Clinical trial NCT01987895
Conditions: Clostridium Difficile Infection
Keywords: Post-antibiotic diarrhea Clostridium difficile infection
Sponsor: Actelion
Start date: 2014-03-27; Completion date: 2017-03-24
Enrollment: 632 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This clinical study is conducted to assess the efficacy of cadazolid compared to vancomycin in subjects with Clostridium difficile-associated diarrhea (CDAD).

Detailed description:
Subjects selected to participate in the study are treated either with cadazolid or vancomycin for 10 days. At the end of treatment, clinical cure is assessed; subjects are then followed-up to assess any disease recurrence.

Arms: arm 1: Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days arm 2: Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Interventions: intervention 1: Cadazolid intervention 2: Vancomycin intervention 3: Cadazolid-matching placebo intervention 4: Vancomycin-matching placebo
Intervention descriptions: intervention 1: Cadazolid 250 mg as oral suspension twice daily. intervention 2: Vancomycin 125 mg as oral capsules 4 times daily. intervention 3: Placebo matching cadazolid and administered orally twice daily intervention 4: Placebo capsules matching vancomycin and administered orally 4 times per day

Protocol documents:
Prot_001.pdf: 
 
 
 
 
 
 
 
 
Cadazolid/ACT-179811 
 
 
 
Protocol AC-061A301 
 
 
A multi-center, randomized, double-blind study to compare the efficacy and safety 
of cadazolid versus vancomycin in subjects with Clostridium difficile-associated 
diarrhea (CDAD) 
 
  
 
NCT Number 
NCT01987895 
 
 
Document Version,  Date 
Final Version 3, 22 October 2015 
 
 
Document History: 
 
- Original Version 
29 August 2013 
- Amendment 1 
11 December 2014 
- Amendment 2 
22 October 2015 
 
Main reason for Amendment 1 
The main analysis of the primary endpoint Clinical Cure will be conducted on two co-primary analysis 
sets (i.e., modified intent-to-treat [mITT] analysis set and Per-protocol analysis set [PPS]) instead of 
sequential analysis.  
Further changes include the addition of an emerging hypervirulent Clostridium difficile strain, the 
addition of endpoints related to susceptibility testing of C. difficile and vancomycin-resistant 
enterococci, and general clarifications of eligibility criteria and statistical analyses including a 
modification to the definition of recurrence for analyses of secondary variable sustained cure rate. 
 
Main reason for Amendment 2 
To remove the interim analysis originally planned after the randomization of 67% of the subjects. 
 
 
 
 
 
 
 
 
 
Confidentiality statement 
 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or otherwise disclosed 
without the consent of Actelion Pharmaceuticals Ltd 
 
 
 


Cadazolid/ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
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SPONSOR CONTACT DETAILS 
SPONSOR  
 
ACTELION Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
Clinical Trial Physician  
 
 
 
MEDICAL HOTLINE 
Toll phone number: 
 
+41 61 227 05 63  
Site-specific toll telephone numbers and toll-free numbers for the Medical Hotline can be 
found in the Investigator Site File. 
 
ACTELION CONTRIBUTORS TO THE PROTOCOL 
Clinical Trial Physician  
 
Clinical Science Program Head 
 
Clinical Trial Scientist 
 
Trial Statistician 
 
 
Clinical Trial Pharmacologist 
 
Drug Safety Physician 
 
 
 
COORDINATING INVESTIGATOR 
Name / Title 
Address 
 
 
 
 
 
 


Cadazolid/ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
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CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
CENTRAL LABORATORY 
 
 
 
CENTRAL RANDOMIZATION 
 
 
 
ECG reading (some sites) 
 
 
Independent Statistical Data 
Analysis Center 
 
 
CONTRACT RESEARCH 
ORGANIZATIONS (CRO) 
 
 
 
A list of site-specific contact details for CROs can be found in the Investigator Site File. 
 
 
 


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Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
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SIGNATURE PAGE FOR ACTELION PHARMACEUTICALS LTD 
Hereinafter called Actelion 
 
Drug name / number 
Cadazolid / ACT-179811 
Indication 
Clostridium difficile-associated diarrhea 
Protocol number, study title 
AC-061A301,  a multi-center,  randomized,  double-blind  study  to  compare  the  efficacy 
and  safety  of  cadazolid  versus  vancomycin  in  subjects  with 
Clostridium difficile-associated diarrhea (CDAD). 
 
I approve the design of this study. 
TITLE 
NAME 
DATE 
 
SIGNATURE 
Clinical Trial 
Physician 
 
 
Clinical Trial 
Statistician 
 
 
 
 
 
 


Cadazolid/ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
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INVESTIGATOR SIGNATURE PAGE 
Drug name / number 
Cadazolid / ACT-179811 
Indication 
Clostridium difficile-associated diarrhea 
Protocol number, study title 
AC-061A301, a multi-center, randomized, double-blind study to compare the efficacy 
and 
safety 
of 
cadazolid 
versus 
vancomycin 
in 
subjects 
with 
Clostridium difficile-associated diarrhea (CDAD). 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
Case Report Form (CRF), and any other protocol-related documents. I fully understand 
that any changes instituted by the investigator(s) without previous agreement with the 
Sponsor would constitute a violation of the protocol, including any ancillary studies or 
procedures performed on study subjects (other than those procedures necessary for the 
well-being of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines, and applicable regulations and laws. In particular, I will obtain approval by an 
Institutional Review Board or Independent Ethics Committee (IRB/IEC) prior to study 
start and signed informed consent from all subjects included in this study. If an 
amendment to the protocol is necessary, I will obtain approval by an IRB/IEC and ensure 
approval by regulatory authorities (if applicable) have been obtained before the 
implementation of changes described in the amendment. In addition, I will allow direct 
access to source documents and study facilities to Sponsor representative(s), particularly 
monitor(s) and auditor(s), and agree to inspection by regulatory authorities or IRB/IEC 
representatives. I will ensure that the study drug(s) supplied by the Sponsor are being 
used only as described in this protocol. Furthermore, I confirm herewith that the Sponsor 
is allowed to enter and utilize my professional contact details and function in an 
electronic database for internal purposes and for submission to Health Authorities 
worldwide. 
 
Country 
Site 
number 
Town 
Date 
 
Signature 
Site Principal 
Investigator 
 
 
 
 
 
 
 
 


Cadazolid/ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
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TABLE OF CONTENTS 
 
SPONSOR CONTACT DETAILS ......................................................................................2 
ACTELION CONTRIBUTORS TO THE PROTOCOL .....................................................2 
COORDINATING INVESTIGATOR.................................................................................2 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................13 
PROTOCOL SYNOPSIS AC-061A301 ............................................................................16 
CORE PROTOCOL ...........................................................................................................23 
1 
BACKGROUND AND RATIONALE .......................................................................23 
1.1 
Indication ......................................................................................................23 
1.1.1 
Introduction .......................................................................................23 
1.1.2 
Epidemiology ....................................................................................24 
1.1.3 
Current and future therapies .............................................................24 
1.2 
Study drugs ...................................................................................................25 
1.2.1 
Cadazolid ..........................................................................................25 
1.2.2 
Vancomycin ......................................................................................26 
1.3 
Purpose and rationale of the study ................................................................27 
2 
STUDY OBJECTIVES ...............................................................................................27 
2.1 
Primary objective ..........................................................................................27 
2.2 
Secondary objectives ....................................................................................27 
2.3 
Objective of the meta-analysis of AC-061A301 and AC-061A302 .............27 
2.4 
Exploratory objectives ..................................................................................28 
2.5 
Safety objective ............................................................................................28 
2.6 
Objective of the re-treatment extension with cadazolid ...............................28 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................28 
3.1 
Study design .................................................................................................28 
3.2 
Study design rationale ..................................................................................31 
3.3 
Study committees .........................................................................................35 
4 
SUBJECT POPULATION ..........................................................................................35 


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Clostridium difficile-associated diarrhea 
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4.1 
Subject population description .....................................................................35 
4.2 
Inclusion criteria ...........................................................................................36 
4.3 
Exclusion criteria ..........................................................................................37 
5 
TREATMENTS ..........................................................................................................39 
5.1 
Study treatments ...........................................................................................39 
5.1.1 
Study drugs .......................................................................................39 
5.1.2 
Investigational drug (cadazolid) and matching placebo ...................39 
5.1.3 
Comparator (vancomycin) and matching placebo ............................39 
5.1.4 
Dosing scheme ..................................................................................40 
5.1.5 
Treatment assignment .......................................................................41 
5.1.6 
Blinding ............................................................................................42 
5.1.7 
Unblinding ........................................................................................42 
5.1.7.1 
Unblinding for final study analyses and reporting ................. 42 
5.1.7.2 
Unblinding before final analyses ............................................ 42 
5.1.7.3 
Unblinding of a Suspected Unexpected Serious Adverse 
Reaction (SUSAR) ................................................................. 43 
5.1.7.4 
Emergency procedure for unblinding ..................................... 43 
5.1.8 
Study drug supply .............................................................................43 
5.1.8.1 
Study drug packaging and labeling ........................................ 43 
5.1.8.2 
Study drug distribution and storage ........................................ 44 
5.1.8.3 
Study drug return and destruction .......................................... 44 
5.1.9 
Compliance with study treatment .....................................................44 
5.1.10 
Study drug interruption and premature discontinuation of study 
drug ...................................................................................................45 
5.2 
Previous and concomitant medications ........................................................45 
5.2.1 
Prohibited and allowed concomitant medications ............................46 
5.2.2 
Alternative therapy for CDAD .........................................................46 
6 
STUDY ENDPOINTS ................................................................................................47 
6.1 
Efficacy endpoints ........................................................................................47 
6.1.1 
Primary efficacy endpoint .................................................................47 
6.1.2 
Secondary efficacy endpoints ...........................................................48 
6.1.3 
Meta-analysis endpoint .....................................................................50 
6.1.4 
Other efficacy endpoints – supportive of primary and 
secondary efficacy objectives ...........................................................50 
6.2 
Safety and tolerability endpoints ..................................................................54 
6.3 
Pharmacoeconomic endpoints ......................................................................54 
6.4 
Pharmacokinetic endpoints ...........................................................................55 


