOT+16 days, EOT+23days & EOT+30days (EOS)
GI
Gastrointestinal
GGT
Gamma Glutamyltransferase 
H
High
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICR
Initial Clinical Response at EOT
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISN
International Study Number
ITT
Intent To Treat
L
Low
LLOQ
Lower Limit of Quantification
LLN 
Lower Limit of Normal
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
MIC
Minimum Inhibitory Concentration
MPRconc
Metabolite to Parent Ratio concentration
MW
Molecular Weight
N
Normal
OP-1118
Main and active metabolite of Fidaxomicin
OTC
over-the-counter 
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PD
Protocol Deviation 
PI 
Principal Investigator
PK
Pharmacokinetic
PKAS
Pharmacokinetics Analysis Set
PT
Preferred Term


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Abbreviations
Description of abbreviations
RBC
Red Blood Cell
RMS
Root Mean Square
QTc
Corrected Q-T Interval
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SAS 
This is the registered name for particular software for statistical Analysis and 
reporting
SBP
Systolic Blood Pressure
SCR
Sustained Clinical Response at EOT+9days, EOT+16 days, EOT+23days & 
EOT+30days (EOS)
SOC
System Organ Class
TBL
Total Bilirubin
TC
Teleconference / telephone call
TEAE
Treatment Emergent Adverse Event
TLF
Tables, Listings and Figures
TTROD
Time to resolution of diarrhea
UBM
Unformed Bowel Movement
ULN
Upper Limit of Normal
VAN
Vancomycin
WBC
White Blood Cell
WHO-DD
World Health Organization Drug Dictionary


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List of Key Terms
Terms
Definition of terms
Baseline
A baseline measurement is the last available measurement before the start of first 
dosing (Day 1), regardless of whether the measurement was scheduled or 
unscheduled, and the change from baseline is calculated as follows: post-baseline 
value minus baseline value.  Observations on Day 1 are assumed to be pre-dose.
Enroll
To register or enter into a clinical trial. NOTE: Once a patient has been enrolled, 
the clinical trial protocol applies to the patient. 
End of Study
The end of the study is defined as the date of the last patient’s last contact (visit 
or TC) or assessment. 
End of Treatment
The day of the last dose of study drug (fidaxomicin or vancomycin) in the 
treatment period.
Intervention
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study (e.g., health-related 
quality of life, efficacy, safety, pharmacoeconomics).
In this study the interventions being investigated are:

Fidaxomicin twice daily for 10 days

Vancomycin four times daily for 10 days
Investigational 
period
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug is given to a patient, and continues until 
the last assessment after completing administration of the test drug or 
comparative drug. In this study the investigational period is from the first dose of 
study drug until the end of study
Randomization
The process of assigning trial patients to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential patients for enrollment in a trial.
Screen failure
Potential patient who was not randomized and did not receive any study drug.
Screening period
Period of time before entering the investigational period, usually from the time of 
signing consent until just before the test drug or comparative drug is given to a 
patient. 
Start of study
The start of the study is defined as the date that the first Informed Consent Form 
(ICF) is signed. 
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Sustained clinical 
response
Confirmed clinical response (EOT + 2 days) without CDAD recurrence until the 
time of assessment during the Follow-up period.
Time to 
recurrence 
The time (days) from confirmed clinical response until the onset of recurrence as 
defined below in Table 4
Treatment period
Time from the patient’s first dose of study drug (fidaxomicin or vancomycin) 
until their last dose of study drug.  Treatment for recurrence is not included in the 
treatment period
Please see also definitions Section 6 “Analysis Variables”


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data. 
Version 1 of the SAP was finalized on 7Nov20147th Nov2014 prior to First Subject In (FSI).  
If needed, revisions to the approved SAP may be made prior to database hard lock. Revisions 
will be version controlled.
This statistical analysis is coordinated by the responsible biostatistician of Astellas Data 
Sciences. Any changes from the analyses planned in the final SAP will be justified in the 
Clinical Study Report (CSR).
Prior to database hard lock, a final review of data and TLFs meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented. A meeting to determine analysis set classifications may also be held prior to 
database hard lock.
2
FLOW CHART AND VISIT SCHEDULE
Flow Chart
Study Schematic Diagram 
Start and End of Study
The start of the study is defined as the date that the first Informed Consent Form (ICF) is signed. 
The end of the study is defined as the date of the last patient’s last visit (End of Study). 
In case of premature withdrawal or failure during the treatment period, the patient should 
complete the End of Treatment (EOT) visit and End of Study (for safety information). 
In case of recurrence of diarrhea during the Follow-up period and for any other reason that in the 
opinion of the investigator requires a clinic visit, the patient should complete an Unscheduled 
visit for reassessment of CDAD.
Obtain 
informed 
consent
Screening 
period
Confirmation of 
in- and exclusion 
criteria
Treatment period 
(10 days) 
fidaxomicin or 
vancomycin
Follow-up 
period 
(30 days)


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Table 1
Schedule of Assessments
Study Period
Screening period
Treatment perioda
Follow up period
End of Study 
TC/Visit 
(EOS)k
Unscheduled 
Visitl
Screening
Daily Assessment
End of 
Treatment 
(EOT)f,g
Confirmation 
Clinical Response 
TC/Visith
Follow-up 
TC i
Day
-2  to 1
1b
2-4
5-10
10
EOT+2
EOT +9, 16 
& 23
EOT+30
Window (Daysu)
+2
+2
+2
+2
Assessments
Subject information & informed consent
X
Demographics
X
Height and Weight
X
Medical History
X
CDAD History
X
Investigator Evaluation of Signs & Symptoms 
of CDAD
X
X
Inclusion/Exclusion Criteria Check
X
Randomization
X
Study Drug Dosing
X
X
X
Study Drug Compliance Check
X
Previous and Concomitant Medication
X
X
X
X
X
X
X
X
X
CDAD Status (Subject/parent/legal guardian 
interview)e
X
X
X
X
X
X
X
Drug Concentration Blood Samplesn
X
Drug Concentration Stool Sampleo
X
Stool Sample for Toxigenic C.difficile and 
possible microbiology testing
Xm
Xr
Xj
Faecal Rotavirus Testingt
X
Palatabilityp
X
X
Table continued on next page


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Study Period
Screening period
Treatment perioda
Follow up period
End of Study 
TC/Visit 
(EOS)k
Unscheduled 
Visitl
Screening
Daily Assessment
End of 
Treatment 
(EOT)f,g
Confirmation 
Clinical Response 
TC/Visith
Follow-up 
TC i
Day
-2  to 1
1b
2-4
5-10
10
EOT+2
EOT +9, 16 
& 23
EOT+30
Window (Daysu)
+2
+2
+2
+2
Safety
Hematology, Biochemistry and Urinalysiss
X
X
O
Pregnancy Testc
X
X
O
Physical Examination
X
X
O
Vital Signsd
X
X
O
ECGq
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Efficacy
Clinical Response 
X
X
Recurrence j
X
X
Xj
X = required, O=optional
a)
Patients may be treated on an inpatient/outpatient/ or combined basis at the discretion of the investigator. 
b)
After all screening procedures are completed and the patient is eligible, the patient will be randomized and study drug will be administered. This is the start of the Treatment 
Period (i.e., Day 1)
c)
At Screening, at the End of Treatment (EOT) visit and at the Unscheduled visit (if deemed necessary by the investigator) a pregnancy test locally in urine (dipstick) will only be 
performed in women of childbearing potential. 
d)
Includes blood pressure, pulse, and body temperature.
e)
CDAD status will be assessed by interviews with the patient/parent/legal guardian (or hospital staff e.g., when hospitalized). These interviews will be conducted in the morning, 
daily during the treatment period through End of Treatment and at EOT+2; thereafter weekly at 9, 16 and 23 days after the EOT, and at End of Study (EOS) EOT + 30 days, 
following a standardized questionnaire. These interviews may be conducted by telephone (e.g., when not hospitalized). 
f)
Patients who discontinue study drug prematurely should complete the EOT visit as soon as possible after the final dose. 
g)
At EOT, the clinical response will be assessed. All patients will continue in the Follow-up period. 
Patients that have no clinical response will only be contacted at EOT +30 days for safety (adverse events).
Footnotes continued on next page


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h)
Two days after EOT, a telephone contact with the patient/parent/legal guardian or a visit (if the patient is still in the hospital) will take place for all patients with an initial clinical 
response at EOT to confirm the clinical response. All patients will continue in the 30-day Follow-up period. Patients without a confirmed clinical response will only be contacted 
at EOT +30 days for safety (adverse events).
i)
At 9, 16 and 23 days after EOT, for patients who had confirmed clinical response; the patient/parent/legal guardian will be contacted by phone. 
j)
For patients with a recurrence of diarrhea during the Follow-up period, an Unscheduled visit is mandatory, including a stool sample. The stool sample will be split in two aliquots 
one for detection of toxigenic C.difficile at site and one for the reference lab (for possible microbiological and biochemistry testing), for reassessment of CDAD (as per protocol 
criteria). Patients with recurrence of CDAD will after the Unscheduled visit continue in the Follow-up period and will only be contacted at EOT +30 days for safety (adverse 
events). 
k)
30 days after EOT, the EOS TC/visit will take place. For patients that had a confirmed clinical response at EOT +2 days and did not experience a recurrence during the Follow-up 
period, all assessments will be done, including sustained clinical response assessment. For all other patients a telephone call (TC) will be done for safety (adverse events).
l)
Unscheduled visits could take place throughout the study period, if deemed necessary by the investigator. Only those assessments that are relevant according to the investigators 
opinion should be performed. However, evaluation of adverse events (AE) and concomitant medication is mandatory. 
m) Stool sample will be split in two aliquots, one for the detection of toxigenic C. difficile at study site and one for the reference laboratory (for possible microbiological and 
biochemistry testing). Alternatively, a test for toxigenic C. difficile done as standard of care, including pre-consent samples, provided the sample was obtained within 72 hours 
prior to randomization, may be used to assess eligibility and a different sample sent to the reference laboratory. 
n)
For patients receiving fidaxomicin, two blood samples will be taken on any day between Day 5 and 10 inclusive. Every effort should be made to take these samples in conjunction 
with routine blood samples being taken for standard of care. However one sample should be collected within 30 minutes pre-dose and another between 1 to 5 hours post-dose. The 
two samples do not have to be collected on the same day. 
o)
For all patients a stool sample will be taken between Day 5 and 10 inclusive, within 24 hours of a dose.
p)
For patients receiving fidaxomicin oral suspension or vancomycin oral liquid palatability assessment will be performed on Day 1 and Day 7 (± 1 day).
q)
Two ECGs will be performed. One at screening prior to the first dose of study drug and another 1 to 5 hours post-dose (the morning or evening dose for the fidaxomicin arm, or the 
first or the third dose of the day for the vancomycin arm) on any day between days 5 and 10 inclusive, but not within 30 minutes after venipuncture. 
For the ECG at screening, an ECG that is performed before consent is acceptable, provided that it was recorded after the onset of CDAD and within 3 days prior to randomization. 
r)
At the EOT visit a stool sample will be split in two aliquots, one for direct or indirect testing for presence of toxigenic C.difficile at study site and one for the reference laboratory 
(for possible microbiological and biochemistry testing). 
s)
For hematology, biochemistry and urinalysis at Screening, results that were obtained per standard of care before consent (historical sample) are acceptable, provided that the 
sampling was done after the onset of CDAD and within 3 days prior to randomization. For the hematology, biochemistry and urinalysis at EOT visit, results that were obtained as 
part of standard of care between Day 8 and Day 10 (inclusive) (standard of care sample) are acceptable. The most recent results should be used for eCRF completion. The 
historical or standard of care sample may not include all parameters as described in Table 5, Section 6.2.2. A historical/standard of care samples without parameter(s) indicated 
with * in the table is acceptable.
t)
The window of +2 days allows the assessment to be up to 2 days later than the specified target, but no earlier
u)
For patients < 5 years only, a rotavirus test is required. A pre-consent standard of care result may be used (historical sample), provided the sample was taken after the onset of 
diarrhea and within 3 days prior to randomization.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
3.1.1
Primary Objective
The primary objective of this study is to investigate the clinical response to fidaxomicin oral 
suspension or tablets and vancomycin oral liquid or capsules of pediatric patients with 
Clostridium difficile-associated diarrhea (CDAD) from birth to < 18 years of age.
3.1.2
Secondary Objective
The secondary objectives of this study are to investigate the recurrence/sustained clinical 
response and safety of fidaxomicin and vancomycin in pediatric patients with Clostridium 
difficile-associated diarrhea (CDAD) from birth to < 18 years of age, as well as palatability 
(acceptance) of the fidaxomicin oral suspension formulation. 
3.2
Study Design
This is a multicenter, investigator-blind, randomized parallel group study to investigate the 
safety and efficacy of a 10-day course of fidaxomicin oral suspension or tablets and a 10-day 
course of vancomycin oral liquid or capsules in patients from birth to < 18 years of age with 
confirmed CDAD. Note that in the United States of America patients can only be included if 
aged ≥ 6 months to < 18 years.
In order to reduce differential assessment of safety and efficacy outcomes, typically a double-
blind study would be preferred. However, due to nature of the active treatment and the 
comparator (e.g., formulation differences, dosing regimen differences), double blinding of 
the study drug for this pediatric study population is not feasible, given dosing constraints. 
Therefore the study will be partially blinded at site – the study will be investigator-blinded, 
and sites will have blinded staff to carry out blinded assessments.  There will be blinded and 
unblinded CRAs, data managers, study managers and statisticians.  This SAP is written by 
the blinded statistician. The programming team will remain unblinded.
The study will be conducted in North America and Europe across ~65 to 80 sites. A target of 
144 eligible patients, stratified by age at enrollment (screening):
●
birth to < 24 months (2 years) (6 months to < 24 months at US sites), 
●
>= 2 years to < 6 years, 
●
>= 6 years to < 12 years, and 
●
>= 12 years to < 18 years 
A minimum of 24 patients will be in each age group. The remaining 48 patients may be in 
any age group.  Eligible patients are those randomized without any violations of inclusion or 
exclusion criteria. All patients randomized with PD1 will not be counted as eligible.
Patients will be randomized to either fidaxomicin or vancomycin arm in a 2:1 ratio, stratified 
by age group. 


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For patients receiving fidaxomicin, plasma and stool samples will be analyzed. Palatability 
will be assessed for all patients receiving fidaxomicin oral suspension or vancomycin oral 
liquid.
An independent external Data and Safety Monitoring Board (DSMB) will be established for 
this study.
3.3
Randomization
Patients will be randomized to either fidaxomicin or vancomycin arm in a 2:1 ratio, stratified 
by age group at enrollment (screening) from birth to < 24 months, >= 2 years to < 6 years, >= 
6 years to < 12 years, and >= 12 years to < 18 years.
Randomization will be performed via Interactive Response Technology (IRT), by the 
Sponsor’s designee (
). Prior to the first study drug 
administration, the unblinded site staff will contact the IRT system in order to determine the 
randomly assigned treatment. Specific procedures for randomization through the IRT are 
contained in the Study Procedures Manual (ASTEL00020201).  Treatment codes and other 
information (e.g., stratification) will be made available electronically to unblinded staff only.  
4
SAMPLE SIZE
One hundred forty four eligible patients will be randomized to either fidaxomicin or 
vancomycin in a 2:1 ratio (96 randomized to fidaxomicin and 48 to vancomycin), stratified by 
age at screening:
●
from birth to < 24 months (2 years) (6 months to < 24 months at US sites),
●
>= 2 years to < 6 years, 
●
>= 6 years to < 12 years, and 
●
>= 12 years to < 18 years. 
At least 24 patients will be in each age group (i.e., a minimum of 16 randomized to 
fidaxomicin and 8 to vancomycin). 
The sample size for this study was agreed with the Pediatric Development Committee as part 
of the Pediatric Investigational Plan (EMEA, 2012), and is based on clinical and practical 
considerations as the prevalence of the target disease in the study population is low. 
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of patients to analysis sets will be determined prior to database hard lock.


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5.1
Full Analysis Set (FAS)
The Full Analysis Set (FAS) consists of all randomized patients who received at least one 
dose of study drug (fidaxomicin or vancomycin), which is the primary analysis population.
In the FAS, patients will be allocated to the treatment arm corresponding to the study 
medication that the patient was randomized to (treatment allocation as randomized).  
The FAS will be used for efficacy endpoint analyses, as well as selected demographic and 
baseline characteristics.
5.2
Intent To Treat (ITT)
The intent-to-treat (ITT) set consists of all randomized patients, irrespective of a patient
having received a study drug (fidaxomicin or vancomycin) or not.
In the ITT, patients will be allocated to the treatment arm corresponding to the study 
medication that the patient was randomized to (treatment allocation as randomized).
The ITT will be used for efficacy endpoint analyses, as well as selected demographic and 
baseline characteristics when necessary. The ITT set was requested by the FDA.
5.3
Safety Analysis Set (SAF)
The Safety Analysis Set (SAF) consists of all randomized patients who received at least one 
dose of study drug (fidaxomicin or vancomycin). In the SAF, a patient will be allocated to the 
treatment arm corresponding to the study drug that was first administered (fidaxomicin or 
vancomycin), even if it differs from the treatment arm the patient was randomized to.
The SAF will be used for summaries of demographic and baseline characteristics and all 
safety and tolerability related variables. 
5.4
Pharmacokinetics Analysis Set (PKAS)
The Pharmacokinetics Analysis Set (PKAS) consists of all patients randomized to 
fidaxomicin, having received at least one dose of fidaxomicin and having at least one valid 
measurement of plasma concentration or faecal concentration of fidaxomicin or its main 
metabolite OP-1118.
Additional patients may be excluded from the PKAS at the discretion of the 
pharmacokineticist. Any formal definitions for exclusion of patients or time-points from the 
PKAS will be documented in the Classification Specifications.
The PKAS will be used for summarizing the Pharmacokinetic (PK) data.


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6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Primary Efficacy Endpoint
The primary efficacy endpoint is:

The proportion of patients with Confirmed Clinical Response (CCR) assessed by 
the investigator at EOT+2 days.
The CCR is a binary variable with a positive (Yes) or negative (No) outcome, which is 
recorded in the relevant CRF page. The Initial Clinical Response (ICR) will be evaluated at 
EOT. The ICR is a binary variable with a positive (Yes) or negative (No) outcome, which is 
also recorded in the relevant CRF page, similar to CCR. 
The definition of both CCR and ICR is age dependent and their definitions are given below 
on Table 2
Table 2
Definition of Clinical Response at EOT and Confirmed Clinical Response 
at EOT+2 days
Age
Clinical response
patients
from birth
to < 2 years
Absence of watery diarrhea for 2 consecutive days during treatment and patients 
remain well until the time of study drug discontinuation (initial clinical 
response). 
In addition, patients should not require further CDAD therapy within 2 days after 
completion of study drug (confirmed clinical response). 
Resolution of diarrhea is assessed during interviews of the patient/parent/ legal 
guardian supplemented by a review of the patient’s personal records for the day 
(if hospitalized), and the presence of watery diarrhea.
patients aged 
>= 2 years
to < 18 years
Improvement in the number and character of bowel movements as determined by 
< 3 unformed bowel movements (UBMs) per day for 2 consecutive days during 
treatment and patients remain well until the time of study drug discontinuation 
(initial clinical response). 
In addition, patients should not require further CDAD therapy 2 days after 
completion of study drug (confirmed clinical response). 
Resolution of diarrhea is assessed during interviews of the patient/parent/legal 
guardian, supplemented by a review of the patient’s personal records for the 
day (if hospitalized), and the number of UBMs.


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6.1.2
Secondary Efficacy Endpoints
The following endpoints are used to assess the study’s secondary efficacy objectives:
6.1.2.1 Proportion of Patients with Global Cure and Sustained Clinical Response at the 
EOS (EOT +30 days)
Sustained clinical response at EOS (EOT +30 days) and Global cure at EOS (EOT +30 days) 
are derived programmatically as follows:
●
Sustained clinical response (SCR) is assigned a positive outcome (SCR=Yes) at 
the EOS (EOT +30 days), for any patient that has a confirmed clinical response 
(CCR=Yes) at EOT + 2 days without CDAD recurrence (as defined below) until 
EOS (EOT +30 days) inclusive 
●
Sustained clinical response (SCR) is assigned a negative outcome (SCR=No) at 
the EOS (EOT +30 days), for any patient that has a confirmed clinical response 
(CCR=Yes) at EOT + 2 days with CDAD recurrence (as defined below) until 
EOS (EOT +30 days)
●
Global cure at EOS will be positive if SCR=Yes at EOT+30 days and negative 
otherwise (i.e., SCR=No or Missing).
6.1.2.2 Proportion of Patients with Global Cure and Sustained clinical response at 
EOT + 9, 16 and 23 days
Global cure and Sustained clinical response (SCR) at EOT + 9, EOT + 16 and EOT + 23 days 
is derived as for EOT+30 days, but replacing 30 days with 9, 16 or 23. 
6.1.2.3 Time to resolution of diarrhea (TTROD) 
Time to resolution of diarrhea (TTROD) (in hours rounded up from minutes > 30) definition 
is age dependent and its definition is given on Table 3 below.
Table 3
Definition of Time To Resolution Of Diarrhea (TTROD)
Age
Time to resolution of diarrhea (TTROD)
patients
from birth 
to < 2 years
The time elapsing (in hours rounded up from minutes > 30) 
from the start of treatment (time of first dose of study medication) 
to resolution of diarrhea (time of last episode of watery diarrhea the day 
prior to the first of 2 consecutive days without watery diarrhea that was 
sustained through EOT).
patients aged 
>= 2 years
to < 18 years
The time elapsing (in hours rounded up from minutes > 30) 
from the start of treatment (time of first dose of study medication) 
to resolution of diarrhea (time of the last UBM the day prior to the first of 
2 consecutive days of <3 UBMs that were sustained through EOT).


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TTROD is derived programmatically as follows:
TTROD (rounded up from minutes > 30) = (‘Date and Time* of resolution of diarrhea’ -
‘Date and Time of first dose of study medication**’) + 1
*= [Start Date and Start Time of last episode of watery diarrhea (children < 2 yrs) or 
unformed bowel movements < 3 (children >= 2 yrs) captured on the ‘Patient/Legal Guardian 
Interview Treatment Period’ page of the CRF]
**= [Start Date and Start Time of Treatment on ‘Study Drug Dosing’ page of the CRF]
6.1.2.4 Proportion of Patients with Recurrence of CDAD during or at the end of the 
Follow-up period.
The recurrence of CDAD is a binary variable with a positive (Yes) or negative (No) outcome, 
which is recorded in the relevant CRF page. 
The assessment of recurrence of CDAD during or at the end of the Follow-up period is 
applicable only to patients with an assessment of confirmed positive clinical response 
(CCR=Yes) at EOT+2 Days. The definition of recurrence is age dependent and its definition 
is given on Table 4 below.
Table 4
Definition of Recurrence
Age
Recurrence
patients 
from birth
to < 2 years
The re-establishment of watery diarrhea after confirmed clinical response 
to an extent that is greater than that noted on the last day of study drug 
with the demonstration of a positive direct or indirect testing for the 
presence of toxigenic C.difficile in stool and that, in the investigator's 
opinion, would require retreatment with CDAD anti-infective therapy.
patients aged 
>= 2 years
to < 18 years
The re-establishment of diarrhea after confirmed clinical response 
to an extent (as measured by the frequency of passed unformed stools) that 
is greater than that noted on the last day of study drug 
with the demonstration of a positive direct or indirect testing for the 
presence of toxigenic C.difficile in stool and 
that, in the investigator's opinion, would require retreatment with CDAD 
anti-infective therapy.


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6.1.2.5 Time to recurrence during or at the end of the Follow-up period.
Time to recurrence of CDAD is defined as the time (days) from confirmed clinical response 
until the onset of recurrence of CDAD as defined above. 
Time to recurrence of CDAD is derived programmatically in the database as follows:
Time to recurrence of CDAD (days) = (‘Date* first recurrence of CDAD -
‘Date** of CCR=Yes’) + 1
* = [Start Date of Clinical Event on ‘CDAD Status Recurrence’ page of the CRF]
**= [Start Date of Clinical Event on ‘CDAD Status Clinical Response’ page of the CRF]
Time to recurrence of CDAD assessment is applicable only to patients with a confirmed 
positive clinical response (CCR=Yes) at EOT+2 visit.
6.1.2.6 Palatability
Acceptance of formulation at first administration of study drug and at Day 7 (± 1 day) will be 
evaluated in all patients receiving fidaxomicin oral suspension and vancomycin oral liquid 
(i.e., patients from birth to =< 6 years and patients > 6 years unable to swallow tablets) on 
Day 1 and on Day 7 (±1 day) by means of a five-point rating scale by unblinded staff if 
hospitalized, and by the patient/parents/legal guardian when at home.
In case the drug product is rejected without actual oral administration, the response cannot be 
rated. This will be recorded in the eCRF.
6.1.3
Exploratory Efficacy Endpoints
 
 
 
 
 
 
 


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6.1.4
Other Efficacy Endpoints
●
Diarrhea status (Normal/ Diarrhea) for patients from birth to < 2 years, during the 
treatment period, as recorded daily in the CRF.
●
Number of UBM for patients aged ≥ 2 years to < 18 years, during the treatment 
period, as recorded daily in the CRF.
●
Diarrhea status (Normal/ Diarrhea) for patients ≥2 years will be derived based on the 
Number of UBM. Specifically, patients ≥ 2years, with UBM 0, 1, 2 will be set as 
“Normal”, while patients with 3 or more UBMs will be considered as “Diarrhea”.
6.2
Safety Variables
Safety will be assessed mainly by evaluation of the following variables:
●
Treatment-emergent adverse events (TEAEs; frequency, severity, seriousness, and 
relationship to study drug).
●
Clinical laboratory variables (hematology, biochemistry including liver function tests, 
and urinalysis)
●
Vital signs (systolic and diastolic blood pressure, pulse rate and body temperature)
●
12-lead electrocardiogram (ECG)
6.2.1
Adverse Events
Collection of adverse events (AEs) begins at the time the ICF is signed and continues through 
to the last assessments at the EOS Visit (Day 30). Any clinical signs or symptoms present 
prior to signing informed consent are to be recorded as medical history at the Baseline Visit 
(Day 1). Baseline conditions that worsen during the study are to be recorded as AEs. AEs 
beginning after patients had completed the last EOS assessments were not captured.
AEs ongoing at the EOS Visit (Day 30) are to be followed up for as long as necessary to 
adequately evaluate the patient’s safety or until the event stabilized. If the event resolved 
during the study, a resolution date was to be documented in the eCRF prior to patient’s study 
withdrawal.
Data to be recorded for AE included a description of the event, onset and end date, outcome, 
severity, seriousness, action taken for study drug, treatment required and relationship to the 
study drug.
Serious adverse events (SAEs) related to study drug were to be reported until 30 days after 
the EOS Visit (Day 30), but were not to be recorded in the eCRF.
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 17.0. 
The specified AEs / findings of interest for this study are shown below: 
●
Hypersensitivity to fidaxomicin
●
Gastrointestinal (GI) hemorrhage
●
Haematological AEs: Decreases in white blood cell (WBC), neutrophil and 
lymphocyte counts 


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●
Hepatic laboratory value abnormalities, Drug Induced Liver Injury (DILI) cases (refer 
to Section 6.2.2)
●
QT-interval prolongation 
●
Renal AEs: Laboratory value abnormalities
AEs of interest will be identified using Standardized MedDRA queries (SMQ) if available or 
sponsor-defined list of search term (refer to Appendix 10.3).
The development of antimicrobial resistance to fidaxomicin is a finding of interest (Protocol 
Section 5.5.1). This will be identified (if present) through the microbiological tests on the 
C. difficile through the study, rather than through adverse event reports.  This is because the 
results of the microbiological tests are available sometime after the patient has completed the 
study, and is not available to the investigator. Antimicrobial resistance might be difficult to 
assess using the microbiological results as there are no cutoff values to define what is a 
resistant or not resistant isolate. 
The lack of efficacy/lack of effect/treatment failure is also a finding of interest (Protocol 
Section 5.5.1). This will be assessed using the efficacy results rather than through adverse 
event reports. 
Definitions
TEAE is defined as an adverse event observed after starting administration of the test 
drug/comparative drug.  If the adverse event occurs on Day 1 and the onset check box is 
marked “Onset after first dose of study drug” or the onset check box is left blank, then the 
adverse event will be considered treatment emergent. If the adverse event occurs on Day 1 
and the onset check box is marked “Onset before first dose of study drug”, then the adverse 
event will not be considered treatment emergent. If a patient experiences an event both 
during the screening period and during the investigational period, the event will be 
considered as TEAE only if it has worsened in severity (i.e., it is reported with a new start 
date). 
A drug-related TEAE is defined as any TEAE with at least possible relationship to study 
treatment as assessed by the investigator or with missing assessment of the causal 
relationship. 
The severity of an AE is categorized as mild, moderate or severe.
6.2.2
Laboratory Assessments
Routine safety laboratory assessments will be performed at the Screening and End of 
Treatment visit by the local laboratory and recorded in the eCRF. Additional laboratory 
testing may be carried out by the investigator if deemed necessary.
In Table 5 the laboratory tests that will be performed during the conduct of the study are 
listed. See the Schedule of Assessments for study visit collection dates. It is not required that 
the patients are fasting prior to blood sampling for these assessments. Please refer to study 


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protocol Appendix 12.2 for additional Drug Induced Liver Injury (DILI) laboratory testing 
requirements and timing. 
For the hematology, biochemistry and urinalysis at Screening, results that were obtained as 
part of standard of care before consent (“historical sample”) are acceptable, provided that the 
sampling was done after the onset of CDAD and within 3 days prior to randomization. For 
the hematology, biochemistry and urinalysis at EOT visit, results that were obtained as part 
of standard of care between Day 8 and Day 10 (inclusive) (“standard of care sample”) are 
acceptable. The most recent results should be used for eCRF completion. If such results are 
not available, samples should be taken for the purpose of the study. The historical or standard 
of care sample may not include all parameters as described in Table 5  A historical/standard 
of care sample without parameter(s) indicated with * in the table is acceptable.
During screening, at the EOT visit and at the unscheduled visit (if deemed necessary by the 
investigator) the pregnancy test will be done locally in urine (dipstick). 
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/sub-investigator who is a qualified physician.
Any changes in laboratory values are to be evaluated by the investigator. Clinically relevant 
changes will be recorded as AEs in the eCRF.
Drug Induced Liver Injury (DILI) cases are defined as:
●
Moderate: ALT or AST > 3xULN or Total Bilirubin > 2xULN
●
Severe:     ALT or AST > 3xULN and Total Bilirubin > 2xULN.
In addition, the patient should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8xULN
●
ALT or AST > 5xULN for more than 2 weeks
●
ALT or AST > 3xULN and INR > 1.5 (If INR testing is applicable/evaluated).
●
ALT or AST > 3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).