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Clostridium difficile-associated diarrhea 
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7 
STUDY ASSESSMENTS ...........................................................................................55 
7.1 
Baseline parameters ......................................................................................55 
7.2 
Efficacy assessments ....................................................................................56 
7.2.1 
Stool diary .........................................................................................56 
7.2.2 
Subject interviews .............................................................................57 
7.2.3 
Investigator assessments ...................................................................58 
7.2.4 
CDAD DaySyms PRO ......................................................................58 
7.2.5 
Stool microbiology ...........................................................................60 
7.2.5.1 
C. difficile GDH and toxin A/B tests ..................................... 60 
7.2.5.2 
C. difficile strain identification and susceptibility ................. 61 
7.2.5.3 
Vancomycin-resistant enterococci (VRE) quantitative 
culture and susceptibility ........................................................ 61 
7.3 
Safety and tolerability assessments ..............................................................62 
7.3.1 
Vital signs .........................................................................................62 
7.3.2 
ECG ..................................................................................................62 
7.3.3 
Weight and height .............................................................................63 
7.3.4 
Physical examination ........................................................................63 
7.3.5 
Laboratory assessments ....................................................................63 
7.3.5.1 
Type of laboratory .................................................................. 63 
7.3.5.2 
Laboratory parameters ............................................................ 64 
7.4 
Pharmacoeconomic assessments ..................................................................65 
7.4.1 
Work Productivity and Activity Impairment Questionnaire: 
Clostridium difficile-associated diarrhea V2.0 (WPAI:CDAD) .......65 
7.4.2 
Other pharmacoeconomic assessments .............................................66 
7.5 
Pharmacokinetic assessments .......................................................................66 
8 
SCHEDULE OF VISITS ............................................................................................68 
8.1 
Screening and Randomization / Visit 1 ........................................................68 
8.2 
Treatment period ...........................................................................................70 
8.2.1 
Visit 2 ................................................................................................70 
8.2.2 
Visit 3 ................................................................................................71 
8.3 
Follow-up period ..........................................................................................71 
8.3.1 
Visit 4 ................................................................................................71 
8.3.2 
Unscheduled visits for recurrence .....................................................72 
8.3.3 
Visit 5 ................................................................................................72 
8.3.4 
Unscheduled visits ............................................................................73 
8.4 
Re-treatment extension with cadazolid (optional) ........................................73 
9 
STUDY COMPLETION .............................................................................................79 


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Clostridium difficile-associated diarrhea 
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9.1 
Withdrawal from study .................................................................................79 
9.2 
End of the trial ..............................................................................................79 
9.3 
Premature termination or suspension of the study ........................................79 
9.4 
Medical care of subjects after the End-of-Treatment ...................................80 
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................80 
10.1 
Adverse events ..............................................................................................80 
10.1.1 
Definitions of adverse events ............................................................80 
10.1.2 
Intensity of adverse events ................................................................81 
10.1.3 
Relationship to study drug ................................................................82 
10.1.4 
Reporting of adverse events ..............................................................82 
10.1.5 
Follow-up of adverse events .............................................................82 
10.2 
Serious adverse events ..................................................................................82 
10.2.1 
Definitions of serious adverse events ...............................................82 
10.2.1.1 
Serious adverse events ............................................................ 82 
10.2.1.2 
Serious adverse events associated to study design or 
protocol mandated procedures ................................................ 83 
10.2.2 
Reporting of serious adverse events .................................................83 
10.2.2.1 
During screening period ......................................................... 83 
10.2.2.2 
During treatment period ......................................................... 83 
10.2.2.3 
During follow-up period ......................................................... 83 
10.2.3 
Follow-up of serious adverse events .................................................83 
10.2.4 
After the follow-up period ................................................................83 
10.2.5 
Reporting procedures ........................................................................84 
10.3 
Pregnancy .....................................................................................................84 
10.3.1 
Reporting of pregnancy ....................................................................84 
10.3.2 
Follow-up of pregnancy ....................................................................84 
10.4 
Study safety monitoring ................................................................................85 
11 STATISTICAL METHODS .......................................................................................85 
11.1 
Variables .......................................................................................................85 
11.1.1 
Primary variable ................................................................................85 
11.1.2 
Secondary variables ..........................................................................86 
11.1.2.1 
Sustained cure rate (SCR) ...................................................... 86 
11.1.2.2 
Time to Resolution of Diarrhea (ROD) .................................. 87 
11.1.2.3 
Absolute change from baseline in CDAD DaySyms PRO 
total daily score ...................................................................... 88 
11.1.2.4 
Other efficacy variables .......................................................... 88 
11.1.3 
Safety variables .................................................................................91 
11.1.4 
Other variables ..................................................................................91 


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Clostridium difficile-associated diarrhea 
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11.1.4.1 
Exposure to study drug ........................................................... 91 
11.1.4.2 
Demographic variables ........................................................... 92 
11.1.4.3 
Baseline disease characteristics variables .............................. 92 
11.1.4.4 
Pharmacoeconomic variables ................................................. 92 
11.1.4.5 
Pharmacokinetic variables ...................................................... 93 
11.1.4.6 
Re-treatment extension with cadazolid variables ................... 93 
11.2 
Analysis sets .................................................................................................93 
11.2.1 
Screened analysis set (SCRAS) ........................................................93 
11.2.2 
Full analysis set (FAS) ......................................................................93 
11.2.3 
Modified intent-to-treat (mITT) analysis set ....................................93 
11.2.4 
Per-protocol analysis set (PPS) .........................................................93 
11.2.5 
Hypervirulent analysis set (HVAS) ..................................................94 
11.2.6 
PRO analysis set (PROAS) ...............................................................94 
11.2.7 
Safety set (SS) ...................................................................................95 
11.2.8 
Re-treatment extension with cadazolid Set (ES) ..............................95 
11.2.9 
Pharmacokinetic analysis set (PKS) .................................................95 
11.2.10 
Role of the different analysis sets .....................................................95 
11.2.11 
Randomization and stratification ......................................................95 
11.3 
Description of statistical analyses .................................................................96 
11.3.1 
General considerations ......................................................................96 
11.3.2 
Analysis of subject disposition and study completion / 
withdrawal ........................................................................................97 
11.3.3 
Analysis of the primary variable .......................................................97 
11.3.3.1 
Hypotheses and statistical inference ....................................... 97 
11.3.3.2 
Statistical model ..................................................................... 98 
11.3.3.3 
Main analysis .......................................................................... 98 
11.3.3.4 
Supportive/sensitivity analyses .............................................. 98 
11.3.4 
Analysis of the secondary variables ..................................................99 
11.3.4.1 
Sequential test strategy for secondary variables ..................... 99 
11.3.4.2 
Hypotheses and statistical inference ..................................... 100 
11.3.4.3 
Analysis for secondary variables .......................................... 100 
11.3.4.4 
Supportive/sensitivity analyses of Sustained Cure ............... 101 
11.3.4.5 
Analysis of the other efficacy variables ............................... 102 
11.3.5 
Analysis of the safety variables ......................................................103 
11.3.5.1 
Adverse events ..................................................................... 103 
11.3.5.2 
Deaths ................................................................................... 103 
11.3.5.3 
Vital signs ............................................................................. 103 
11.3.5.4 
ECGs .................................................................................... 103 
11.3.5.5 
Hematology, coagulation and chemistry .............................. 104 
11.3.6 
Analysis of other variables .............................................................104 