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Table 5
Clinical Laboratory Tests to be Performed
Assessment Time Point
Screening;  End of Treatment ;  Unscheduled visit, as applicable
Hematology
Biochemistry
Urinalysis 
Hemoglobin
Hematocrit
Red Blood Cell (RBC)
WBC
Neutrophils
Segmented neutrophils*
Band neutrophils*
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Sodium*
Potassium
Calcium
Chloride*
Glucose*
Creatinine
C-reactive protein (CRP)*
Alkaline phosphatase
Aspartate Transaminase (AST)
Alanine Transaminase (ALT)
Gamma glutamyltransferase (GGT)*
Total bilirubin
Direct bilirubin*
Total protein*
Albumin
Protein*
Glucose*
pH*
Blood*
Beta hCG (females of 
child-bearing potential 
only)
* A historical / standard of care samples (see above) without parameter(s) indicated with * is acceptable. 
6.2.3
Vital Signs
Systolic and diastolic blood pressure, pulse rate and body temperature will be measured as 
indicated in the Schedule of Assessments.  
Wherever possible, for blood pressure and pulse rate measurements the same arm should be 
used throughout the study, and with the patient in the same position (sitting or supine). The 
size of the sphygmomanometer cuff should be age appropriate and not change throughout the 
study.
Whenever possible, the route and device used to measure body temperature should remain 
unchanged throughout the study.
6.2.4
Electrocardiogram (ECG)
Two 12 lead ECGs will be performed: one at Screening prior to the first dose of study drug 
and another 1 to 5 hours post-dose (the morning or evening dose for the fidaxomicin arm, or 
the first or the third dose of the day for the vancomycin arm) on any day between Days 5 and 
10 inclusive, but not within 30 minutes after venipuncture. 
For the ECG at Screening, an ECG that is performed as a part of standard of care before 
consent is acceptable, provided that it was recorded after the onset of CDAD and within 
3 days prior to randomization.


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ECG traces will be evaluated by the investigator who will give an overall interpretation and 
may leave a qualifying comment in the eCRF. The overall interpretation will be recorded as:
o
Normal, or
o
Abnormal – not clinically significant, or
o
Abnormal – clinically significant
Original ECGs will be collected for central ECG reading and returned to site if requested. 
Central ECG read data will be transferred electronically to the sponsor.  The central ECG will 
identify any potential abnormalities as findings; the ECG will then be assessed as to whether 
or not the ECG as a whole should be described as normal or abnormal.  In particular, if the 
ECG contained changes such as sinus tachycardia or sinus bradycardia and nothing else, 
these changes are quite common and the overall interpretation of the ECG is normal.
Any clinically significant adverse changes on the ECG will be reported as AEs in the eCRF. 
As well as the overall interpretation, the following ECG variables will be supplied by the 
central laboratory: PR duration (msec), RR duration (msec), QRS duration (msec), QT 
duration (msec), QTcB (msec), QTcF (msec) and Heart rate (beats/min).
6.2.5
Physical Examination
The patient’s physical state will be examined and recorded at Screening, End of Treatment, 
and if deemed necessary by the investigator at an Unscheduled visit. This includes 
examination of main body systems. The date of the physical examination only will be 
recorded in the eCRF. Any clinically relevant adverse change will be recorded as an AE in 
the eCRF.
6.2.6
CDAD Signs and Symptoms
CDAD signs and symptoms (highest body temperature in the 3 days prior to first dose, 
highest white blood cell in the 3 days prior to first dose, abdominal discomfort, and 
abdominal tenderness) will be recorded at Screening. Abdominal discomfort and abdominal 
tenderness will be recorded at End of Treatment. Any clinically relevant change will be 
recorded as an AE in the eCRF.
6.3
Drug Concentration Variables
Plasma and stool samples are collected and analyzed for fidaxomicin and its main metabolite 
OP-1118 concentrations. 
●
Plasma concentrations of fidaxomicin and its main metabolite (OP-1118) within 
30 minutes pre-dose (Ctrough) and 1 to 5 hours post-dose taken on any day between Day 5 
and 10 inclusive. 
●
Faecal concentration of fidaxomicin and its main metabolite (OP-1118) within 24 hours 
after dosing between Day 5 and 10 inclusive.
●
Metabolite to Parent concentration Ratio MPRconc: 


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MPRconc= [concentration of OP-1118]*[molecular weight (MW) of 
fidaxomicin]/[concentration of fidaxomicin]*[MW of OP-1118].
MW fidaxomicin(=parent)= 1058.04 g/mol, MW OP-1118(=metabolite) = 987.949 g/mol.
6.4
Other Variables
6.4.1
Demographic Data and Baseline Characteristics
The patient’s age, gender, race and ethnicity (if permitted), height and weight will be 
recorded at screening visit.
6.4.2
Medical History
Medical history (other than for CDAD) for each patient will be obtained at Screening. 
Relevant past and present conditions, as well as prior surgical procedures will be recorded in 
the eCRF.
6.4.3
Diagnosis of the Target Disease, Severity, and Duration of Disease 
A detailed diarrhea history for each patient will be obtained during Screening. This includes 
start and stop date, antibiotic treatment, and all CDAD episodes that occurred in the last three 
months prior to screening. Additionally, start date and signs and symptoms of the current 
CDAD episode will be collected, including number of UBMs/ presence of watery diarrhea 
within 24 hours prior to randomization. The following risk factors will be collected in the 
eCRF: Antibiotics/ Cancer/ Other, if applicable.
6.4.4
Rotavirus
For patients < 5 years only, a rotavirus test is required at Screening. A pre-consent standard 
of care result (historical sample) may be used, provided the sample was taken after the onset 
of diarrhea and within 3 days prior to randomization.
6.4.5
Duration of exposure
For each patient, the Length of Time on study drug will be calculated in days, using the 
following formula:
Length of Time on treatment (days) = (‘Date last dose of study drug’ - ‘Date first dose’) + 1
[Date of First/Last Dose of Study Drug, captured on the ‘Study Drug Dosing’ CRF] 
6.4.6
Treatment compliance
Overall compliance to the dosing schedule will be examined for patients in the safety 
population and in the efficacy population. Percent treatment compliance is defined as:
                                                           Actual amount of study drug used x 100
Treatment compliance (%) = ----------------------------------------------------------------------------
                                               Planned amount of drug that should have been used in 10 days


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Although dosing by weight bands is preferred according to dosing instruction, some patients 
may have been dosed based on individual weight (mg/kg) rather than by weight bands. The 
protocol mentions both weight band dosing and dosing according to mg/kg/day. This is the 
reason treatment compliance will be calculated based on both dosing options (weight bands 
and individual weight).
Details on compliance calculation can be found in Appendix 10.6
If a patient discontinues study drug early due to an AE, this is not a deviation because the 
protocol was followed. There is no need to report a deviation if there is an explanation such 
as dropping tablets down the sink by accident, provided that the correct dose was received by 
the patient (e.g., tablets replaced). 
For patients who completed the treatment period and have no data for study drug returned or 
partially missing data (e.g., 2 bottles were dispensed but only one was returned), but do have 
data for study drug dispensed, compliance will be missing. For all calculations empty bottle 
weight for fidaxomicin is 109.6 g, while for vancomycin is 27.2 g.
Table 6
Comparative dosing scheme in mg per day
Fidaxomicin
Vancomycin
Weight band of patient
Oral Suspension
Tablets
Oral Liquid
Capsules
≤ 3.9 kg
  80 mg
400 mg
100 mg
500 mg
4.0-6.9 kg
160 mg
200 mg
7.0-8.9 kg
240 mg
300 mg
9.0-12.4 kg
320 mg
400 mg
≥ 12.5 kg
400 mg
500 mg
Table 7
Planned dose in mg for complete treatment (10 days)
Fidaxomicin
Vancomycin
Weight band of patient
Oral Suspension
Tablets
Oral Liquid
Capsules
≤ 3.9 kg
  800 mg
4000 mg
1000 mg
5000 mg
4.0-6.9 kg
1600 mg
2000 mg
7.0-8.9 kg
2400 mg
3000 mg
9.0-12.4 kg
3200 mg
4000 mg
≥ 12.5 kg
4000 mg
5000 mg
6.4.7
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy)
Previous medication (medication history) taken within a month prior to screening will be 
entered in the Electronic Case Report Form (eCRF).  Any treatments of relevance to CDAD, 


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either as treatments for CDAD or causative agents such as antibiotics or anti-cancer therapies 
used within 3 months prior to screening should be recorded in the eCRF.
Concomitant medication (CM) includes relevant therapies prescribed by the study doctor, 
other doctors and over the counter drugs taken from Day 1 until the EOS (EOT visit + 30 
days) and should be recorded in the eCRF.
Medication history and concomitant treatment consists of drug and non-drug therapies, 
prescribed and over-the-counter (OTC) and all alternative medicines (e.g.,
herbal/homeopathic medicines). This also includes drugs used on a chronic and as-needed 
basis. Patients will be instructed not to start any new medication during the screening period 
through EOS, both prescribed and OTC, without prior consultation of the investigator 
wherever possible.
6.4.8
Prohibited Medication
Identification of prohibited medications will be detailed in the medical review plan.
It is preferred that prior to randomization, no pretreatment for CDAD is given. However, if 
the investigator feels there is a clinical imperative to begin treatment before knowing the 
laboratory result of direct or indirect testing for presence of toxigenic C.difficile, up to four 
doses but no more than 24 hours of treatment with metronidazole, oral vancomycin or any 
other effective treatment for CDAD are allowed.
Co-administration of potent P-glycoprotein inhibitors such as cyclosporine, ketoconazole, 
erythromycin, clarithromycin, verapamil, dronedarone and amiodarone is not recommended, 
but these medications are not prohibited.
Whenever possible, drugs which could affect peristalsis should be avoided. 
Part A - Prohibited Medications 
No other antibacterial agents potentially useful in the treatment of CDAD (e.g., 
metronidazole, oral vancomycin, oral bacitracin, fusidic acid, rifaximin, nitazoxanide) or 
faecal transplantation should be given during the study unless they are specifically given 
because of a primary treatment failure or suspected CDAD recurrence after initial clinical 
response. Faecal transplantation will be confirmed by Medical review.
Drugs to control diarrhea (e.g., loperamide) should also be withheld during the study period.
Use of these medications is prohibited during the entire study, unless they are specifically 
given because of a primary treatment failure or suspected CDAD recurrence after initial 
clinical response. 
Part B - Medications Permitted With Restrictions 
The use of these medications is to be avoided between Screening and End of Study. They are 
permitted provided the patient has been taking this medication on a long-term basis on the 
same dose and will continue with the same dose during the study. 


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Patients receiving opioids for pain prior to randomization may continue to receive the same 
opioid and dose during the treatment phase if required. 
Table 8
Prohibited Medication 
Part A
Part B
CDAD treatment 
Drugs to that could affect peristalsis
Oral vancomycin
Loperamide 
Metronidazole 
Codeine
Oral bacitracin 
Morphine
Fusidic acid 
Pethidine
Rifaximin 
Fentanyl
Nitazoxanide  
Methadone
Linezolid 
Tramadol
Rifampicin 
Other opioids
Faecal transplantation
Antiinfectives for Systemic Use
Intestinal Antiinfectives 
Drugs for Constipation
These lists are not exhaustive. In case of doubt, the investigator should contact the local 
study monitor. 
Note – the medications are prohibited unless they are specifically given because of a primary 
treatment failure or suspected CDAD recurrence after initial clinical Response.  So 
medications in the above categories should be counted as prohibited from randomization to 
treatment failure (ICR=No, CCR=No or Recurrence) or 30 days after EoT – whichever 
comes first.  Medications marked as for “CDAD recurrent episode” should be checked by 
medical review.
Opioids are allowed if kept at the same dose from before randomization and through the trial.
The route should also be taken into account.  Topically used drugs only have a local effect 
and therefore are allowed. The following routes are exempt for prohibited/restricted used: 
topical, ophthalmological, otic, intranasal, intravaginal, intradermal and intraarticular. If the 
route is missing – this should be checked by medical review.  
Identification of prohibited and restricted medications will be handled programmatically 
using ATC codes and WHO Drug codes provided by the Medical Coding group, and will be 
checked and confirmed by medical review.


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7
STATISTICAL METHODOLOGY
7.1
General Considerations
For continuous variables, descriptive statistics will include the number of patients (n), mean, 
standard deviation, median, minimum and maximum. When needed, the use of other 
percentiles (e.g., 10%, 25%, 75% and 90%) will be mentioned in the relevant section. 
Frequencies and percentages will be displayed for categorical data. Percentages by categories 
will be based on the number of patients with no missing data, i.e. will add up to 100%. Where 
results for missing values are imputed, according to the rules in this document, these patients 
will be included in the denominator.
All statistical comparisons will be made using two sided tests at α=0.05 significance level 
unless specifically stated otherwise.
All data processing, summarization, and analyses will be performed using SAS® Version 9.3 
(SAS Enterprise Guide 4.1) on UNIX. Specifications for table, figures, and data listing 
formats can be found in the TLF specifications for this study.
Generally, listings will be provided for all available patients that passed screening, unless 
specified otherwise (see TLF Specifications for further details). Patient(s) with missing data 
for variables related to a particular listing will be excluded from that listing.
7.1.1
Definitions
Baseline: Unless otherwise specified, a baseline measurement is the last available 
measurement before the start of first dosing (Day 1), regardless of whether the measurement 
was scheduled or unscheduled, and the change from baseline is calculated as follows: post-
baseline value minus baseline value.  Observations for the screening visit on Day 1 are 
assumed to be pre-dose.
Treatment:  All summaries will be presented by treatment arm and overall. For all efficacy 
summaries, patients will be considered part of the treatment arm corresponding to the 
planned treatment they were randomized to (see FAS, ITT definition on Section 5). For all 
safety summaries, patients will be considered part of the treatment arm corresponding to the 
actual treatment they received even if this is different from the one they were randomized to 
(see SAF definition on Section 5).
7.1.2
General Stratification Criteria
All summary tables are to be provided by treatment arm: 
                  Treatment arm:           fidaxomicin / vancomycin.


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Additionally, summary tables (except tables presenting endpoints using multiple imputation) 
will be further stratified by age categories as defined below:
Table 9
Age group categories
Age Group (Years)
Overall [From birth  to < 18 years]

From 6 months to < 18 years  

From birth to < 2 years (24 months) 

From birth to < 6 months

>= 6 months to < 2 years

>= 2 years to < 18 years

>= 2 years to < 6 years

>= 6 years to < 12 years

>= 12 years to < 18 years
For summary tables presenting confirmed clinical result, global cure, sustained clinical result 
and recurrence with multiple imputation (MI), age stratification will include the following 
unique age levels:
●
From birth to < 2 years
●
>= 2 years to < 6 years
●
>= 6 years to < 12 years
●
>= 12 years to < 18 years
For listings where age group information is presented as well, the following 5 unique age 
groups will be displayed:
●
From birth to < 6 months
●
>= 6 months to < 2 years
●
>= 2 years to < 6 years
●
>= 6 years to < 12 years
●
>= 12 years to < 18 years
Further factors to be considered for by subgroup analyses are mentioned in Section 7.8
7.2
Study Population
7.2.1
Disposition of Patients
●
Number and percentage of patients with informed consent, discontinued before 
randomization, randomized by age group (overall only and not by treatment group) ;
●
Number and percentage of patients randomized in each analysis set, by treatment group
and overall, by age group and overall;
●
Number and percentage of patients completed and discontinued treatment, by primary 
reason for treatment discontinuation for randomized patients, by treatment group and by 
age group; 


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●
Number and percentage of patients completed and discontinued the study, by primary 
reason for study discontinuation for randomized patients and by treatment group and by 
age group; 
7.2.2
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. For the purposes of this protocol, deviations 
requiring notification to Sponsor are defined as any patient who: 
●
Entered into the study even though they did not satisfy entry criteria. 
●
Developed withdrawal criteria during the study and was not withdrawn.
●
Received wrong treatment or incorrect dose. 
●
Received excluded concomitant treatment. 
Protocol deviations will be assessed for all randomized patients. The number and percentage 
of patients meeting any criteria will be summarized for each criterion and overall, by 
treatment group and total and separately by age group. Patients deviating from a criterion 
more than once will be counted once for the corresponding criterion. Any patients who have 
more than one protocol deviation will be counted once in the overall summary. A data listing 
will be provided by site and patient.
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:
●
PD1 - Entered into the study even though they did not satisfy entry criteria, 
●
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
●
PD3 - Received wrong treatment or incorrect dose,
●
PD4 - Received excluded concomitant treatment. 
PD3 will be divided in 2 sub categories:
●
PD3_1 – Wrong study medication or expired medication dispensed to the patient or 
study drug has expired or considered damaged due to a temperature excursion
●
PD3_2 – Incorrect dose of study medication dispensed to the patient or compliance 
<80% or >120% between first dose and last dose of study drug intake
7.2.3
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized by descriptive statistics.
Number and percentage of patients randomized in each country and site will be presented by 
treatment group for the ITT, FAS and SAF.
Descriptive statistics for age, weight, and height at study entry will be presented.  Frequency 
tabulations for sex, age group (defined in Section 7.8), ethnicity and race (where available) 
will be presented. This will be done for the all randomized patients (ITT), as well as for the 
SAF and FAS by treatment group and by age group.