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Clostridium difficile-associated diarrhea 
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11.3.7 
Exposure to study drug ...................................................................104 
11.3.8 
Demographic and baseline characteristics ......................................105 
11.4 
Meta-analysis ..............................................................................................105 
11.5 
Interim analyses ..........................................................................................106 
11.6 
Sample size .................................................................................................106 
11.6.1 
Sample size justification .................................................................106 
11.6.2 
Sample size sensitivity ....................................................................106 
11.6.3 
Sample size re-estimation ...............................................................107 
12 DATA HANDLING ..................................................................................................108 
12.1 
Data collection ............................................................................................108 
12.2 
Maintenance of data confidentiality ...........................................................108 
12.3 
Database management and quality control .................................................109 
13 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................110 
13.1 
Ethics and Good Clinical Practice ..............................................................110 
13.2 
Independent Ethics Committee / Institutional Review Board ....................110 
13.3 
Informed consent ........................................................................................110 
13.4 
Compensation to subjects and investigators ...............................................112 
13.5 
Protocol adherence/compliance ..................................................................112 
13.6 
Protocol amendment ...................................................................................112 
13.7 
Essential documents and retention of documents .......................................113 
13.8 
Equipment considerations and quality requirements ..................................114 
13.9 
Monitoring ..................................................................................................114 
13.10 
Audit ...........................................................................................................115 
13.11 
Inspections ..................................................................................................115 
13.12 
Reporting of study results and publication .................................................115 
14 REFERENCES ..........................................................................................................117 
 
LIST OF TABLES 
Table 1 
Visit and assessment schedule ................................................................... 22 
Table 2 
Dosing scheme .......................................................................................... 41 
Table 3 
Visit and assessment schedule for the re-treatment extension with 
cadazolid .................................................................................................... 78 
Table 4 
Sample size sensitivity for main analysis (PPS) ..................................... 107 
Table 5 
Sample size sensitivity for secondary variable Sustained Cure Rate ...... 107 
 


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Clostridium difficile-associated diarrhea 
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LIST OF FIGURES 
 
Figure 1 
Study design .............................................................................................. 31 
Figure 2 
Study design including re-treatment extension ......................................... 76 
Figure 3 
Hierarchical testing strategy ...................................................................... 99 
 
 
LIST OF APPENDICES 
Appendix 1 
Equivalence between opiates ................................................................... 122 
Appendix 2 
Stool diary ............................................................................................... 123 
Appendix 3 
CDAD DaySyms PRO ............................................................................ 124 
Appendix 4 
Definitions of marked abnormalities for safety parameters .................... 125 
Appendix 5 
Central Laboratory Normal Reference Ranges ....................................... 127 
Appendix 6 
Work Productivity and Activity Impairment Questionnaire ................... 129 
Appendix 7 
Justification of the non-inferiority margin .............................................. 132 
 
 
 
 


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Clostridium difficile-associated diarrhea 
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LIST OF ABBREVIATIONS AND ACRONYMS 
AE  Adverse event 
ALT  Alanine aminotransferase 
ANCOVA  Analysis of covariance 
aPTT  Activated partial thromboplastin time  
AST  Aspartate aminotransferase 
ATC  Anatomic therapeutic chemical 
b.i.d.  bis in diem, twice a day 
BM  Bowel movement 
BMI  Body mass index 
BP  Blood pressure 
bpm  Beats per minute 
CCR  Clinical cure rate 
CCRc  Clinical cure rate for cadazolid  
CCRv  Clinical cure rate for vancomycin  
CDAD  Clostridium difficile-associated diarrhea 
CDI  Clostridium difficile infection 
CI  Confidence interval 
CLSI  Clinical and Laboratory Standards Institute 
Cmax  Maximum plasma concentration 
CRA  Clinical research associate 
CRF  Case report form 
CRO  Contract research organization 
CTCAE  Common Terminology Criteria for Adverse Events 
CV  Curriculum vitae 
DBP  Diastolic blood pressure 
ECCR  Early clinical cure rate 
ECG  Electrocardiogram 
EIA  Enzyme immunoassay 
EMA  European Medicines Agency 
EOS  End-of-Study 
EOT  End-of-Treatment 
  
 
ES  Re-treatment extension with cadazolid set 
ESCMID  European Society of Clinical Microbiology and Infectious 
Diseases 
ETR  Early treatment response  
FAS  Full analysis set 
FDA  Food and Drug Administration 
FMT  Fecal microbiota transplant 


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Clostridium difficile-associated diarrhea 
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GCP  Good clinical practice 
GDH  Glutamate dehydrogenase 
h  Hour 
HR  Heart rate 
HVAS  Hypervirulent analysis set  
IB  Investigator’s brochure 
ICF  Informed consent form 
ICH  International Conference on Harmonisation 
ICR  Investigator’s judgment of clinical response  
ICRR  Investigator’s judgment of clinical response rate 
ICU  Intensive care unit 
IDMC  Independent Data Monitoring Committee 
IDSA  Infectious Diseases Society of America 
IEC  Independent Ethics Committee 
INR  International normalized ratio 
IRB  Institutional Review Board 
ISDAC  Independent Statistical Data Analysis Center 
ISF  Investigator site file 
ISR  Investigator’s judgment of sustained response  
ISRR  Investigator’s judgment of sustained response rate 
IVRS  Interactive voice response system 
LC-MS/MS  Liquid chromatography-tandem mass spectrometry 
LOQ  Limit of quantification 
MAD  Multiple-ascending dose 
MedDRA  Medical Dictionary for Regulatory Activities 
MIC  Minimal inhibitory concentration 
mITT  Modified intent-to-treat 
MTF  Metronidazole treatment failure 
NBM  Normalization of bowel movements 
NBMR  Normalization of bowel movement rate 
NDA  New drug application 
NED  New episode of diarrhea 
NI  Non-inferiority 
PCR  Polymerase chain reaction 
PI  Package insert 
PKS  Pharmacokinetic analysis set 
PP  Per-protocol 
PPI  Proton pump inhibitor 
PPS  Per-protocol analysis set 
PRO  Patient reported outcomes  


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Clostridium difficile-associated diarrhea 
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PROAS  PRO analysis set 
q.i.d.  Four times a day 
QTc  QT interval corrected for heart rate 
QTcB  QT corrected with Bazett’s formula 
 
QTcF  QT corrected with Fridericia’s formula 
REA  Restriction endonuclease assay 
ROD  Resolution of diarrhea 
RR  Recurrence rate  
SAE  Serious adverse event 
SAP  Statistical analysis plan 
SBP  Systolic blood pressure 
SI  Standardized International 
SCR  Sustained cure rate 
SCRAS  Screened analysis set 
SCRc  Sustained cure rate cadazolid 
SCRv  Sustained cure rate vancomycin 
SD  Standard deviation 
SE  Standard error 
SHEA  Society for Healthcare Epidemiology of America 
SOC  System organ class 
SOP  Standard operating procedure 
SS  Safety set 
SUSAR  Suspected unexpected serious adverse reaction 
TEAE  Treatment-emergent adverse event 
TOC  Test-of-cure 
UBM  Unformed bowel movement 
ULN  Upper limit of the normal range 
US  United States 
USPI  United States package insert 
VRE  Vancomycin-resistant enterococci 
WHO  World Health Organization 
WPAI  Work productivity and activity impairment 
 
 
 


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Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
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PROTOCOL SYNOPSIS AC-061A301 
TITLE 
AC-061A301, A multi-center, randomized, double-blind study 
to compare the efficacy and safety of cadazolid versus 
vancomycin in subjects with Clostridium difficile-associated 
diarrhea (CDAD). 
MAIN OBJECTIVES 
Primary objective 
To determine whether the clinical response after 10-day oral 
administration of cadazolid is non-inferior to oral vancomycin 
in subjects with CDAD. 
Secondary objectives 
To determine whether oral administration of cadazolid for 
10 days is superior to oral vancomycin in the sustained clinical 
response of subjects with CDAD. 
To determine whether the resolution of diarrhea (ROD) is 
more rapid with oral administration of cadazolid compared to 
vancomycin. 
To determine whether CDAD symptoms, as reported by the 
subject, show larger improvements from baseline with oral 
administration of cadazolid compared to vancomycin. 
Meta-analysis objective 
To determine whether oral administration of cadazolid for 
10 days is superior to oral vancomycin in the sustained clinical 
response of subjects with CDAD due to hypervirulent strains. 
Safety objective 
To determine safety and tolerability of an oral administration 
of cadazolid compared to vancomycin. 
Exploratory objectives are described in the core protocol. 
DESIGN 
See Section 3 
Prospective, 
multi-center, 
double-blind, 
double-dummy, 
randomized, parallel group, active controlled Phase 3 study 
PERIODS  
See Section 3 
Screening Period starts with the signature of the informed 
consent form (ICF) and ends with subject randomization 
(within 48 hours of the signature of the ICF). 
Treatment Period starts after randomization, with the first 
dose of study drug, and ends on the day of the last dose of 
study drug (EOT) 10 days later. 