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7.2.3.1 Diagnosis of the Target Disease
Frequency tables for the screening characteristics related to diagnosis of the target disease 
will be produced. This includes occurrences of previous CDAD episodes, presence of watery 
diarrhea within 24 hours prior to randomization (for patients less than 2 years of age), use of 
antibiotics, and CDAD treatment outcome for all CDAD episodes that occurred in the last 
three months prior to screening, contributing risk factors for current CDAD episode, rotavirus 
test result and result of the rapid CDI test.
Descriptive statistics will be provided for the number of UBM (for patients aged 2 years or 
more).
All summary tables will be produced by treatment arm and overall for each age group 
category for the FAS, ITT and SAF population.
All data related to the diagnosis of the target disease at screening, including result from the 
rapid CDI test and stool sample analyses will be listed.
For the rapid CDI test, all results obtained on or prior the day of first dose will be listed. For 
the summary tables, the value obtained from the CRF visit labeled as screening will be used. 
If missing, the first non-missing value on or prior the day of first dose will be used. 
7.2.3.2 CDAD Signs and Symptoms at Screening
CDAD signs and symptoms (highest body temperature in the 3 days prior to first dose, 
highest white blood cell in the 3 days prior to first dose, abdominal discomfort, and 
abdominal tenderness) will be presented in frequency tables for the ITT, FAS and SAF.  
The above tables will be repeated by age group.
All data related to CDAD signs and symptoms at screening will be listed.
7.2.3.3 Medical History
Medical history is coded in MedDRA version 17.0, and will be summarized by System Organ 
Class (SOC) and Preferred Term (PT) as well as by PT alone, by treatment group and by age 
group for the ITT, FAS and SAF. 
7.2.4
Previous and Concomitant Medications
Previous medications are coded with WHO-DD, and will be summarized by Group (ATC 1st
level), therapeutic subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and 
preferred WHO name by treatment group for the ITT, FAS and SAF. 
As with previous medication, concomitant medication will be summarized for each treatment 
group by Group (ATC 1st level), therapeutic subgroup (ATC 2nd level) and chemical 
subgroup (ATC 4th level) and preferred WHO name for the FAS and SAF. Patients taking the 
same medication multiple times will be counted once per medication and investigational 
period. A medication which can be classified into several chemical and/or therapeutic 
subgroups is presented in all chemical and therapeutic subgroups.


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In addition, prohibited and restricted/concomitant medication treatment use will be 
summarized separately for each treatment group by Group (ATC 1st level), therapeutic 
subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name 
by age group and overall. The list of medications will be reviewed and the list of codes for 
prohibited medications updated accordingly during the course of the study. 
Listings of all prior and concomitant medications will also be provided.
7.3
Study Drugs
7.3.1
Exposure
The following information on drug exposure will be presented for each treatment group for 
the FAS and SAF:
●
Descriptive statistics for cumulative amount of the drug patient was exposed to and 
average daily dose; 
●
Duration of exposure will be summarized in two ways:
o
Descriptive statistics will be presented by treatment group and age group.
o
Exposure time will be categorized according to the following categories by 
treatment group and age group:

< 5 days

>= 5 days,  < 8 days 

>=  8 days, ≤ 11 days 

> 11 days

Unknown.
Counts and percentages of patients in each of these categories will be summarized for each 
treatment group for the FAS and SAF.
Exposure and duration will be calculated as defined in Section 6.4.5
7.3.2
Treatment Compliance
Overall compliance with the dosing schedule will be examined for patients in the FAS and 
SAF whose total study drug count and first and last days of treatment are known.
Percent overall compliance will be summarized in two ways for the FAS and SAF:
●
Descriptive statistics will be presented by treatment group and age group.
●
Percent compliance will be categorized according to the following categories by 
treatment group and age group:
○
less than 50%
○
equal to or greater than 50%, less than 80%
○
equal to or greater than 80% less than or equal to 120%
○
greater than 120%
○
Unknown.


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Compliance will be calculated as defined in Section 6.4.6 The percent compliance for the 
FAS will be calculated based on the study drug that was first administered but will be 
summarized to the treatment arm corresponding to the study drug that was randomized to.
7.4
Analysis of Efficacy 
7.4.1
Analysis of Primary Endpoint
The primary efficacy endpoint of confirmed clinical response (CCR) at EOT+2 days as 
assessed by the Investigator will be analyzed using the primary analysis set of FAS.
For patients with ICR=No, it is expected to have CCR=No; if this is not the case then CCR 
will be set to No, for the purpose of this analysis. This is the definition of CCR endpoint.
The CCR is a binary variable with a positive (Yes) or negative (No) outcome. A missing 
CCR outcome or a CCR assessment marked as “Not done” will be imputed using logical 
derivation (based on rules presented in Section 7.11.1) and multiple imputation (MI) 
approach (Rubin 1987). Details on the multiple imputation method to be applied for the 
primary analysis are described in Section 7.11.1.1
Within each treatment arm, the proportion of patients with confirmed clinical response 
(CCR=Yes) at EOT+2 days will be calculated based on the entire number of FAS patients, 
and also based on patients with non-missing CCR (Yes/No). The corresponding two-sided 
95% CI will be calculated based on an exact binomial distribution for each treatment group. 
The unadjusted difference of proportions (FID - VAN) will be calculated as well.
The proportion of patients with CCR and the unadjusted difference proportion will also be 
presented using the multiple imputation method (using exact binomial distribution for 95% 
CI). 
In addition, the adjusted treatment difference of proportions (fidaxomicin-vancomycin) (FID-
VAN) will be calculated using a stratified Cochran-Mantel-Haenszel (CMH) method, where 
the 95% CI will be calculated using Newcombe method (Mehrotra et al., 2000, Yeonhee K. 
et al. 2013). The strata will consist of the age grouping levels, used during the stratified 
allocation of patients at screening (birth to < 24 months, ≥ 2 years to < 6 years, ≥ 6 years to 
< 12 years, and ≥ 12 years to < 18 years).
7.4.1.1 Sensitivity Analysis of Primary Endpoint
The following analyses will be conducted as sensitivity analysis for the primary efficacy 
endpoint of CCR at EOT+2 days using FAS dataset.
The statistical methods described in Section 7.4.1 will be applied to patients that have 
completed the 10-day treatment period (completers). In this case the proportion of patients 
with confirmed clinical response (CCR=Yes) at EOT+2 days in each treatment group will be 
calculated based on completers and not on the entire population (FAS).
Furthermore, the primary endpoint analysis will be repeated excluding the data of site 
 
(two patients: 
). It was determined that the Principal Investigator 
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the IRB terminated all the studies of the PI. The Quality Counsel of Astellas recommended 
that the efficacy data from this site be included in the primary analysis as no signs of fraud 
have been observed for these two patients. The sensitivity analysis will be conducted to 
confirm that there is no change in the results of the primary endpoint with and without these 
two patients. 
7.4.1.2 Other Analysis of Primary Endpoint
An analysis of the primary endpoint will be conducted on the ITT set as well. The method 
used for this analysis will be similar to the primary analysis described in Section 7.4.1  The 
proportion of patients with confirmed clinical response (CCR=Yes) at EOT+2 days within 
each treatment group as well as the adjusted treatment difference of proportions will be 
calculated based on the entire number of ITT patients.
7.4.1.3 Subgroup Analysis of Primary endpoint
Subgroup analyses will be conducted on the FAS and ITT. 
The proportions of patients with confirmed clinical response (CCR=Yes) at EOT+2 days, for 
each age group (as defined in Section 7.1.2), will be calculated based on the number of 
patients within each age group. The corresponding two-sided 95% CI will be calculated for 
each age group within each treatment arm, based on an exact binomial distribution, in the 
same manner as for the analysis of the primary efficacy endpoint (Section 7.4.1). The 
unadjusted difference of proportion (FID – VAN) will be calculated as well, along with its 
95% CI (using exact binomial distribution).
In addition, the following sub analysis will be performed. The statistical methods described 
in Section 7.4.1 will be applied to a subset of FAS. This subset will include patients with 
confirmed C. difficile at baseline. Patients with confirmed C. difficile are patients having a 
positive C. difficile result for two test types, at least one from group A and at least one from 
group B, according to the ESCMID guidelines on diagnosis of CDI (Crobach M.J.T. et al., 
2009 and 2016). Confirmed CDI is also possible when both antigen (normally GDH) and 
Toxin A/B are detected by Enzyme Immunoassays (EIA) using dual laboratory techniques 
(group C):
●
Group A: Detection of C. difficile antigens (typically GDH) OR C. difficile DNA 
(typically the Toxin A and/or B genes)
●
Group B: Demonstration of the presence OR activity of free C. difficile Toxin A/B 
(Toxin A/B EIA/ELISA at central or local laboratory)
●
Group C: Positive for both A AND B when using a dual testing system (e.g.,
C. difficile Quik Check Complete)
The following combinations of C. difficile test results at baseline will be used:
●
Local test positive using Direct Detection of Toxin (Group B) AND [central 
PCR/BioFire positive for C. difficile (Group A) OR central Culture positive for 
C. difficile if PCR/Biofire data not available (missing)]


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●
Local test positive using Culture (Group A, assuming that Culture refers to anaerobic 
culture) AND central ELISA positive (Group B)
●
Local test positive using PCR (Group A) AND central ELISA positive (Group B)
●
Central ELISA positive (Group B) and PCR/BioFire positive for C. difficile (Group 
A)
For local tests using other method than direct detection of toxin, PCR or culture, the results of 
central ELISA and PCR/Biofire tests will first be considered to determine confirmed C. 
difficile. If central results are missing or negative, a manual review of local test method will 
be conducted to determine to which group the local result belongs to (Group A, B or C). 
In this case the proportion of patients with confirmed clinical response (CCR=Yes) at EOT+2 
days in each treatment group, as well as the adjusted treatment difference of proportions , 
will be calculated based on the above defined subset population of FAS and not on the entire 
population (FAS).
Furthermore, a similar approach will be applied to a subset of FAS excluding patients with 
central BioFire test positive for gastrointestinal (GI) pathogens other than C. difficile at 
baseline or at EOT. 
The primary analysis of the primary endpoint will also be repeated by the following 
subgroups based on central BioFire PCR results at baseline:
●
Patients with confirmed C. difficile and no other GI pathogens detected
●
Patients with confirmed C. difficile and other GI pathogens detected
●
Patients with no confirmed C. difficile and other GI pathogens detected
●
Patients with no confirmed C. difficile and no other GI pathogens detected
The last 2 subgroups might be dropped if they do not include sufficient number of patients.
7.4.2
Analysis of Secondary Endpoints 
Analysis of the secondary efficacy endpoints except for palatability will be based on the FAS 
and ITT analysis sets when applicable.
7.4.2.1 Global Cure at EOS (EOT +30 days)
Global cure (Yes/No) at the EOS will be analyzed using the same statistical methods as 
outlined in Section 7.4.1. The proportions s of patients with global cure in each treatment 
arm, and the difference in these proportions (FID-VAN) between the treatment arms will be 
provided along with 95% CIs.
Global Cure will be calculated using Sustained Clinical Response (SCR) and ICR/CCR 
values according to the following conditions:
●
if ICR/CCR=Yes and SCR=Yes, then Global Cure will be Yes.
●
if ICR/CCR=Yes and SCR =No, then Global Cure will be No.
●
if ICR/CCR=No (SCR not assessed), then Global Cure will be No.
●
if ICR/CCR=Missing (SCR not assessed), then Global Cure will be set to No.


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ICR/CCR and SCR results after logical derivation will be used.
The proportion for each treatment arm is calculated as:
                                     # of patients with Global cure at EOS (EOT +30 days)
Proportion (%) = -----------------------------------------------------------------------x 100
                                                             # Of FAS (or ITT) patients                            
Note the denominator will be # of FAS patients, regardless of ICR/CCR status.
Additionally, Global Cure will be derived using Multiple Imputation in case 
ICR/CCR=Missing (SCR not assessed) following Rubin’s multiple imputation method. 
Details of MI method are described in Section 7.11.1.2
Within each treatment arm, the proportion of patients with GC at EOS will be calculated 
based on the entire number of FAS patients regardless of ICR/CCR status. In addition, the 
proportion of patients with GC at EOS will be calculated based on MI method when missing
value are observed.
7.4.2.2 Global Cure at EOT+9, EOT+16 and EOT+23 days
The proportions of patients with global cure at EOT+9, EOT+16 and EOT+23 days, in each 
treatment arm, and the difference in these proportions (FID-VAN) between the treatment 
arms will be provided along with corresponding 95% CIs in the same manner as for the 
primary analysis of the primary efficacy endpoint. The proportion for each treatment arm is 
defined as:
                           # of patients with Global cure at EOT +9 days (+16 days, +23 days)
Proportion (%) = ---------------------------------------------------------------------------- x 100
                                                       # Of FAS patients                       
Note the denominator will be # of FAS patients, regardless of ICR/CCR status.
Global Cure will be calculated using Sustained Clinical Response and ICR/CCR values 
according to the conditions described in Section 7.4.2.1  Compared to the analysis for Global 
cure at EOS, no Multiple Imputation will be used for Global Cure at EOT+9, EOT+16 and 
EOT+23 days.


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7.4.2.3 Time to resolution of diarrhea (TTROD)
The survival functions in both treatment arms will be estimated using the Kaplan-Meier 
method and displayed graphically. Comparison of the survival curves of the two treatment 
arms will be done using Log-Rank test. Quartile estimates (25th, 50th [median], and 75th) 
along with 80th and 90th Percentile estimates for the time-to-event and corresponding two-
sided 95% CIs will be computed for both treatment arms. 
Patients who complete the 10-day treatment period but do not show resolution of diarrhea 
until EOT (initial clinical response) will be censored at Day 10 (240 hours). 
Patients who do not complete the 10-day treatment period and do not show resolution of 
diarrhea until day of discontinuation will be censored at day of discontinuation or at day of 
last dose taken, the first that occur (days converted to hours).
Patients who do not receive study drug (possibly received another drug for Diarrhea), 
belonging to ITT population, Day 10 will be used as End of Treatment Date for the TTROD 
analysis.
Patients with last known episode of diarrhea prior to the first dose are included in the analysis 
with a time to resolution to diarrhea of 1 hour.
7.4.2.4 Sustained Clinical Response and Recurrence of CDAD during or at the end of 
the Follow-up period.
The proportion of patients with recurrence in patients with confirmed clinical response at 
EOT+2 days visit in the two treatment arms and the difference in the proportion (FID-VAN) 
between the treatment arms will be provided along with corresponding 95% CIs in the same 
manner as for the primary analysis of the primary efficacy endpoint. The proportion for each 
treatment arm here is defined as:
                       # Of patients with recurrence during or at the end of the Follow-up period 
Proportion (%) = --------------------------------------------------------------------------------x 100
                          # Of patients with confirmed clinical response (CCR=’Yes’) 
                                                 at TC/visit (EOT+2 days)                        
Note the denominator will not be # of FAS patients
The endpoint analysis will be considered in a cumulative way. The first occurrence of 
recurrence event will be used as analysis endpoint. After the first recurrence event, all 
subsequent time points will be considered as having already had a recurrence, for the purpose 
of this analysis.
Sustained clinical response, which is the opposite of recurrence, will be presented similarly.
Additionally, a recurrence of CDAD assessment with a missing outcome or an assessment 
marked as “Not done” will be imputed using a multiple imputation approach in order to 
compensate for the lack of information that could arise during the course of the study. Details 


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on the multiple imputation methods to be applied for the analysis of this secondary endpoint 
are described in Section 7.11.1.2
Within each treatment arm, the recurrence proportion will be calculated based on the number 
of FAS patients with CCR=Yes. In addition, the recurrence proportion will be calculated 
based on logical derivation and based on MI method when missing value are observed.
Sustained clinical response and recurrence will be presented for the FAS only.
7.4.2.5
Time to recurrence of CDAD during or at the end of the Follow-up period.
The survival functions in both treatment arms will be estimated using the Kaplan-Meier 
method and displayed graphically (with 95% CIs). Comparison of the survival curves of the 
two treatment arms will be done using Log-Rank test. Quartile estimates (25th and 50th
[Median]) along with 10th and 20th Percentile estimates for the time-to-event and 
corresponding two-sided 95% CIs will be computed for both treatment arms. 
Patients with confirmed clinical response at EOT+2 days, who complete the Follow-up 
period but do not experience a recurrence of CDAD will be censored at EOT + Day 30.  To 
prevent small numbers at risk distorting the comparison, events after EOT + Day 30 up to 
EOT + Day 35 will be included as at EOT + Day 30 (EOS is allowed to be up to EOT + Day 
32).
Patients with confirmed clinical response at EOT+2 days, who did not complete the Follow-
up period and discontinued during this period and do not experience a recurrence of CDAD 
will be censored at day of discontinuation. For such patients, if there is no information on 
discontinuation, then the patients will be censored at day of last study assessment.
Note that the analysis as well as the censoring rules described above is applicable only to 
patients with confirmed clinical response at EOT+2 days. Patients without a confirmed 
clinical response at EOT+2 days will be excluded from this analysis.
Time to recurrence will be presented for the FAS only.
7.4.2.6 Palatability
Results from the assessments of palatability in the subgroup of patients receiving fidaxomicin 
oral suspension or vancomycin oral liquid, on Day 1 and on Day 7 (±1 day) will be 
summarized by a frequency table using the reported categories, stratified by age group 
(patients from birth to < 2 years, patients aged ≥ 2 years to < 6 years and patients ≥ 6 years 
unable to swallow tablets) for FAS and SAF.
Summary tables for Acceptability and Palatability categories Day 1 vs Day 7, will be 
presented for each treatment group for the total population as well as by age group.
7.4.2.7 Subgroup Analysis of Secondary Endpoints
Analyses of the secondary endpoints will be repeated for two subsets of FAS (see 
Section 7.4.1.3):
●
Patients with confirmed C. difficile.


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●
By the following subgroups based on central BioFire PCR results at baseline:
o
Patients with confirmed C. difficile and no other GI pathogens detected
o
Patients with confirmed C. difficile and other GI pathogens detected
o
Patients with no confirmed C. difficiledifficile and other GI pathogens 
detected
o
Patients with no confirmed C. difficile and no other GI pathogens detected
If the last 2 subgroups might be dropped if they do not include sufficient number 
of patients.
These analyses will be provided for Global Cure at EoT (Section 7.4.2.1) and at EoT+9, +16 
and +23 days (Section 7.4.2), TTROD (Section 7.4.2.3), SCR and recurrence 
(Section 7.4.2.4) and time to recurrence (Section 7.4.2.5).
7.4.3
CDAD Signs and Symptoms Evaluation
CDAD signs and symptoms (abdominal discomfort and abdominal tenderness) will be 
presented in simple frequency tables and Listings for Baseline and End of Treatment 
including summaries to assess the changes from Baseline to End of Treatment in the 
categorical levels. Baseline assessments are collected at Screening.
The above tables will be repeated by age group.
7.4.4
Analysis of Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 


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7.4.5
Analysis of Other Endpoints
●
The status of watery diarrhea (Normal/ Diarrhea) for patients from birth to < 2 years, 
will be summarized for the FAS, by treatment arm and study day
●
Descriptive summary of Number of UBM for patients aged ≥ 2 years to < 18 years per 
day (during treatment period) as recorded in the eCRF will be provided for the FAS, by 
treatment arm, relevant age group and study day (see also Section 7.1.1). 
●
The derived Diarrhea status (Normal/ Diarrhea) for patients ≥2 years will be summarized 
for the FAS, by treatment arm and study day
7.5
Analysis of Safety
All analysis of safety will be presented by treatment group at first instance and by age group 
in addition, for SAF. 
7.5.1
Adverse Events
Summaries and listings of SAEs and Serious TEAEs include SAEs upgraded by the sponsor 
based on review of the Sponsor’s list of Always Serious terms if any upgrade was done.
The coding dictionary for this study will be MedDRA version 17.0. It will be used to 
summarize AEs by SOC and PT.
An overview table will be produced, showing number of patients, percentage of patients and 
total counts (= no. of actual events) by treatment arm and by age group of:
●
TEAEs overall
●
Drug-related TEAEs
●
Deaths
●
Serious TEAEs
●
Drug-related serious TEAEs
●
TEAEs leading to premature discontinuation of study 
●
Drug-related TEAEs leading to premature discontinuation of study.
The number and percentage of patients with TEAEs, as classified by SOC and PT will be 
summarized for each treatment group and for each age group category. Summaries will be 
provided for:
●
TEAEs
●
TEAEs of special interest (as defined for this study in Section 6.2.1)
●
Drug related TEAEs, 


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●
Serious TEAEs, 
●
Drug related serious TEAEs, 
●
TEAEs leading to permanent discontinuation of study drug, 
●
Drug related TEAEs leading to permanent discontinuation of study drug, 
●
TEAEs excluding serious adverse events that equal to or exceed a 
threshold of 5.0% in either treatment group
The number of TEAEs and the number and percentage of patients with TEAEs, as classified 
by SOC and PT will also be summarized by severity and by relationship to study drug. In the 
patient count, if a patient has multiple TEAEs with the same SOC or PT, but with differing 
severity or relationship, then the patient will be counted only once with the worst severity and 
highest degree of relationship, however, if any of the severity or relationship values are 
missing then the patient will be counted only once with missing severity or relationship.  In 
the adverse event count, the adverse events will be presented in each category they were 
classified to. Drug related TEAEs will be presented in a similar way by severity only.
7.5.2
Clinical Laboratory Evaluation
The baseline visit is the last measurement taken prior to initial study drug administration.  
Quantitative clinical laboratory variables, i.e. hematology, biochemistry, and urinalysis will 
be summarized using mean, standard deviation, minimum, maximum and median for each 
treatment group at each visit by age group. Additionally, a within-patient change will be 
calculated as the post-baseline measurement minus the baseline measurement and 
summarized in the same way. Each laboratory result will be classified as low (L), normal (N), 
or high (H) at each visit according to the laboratory supplied reference ranges. 
The number and percentage of patients below and above reference range will be summarized 
for each treatment group at each visit by age group. Reference range for a normal lab value is 
presented in the Appendix 10.4, Table 18  
For hematology and biochemistry two types of shift tables will be presented for each 
treatment group and overall: 
●
Shift tables of common normal range changes from baseline to EOT (low, normal, high), 
and
●
Summary shifts of common normal range changes from baseline to EOT (shift from 
normal or high to low, shift from normal or low to high, categorized increase [shift from 
low to normal or from normal to high], categorized no change [value stays in the same 
reference range], categorized decrease [shift from high to normal or from normal to 
low]).
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented for each treatment group at each visit by age group. 
Clinically significant changes in laboratory parameters were to be reported as AE and 
therefore summarized and listed as described in Section 7.5.1


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7.5.2.1 Liver Enzymes and Total Bilirubin 
The following potentially clinically significant criteria in liver function tests for Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin (TBL), Aspartate 
Transaminase (AST) and their combination are defined. The patient’s highest value during 
the investigational period will be used. 
Table 10
Liver function tests and criteria
Parameter
Criteria
ALT
> 3xULN
> 5xULN
> 8xULN
AST
> 3xULN
> 5xULN
> 8xULN
Total Bilirubin (TBL)
>2 x ULN
INR
>1.5 x ULN
ALT or AST (*)
> 3 × ULN 
with the appearance of fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash and/or eosinophilia (> 5%)
> 5 × ULN 
for more than 2 weeks 
> 8 × ULN
(ALT or AST) AND
INR(*)
(ALT or AST > 3 × ULN )
AND
INR > 1.5 (If INR testing is applicable/ evaluated).
(ALT or AST)
OR 
TBL(*)
(ALT or AST  > 3 x ULN )
OR
TBL > 2 x ULN
(ALT or AST) 
AND
TBL(*)
(ALT or AST  > 3 x ULN)
AND
TBL > 2 x ULN
(*) Combination of values measured within same sample
The number and percentage of patients with potentially clinically significant values in liver 
enzyme and total bilirubin tests during the investigational period will be presented by 
treatment group.
The following data will be presented graphically by treatment group: 
Evaluation of drug-induced serious hepatotoxicity (eDISH) scatter plots, for ALT vs. TBL 
and AST vs. TBL peak values during the study.


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7.5.3
Vital Signs
The baseline visit is the last measurement taken prior to initial study drug administration.  
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate and temperature) will 
be summarized using mean, standard deviation, minimum, maximum and median by 
treatment group and visit for each age group. Additionally, a within-patient change will be 
calculated per visit as the post-baseline measurement minus the baseline measurement and 
summarized by treatment group and visit for each age group and overall.  
Results of vital signs assessments will also be listed.
Normal ranges table is presented in the Appendix 10.5, Table 19. 
Clinically significant changes in vital signs were to be reported as AE and therefore 
summarized and listed as described in Section 7.5.1
7.5.4
Electrocardiograms (ECGs)
ECG variables will be summarized using mean, standard deviation, minimum, maximum and 
median for each treatment group at each treatment visit and time point for each age group, 
including changes from baseline. 
Number and percent of patients with normal, not clinically significant abnormal, and 
clinically significant abnormal results as assessed by investigator for the 12 lead ECG will be 
tabulated by treatment group at each treatment visit and time point by age group. 
Number and percent of patients with 12 lead ECG abnormalities (local and central review)
will be tabulated by treatment group at each treatment visit and time point for each age group. 
7.5.5
Pregnancies
If applicable, a detailed listing of all pregnancies will be provided.
7.6
Analysis of Drug Concentration
7.6.1
Estimation of Pharmacokinetic Parameters
Not applicable. PK parameters will not be calculated for this study.
7.6.2
Statistical Analysis
Descriptive statistics (e.g., n, mean, standard deviation, minimum, median, maximum, 
coefficient of variation and geometric mean, incl. numbers of values below level of 
quantification) will be provided for plasma (pre-dose, post-dose) and faecal concentrations of 
fidaxomicin, its main (active) metabolite OP-1118 and Metabolite to Parent Ratio 
(MPRconc), overall, by age group, by type of fidaxomicin formulation (fidaxomicin oral 
suspension, fidaxomicin 200 mg tablets) and by time point (where applicable), for the 
patients in the PKAS. 
Concentrations corresponding to patients treated with vancomycin will not be sampled,
measured nor reported.


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Graphical summaries by age group will also be considered for plasma and faecal 
concentrations corresponding to treatment arm fidaxomicin.
7.7
Analysis of PD
Please refer to Section 7.4.4 Analysis of Exploratory Endpoints, 
7.8
Subgroup Analyses 
Primary and secondary efficacy endpoints and safety variables will be summarized for each 
treatment group by age group categories as defined in Section 7.1.2  Details are provided 
throughout Sections 7.4.1, 7.4.2 and 7.5.
Primary and secondary efficacy endpoints will also be summarized for two subsets of FAS as 
defined in Sections 7.4.1.3 and 7.4.2.7
7.9
Other Analyses
Not applicable.
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)
No interim analysis is planned.
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Missing data is defined as data that is not entered into the eCRF, and that cannot be 
calculated from available information in the eCRF.
For example, a patient with ICR=No might not have CCR completed in the eCRF; however, 
CCR=No by definition in this case. – Thus this result is available and is not missing.
7.11.1
Missing Data
Missing primary and selected secondary efficacy endpoints will be handled by using logical 
derivations and after that a multiple imputation (MI) approach. More details regarding MI for 
specific primary and secondary endpoints are provided in Sections 7.11.1.1 and 7.11.1.2 as 
well as in the respective Appendix 10.1  
Missing results will be either derived or imputed via MI.
Generally, the idea for data handling will be based in following order:
●
Use original values
●
Use query results
●
Perform logical derivations 
●
Perform MI
Logical derivation and MI will affect only missing values. In any other case original values 
will be used. 
When incompatible data (e.g., ICR=No and CCR=Yes) are observed, data queries will be 
sent.


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Basic Logical Derivation Rules:
ICR and CCR will be derived using the logical derivations rules defined below only for 
patients who completed treatment.
●
Derivation for ICR in case of missing based on CCR=Yes: Set ICR=Yes.
●
Derivation for recurrence in case of missing based on CCR=No: Set Recurrence=No.
●
Valid TTROD information without any lack of efficacy information during treatment 
period/at EOT, would lead to ICR=Yes and/or CCR=Yes in case of ICR and/or CCR 
missing.
Note that patients with TTROD at EOT are those where diarrhea was resolved for at least
2 consecutive days during treatment and sustained through EOT.
●
Lack of efficacy at EOT for any reason (hospitalization for CDAD recurrent episode 
during the treatment period/at EOT), implies no response, i.e., ICR=No and/or CCR=No 
in case of ICR and/or CCR missing.
Hospitalization information for CDAD recurrent episode before ICR or CCR will be used 
for ICR or/and CCR in case of ICR or/and CCR missing:
-
For hospitalizations prior to ICR, only hospitalization records where the patient was 
hospitalized during treatment or at EOT for CDAD recurrence will be considered to 
impute missing ICR.  The latest hospitalization date for each patient during the 
treatment period will be used as a reference in cases where patient was hospitalized 
multiple times for CDAD recurrence during treatment.
-
For hospitalizations prior to CCR, the earliest hospitalization date should be used for 
each patient who was hospitalized for CDAD recurrence after EOT to impute missing 
CCR.
●
In case we have valid TTROD information and hospitalization information for CDAD 
during the treatment period/at EOT, then 
-
For missing ICR :
o
If diarrhea resolution date > date of last hospitalization during treatment (e.g.,
patient was hospitalized during treatment for CDAD recurrence, but then diarrhea 
was resolved after hospitalization), then ICR should be derived as ‘Yes’.
o
If date of diarrhea resolution date ≤date of last hospitalization during treatment, 
then ICR should be derived as ‘No’.
-
For missing CCR :
o
If observed or derived ICR=’Yes’ and patient has valid TTROD data during 
treatment period/at EOT and was hospitalized after EOT (during follow-up) for 
CDAD recurrence and date of first hospitalization date after EOT > EOT date + 4 
days,
then derive CCR as ‘Yes’ (i.e., recurrence occurs after confirmed resolution of 
diarrhea). 
(Note that 4 is added as EOT and EOT+2 both have a window of +2 days).