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Follow-up Period starts after the last dose of study drug and 
ends approximately 30 days after the last dose of study drug 
(Visit 5).  
Re-treatment extension with cadazolid: Subjects who 
experience a recurrence and provide consent may enter a 
re-treatment extension with cadazolid consisting of a 
10-day treatment of cadazolid followed by an approximately 
30-day follow-up period. 
Subject participation in the study will be up to 44 days; up to 
88 days for subjects participating in the re-treatment extension 
with cadazolid. 
PLANNED DURATION 
Approximately 40 months.  
SITES / COUNTRIES  
Approximately 100 sites in approximately 20 countries. 
SUBJECTS / GROUPS 
Approximately 630 subjects will be randomized to cadazolid 
or vancomycin by Interactive Voice Response System (IVRS), 
ratio 1:1, stratified by first occurrence or first recurrence and 
by site. 
KEY INCLUSION 
CRITERIA  
See Section 4.2 
Signed Informed Consent. 
Male or female ≥ 18 years of age. 
Females of childbearing potential must agree to use an 
adequate and reliable method of contraception. 
Subject with a diagnosis of mild-moderate or severe CDAD 
(first occurrence or first recurrence within 3 months) with: 
Diarrhea: a change in bowel habits with > 3 unformed bowel 
movements (UBMs) within 24 hours prior to randomization,  
AND 
Positive C. difficile GDH and toxin test (by enzyme 
immunoassay approved by the sponsor) on the same stool 
sample produced within 72 hours prior to randomization. 
KEY EXCLUSION 
CRITERIA  
See Section 4.3 
More than one previous episode of CDAD in the 3-month 
period prior to randomization. 
Evidence of life-threatening or fulminant CDAD. 
Likelihood of death within 72 hours from any cause. 
History of inflammatory colitides, chronic abdominal pain, or 
chronic diarrhea, or known positive diagnostic test for 
enteropathogens. 


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Inability to take oral medication, or subjects with feeding 
tubes (i.e., when study drug would have to be given by a 
feeding tube).  
Antimicrobial treatment active against CDAD administered 
for > 24 hours except for metronidazole treatment failures 
(MTF). 
Planned treatment with forbidden concomitant medications.  
Fecal microbiota transplant (FMT), immunoglobulin therapy, 
and investigational drug to prevent or treat CDAD within 
1 month prior to randomization 
Monoclonal antibodies against C. difficile within 6 months 
prior to randomization.  
Previous vaccination against C. difficile.  
Previous participation in a clinical trial with cadazolid. 
Known hypersensitivity or contraindication to study drugs, 
oxazolidinones, or quinolones. 
Females who are breastfeeding. 
Investigational site staff members or relatives, and Actelion 
employees. 
Unable or unwilling to comply with all protocol requirements. 
STUDY TREATMENTS  
See Section 5.1 
Investigational drug 
Cadazolid 250 mg or matching placebo granules for oral 
suspension twice daily with or without food. 
Comparator 
Oral vancomycin 125 mg or matching placebo capsules 
4 times daily with or without food. 
CONCOMITANT 
MEDICATIONS  
See Section 5.2 
Prohibited medications 
Antimicrobial treatment active against CDAD and FMT up to 
Visit 5 unless provided for clinical failure or recurrence. 
Other medication active against CDAD (e.g., cholestyramine, 
probiotics) up to Visit 5. 
Initiation of treatment with opiates or change in dose or 
regimen resulting in an increased opiate effect up to 2 days 
after EOT. 
Anti-peristaltic medications, kaolin, pectin and charcoal 
containing anti-diarrheals up to Visit 5. 


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ENDPOINTS  
See Section 6.1 
Primary endpoint 
Clinical Cure defined as: 
• Resolution of Diarrhea (ROD: ≤ 3 UBMs per day for at 
least 2 consecutive days) on study treatment, maintained 
for 2 days after EOT  
AND 
• No additional antimicrobial treatment active against 
CDAD or FMT between first dose and 2 days after EOT 
(inclusive). 
Secondary endpoints 
Sustained Cure defined as:  
• Clinical Cure  
AND 
• No Recurrence 
 
Recurrence is defined for subjects with Clinical Cure as:  
• New episode of diarrhea (NED: > 3 UBMs within 
1 day) occurring between 3 days after EOT and Visit 5 
AND 
• Positive C. difficile GDH and toxin stool test on the 
same stool sample 
AND 
• Antimicrobial treatment active against CDAD or FMT 
started between 3 days after EOT and Visit 5 (or 
participation in the re-treatment extension with cadazolid). 
 
Time to ROD, defined as: 
 
• The time (h) elapsed between the first dose of study drug 
and the time when ROD is considered achieved. 
 
Absolute change from baseline in CDAD DaySyms Patient 
Reported Outcomes (PRO). 
CDAD DaySyms total daily score change from baseline up to 
Day 12. 
 
Meta-analysis endpoint 
• Sustained Cure (as defined above) in hypervirulent strains 
(currently defined as Strains 027, 078, and 244). 
 
Additional endpoints are described in the core protocol. 


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ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY  
See Section 11 
Sample Size: Assuming a Clinical Cure Rate (CCR) of 85% 
in the Per-protocol analysis set (PPS) for cadazolid and 
vancomycin treatment groups, a power of 90%, a fixed type I 
error of 2.5% (one-sided), and a non-inferiority (NI) margin of 
10%, a total sample size of 536 (268 in each treatment group) 
evaluable subjects is required in the PPS. Taking into account 
approximately 15% of subjects not qualifying for the per-
protocol (PP) population, approximately 630 subjects will be 
randomized into the trial. As approximately 95% of the 
randomized subjects are assumed to qualify for the modified 
intent-to-treat (mITT) analysis set (598 subjects), the power 
for demonstrating non-inferiority in clinical cure on this 
population is higher than 90%.  
Main efficacy analysis. Clinical Cure Rate (CCR, %) is the 
variable to be analyzed for the primary endpoint. The aim is to 
demonstrate that the CCR for cadazolid (CCRc) is not inferior 
to the CCR for vancomycin (CCRv), accounting for a NI 
margin of 10%. NI in CCR of cadazolid against vancomycin 
will be assessed based on the difference between proportions 
in CCRc and CCRv. The null hypothesis is:  
H0(1): CCRc − CCRv ≤ −10%  
versus the alternative hypothesis:  
H1(1): CCRc − CCRv > −10%.  
The main analysis will be on the mITT analysis set and on the 
PPS. NI is claimed if it is demonstrated on both analysis sets, 
by a one-sided 0.025 significance level, using the lower bound 
of the two-sided 95% confidence interval (CI) of the 
difference between proportions. 
Secondary efficacy analysis: If NI for CCR is demonstrated 
in both analysis sets, mITT and PPS, the superiority of 
cadazolid on the secondary endpoint Sustained Cure Rate 
(SCR) will be tested on the mITT analysis set at the two-sided 
alpha 0.05. If the lower limit of the two-sided 95% CI is 
greater than zero, the statistical superiority of cadazolid versus 
vancomycin in SCR will be established. After this is 


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demonstrated, the superiority in time to ROD (shorter median 
time) will be tested. If demonstrated, then the superiority in 
the CDAD DaySyms scores changes from baseline will be 
tested. This full hierarchical testing strategy is used to control 
the experimentwise α level at 0.05. 
Meta-analysis: A meta-analysis of this trial and the similar 
Phase 3 trial AC-061A302 will be utilized for the assessment 
of cadazolid superiority in the Sustained Cure of subjects with 
CDAD due to hypervirulent strains. 
Safety analysis: Treatment-emergent adverse events and 
serious adverse events will be summarized per treatment arm 
and overall, by frequency, intensity and relationship to study 
medication. Other safety variables, such as laboratory 
assessments, vital signs and ECGs will be summarized. 
STUDY COMMITTEES 
Steering Committee, Independent Data Monitoring Committee 
SUB-STUDIES 
As part of this protocol, at selected sites and in subjects who 
consent to participate, the plasma concentrations of cadazolid 
will be analyzed. 
In addition, the following sub-studies, independent from the 
core study protocol and at selected sites in subjects who 
consent to participate (through an informed consent separate 
from the main protocol informed consent), will be performed 
according to stand-alone protocols: 
• Psychometric validation of CDAD DaySyms PRO 
• Gut 
microbiome 
assessment 
and 
fecal 
cadazolid 
concentrations. 
 
 


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Table 1 
Visit and assessment schedule 
See Section 7 for complete information.  
PERIODS 
Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
- 
 
Duration 
Up to 48 hours 
10 to 11 days 
28 to 32 days 
- 
VISIT 
Number 
1 
2 
3 
4 
4.a, 4.b,… 
5 
U1, U2, … 
 
Name 
Screening 
Randomization 
 
 
 
NED 
 
Unscheduled 
EVALUATION 
Time 
Day –2 to Day 1 
(within 48 h) 
Day 1 
Day 5 or Day 6 
On site or by phone 
Day 8 to Day 10 
incl. Premature Disc. 
EOT + 2 to 4 days  
On site or by phone 
If applicable, in 
case of NED 5, 6 
EOT + 28 to 32 days  
or Study Withdrawal 
If applicable 
Informed consent 
X 
 
 
 
 
 
 
 
Fecal sampling for microbiology  
X 
 
X 
 
X 
 
 
C. difficile GDH and toxin test 
within 72 h (MTF: 48h) 
 
 
 
 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
X 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
X 
X 
X 
X 
Body weight/height 
X1 
 
X 
 
 
X 
X 
Vital signs / Body temperature 
X1 
 
X 
X 
X 
X 
Hematology/coagulation/chemistry 
X 2 
 
X 
X 
X 
X 
12-lead ECG 
X  
 
X 
 
 
X 
X 
Randomization 
X 
 
 
 
 
 
 
Study Drug 
X3 
and Study Drug Journal completion 
 
 
 
 
Stool Diary 
 
 
 
CDAD DaySyms PRO Diary 
 
 
 
 
Interview (face to face or by phone) 
Daily7 
Twice weekly 
 
Investigator assessment 
 
X 
 
X 
 
X 
 
Pharmacokinetic sample Sub-study 
 
X 
 
 
 
 
WPAI:CDAD  
X 
 
X 
 
 
X 
 
AEs/SAEs 4 
X 
X 
X 
X 
X 
X 
X 
X 
1. Height collected at Visit 1 only. 2. Includes pregnancy test for women of childbearing potential. 3. After randomization. 4. All AEs and SAEs are reported after the first dose of study drug. 
Between informed consent and first dose of study drug, only SAEs are reported. 5. Subject may enter re-treatment extension with cadazolid in case of recurrence [Table 3]. 6. All assessments must 
be performed in the case of a recurrence. 7. Interviews start from Day 2. 
AE = adverse event, C-difficile = Clostridium difficile, CDAD = Clostridium difficile-associated diarrhea, ECG = electrocardiogram, EOT = End-of-Treatment, GDH = glutamate dehydrogenase, 
MTF = metronidazole treatment failure, NED = new episode of diarrhea, PRO = patient reported outcomes, SAE = serious adverse event, WPAI = work productivity and activity impairment.


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CORE PROTOCOL 
1 
BACKGROUND AND RATIONALE 
1.1 Indication 
1.1.1 Introduction 
Clostridium difficile-associated diarrhea (CDAD) is an infectious disease of the 
gastrointestinal tract. CDAD usually occurs in patients with a history of antibiotic use 
that allows C. difficile to grow and elaborate virulent toxins that can cause intestinal 
inflammation and diarrhea. 
C. difficile is a spore-forming Gram-positive anaerobic bacillus present throughout the 
environment. Acid-resistant spores are ingested and passed through the stomach to 
germinate in the small bowel and eventually colonize the colon where they can be a 
harmless component of normal gut flora. Some strains of C. difficile elaborate toxins, 
termed A and B, that cause disease by invading epithelial cells, altering their cytoskeleton 
and resulting in a disruption of the epithelial barrier. These toxins then invade the 
intestinal mucosa where they also function as potent immunostimulatory molecules 
promoting inflammation [Poutanen 2004, Kelly 2008]. The resulting C. difficile infection 
(CDI) usually manifests as diarrhea but can cause a range of clinical symptoms with 
some patients only experiencing a transient nuisance diarrhea, while others rapidly 
progress to frequent loose stools, abdominal pain with fever and marked leukocytosis.  
The typical patient with CDAD is in his or her 60s, often has comorbid illnesses, has 
received antibiotics within the past 2 months [Poutanen 2004, Pachecho 2013], and 
clinically presents with a broad spectrum of severity. CDAD may result in only a mild 
diarrhea lasting a few days that requires no treatment, to the more protracted severe 
disease 
with 
extensive 
colonic 
inflammation, 
associated 
characteristic 
pseudomembranous colitis and signs of systemic toxicity [Dallal 2002, Voelker 2010]. 
Risk factors for severe disease include age greater than 65, comorbid illnesses, 
concomitant acid suppression therapy, low antibody response, and the need to prolong 
inciting antibiotic therapy [Bauer 2009, Louie 2013b]. Although risk factors for severe 
disease have been reported, there is no consensus on a specific CDAD severity index. 
Severe disease is often defined based on fever (temperature > 38.5 °C), leukocytosis 
(> 15,000 cells/mm3), or increase in serum creatinine (1.5 times above the premorbid 
level) [Bauer 2009, Cohen 2010]. Pseudomembranes on endoscopy and imaging criteria 
are sometimes used to define severe disease but information on these criteria are not 
always available. Subjects not meeting these criteria are classified as having  
mild–moderate CDI. When CDAD becomes fulminant and unresponsive to medical 
therapy, a life-saving emergent colectomy is required but can be associated with 
mortality as high as 40% [Bhangu 2012].  


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1.1.2 Epidemiology 
CDAD incidence has been increasing in recent years and disease severity and mortality 
has also been increasing, in part due to the emergence of the 027/BI/NAP1 hypervirulent 
strain. A recent review suggests that on an annual basis in the United States there are 
333,000 cases of CDAD, with 15,000 to 20,000 deaths at a cost of $3.2 billion 
[Dubberke 2010]. In Europe a survey of 34 countries revealed the incidence rate of 
CDAD to be 4.1 per 10,000 patient days per hospital [Bauer 2011]. The increased 
frequency and severity of CDAD in Western countries has been attributed to wider 
antibiotic use in an ever-growing elderly population that is living longer with multiple 
comorbid illnesses and immunosenescence, such that CDAD has now surpassed 
methicillin-resistant Staphylococcus aureus rates of infection in some community 
hospitals [Miller 2011]. Furthermore, severe disease with its associated mortality is also 
on the rise and thought to be related to the increased global spread of a virulent strain 
(genotyped as 027/BI/NAP1) that is capable of elaborating 20-fold more toxin than other 
toxigenic strains [Miao He 2012, Loo 2005]. 
In addition to the morbidity and mortality of the acute episode of CDAD, once cured  
25–30% of patients will experience recurrent CDAD within 1 month of treatment, with 
either the same strain of C. difficile (relapse) or a different strain (re-infection). 
Recurrence rates can range as high as 65%, particularly in older patients and those 
continuing to receive concomitant antibiotics [Garey 2008, Louie 2013b, Hu 2009]. 
1.1.3 Current and future therapies 
Several factors, including the 027/BI/NAP1 hypervirulent strain and the recurrence rate, 
have contributed to the overall morbidity and mortality of CDAD and have resulted in the 
re-emergence of C. difficile as a major global health problem. New drug therapy that 
reduces recurrence rates, or improves outcomes for patients infected with the 
hypervirulent strain or those with severe disease, remains a significant unmet medical 
need. 
Discontinuation of concurrent antibiotics may allow the normal colonic flora to 
regenerate and may prevent further C. difficile growth. However, discontinuing 
antibiotics often does not resolve CDAD, and many patients are unable to discontinue 
antibiotics for an ongoing intercurrent infection. 
Approved in 1986, oral vancomycin remains the mainstay of therapy, alongside 
metronidazole. Vancomycin has been proven efficacious in mild–moderate disease in the 
setting of clinical trials and is approved in many countries for the treatment of CDAD 
without any qualifier on the severity of disease. It is generally not used in the initial 
episode of mild–moderate disease. Current standard of care for mild–moderate disease in 
patients with an initial episode of CDAD remains metronidazole [Cohen 2010, 


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Bauer 2009]. Randomized data from the control arms of the recent tolevamer trials also 
suggested lower clinical response rates in metronidazole subjects compared to 
vancomycin subjects (72.7% versus 81.1%; odds ratio [95% confidence interval (CI)]: 
1.681 [1.114, 2.537], p = 0.0134) [Johnson 2012]. For severe disease in the initial episode 
or in recurrences, vancomycin at the dose of 125 mg 4 times daily is recommended 
therapy by the Society for Healthcare Epidemiology of America / Infectious Diseases 
Society of America (SHEA/IDSA) and European Society of Clinical Microbiology and 
Infectious Diseases (ESCMID) guidelines. It is also recommended to treat patients with 
multiple recurrences with an extended course of vancomycin, often with a tapering or 
pulsed regimen. 
Fidaxomicin has proven to be comparable to vancomycin with regard to cure rates, and 
importantly, has demonstrated higher Sustained Cure Rate (SCR) in 2 randomized 
double-blind trials [Louie 2011, Cornely 2012]. The decrease in recurrence rate is 
thought to be due to the reduced attenuation of colonic flora with fidaxomicin treatment 
compared with vancomycin treatment [Tannock 2010]. However, fidaxomicin’s SCR 
against the virulent 027/BI/NAP1 strain was not better than vancomycin. 
1.2 Study drugs 
1.2.1 Cadazolid 
This section is a brief summary of available data about cadazolid that is relevant to the 
study. For more detailed information, please see the Investigator’s Brochure (IB) 
[Cadazolid IB]. 
Cadazolid is a novel antibiotic with bactericidal activity against C. difficile, including 
hypervirulent and moxifloxacin-resistant strains such as 027/BI/NAP1.  
Minimal inhibitory concentrations (MICs) of cadazolid against clinical isolates of 
C. difficile range from 0.06 to 0.5 µg/mL. Cadazolid retains its activity against C. difficile 
over the pH range 6.2–7.5, which is found at relevant segments of the affected gut. 
Cadazolid is a potent inhibitor of bacterial protein synthesis and strongly inhibits toxin 
synthesis in cultures of toxigenic C. difficile strains in a manner superior to vancomycin 
and metronidazole. In contrast to vancomycin, in vitro experiments demonstrate that 
cadazolid prevents sporulation in vegetative cells at sub-MIC concentrations.  
Two Phase 1 studies with cadazolid were conducted in healthy subjects: a 
single-ascending dose study (AC-061-101) and a multiple-ascending dose (MAD) study 
(AC-061-102). In these studies, 48 healthy male subjects were exposed to cadazolid at 
single oral doses of 30–3000 mg or multiple doses of 300–3000 mg twice daily for 
10 days. All oral doses of cadazolid were well tolerated. Systemic cadazolid exposures 
were extremely low (maximum plasma concentration: 6.88 ng/mL), and increased in a 
less than dose-proportional manner over the dose range tested. 