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o
If derived ICR≠’No’ (ICR=Yes or missing/ND) and patient was hospitalized for 
recurrence after EOT and date of first hospitalization after EOT<=EOT date+4, 
then derive CCR as ‘No’ (i.e., recurrence occurs before CCR assessment)
●
Hospitalization information for CDAD recurrent episode (during follow-up period) will 
be used in case of recurrence information is missing.
●
If at EoS (EoT+30) recurrence=No and some or all the previous time points (EoT+9, 
EoT+16, EoT+23) have missing recurrence then set them to No.
Basic Multiple Imputation Rules:
●
No MI for ICR
●
Recurrence does NOT affect CCR or ICR results.
●
MI will be performed AFTER Logical Derivation
●
MI for recurrence will be done by time point independently (i.e., regardless of previous-
next time points), after considering the cumulative nature of recurrence defined in logical 
derivation previously.  
●
MI will be performed for CCR and recurrence. It will also be performed for Global Cure 
at EOS (EoT+30 days), in addition to the logical derivation based on sustained clinical 
response (SCR) and ICR/CCR. Any other endpoint related to recurrence (i.e., SCR) will 
be derived, based on recurrence MI dataset.
In addition, missing records of bowel movement data and dates and or times, for time to event 
endpoints will be imputed at certain cases as described in Section 7.11.1.3
As a general principle, no imputation of missing data for other variables will be done. 
Exceptions are the start and stop dates of AEs and concomitant medication (Section 7.11.1.4). 
The imputed dates will be used to allocate the concomitant medication and AEs to a treatment 
group, in addition to determining whether an AE is/is not treatment emergent. Listings of the 
AEs and concomitant medications will present the actual partial dates; imputed dates will not 
be shown.
7.11.1.1 Multiple Imputation for Analysis of Primary Efficacy Endpoint (CCR) 
CCR data that are missing or not done will be imputed using the MI method introduced by 
Rubin (1987). Multiple imputations will deal directly with the uncertainty of missing data by 
estimating multiple plausible values for each missing data point of CCR and accounting for 
the variability of these imputed values in the analysis of filled-in data.
In SAS, PROC MI provides functionality for imputing binary variables (SAS User’s Guide, 
2011) like CCR, for example, of which imputation based on a logistic regression model is the 
most appropriate choice due to the binary nature of CCR. Once CCR is imputed using MI, 
multiple datasets are created where observed values are the same across all datasets, but 
imputed values differ from one dataset to another. For example, if n observations are missing 
in the observed data, PROC MI can be used to generate a sample of n observations, which 
when combined with the observed data will create one complete dataset. Repetition of this 
process can create multiple datasets. Each of these multiple datasets will then be analyzed 
using the method in Section 7.4.1  The results from the analysis of these multiple datasets are 


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combined (pooled) for overall inference in a way that accounts for the variability between 
imputations. SAS PROC MIANALYZE provides functionality for combining results from 
multiple datasets (SAS User’s Guide, 2011) which can be readily used after performing a 
wide range of complete-data analyses.
Analysis with multiple imputations for CCR will be carried out in three steps:
1. Creating Derived Complete Data Sets: missing data of CCR are imputed using PROC MI 
method. Repeat the same method M (>1) times to construct M different complete data 
sets of CCR. 
2. Intermediate Analyses: each of the M imputed datasets is analyzed separately using the 
statistical methods described in Section 7.4.1
3. Final Analysis: analysis results from M imputed datasets obtained from step 2 are 
combined into one overall result. This step can be carried out using SAS PROC 
MIANALYZE.
After getting 100 estimations of the 95%CI of the adjusted treatment difference 
calculated using Newcombe method, a combined standard error (SE) estimation will be 
computed using Root Mean Square (RMS) of the upper and lower SE factors of the CI. 
The combined SE will be used as input in the SAS PROC MIANALYZE, along with the 
point estimation, to calculate the overall 95%CI.
The choice of predictors that will be used in PROC MI method is driven by the definition 
CCR as defined in Table 2 in Section 6.1.1, and are chosen to reflect on the underlying 
mechanism that leads to the assessment of CCR. 
The following variables will be used as a minimum:
●
Age group (unique categories) (birth to <2 years, >= 2 years to < 6, >= 6 years to 
< 12 years, and >= 12 years to < 18 years).
●
Baseline status, including:
●
Prior diarrhea episodes (Yes/No).
●
Current treatment with antibacterial at baseline (Yes/No).
●
Existence of CDAD risk factors. Specifically: antibiotics or/and cancer (at 
least one / none)
●
High body temperature from baseline Vital Signs, above 38.0 degrees 
C°(Yes/No)
●
White blood cells at baseline (High/Normal/Low) according to common 
normal ranges defined in Appendix 10.4
The assumption made is that the dataset created, consisting of the variables mentioned above 
will follow a non-monotone missingness pattern. Non-monotone missingness arises when 
patients miss some intermediate visits but remain in the study and have available assessments 
later on. This is suggested by the fact that the study design instructions expect patients who 
discontinue study drug prematurely should complete the EOT visit relevant assessments as 
soon as possible after the final dose. 


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The assumption of non-monotone missing data pattern justifies the use of Fully Conditional 
Specifications (FCS) imputation method (Van Buuren, 2007) in PROC MI under which the 
logistic regression imputation model will be used to impute missing values of CCR.
Multiple imputation approach as defined above operates under a Missing at Random (MAR) 
assumption about the missingness mechanism of CCR. Under MAR, withdrawn patients are 
assumed to have the same probability distribution for response to treatment at time points 
after their study discontinuation as patients who remained in the study, conditional on 
baseline and pre-withdrawal data included in the analysis. In other words, discontinued 
patients are assumed to have the same probability of response as similar patients who 
remained in the study.
The number of M imputed datasets that will be created at step 1, will be set to M=100 based 
on recommendations from recent literate (Graham et al. (2007) and O’Kelly et al. (2014)). 
This choice is considered more than sufficient based on the relatively low number of 
expected missing cases for CCR.
The random seed to be used in PROC MI, which specifies the positive integer to start the 
pseudo-random number generator, will be set to SEED= 456784. This seed will be used for 
each planned invocation of the multiple-imputation procedure.
The FCS logistic regression model might not be able to find the MLEs of the parameters due 
to perfect classification (i.e., for a linear combination of predictors, imputed response is 
always same), for example. If it is the case, FCS logistic regression will be performed with 
augmentation, or else, the missing data will be imputed first by a Bernoulli (p=0.5) random 
number prior to be entering into the MI algorithm.
7.11.1.2 Multiple Imputation for Analysis of Secondary Endpoints 
MI approach will also be used for Global Cure (only at EOS [EOT+30 days], in addition to 
the logical derivation based on SCR and ICR/CCR values). Methodology will be similar to 
the MI approach described for the primary objective in Section 7.11.1.1
For SCR at EOS (EOT visit+30 days), and also at EOT+9, EOT+16 and EOT+23 days and 
for recurrence of CDAD during or at the end of the follow-up period, only patients with 
logically derived CCR (CCR=Yes) at EoT+2 days will be included.
The choice of predictor that will be used in the PROC MI method, is driven by the definition 
of these secondary endpoints as provided in Section 6.1.2, and is chosen to reflect on the 
underlying mechanism that leads to the assessment of these endpoints. For patients where 
CCR=No after logical derivation and data query completion, value of recurrence will be set 
to No if missing. For patients with CCR=Yes, MI model will include same predictors used 
above for CCR. Global Cure at EOS only will also be derived using MI in case 
ICR/CCR=Missing (SCR not assessed).


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7.11.1.3 Missing Data for Efficacy Related Variables
The following imputation of completely missing information for the assessment of efficacy 
related variables/endpoint is foreseen:
Missing information for time to resolution of diarrhea
●
Missing time of last episode of watery diarrhea (children < 2 yrs) or unformed bowel 
movements (children ≥ 2 yrs) (00:00 - 23:59) on this day it will be imputed by the default 
time 23:59 when both hours and minutes are missing or by XX: 59 when minutes are 
missing, only if the patient has a record confirmed clinical response (CCR=Yes).
Missing values of UBM and presence of watery diarrhea are imputed only for time to 
resolution of diarrhea analysis. 
Missing Data for Unformed Bowel Movements: 
For imputing missing number of UBMs for patients aged ≥ 2 years to < 18 years the 
following rules will be applied:
●
Missing number of UBM data at the baseline will be replaced by max of (3, number of 
UBMs on first non-missing observation)
●
Missing number of UBM during the treatment period prior to EOT will be replaced by 
maximum of previous and next non-missing observed bowel movement, when there are 
available values either side.
●
Missing number of UBM after last available value will be replaced:
o
by max of ‘3’ and LOCF for patients classified as having negative or missing 
initial response (ICR=’No’ or ‘Missing’) and 
o
by the min of ‘2’ and LOCF for patients classified as positive initial clinical 
responders (ICR=’Yes’).
When looking at previous and non-missing values of number of UBM, the scheduled and 
unscheduled visits will be considered.
Missing Data for status of watery diarrhea: 
For imputing missing status of watery diarrhea for patients birth to < 2 years the following 
rules will be applied:
●
Missing status of watery diarrhea at the baseline will be replaced by presence.
●
Missing status (number) of watery diarrhea episodes during the treatment period prior to 
EOT:
○
Will be replaced by “Absence”, if the observations either side (the previous and 
next non-missing values) are “Absence”.
○
Otherwise replace by ‘Presence’.
●
Missing status of watery diarrhea after the last observed status until EOT+2 days:


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○
Will be replaced by ‘Presence’ for patients classified as treatment failure 
(ICR=’No’). 
○
Will be replaced by ‘Absence’ for patients classified as positive initial clinical 
responders (ICR=’Yes’).
When looking at previous and non-missing status of watery diarrhea, the scheduled and 
unscheduled visits will be considered.
7.11.1.4 Missing Adverse Event Dates
If a patient experiences an event both before and after the first dose of study medication, the 
event will be considered as TEAE only if it has worsened in severity (i.e., it is reported with a 
new start date). For AEs with incomplete or missing start or date and/or time, a worst-case 
scenario will be used to determine treatment emergence of this adverse event:
●
If the investigator has ticked the box that AE onset was after the first dose of study drug 
then the AE will be considered TEAE.
●
If the AE start time is missing and the investigator has not ticked the box that the onset 
was before the first dose of study drug AND:
○
if the AE start date is non-missing and equal or greater to the date of treatment 
start then the AE will be considered TEAE;
○
if the AE day is missing, then if the AE month / year is equal or greater the 
month / year in which treatment was administered then the AE will be 
considered TEAE;
○
if the AE month is missing and the AE year is equal or greater the year in 
which treatment was administered then the AE will be considered TEAE;
○
if the AE year is missing then the AE will be considered TEAE;
○
for TEAEs with partial dates the AE will be allocated to the investigational 
period using the available partial information, without imputations. 
●
Other cases of incomplete onset date of an AE will be addressed prior to or during the 
Final Data Review and TLF meeting in order to determine whether the AE must be 
considered treatment emergent or not. 
The duration of each AE will be calculated as the difference between the onset date/time and 
the end date/time, and presented in (days, hours, and minutes). In case of ongoing TEAEs, 
the duration is calculated by using the date of the ESV as the end date for the event; a default
time of 23:59 should be used. For an incomplete date use the following algorithm:
●
Incomplete Start Day: use the later of (first day of the month, first dosing day if first 
dosing month); 
●
Incomplete End Day: use the earliest of (last day of the month, day of the ESV, date of 
death);
●
Incomplete Month or Year: the duration is considered to be missing.
If the start time is missing then use 0:00 as time and if the end time is missing then use 23:59 
as time for calculation of duration.


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For all TEAE, the time since study drug is defined as the number of days elapsed since the 
dose of study medication to the start of the TEAE. If the start day of the TEAE is missing, 
and a) it is the dosing month, then day will be imputed by the day on which the study 
medication was taken, otherwise, b) if it is a month later than the dosing month, calculate 
time since drug using an imputed first day of the month for the TEAE start date. If the month 
or year are missing then time since drug is to be considered missing. For pre-treatment AEs, 
the time since drug is preceded by a negative sign (for TEAE with a missing onset time, the 
day prior to the first dose is designated as Day –1).
Listings will always show the original date and time information without imputation, but 
derived parameters (TEAE indicator and duration of AEs) would be flagged.
7.11.1.5 Missing Concomitant Medication Dates
For previous or concomitant medications, including rescue medications, incomplete (i.e., 
partial missing) start date and/or stop date will be imputed. When the start date and the stop 
date are both incomplete for a patient, impute the start date first.
●
Incomplete start date
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date.
○
Missing day and month
January 1st will be assigned to the missing fields.
○
Missing Month Only
Treat day as missing and replace both month and day according to the above procedure.
○
Missing Day Only
The first day of the month will be assigned to the missing day.
○
Completely missing 
For completely missing start date i.e., for missing day, month, and year, no 
imputation will be performed but the medication/non-medication therapy is assumed 
to have been started prior to first dose date (seen as a previous medication/non-
medication therapy). 
●
Incomplete Stop Date
The following rules will be applied to impute the missing numerical fields. If the imputed stop 
date is before the start date (imputed or non-imputed start date), then the imputed stop date will 
be equal to the start date.
○
Missing day and month
December 31 will be assigned to the missing fields.


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○
Missing Month Only
Treat day as missing and replace both month and day according to the above procedure.
○
Missing Day Only
The last day of the month will be assigned to the missing day (or the date of death if 
this is earlier).
○
Completely missing
For completely missing end date i.e., for missing day, month, and year, no imputation 
will be performed but the medication/non-medication therapy is assumed to have 
been stopped at the EOS date (seen as a concomitant medication/non-medication 
therapy). 
7.11.1.6 Missing Medical History Dates
For start dates of medical history, the following applies:
●
In case of a missing start day, the first of the month will be imputed.
●
For missing start day and month, 1st January will be imputed.
●
For missing day, month, and year, no imputation will be performed but the medical 
history is assumed to have been started prior to baseline date.
For stop dates of medical history missing stop dates will be imputed only if event is not 
marked as Ongoing:
●
If the day of the stop date is missing, then the last day of the month will be imputed 
for the missing day.
●
If day and month of the stop date are missing, then December 31st will be imputed.
In case the imputed stop date is after Day 1 of the study, then stop date will not be 
imputed.
If all date parts are missing, then the stop date will remain missing but the medical 
history event is assumed to have been stopped prior to Day 1 of the study. 
7.11.2
Outliers
All values will be included in the analyses.
7.11.3
Visit Windows
The study protocol gives the overall study schedule and the permissible intervals for these 
visits. Please refer to Table 1, Schedule of Assessments.
The summary for TEAE and concomitant medication will include data that were collected up 
until EOS (EOT+30 days) where EOT is the last dose of treatment.
The following analysis windows as presented in Table 11 and Table 12 will be used for the 
main safety and efficacy assessments respectively:


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Table 11
Analysis Windows for Safety Assessments
Applicable 
Safety 
Assessments
Analyzed 
Visit
CRF Visit**
Details
All
Screening#
Screening
All assessments till Day (1), prior to baseline where 
scheduled CRF visit=Screening. If there are no 
scheduled assessments where CRF visit=Screening, 
then assign Screening analysis visit as last 
assessment prior to baseline regardless of CRF visit.
All
Baseline
NA
Last assessment with non-missing results prior to 
first dose performed on or before Day 1, irrespective 
of CRF visit.
All 
EOT
End of 
Treatment
Last observation where CRF visit=End of 
Treatment. If there are no scheduled assessments 
where CRF visit=End of Treatment, then assign 
EOT analysis visit as last post-baseline assessment 
performed up to last dose +3 days if present, or last 
post-baseline assessment performed up through day 
14 if last dose is not present, regardless of CRF visit. 
End of Treatment (EOT) Actual Assessment Day 
will include assessments from Day 1 post dose to 
Day 12. ***
All
Unscheduled
Unscheduled*
Treatment period is for ECG only (instead of EoT).
*Optional unscheduled assessments. 
**Analyzed visits for safety assessments refer to scheduled (CRF) visits unless otherwise specified. 
*** In cases where Day 1 should be included, a footnote should be added to clarify that Day 1 refers to 
assessments performed on Day 1 after first dose. 
For safety, the assessments collected during the scheduled visits (i.e., CRF visits) have priority and will be used 
for summaries. When no CRF visit is available, then unscheduled visits or scheduled visits corresponding to the 
targeted analysis visit will be remapped as specified in Table 11  Unscheduled visits occurring on Day 1 prior to 
baseline could also be remapped as Screening. 