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An open-label study (AC-061-103) was completed in subjects with severe CDAD to 
investigate the pharmacokinetics, safety, and tolerability of cadazolid following a single 
oral dose of 3000 mg in 6 subjects (4 males, 2 females). This dose was well tolerated in 
all subjects. Peak cadazolid plasma concentrations (Cmax) (geometric mean 2.6 ng/mL) 
were low and were comparable to those observed in healthy subjects. 
In healthy subjects, negligible quantities of drug were detected in the urine: on Day 10 
approximately 0.01% or less of the oral dose was excreted in urine following the  
300–3000 mg b.i.d. dosing regimen (Study AC-061-102). Almost the entire oral dose was 
recovered as unchanged drug in the feces. Similar results were observed in subjects with 
severe CDAD (AC-061-103). Thus, the majority of the oral dose is available to exert its 
maximum clinical effect in the gastrointestinal tract.  
A Phase 2 study (AC-061A201) investigating the efficacy and safety of cadazolid in 
84 adult subjects with CDAD has been completed. This study had a prospective, 
multi-center, double-blind, randomized, stratified, parallel-group, double-dummy design, 
and included a vancomycin reference arm. Three doses of cadazolid (250 mg, 500 mg, 
and 1000 mg, orally, b.i.d.) and vancomycin (125 mg orally, q.i.d.) administered for 
10 days were evaluated. The modified Clinical Cure rates defined as the proportion of 
subjects having 3 or fewer unformed stools for at least 2 days and no further need for 
CDAD therapy at test-of-cure (TOC) 24–72 hours after the last dose of study treatment 
showed that all cadazolid doses were similarly effective, providing similar or numerically 
higher results versus vancomycin; e.g., 100% for the cadazolid 250 mg dose group versus 
89.5% for vancomycin in the Per-protocol analysis set (PPS). Modified recurrence rates, 
defined as the proportion of subjects clinically cured who subsequently had a new 
episode of diarrhea and a positive C. difficile toxin test up to 4 weeks after the last dose 
of study treatment, were 18.8% for cadazolid 250 mg dose group versus 36.8% for 
vancomycin modified intent-to-treat (mITT) analysis set. The resulting modified 
Sustained Cure (Modified Clinical Cure without modified recurrence) rate was higher for 
cadazolid 250 mg dose group than for vancomycin (76.5% versus 54.5%, mITT analysis 
set) [Louie 2013a]. 
In the Phase 2 study, similar to that observed in both healthy subjects and subjects with 
severe CDAD, cadazolid showed very low systemic availability (maximum individual 
plasma concentration: 18.9 ng/mL in the cadazolid 1000 mg dose group). All oral doses 
of cadazolid were well tolerated. 
1.2.2 Vancomycin 
See Section 1.1.3 for information on vancomycin in the treatment of CDAD.  


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1.3 Purpose and rationale of the study 
Cadazolid has demonstrated activity against C. difficile in nonclinical in vitro and animal 
studies. High concentrations of cadazolid in the intestine and low systemic absorption 
make it an attractive candidate for the treatment of CDAD in man. Phase 2 study results 
have suggested clinical response similar to or numerically higher than vancomycin, and 
higher Sustained Cure rates than vancomycin. Based on the Phase 2 results, a cadazolid 
dose of 250 mg twice daily for 10 days was chosen for further evaluation in a Phase 3 
program. The selected dose is expected to optimize the clinical response and the impact 
on the gut microbiome, leading to improved Sustained Cure relative to comparator.  
This study is 1 of 2 pivotal Phase 3 trials with identical design, each aimed at determining 
the efficacy and safety of the studied regimen of cadazolid relative to that of vancomycin 
in subjects with mild–moderate or severe CDAD. The identical study design will allow a 
pooled analysis of these 2 pivotal Phase 3 trials, including a predefined assessment of 
Sustained Cure in subjects with CDAD due to hypervirulent strains (defined currently as 
Polymerase Chain Reaction [PCR] ribotypes 027, 078, and 244). In addition, the 
2 identical Phase 3 studies will allow specific analyses to be performed through the 
enrollment of subjects into shared protocol sub-studies (pharmacokinetic, gut 
microbiome, and the CDAD DaySyms Patient Reported Outcomes (PRO) psychometric 
validation). 
2 STUDY OBJECTIVES 
2.1 Primary objective 
To determine whether the clinical response after 10-day oral administration of cadazolid 
is non-inferior to oral vancomycin, in subjects with CDAD. 
2.2 Secondary objectives 
• To determine whether oral administration of cadazolid for 10 days is superior to oral 
vancomycin in the sustained clinical response of subjects with CDAD. 
• To determine whether the resolution of diarrhea (ROD) is more rapid with oral 
administration of cadazolid compared to vancomycin. 
• To determine whether CDAD symptoms as reported by the subject show larger 
improvements from baseline with oral administration of cadazolid compared to 
vancomycin. 
2.3 Objective of the meta-analysis of AC-061A301 and AC-061A302  
To determine through a meta-analysis of both studies whether oral administration of 
cadazolid for 10 days is superior to oral vancomycin in the sustained clinical response of 
subjects with CDAD due to hypervirulent strains.  


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2.4 Exploratory objectives 
To evaluate the plasma cadazolid concentration at approximately 2 h post-dose. 
2.5 Safety objective 
To determine safety and tolerability of an oral administration of cadazolid compared to 
vancomycin.  
2.6 Objective of the re-treatment extension with cadazolid 
To describe the clinical response, sustained clinical response and safety in subjects with a 
first occurrence of CDAD at study entry (cadazolid or vancomycin subjects), who 
experience a recurrence of CDAD and are re-treated with cadazolid for 10 days. 
3 OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a prospective, multi-center, double-blind, double-dummy, randomized, parallel 
group, active controlled, Phase 3 study. The study will be conducted in approximately 
100 sites in approximately 20 countries worldwide. 
Approximately 630 adult subjects will be randomized 1:1, stratified by first occurrence or 
first recurrence and by site, to the 2 treatment groups (approximately 315 subjects per 
group): cadazolid and vancomycin to ensure that at least 536 subjects will be included in 
the PPS. 
Randomization will proceed until the required number of subjects has been reached and 
will be competitive across participating sites. 
The study consists of the following study periods: 
Screening Period lasts up to 48 hours from signature of the informed consent form (ICF) 
and ends with subject randomization. Subjects (or the legally authorized representative) 
must sign the ICF prior to protocol specified screening procedures. Baseline is defined as 
the last assessment prior to initiation of study treatment. 
Treatment Period starts after randomization with the first dose of study drug at the end 
of Visit 1 (Day 1 of study), and ends with End-of-Treatment (EOT) on the day of the last 
dose of study drug (which is either Day 10 or Day 11 of the study to account for 
10 complete days of treatment).  
During this period, the following evaluations are performed: 
• Visit 2 (on site or by telephone) on Day 5 of study (or Day 6 if the visit cannot take 
place on Day 5). This evaluation may be done by telephone if, in the investigator’s 


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opinion, a face-to-face visit is not necessary. At this visit, the investigator’s 
assessment of Early Treatment Response (ETR) occurs. 
• Visit 3 (on site), on Day 8–10 of study, is performed while the subject is taking study 
drug. In case of premature discontinuation of study drug, Visit 3 is performed and the 
follow-up period takes place as planned. 
In addition, unscheduled visits may also take place anytime during the treatment period.  
Follow-up period starts immediately after the last dose of study drug, and ends 
approximately 30 days after the last dose of study drug, at Visit 5. 
During this period, the following evaluations are performed: 
• Visit 4 (on site or by telephone) occurs 2–4 days after the EOT. This visit may be 
done by telephone if, in the investigator’s opinion, a face-to-face visit is not 
necessary. At this visit, the investigator will evaluate and record in the case report 
form (CRF) the Clinical Cure [according to the primary endpoint definition – see 
Section 6.1.1] on which the investigator will base the management of the subject for 
the rest of the study. In addition, the investigator will provide his/her judgment of 
Clinical Response [Section 6.1.2]. 
• Unscheduled visits (Visit 4.a, 4.b, etc.) to evaluate for recurrence occur when a 
subject experiences a new episode of diarrhea (NED) at any time between Visit 4 and 
5. When a NED happens, the subject must contact the site immediately and an 
unscheduled visit (on site) should be organized within 48 h. 
• Visit 5 (on site) occurs 30 ± 2 days after the EOT. At this visit, the investigator’s 
judgment of sustained response (ISR) occurs. In case of early study withdrawal, 
Visit 5 should be scheduled within 48 h. 
In addition, unscheduled visits (not due to a NED) may also take place during the 
treatment and follow-up periods, in which case study-related information will be 
collected.  
The study also includes an extension: 
Re-treatment extension with cadazolid: Subjects who experience a recurrence during 
the study, whether they have been treated with cadazolid or vancomycin, may enter a 
re-treatment extension with cadazolid (after providing a specific informed consent) 
consisting of a 10-day treatment of cadazolid followed by an approximately 30-day 
follow-up period (full details of visit and assessment schedule is provided in Section 8.4). 


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Study diaries 
During the study (from Visit 1 to Visit 5), diaries and a journal are completed daily for 
each subject to collect the following information: 
1. Frequency and consistency of stools [Section 7.2.1]. 
2. Study drug intake [Section 5.1.9]. 
3. CDAD DaySyms PRO – completed by all subjects who personally signed the ICF (i.e., 
not signed by a legally authorized representative) [Section 7.2.4]. 
Subjects should be contacted daily up to Visit 4 and twice weekly thereafter for 
interviews (either face-to-face or by telephone) to encourage diary compliance and for 
investigator evaluation of CDAD status based on the stool diary completion (i.e., 
frequency and consistency of stools). 
Sub-studies 
As part of this protocol, at selected sites and in subjects who consent to participate, the 
plasma concentrations of cadazolid will be analyzed [see Section 7.5]. 
• Pharmacokinetics: 
To have at least 50 subjects with a cadazolid sample, a sub-population of at least 
120 participating subjects from this study and study AC-061A302 will be recruited. In 
these subjects, plasma concentration of cadazolid will be determined. 
In addition, the following sub-studies independent from the core study protocol and at 
selected sites in subjects who consent to participate (through an informed consent 
separate from the main protocol informed consent) will be performed according to 
stand-alone protocols: 
• Psychometric validation of CDAD DaySyms PRO:  
In a sub-population of approximately 165 participating subjects from this study and study 
AC-061A302 who personally signed the ICFs (i.e., not signed by a legally authorized 
representative) for AC-061A301 and for the sub-study, data required for the assessment 
of the final content validity of the CDAD DaySyms PRO as well as its psychometric 
properties will be collected. Subjects will be asked to complete 4 additional 
questionnaires at Visit 1 and Visit 3. 
• Gut microbiome assessment and fecal cadazolid concentrations: 
In a sub-population of approximately 100 participating subjects from this study and study 
AC-061A302, subjects will provide stool samples with the objective of analyzing 


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intestinal flora diversity and its variation on treatment and after treatment, the emergence 
of resistance, and, if needed, determining the fecal cadazolid concentration. 
Study duration 
Subject participation in the study will be up to 44 days; up to 88 days for subjects 
participating in the re-treatment extension with cadazolid.  
Table 1 shows a schematic representation of the assessments during the study, and the 
overall study design is depicted in Figure 1. 
Figure 1 
Study design 
 
3.2 Study design rationale 
This is a prospective, multi-center, double-blind, double-dummy, randomized, stratified, 
parallel group, active controlled, Phase 3 study comparing the efficacy and safety of 
cadazolid versus vancomycin in subjects with CDAD, including hypervirulent strains.  


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Subjects with mild–moderate or severe CDAD will be enrolled in the study based on the 
diarrhea criteria documented within a pre-specified period and a positive result from 
a C. difficile GDH and toxin assay, as suggested in the addendum to the note for guidance 
on evaluation of medicinal products indicated for treatment of bacterial infections 
(CPMP/EWP/558/95 REV 2) [EMA 2011]. Only subjects with first occurrence or first 
recurrence of CDAD will be eligible since treatment for subjects with multi-recurrences 
is not standardized by regimen, dose, and/or duration. 
Given the higher recurrence rate in subjects with a prior episode of CDAD, 
randomization is stratified on this factor (first occurrence versus first recurrence) to avoid 
imbalance between the treatment arms within each of these two strata. In addition, 
randomization will be stratified by site to avoid imbalance between treatment arms. Many 
factors can affect the Clinical Cure, recurrence and Sustained Cure of subjects with 
CDAD; in addition to the first occurrence versus first recurrence, age, comorbidity, 
immunosuppression, severity of illness, concomitant antibiotic use, and the hypervirulent 
strain may also impact the clinical outcome, alone or in combination. The study does not 
exclude subjects with immunosuppression, subjects requiring antibiotics, severe disease, 
subjects currently failing metronidazole, and CDAD due to hypervirulent strains. It is 
impractical to include all these factors for stratification. However, the site could show 
specific characteristics about the kind of patients that enroll (in-patients versus 
out-patients, severe subjects versus mild–moderate, the incidence of hypervirulent strains, 
etc.). An imbalance of the treatment groups within confounding factors could occur with 
central 1:1 randomization. Given the importance of these variables on outcome, including 
the hypervirulent strains, block randomization by site will more uniformly distribute the 
treatment arms across these factors. 
The recruitment of subjects with CDAD due to hypervirulent strains currently defined as 
ribotypes 027, 078, and 244 will be monitored on an ongoing basis to ensure that the 
pooled analysis will have sufficient power to achieve its objective. Assuming 
approximately 25% of subjects enrolled present with hypervirulent strain, the pooled 
analysis will have 80% power to detect superiority of 15% on SCR. Consequently, to 
ensure recruitment of at least 315 subjects with hypervirulent strain in both clinical trials, 
geography or historical evidence of high incidence of these cases will be considered in 
site selection. 
In study AC-061A201, the 250 mg b.i.d. dose was effective on the primary endpoint of 
Clinical Cure after a 10-day oral administration and no further improvement was 
observed with higher doses. For the secondary endpoints, recurrence and Sustained Cure, 
cadazolid 250 mg b.i.d. was also consistently effective with no further improvement at 
higher doses. In addition, this dose markedly decreased C. difficile vegetative forms as 
well as spores with no-to-minimal impact on the intestinal microflora. In addition, 


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cadazolid was well tolerated at all doses tested. As a result, the 250 mg dose has been 
selected for the Phase 3 studies. 
Vancomycin has been proven efficacious in mild–moderate disease in the setting of 
clinical trials and is approved in many countries for the treatment of CDAD without any 
qualifier on the severity of disease. It is generally not used in the initial episode of  
mild–moderate disease. Vancomycin at a dose of 125 mg 4 times daily orally 
administered is approved for the treatment of CDAD in the United States (US) 
[Vancomycin USPI] and in Europe. The use of oral vancomycin is recommended as the 
treatment of choice for severe CDAD by both ESCMID and SHEA/IDSA guidelines and 
for recurrent episodes of CDAD in many countries [Bauer 2009, Cohen 2010], because of 
relatively high failure rates of metronidazole in recent reports and a slower clinical 
response to metronidazole compared with oral vancomycin treatment [Wilcox 1995, 
Musher 2005, O’Brien 2007, Zar 2007]. Metronidazole, though commonly used in the 
initial treatment of mild–moderate CDAD, is not licensed for this indication. Therefore, 
oral vancomycin, a licensed antibiotic for the treatment of CDAD, has been chosen as the 
comparator. The non-inferiority (NI) trial design is justified, as oral vancomycin has 
clearly demonstrated to be an effective treatment in CDAD. The justification for a 10% 
NI margin is provided in Appendix 7.  
The use of kaolin or related products, charcoal containing anti-diarrheals, or binding 
agents such as cholestyramine is prohibited during the trial, and should not be 
administered, if possible, during the screening period. Co-administration of kaolin, 
activated charcoal, and tolevamer with cadazolid resulted in a 4- to 8-fold increase in 
cadazolid MIC with kaolin to more than a 64-fold increase in cadazolid MIC with 
charcoal (Actelion data on file).  
The primary endpoint is Clinical Cure, which is defined by the ROD using records of 
stool frequency and consistency, and provided that no new antimicrobial treatment for 
CDAD is initiated, using concomitant medications records. The definition of the endpoint 
is similar to, albeit more stringent than the clinical Phase 3 studies of fidaxomicin. While 
in the pivotal studies of fidaxomicin (most recent trials having led to registration in 
CDAD) Clinical Cure was determined by the investigator based on a composite definition 
of cure at the EOT (including objective components such as unformed bowel movements 
[UBMs] and treatment but also the subjective component of investigator clinical 
judgment of significant improvement), in this study Clinical Cure is determined based on 
ROD, at a fixed time point: EOT + 2 days. This is a more robust definition which avoids 
different clinical judgment among investigators. This feature of the endpoint was 
criticized during the fidaxomicin NDA review. However, to allow fair comparison with 
the fidaxomicin trials an investigator judgment of clinical response is added as 
exploratory objective. 