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Table 12
Analysis Window for Efficacy Assessments
Assessments
CRF visit
Target 
day
Actual assessment 
day
Details
Analyzed 
visit
CDAD status 
assessed via 
Questionnaire 
and Taste 
Questionnaire 
(except 
recurrence)*
Screening
Day -2 
to Day 
1
All assessment prior 
to baseline where 
scheduled CRF 
visit=Screening. 
Screening
Baseline
D1
Last non-missing 
assessment on or 
prior to first dose, 
irrespective of the 
CRF visit
Baseline
Treatment 
Period 
(scheduled and 
unscheduled)
D1-D10
Any assessments after 
baseline to end of 
treatment visit
Treatment 
period
Initial Clinical 
Response
End of 
Treatment Visit
D10 
As soon as possible 
after the last dose: 
D10 to D12
EOT
Confirmed 
Clinical 
Response
Follow Up EOT 
+ 2
EOT+2 
days 
2 days after EOT:
D12 to D14 (i.e., D2 
to D4 post-dose)
EOT+2
Recurrence
Follow Up EOT 
+ 9
EOT+9 
days 
9 days after EOT:
D10 to D12 post-dose
CCR date + 1 
<= ADT <= 
EOT+13
If CCR date is 
missing,
EOT+3 <= 
ADT <= 
EOT+13
EOT+9
Follow Up EOT 
+ 16
EOT+1
6 days 
16 days after EOT:
D17 to D19 post-dose
EOT+14 <= 
ADT <= 
EOT+20
EOT+16
Follow Up EOT 
+ 23
EOT+2
3 days 
23 days after EOT:
D24 to D26
EOT+21 <= 
ADT <= 
EOT+27
EOT+23
End of Study
EOT+3
0 days
30 days after EOT:
D31 to D33
EOT+27 < 
ADT
EOT+30 
(EOS)
* CDAD status questionnaire data: bowel movements prior to screening, last episode of watery diarrhea or 
UBM. Recurrence data assessed via CDAD status questionnaire are analyzed similarly to Recurrence.
Consider date information from unscheduled Recurrences (Recurrence=Yes).
ADT = recurrence date.


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ICR and CCR are collected at CRF visit only, no unscheduled visit is available. Hence, no 
remapping will be done for these two parameters.
For Recurrence, the starting point of the visit window is the CCR assessment date. All 
unscheduled visits for recurrence will be remapped as per Table 12. If there are multiple 
recurrence assessments within a same visit window, then the worst will be used (i.e., earliest 
record with recurrence=yes).
MB data (local and central) will be remapped to Screening and EOT analysis visit windows 
for summary tables using a similar logic as safety assessment (as per Table 11), except that 
all data (including CRF visit) will be considered for the remapping.  For MB data assessed 
after CCR assessment (EOT+2days), the earliest assessment from central lab will be 
remapped to Recurrence analysis visit window using the same logic as recurrence assessment 
(as per Table 12). Indeed, we are assuming that all unscheduled MB data sent to the central 
lab were previously locally tested as positive. A corresponding visit should then be found in 
local data.
Baseline value for local and central MB data, used to define the subset of patients with 
confirmed C. difficile (see Section 7.4.1.3), will correspond to the last non-missing 
assessment on or prior the first dose.








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Version
Date
Changes
Comment/rationale 
for change
Section 6.2.4: Unneeded details around ECG 
assessments removed and ECG parameters measured 
added
To give the correct 
details, as per SAP 
template
Section 6.4.5: Remove the use of time in duration of 
exposure derivation
To match the TLFs 
specs and be consistent 
with other FDX studies
Section 7.2.1: Time to treatment discontinuation 
analysis removed
Assessed as not 
relevant by the team
Section 7.2.2: Details of PD3 subcategories added
To match with PD 
reconciliation 
spreadsheet
Section 7.4.1.1: Sensitivity analysis of the primary 
endpoint added (repeat the primary analysis excluding 
data from one site – 2 patients, after IRB site’s 
termination)
As per recommendation 
of Astellas’s Quality 
Counsel
Section 7.4.1.3 (& 7.4.2.7): Subgroup analyses of the 
primary and secondary endpoints based on MB data 
added (Confirmed C. diff subgroup, + GI pathogens, 
excluding patients with other than C. diff GI pathogens)
To provide relevant 
efficacy analyses using 
the MB data
Section 7.4.2.1: Additional sentence to specify that 
logical derivation endpoints will be used to derive GC
To clarify the analysis
Section 7.4.4: MB summary tables will be presented 
for FAS, and MB listings for ITT. 
Addition of Culture and susceptibility analyses.
MB data are efficacy 
data
As per MB data specs
Section 7.5.2: Shift summaries for hematology and 
biochemistry labs added.
As per Medical team 
request
Section 7.11.1.1: Additional sentence to specify that 
ICR/CCR will be derived using logical derivation rules 
only for patients who completed treatment. 
To clarify the analysis
Section 7.11.1.1: Additional text to detail how to 
compute 95%CI using Newcombe after MI 
To clarify the analysis
Section 7.11.1.1: Additional paragraph to specify 
which method to follow when convergence issues are 
observed during MI.
To clarify the analysis
Section 7.11.1.3: Imputation of missing UBM/presence 
of diarrhea is to be done only for time to resolution 
derivation. UBM/presence of diarrhea summaries will 
be presented on non-imputed values (i.e., CRF values)
To clarify the 
imputation of TTROD
Section 7.11.1.5: Changes in imputation rule for 
missing CM dates
To adopt the most 
conservative approach 
Sections 7.11.1.5 & 7.11.1.6: Amend imputation of 
partially missing CM & MH dates  
To adopt the most 
conservative approach
Section 7.11.3: Add further details on efficacy & safety 
VWs
To clarify the analyses 
and give detailed 
guidance to the 
programming team


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9
REFERENCES
ASTEL00020201; Almac Clinical Technologies: IXRS® User Requirements Specification (URS) 
V7.V7. ; 02 Nov 2015.
Crobach M.J.T., Dekkers O.M., Wilcox M.H. and Kuijper E.J. 2009. European Society of Clinical 
Microbiology and Infectious Diseases (ESCMID): Data review and recommendations for 
diagnosing Clostridium difficile-infection (CDI). Clinical Microbiology and Infection. Vol. 15, 
Issue 12, p1053-1066.
Crobach M.J.T., Planche T., Eckert C., Barbut F., Terveer E.M., Dekkers O.M., Wilcox M.H. and 
Kuijper E.J. 2016. European Society of Clinical Microbiology and Infectious Diseases 
(ESCMID): Update of the diagnostic guidance document for Clostridium difficile-infection 
(CDI). Clinical Microbiology and Infection. Vol. 22, Supl. 4, pS63-S81.
EMEA-000636-PIP01-09-M01; Application for Modification of an Agreed Pediatric Investigation 
Plan (Parts B-E); December 2012
Graham, J. W., Allison E. Olchowski and Tamika D. Gilreath (2007). How many imputations are 
really needed? Some practical clarifications of multiple imputation theory. Prevention Science 
8: 206–213.
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)
Mehrotra D.V. and Railkar R. 2000, Minimum risk weights for comparing treatments in stratified 
binomial trials, Statistics in Medicine 2000; 19:811-825.
O’Kelly M. and Ratitch B. 2014. Clinical Trials with Missing Data. A Guide for Practitioners. 
(Statistics in Practice) Wiley  
Ratitch B. and Lipkovich I., O’Kelly M., 2013 Combining Analysis Results from Multiply Imputed 
Categorical Data. PharmaSUG 2013 - Paper SP03
Rubin DD.B. 1987. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley and 
Sons.
SAS Institute Inc. 2011. SAS/STAT® 9.3 User’s Guide. Cary, NC: SAS Institute Inc.
SAS Institute Inc 2011a. SAS/STAT Product Documentation. SAS Institute Inc., Cary, NC.              
URL http://support.sas.com/documentation/onlinedoc/stat/.
SAS Institute Inc 2011b. SAS/STAT User's Guide Procedures. SAS Institute Inc., Cary, NC.        
URL http://support.sas.com/documentation/onlinedoc/stat/indexproc.html#stat93.
Van Buuren, S. 2007. Multiple Imputation of Discrete and Continuous Data by Fully Conditional 
Specification. Statistical Methods in Medical Research, 16, 219–242.
Yeonhee K. and Seunghyun W. 2013. Adjusted proportion difference and confidence interval in 
stratified randomized trials, PharmaSUG 2013 - Paper SP04




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Table 15
Logical Derivation/Multiple Imputation for Recurrence
Initial Values
Derived/MI
9
16
23
30
9
16
23
30
1
Y
*
*
*
Y
Y
Y
2
N
Y
*
*
Y
Y
3
N
N
Y
*
Y
4
N
N
N
Y
5
N
N
N
N
6
N
N
N
M
MI
7
N
N
M
Y
MI
8
N
N
M
N
N
9
N
N
M
M
MI
MI
10
N
M
Y
*
MI
Y
11
N
M
N
Y
N
12
N
M
N
N
N
13
N
M
N
M
N
MI
14
N
M
M
Y
MI
MI
15
N
M
M
N
N
N
16
N
M
M
M
MI
MI
MI
17
M
Y
*
*
MI
Y
Y
18
M
N
Y
*
N
Y
19
M
N
N
Y
N
20
M
N
N
N
N
21
M
N
N
M
N
MI
22
M
N
M
Y
N
MI
23
M
N
M
N
N
N
24
M
N
M
M
N
MI
MI
25
M
M
Y
*
MI
MI
Y
26
M
M
N
Y
N
N
27
M
M
N
N
N
N
28
M
M
N
M
N
N
MI
29
M
M
M
Y
MI
MI
MI
30
M
M
M
N
N
N
N
31
M
M
M
M
MI
MI
MI
MI
Blank for Derived/MI, means we keep initial value.
*Any result (Y, N, M)
Prior to performing above – if recurrence is only recorded at Day 30, and the recurrence date 
is at (say) Day 6, then Days 9, 16 and 23 can marked with recurrence=Y as a logical 
derivation.


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Table 16
Global Cure Derivation for EOS (EoT+30 days)
Sustained
Clin. 
Response
Global 
Cure
ICR
CCR
Original Values
Derived 
Values
Result
Sensitivity Analysis 
using MI
1
Y
Y
Y
Y
Y
2
Y
Y
N
N
N
3
Y
Y
M
Y
Y
4
Y
Y
M
N
N
5
Y
Y
M
M
N#
MI@
6
Y
N
NA
NA
N#$
7
N
N
NA
NA
N#$
8
N
M
NA
N
N#
MI@
9
N
M
NA
NA
N#
MI@
10
M
N
NA
NA
N#$
11
M
M
NA
Y
Y
MI@
12
M
M
NA
N
N
MI@
13
M
M
NA
NA
N
MI@
Y: Yes, N: No, NA: Not Applicable.
* Based on logically derived CDAD Recurrence values.
# By definition Global Cure is No when Sust. Clin. Resp. is not equal to Yes.
$ When CCR=No then Global Cure=No.
@ Additional Sensitivity analysis.


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10.2
Appendix 2: Multiple Imputation Programing Guidelines, General 
Considerations:
Confirmed Clinical Response:
●
All patients regardless of ICR status will be included.
o
Number of patients with ICR=Yes, followed by ICR=No and ICR=Missing 
will be presented.
o
Percentages over all patients regardless of ICR status, as well as percentages 
over patients with valid CCR (i.e., non-missing CCR) will be presented.
For MI imputed estimations we are using ALL patients (regardless of ICR status) and 
perform Logical Derivations (e.g., when CCR=Y and ICR=missing, we set ICR=Y). After 
Logical Derivations we will perform Multiple Imputation. We will not have missing CCR 
after MI.
CDAD Recurrence: 
●
Only patients with Confirmed Clinical Response at EoT+2 after logical derivations
are considered (CCR=Y). First line of the table presents number of patients with 
CCR=Y.

Based on those patients that have CCR=Y, we present number of patients 
with Non-missing and Missing RECUR status at the end of the Table. 
Percentages over total of Patients with CCR=Y.

Based on patients with Non-missing RECUR information we create the part 
of the table based on the observed data estimates. Percentages over total of 
Patients with CCR=Y AND valid (non-missing) RECUR.
For MI imputed estimations, we are using ALL patients (Regardless of CCR status) and 
perform Logical Derivations.
After Logical Derivations we use the restriction of CCR=Y and perform Multiple Imputation. 
The percentages will then be based over the total of patients with CCR=Y AFTER Logical 
Derivation. We will not have missing RECUR after MI.
Sustained Clinical Response: 
Based on patients with Non-missing Sustained Clinical Response information we create the 
part of the table based on the observed data estimates. Percentages over total of Patients with 
CCR=Y AND valid (non-missing) Sustained Clinical Response.
For MI imputed estimations, we are using ALL patients (Regardless of CCR status) and 
perform Logical Derivations (already performed for RECURRENCE).
After Logical Derivations we use the restriction of CCR=Y and perform Multiple Imputation 
(already performed for RECURRENCE). Percentages will be based over the total of patients 
with CCR=Y AFTER Logical Derivation. We will not have missing Sustained Clinical
Response after MI.


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Global Cure:
Only for EOS (EoT+30 days), in cases ICR/CCR are missing and SCR not assessed, Multiple 
Imputation will be used, in addition as Sensitivity Analysis. 
Multiple Imputation will be performed after Logical Derivation of CDAD Status related 
Endpoints (i.e., Recurrence and Sustained Clinical Response).


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10.3
Appendix 3: Pre-Specified Criteria for Adverse Events of Interest
Table 17 presents a list of AE terms to programmatically flag patients with AE’s of interest 
(see Section 6.2.1).
Table 17
Search strategies for Adverse Events of Interest
AE of Interest
Type
Term
MedDRA 17.0 
Search Criteria
Hypersensitivity
PT
All preferred terms
Hypersensitivity SMQ (narrow) 
Haematological AEs (Decreases 
in WBC, neutrophil and 
lymphocyte counts)
Events will be 
identified via Medical 
Review
Renal AEs (Renal Lab value 
abnormalities)
PT
All preferred terms
Acute renal failure SMQ (broad) 
Gastrointestinal hemorrhage
PT
All preferred terms
Gastrointestinal haemorrhage  
sub- SMQ (narrow)
QT prolongation
PT
All preferred terms
Torsade de pointes/
QT prolongation SMQ (broad) 
Hepatic lab value abnormality events are identified through DILI, please refer to SAP 
Section 6.2.2


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10.4
Appendix 4: Laboratory results Normal ranges
Table 18 presents the Normal ranges used in summary tables for laboratory results (see Section 7.5.2).
Table 18
Common Normal ranges for Hematology and Biochemistry
Laboratory Parameter
SI Units
Gender
Age Groups
Low Range
High Range
HEMATOLOGY
Absolute Neutrophil Count
106/L
Male/Female
0-30 days
6000
23500
1 month
1000
9000
2-11 months
1000
8500
1-12 years
1500
8000
13-18 years
1800
8000
Basophils
106/L
Male/Female
0-30 days
0
340
1 month
0
195
2-11 months
0
175
1-12 years
0
145
13-18 years
0
135
Basophils/Leukocytes
Fraction
Male/Female
All ages
0
0.01
Eosinophils
106/L
Male/Female
0-30 days
0
680
1 month
0
585
2-11 months
0
525
1-12 years
0
435
13-18 years
0
405
Eosinophils/Leukocytes
Fraction
Male/Female
All ages
0
0.03


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Laboratory Parameter
SI Units
Gender
Age Groups
Low Range
High Range
Hematocrit
Fraction
Male/ Female
0-30 days
0.44
0.70
1 month
0.32
0.42
2-6 months
0.29
0.41
7 months - 2 years
0.33
0.39
3-6 years
0.34
0.40
7-12 years
0.35
0.45
Female
13-18 years
0.36
0.45
Male
13-18 years
0.37
0.49
Hemoglobin 
g/L
Male/ Female
0-30 days
150
220
1 month
105
140
2-6 months
95
135
7 months - 2 years
105
140
3-6 years
115
145
7-12 years
115
155
Female
13-18 years
120
160
Male
13-18 years
130
160
International Normalized Ratio (INR)
Fraction
Male/ Female
All ages
0.8
1.2
Lymphocytes
106/L
Male/ Female
0-30 days
2275
12580
1 month
1400
16380
2-11 months
2040
15400
1-6 years
850
9715
7-12 years
750
8845
13-18 years
675
7425


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Laboratory Parameter
SI Units
Gender
Age Groups
Low Range
High Range
Lymphocytes/Leukocytes
Fraction
Male/ Female
0-30 days
0.25
0.37
1 month
0.28
0.84
2-11 months
0.34
0.88
1-6 years
0.17
0.67
7-12 years
0.15
0.61
13-18 years
0.15
0.55
Monocytes
106/L
Male/Female
0-30 days
0
3060
1 month
0
1365
2-11 months
0
875
1-12 years
0
725
13-18 years
0
540
Monocytes/Leukocytes
Fraction
Male/Female
0-30 days
0
0.09
1 month
0
0.07
2 months - 12 years
0
0.05
13-18 years
0
0.04
Neutrophils (Segmented Neutrophils, 
Absolute Units)
106/L
Male/Female
0-30 days
2912
22780
1 month
1000
8970
2-11 months
1200
8400
1-6 years
1850
10295
7-12 years
1650
11020
13-18 years
1485
10260
Neutrophils Band Form (Band 
Neutrophils, Absolute Units)
106/L
Male/ Female
0-30 days
0
2720.0
1 month
0
877.5
2-11 months
0
665.0
1-12 years
0
145.0
13-18 years
0
135.0


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Laboratory Parameter
SI Units
Gender
Age Groups
Low Range
High Range
Neutrophils Band Form/Leukocytes (Band 
Neutrophils)
Fraction
Male/Female
0-30 days
0
0.080
1 month
0
0.045
2-11 months
0
0.038
1-18 years
0
0.010
Neutrophils/Leukocytes (Segmented 
Neutrophils)
Fraction
Male/Female
0-30 days
0.32
0.67
1 month
0.20
0.46
2-11 months
0.20
0.48
1-6 years
0.37
0.71
7-18 years
0.33
0.76
Platelets
109/L
Male/Female
All Ages
150
450
Erythrocytes
1012/L
Male/Female
0-30 days
4.1
6.7
1 month
3.0
5.4
2-6 months
2.7
4.5
7 months - 2 years
3.7
5.3
3-6 years
3.9
5.3
7-12 years
4.0
5.2
Female
13-18 years
4.1
5.1
Male
13-18 years
4.5
5.3
Leukocytes
109/L
Male/Female
0-30 days
9.1
34.0
1 month
5.0
19.5
2-11 months
6.0
17.5
1-12 years
5.0
14.5
13-18 years
4.5
13.5


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Laboratory Parameter
SI Units
Gender
Age Groups
Low Range
High Range
BIOCHEMISTRY
Albumin
g/L
Male/Female
0-30 days
29
55
1-3 months
28
50
4-11 months
39
51
>= 1 year
37
55
Alkaline Phosphatase
U/L
Male/Female
0-5 days
110
300
6 days - 11 months
110
320
1-3 years
145
320
4-6 years
150
380
7-9 years
175
420
Female
10-11 years
130
560
Male
10-11 years
135
535
Female
12-13 years
105
420
Male
12-13 years
200
495
Female
14-15 years
70
230
Male
14-15 years
130
525
Female
16-18 years
50
130
Male
16-18 years
65
260
Alanine Aminotransferase
U/L
Male/Female
0-11 months
6
50
1-3 years
6
45
4-6 years
10
25
7-9 years
10
35


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Laboratory Parameter
SI Units
Gender
Age Groups
Low Range
High Range
Alanine Aminotransferase (continued)
U/L
Female
10-11 years
10
30
Male
10-11 years
10
35
Female
12-13 years
10
30
Male
12-13 years
10
55
Female
14-15 years
6
30
Male
14-15 years
10
45
Female
16-18 years
6
35
Male
16-18 years
10
40
Aspartate Aminotransferase
U/L
Male/Female
0-5 days
35
140
6 days-3 years
20
60
4-6 years
15
50
7-9 years
15
40
Female
10-11 years
10
40
Male
10-11 years
10
60
Female
12-15 years
10
30
Male
12-15 years
15
40
Female
16-18 years
5
30
Male
16-18 years
10
45
Direct Bilirubin
umol/L
Male/Female
All Ages
1.7
5.1
Bilirubin
umol/L
Male/Female
All Ages
5
21
C-Reactive Protein (CRP)
mg/L
Male/Female
All Ages
NA
10
Calcium
mmol/L
Male/Female
0-11 months
2.0
2.7
1-11 years
2.2
2.5
12-13 years
2.2
2.7


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Laboratory Parameter
SI Units
Gender
Age Groups
Low Range
High Range
Calcium (continued)
mmol/L
Male/Female
14-15 years
2.3
2.7
>=16 years
2.2
2.7
Chloride
mmol/L
Male/Female
All Ages
95
105
Creatinine
umol/L
Male/Female
All Ages
9.150
80.825
Gamma Glutamyl Transferase
U/L
Male/Female
0-5 days
34
263
6 days – 2 months
10
160
3-11 months
11
82
1-3 years
10
19
4-6 years
10
22
7-9 years
13
25
Female
10-11 years
17
28
Male
10-11 years
17
30
Female
12-13 years
14
25
Male
12-13 years
17
44
Female
14-15 years
14
26
Male
14-15 years
12
33
Female
16-18 years
11
28
Male
16-18 years
11
34
Glucose
mmol/L
Male/Female
All Ages
3.9
6.1
pH
NA
Male/Female
All Ages
4
9
Potassium
mmol/L
Male/Female
0-30 days
4.5
7.5
1-2 months
4
6.2
3-11 months
3.7
5.6
>= 1 year
3.5
5.5
Protein
g/L
Male/Female
0-30 days
44
76
1-3 months
42
74
4-11 months
56
72


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Laboratory Parameter
SI Units
Gender
Age Groups
Low Range
High Range
Protein (continued)
g/L
Male/Female
>= 1 year
60
80
Sodium
mmol/L
Male/Female
0-11 months
133
142
>= 1 year
136
145
Source: 
Gregory's Pediatric Anesthesia, Fifth Edition. Edited by George A. Gregory, Dean B. Andropoulos.
© 2012 Blackwell Publishing Ltd. Published 2012 by Blackwell Publishing Ltd. (http://onlinelibrary.wiley.com/doi/10.1002/9781444345186.app2/pdf)


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10.5
Appendix 5: Vital Signs Normal Ranges
Table 19 presents the Normal ranges used in summary tables for Vital Sign results (see 
Section 7.5.3).
Table 19
Common Normal ranges for Vital Signs
Vital Sign Parameter
SI Units
Gender
Age Groups
Low 
Range
High 
Range
Systolic Blood Pressure 
(SBP)
mmHg
Male/Female
0-5 months
65
90
6-11 months
80
100
1-11 years
90
110
>=12 years
110
135
Diastolic Blood Pressure 
(DBP)
mmHg
Male/Female
0-5 months
45
65
6-11 months
55
65
1-11 years
55
75
>=12 years
65
85
Pulse Rate (PR)
beats/min
Male/Female
0-11 months
100
160
1-11 years
70
120
>=12 years
60
100
Temperature (T)
C
Male/Female
All ages
36.6
38.0
Source: 
Harman M, et al. (2011). Pediatric emergency and resuscitation. In RM Kliegman et al., eds., Nelson Textbook 
of Pediatrics, 19th ed., p. 280. Philadelphia: Saunders Elsevier. (http://www.webmd.com/children/tc/vital-signs-
in-children-topic-overview) 


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10.6
Appendix 6: Treatment Compliance
Overall compliance to the dosing schedule will be examined for patients in the safety 
population. Percent treatment compliance is defined as:
                                                           Actual amount of study drug used x 100
Treatment compliance (%) = ----------------------------------------------------------------------------
                                               Planned amount of drug that should have been used in 10 days
Due to the nature of the population under study there is a different drug formulation to be 
used depending on the age of the patient. Therefore, treatment compliance is adjusted based 
on the age of patients (<6 / >=6 years old).
Although dosing by weight bands is preferred according to dosing instruction, some patients 
may have been dosed based on individual weight (mg/kg) rather than by weight bands. The 
protocol mentions both weight band dosing and dosing according to mg/kg/day. This is the 
reason treatment compliance will be calculated based on both dosing options (weight bands 
and individual weight).
Table 20
Comparative dosing scheme in mg per day
Fidaxomicin
Vancomycin
Weight band of patient
Oral Suspension
Tablets
Oral Liquid
Capsules
≤ 3.9 kg
80 mg
400 mg
100 mg
500 mg
4.0-6.9 kg
160 mg
200 mg
7.0-8.9 kg
240 mg
300 mg
9.0-12.4 kg
320 mg
400 mg
≥ 12.5 kg
400 mg
500 mg
Table 21
Planned dose in mg for complete treatment (10 days)
Fidaxomicin
Vancomycin
Weight band of subject
Oral Suspension
Tablets
Oral Liquid
Capsules
≤ 3.9 kg
800 mg
4000 mg
1000 mg
5000 mg
4.0-6.9 kg
1600 mg
2000 mg
7.0-8.9 kg
2400 mg
3000 mg
9.0-12.4 kg
3200 mg
4000 mg
≥ 12.5 kg
4000 mg
5000 mg


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
Patients from birth to < 6 years of age:
●
Patients randomized to fidaxomicin will receive fidaxomicin oral suspension 
(approximately 32 mg/kg/day with a maximum dose of 400 mg/day, divided in 
2 doses) 2 times daily for 10 days; or
●
Patients randomized to vancomycin will receive oral liquid (approximately 
40 mg/kg/day with a maximum dose of 500 mg/day divided in 4 doses) 4 times 
daily for 10 days.
For fidaxomicin oral suspension and vancomycin oral liquid, the weight of drug 
suspension/liquid is not the weight of drug. Table 22 and Table 23 present the 5 standard 
dose levels based on the respective weight intervals, including the last category (>=12.5 kg) 
where we have the maximum dose of 200 mg/dose or 400mg/dose for fidaxomicin and 
vancomycin respectively. Patients over 6 years of age with ability to swallow will be 
administered with fidaxomicin tablets or vancomycin capsules. For cases of patients over 
6 years of age not able to swallow tablets/capsules, fidaxomicin oral suspension or
vancomycin oral liquid will also be administered based on their weight level.
Oral Suspension / Oral Liquid calculations
●
Amount of study drug dispensed = 4.4g = 4400mg per bottle for fidaxomicin
●
Amount of study drug dispensed = 5.0g = 5000mg per bottle for vancomycin
●
If both dispensed and return bottle weights are available:
o
Actual weight of study drug used (mg)
= [Dispensed Bottle Weight (g) –Returned Bottle Weight (g)] * Study Drug 
Concentration (mg/g)
= [Dispensed Bottle Weight (g) - Returned Bottle Weight (g)] * 39.04 for 
fidaxomicin
= [Dispensed Bottle Weight (g) - Returned Bottle Weight (g)] * 24.06 for 
vancomycin
o
Returned Amount of study drug (mg) 
= Dispensed Amount of study drug (mg) – Amount of study drug used (mg)
●
If the dispensed bottle weight is not available, but the return bottle weight is available:
o
Returned amount of study drug (mg)
= [Returned Bottle Weight (g) – Container Weight (g)] * Study Drug 
Concentration (mg/g)
= [Returned Bottle Weight (g) –109.6] * 39.04 for fidaxomicin
= [Returned Bottle Weight (g) –27.2] * 24.06 for vancomycin
o
Actual weight of study drug used (mg) 
= Dispensed Amount of study drug (mg) – Returned Amount (mg)
●
If the return bottle weight is not available:
o
Returned amount of study drug = missing
o
Actual weight of study drug used = missing
o
Compliance = missing






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Compliance calculation formula:
(Number of Tablets dispensed – Number of Tablets returned)
Treatment compliance (%) = ---------------------------------------------------------------------------- x 100
Planned number of Tablets per 10 days 
Considering that for fidaxomicin 10 days treatment, the number of tablets is 20, we have:
(Number of Tablets dispensed – Number of Tablets returned)
Treatment compliance (%) = ---------------------------------------------------------------------------- x 100
20
Actual amount of Drug (g) could be calculated using of Number of Tablets, according to the 
following formula:
Actual drug weight for (g) Fidaxomicin = Number of fidaxomicin Tablets*200 mg
Vancomycin capsules
Actual amount of drug used is the number of vancomycin 125 mg capsules used during 
the treatment period as recorded in the relevant CRF is defined as:
Actual amount of drug used (n) = 
(total number of capsules dispensed) – (total number of capsules returned).
In addition
Actual weight of drug used (mg) = 
[(total number of capsules dispensed) – (total number of capsules returned)]* 125(mg)
Planned drug amount is calculated as:
Planned amount of drug (n) = 40
=10 (days), multiplied by 4 
(four times daily administration of 125 mg capsule). 
Planned weight of drug (mg) = 40 * 125 (mg) = 5000 mg
Compliance calculation formula:
(Number of Capsules dispensed – Number of Capsules returned)
Treatment compliance (%) = ---------------------------------------------------------------------------- x 100
Planned number of Capsules per 10 days 


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Considering that for vancomycin 10 days treatment, the number of Capsules is 40, we 
have:
(Number of Capsules dispensed – Number of Capsules returned)
Treatment compliance (%) = ---------------------------------------------------------------------------- x 100
40
Actual amount of Drug (g) could be calculated using of Number of Capsules, according to 
the following formula:
Actual drug weight for (g) Vancomycin = Number of Vancomycin Capsules *125 mg
For patients aged >= 6 years to < 18 years prior to randomization the ability for the patient to 
swallow tablets or capsules will be determined. If a patient aged >= 6 years to < 18 years
cannot swallow tablets or capsules, fidaxomicin oral suspension or vancomycin oral liquid
can be given as per the patient’s treatment allocation.
Patients >= 6 to <18 years of age:

Unable to swallow Tablets/Capsules:
Fidaxomicin Oral Suspension
     Compliance calculation formula:
           (Actual weight of study drug used) (mg)(*)
Treatment compliance (%) = --------------------------------------------------------------------- x 100
Planned weight of study drug per 10 days (mg)(1)
(1)
Based on the last column of Table 22, according to patient’s weight level, one of the 5 standard Doses and 
additionally based on individual weight.
(*)  Refer to section “patients from birth to <6 years old of age”
Vancomycin Oral Liquid
    Compliance calculation formula:
            (Actual weight of study drug used) (mg) (*)
Treatment compliance (%) = --------------------------------------------------------------------- x 100
Planned weight of study drug per 10 days (mg)(2)
(2)
Based on the last column of Table 23, according to patient’s weight level, one of the 5 standard Doses and 
additionally based on individual weight.
(*)  Refer to section “patients from birth to <6 years old of age”


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If a patient discontinues study drug early due to an AE, this is not a deviation because the 
protocol was followed. There is no need to report a deviation if there is an explanation such 
as dropping tablets down the sink by accident. 
For patients who completed the treatment period and have no data for study drug returned or 
partially missing data (e.g., 2 bottles were dispensed but only one was returned), but do have 
data for study drug dispensed, compliance will be missing. For all calculations empty bottle 
weight for fidaxomicin is 109.6 g, while for vancomycin is 27.2 g.


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10.7
Appendix 7: Changes from Planned Analysis
Section
Changes
Comment/rationale for change
6.1.4 Other 
Efficacy 
Variables
Additional efficacy variables:
- Diarrhea status (Normal vs 
Presence) for both <2 years and 
>=2 years
- Number of UBM for patients 
aged >=2 years to <18 years
The variables added are used in primary endpoint 
derivation. 
6.2.1 Adverse 
Events
“Lack of efficacy/lack of 
effect/treatment failure” & 
“Development of microbial 
resistance to Fidaxomicin” 
removed from the AEs of 
Interest section
“Lack of efficacy” will be assessed in the CSR 
by looking at the primary endpoint result (CCR) 
and efficacy results and “Development of 
microbial resistance to Fidaxomicin” will be 
assessed through the microbiological tests. Both 
events cannot be assessed via the AE reports. 


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10.8
Appendix 8: Key Contributors and Approvers
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author (s)
Contributors and Reviewers
Astellas Data Sciences
Astellas Medical Science
Astellas Medical Science
Astellas Clinical Science
Astellas Clinical Science 
Astellas Clinical Sciences
Astellas Medical Affairs


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Author and Approver Signatories 
 Astellas Data Science was the 
for this study.
 Astellas Data Science was the 
 peer reviewer of this 
Statistical Analysis Plan
This Statistical Analysis Plan was approved by:
 Astellas Medical Science