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The secondary endpoint, sustained cure, is consistent with the endpoints suggested in the 
EMA guidance and consistent with the endpoint used in the evaluation of fidaxomicin to 
treat CDAD [Louie 2011]. Showing NI clinical cure rate (CCR) and superior SCR versus 
vancomycin, by hierarchical testing should provide robust evidence of reduction of 
recurrence of CDAD with cadazolid. 
There is an unmet medical need for a treatment with improved SCR in subjects with 
CDAD due to hypervirulent strains. A central microbiology laboratory is required to 
determine if CDAD is due to hypervirulent strains. The proportion of subjects at the time 
of randomization with infection due to hypervirulent strains is expected to be 
approximately 25% based on the clinical Phase 3 studies of fidaxomicin. A meta-analysis 
using the data from the two pivotal Phase 3 trials will provide a sufficient number of 
subjects to evaluate the Sustained Cure of CDAD caused by hypervirulent strains. 
Deviation from adherence to protocol tends to reduce the ability of a clinical trial to 
discriminate between treatments and therefore favors the demonstration of equivalence or 
NI. Every effort will be made to prevent violation of the protocol by providing clear 
instructions to the investigators, closely monitoring the data collected, and taking 
corrective actions in a timely fashion. In this study, with a primary analysis based on NI, 
both the PPS and the mITT analysis set are considered equally important. Subjects with 
protocol non-compliance that impacts the assessment of Clinical Cure will be excluded 
from the PPS. The sample size calculation has accounted for the potential exclusion of up 
to 15% of subjects from the PPS [see Section 11.2.4 for reasons for exclusion]. Sample 
size estimations were used to determine the number of subjects necessary to ensure 90% 
power in statistical analysis on the PPS, which implies a power over 90% for the 
statistical analysis on the co-primary population mITT. 
The pharmacokinetics sub-study is performed to explore the range of systemic cadazolid 
plasma concentrations in subjects with CDAD administered the granule formulation. The 
2 h post-dose has been shown in previous healthy subjects (AC-061-101 and 
AC-061-102) to represent the peak cadazolid concentrations. This single sample was used 
in study AC-061A201 in subjects with CDAD, where the powder formulation was 
administered. In order to get a good estimate of the plasma concentration range, 
approximately 50 evaluable samples from subjects on cadazolid treatment are required, 
accounting for the 1:1 randomization scheme.  
In clinical practice, recurrences are common following treatment for CDAD. The 
re-treatment extension with cadazolid has been added to collect additional information on 
cadazolid treatment of first recurrences. The re-treatment extension with cadazolid will 
involve only subjects (cadazolid or vancomycin) with a first occurrence of CDAD at 
initial study entry who experience a first recurrence of CDAD during the study. Given the 
limited number of potential subjects who experience a recurrence and who are eligible for 


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the re-treatment extension with cadazolid in this study, and in order to maximize the data 
treating recurrences with cadazolid, all subjects who agree to participate will be given 
open-label cadazolid, as opposed to continuing the same treatments used in the first 
occurrence or to re-randomizing subjects to cadazolid or vancomycin. This re-treatment 
extension with cadazolid provides several unique opportunities to study: 
• First recurrences following vancomycin treatment. Guidelines generally recommend 
metronidazole for first occurrence; therefore most of the subjects who enter the trial 
as a first recurrence in the main study will have been previously treated with 
metronidazole. The re-treatment extension with cadazolid will provide an opportunity 
to describe cadazolid efficacy and safety in a subset of subjects who have experienced 
a first recurrence following vancomycin treatment. 
• First recurrences following cadazolid treatment. Since many first recurrences are 
treated with a second course of the same antibiotic, per guidelines, the re-treatment 
extension with cadazolid will provide an opportunity to describe cadazolid efficacy 
and safety in subjects who have experienced a first recurrence following cadazolid 
treatment. 
3.3 Study committees  
A Steering Committee composed of external experts has been established to participate in 
the design of the protocol, oversee the conduct of the study, evaluate the results and 
support publications. The Steering Committee is governed by a charter.  
An Independent Data Monitoring Committee (IDMC) will be established prior to first 
subject randomization. The IDMC will have the overall responsibility for continuously 
safeguarding the interests of subjects by periodically monitoring study data as well as all 
relevant product-related information that may emerge during the conduct of the program. 
The IDMC is governed by a charter. 
4 SUBJECT POPULATION 
4.1 Subject population description  
The study will enroll adult subjects aged 18 and older with CDAD. 
CDAD is defined by the presence of diarrhea within 24 h prior to randomization with a 
stool test within 72 h prior to randomization positive for C. difficile GDH and toxin A/B 
by an enzyme immunoassay (EIA). 
Enrollment will proceed until at least 630 subjects are randomized, to ensure that at least 
536 subjects will be included in the PPS. 
Subjects are allowed to be re-screened if they failed eligibility and were not randomized. 


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4.2 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled: 
1. Signed informed consent prior to any study-mandated procedure. 
2. Male or female ≥ 18 years of age at the screening visit. 
Non-pregnant women of childbearing potential: 
A woman is considered to be of childbearing potential unless she meets at least one of 
the following criteria: 
• Previous bilateral salpingo-oophorectomy or hysterectomy; 
• Premature ovarian failure confirmed by a health care professional; 
• XY genotype, Turner syndrome, uterine agenesis; 
• Postmenopausal, defined as 12 consecutive months with no menses without an 
alternative medical cause (ICH M3 definition). 
 
A non-pregnant woman of childbearing potential is eligible only if: 
• The absence of pregnancy is confirmed by a negative urine (or plasma/serum) 
pregnancy test at Visit 1; 
• She agrees to use one of the following methods of contraception from Visit 1 
until 7 days after study drug discontinuation: 
− Condoms, diaphragm or contraceptive sponge if used in combination with 
a spermicide.  
− Intra-uterine devices.  
− Injectable contraceptive agents, levonorgestrel implants, or transdermal 
contraceptive hormone patches. If a hormonal contraceptive is chosen, it 
must be taken for at least 1 month prior to randomization. 
− Alternatively a sterilization method (tubal ligation or partner’s vasectomy) 
is considered acceptable. 
She is in a situation of abstinence from intercourse with a male partner, when this 
is in line with the preferred lifestyle of the subject (e.g., homosexual women or 
women in a religious order – e.g., nuns).  
In case of oral contraception, an additional method must be employed, as diarrhea 
may affect the effectiveness of the oral contraceptive pill.  
Rhythm methods or the use of a condom by a male partner alone are not 
considered as acceptable methods of contraception. 


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3. Subject with a diagnosis of mild–moderate or severe CDAD (first occurrence or first 
recurrence within 3 months of randomization) with: 
• Diarrhea, defined as a change in bowel habits with > 3 UBMs, in the 24 h 
prior to randomization,  
AND 
• Positive C. difficile GDH and toxin A and/or B stool test, on the same sample 
collected no more than 72 h prior to randomization using an EIA test 
approved by the sponsor. 
Note 1: If a positive test using an EIA test approved by the sponsor has been performed 
prior to screening within the time window mentioned above, the test does not need to be 
repeated and its result will document eligibility. If a non-approved test has been used for 
the diagnosis of CDAD prior to screening, an EIA test approved by the sponsor must 
show a positive result on a sample collected no more than 72 h prior to randomization, 
after the subject has signed the ICF to confirm eligibility. 
Note 2: MTFs may be enrolled in the study. An MTF is defined as a subject who has 
received metronidazole for at least 72 hours for the current CDAD episode and is failing 
therapy defined as 1) continue to meet the definition of diarrhea (> 3 UBMs) without 
significant clinical improvement in the judgment of the investigator, and 2) remain GDH 
and toxin positive (with a positive stool test done on the same sample collected no more 
than 48 h prior to randomization). Metronidazole therapy must be stopped prior to first 
dose of study drug. 
4.3 Exclusion criteria 
For inclusion in the study, none of the following exclusion criteria must be met: 
1. More than one previous episode of CDAD in the 3-month period prior to 
randomization. 
2. Fulminant or life-threatening CDAD. If in the judgment of the investigator there is a 
suspicion of fulminant or life-threatening CDAD, the presence of any of the 
following criteria during the 72 h period prior to randomization and related to the 
fulminant or life-threatening CDAD episode excludes the potential subject from the 
study: 
• Septic shock – a systolic blood pressure (BP) < 90 mmHg or a mean arterial 
pressure < 70 mmHg in the absence of other causes of hypotension and that 
persists despite adequate fluid resuscitation 
• Peritonitis 
• Ileus 


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• Toxic megacolon  
• Significant dehydration based on investigator judgment  
• White blood cells count > 30.0 × 109/L  
• Core body temperature > 40 °C 
 
3. Concurrent immediately life-threatening disease or condition (likelihood of death 
within 72 h). 
4. History of inflammatory colitides (e.g., ulcerative colitis or Crohn’s disease, 
microscopic colitis, collagenous colitis) or chronic abdominal pain or chronic 
diarrhea of any etiology, or known positive diagnostic test for enteropathogens. 
5. Vomiting or other condition that interferes with the ability to take oral medication or 
subjects with feeding tubes (i.e., when study drug would have to be given by the 
feeding tube). 
6. Antimicrobial treatment active against CDAD administered for > 24 h except for 
metronidazole treatment failures [see Note 2 to Section 4.2]. 
Note 3: Although the screening period is 48 hours, the subject must have ≤ 24 hours 
of antimicrobial treatment active against CDAD to qualify for the study, unless an 
MTF (see Note 2).  
7. Planned additional treatment with antimicrobial medication active against CDAD, 
fecal microbiota transplant (FMT), or any forbidden concomitant medications [see 
Concomitant medications, Section 5.2].  
8. FMT, intravenous immunoglobulins, or any investigational drug to prevent or treat 
CDAD in the 1 month (or 5 half-lives in case of investigational drug, whichever is 
longer) period prior to randomization. 
9. Treatment with monoclonal antibodies against C. difficile in the 6-month period prior 
to randomization. 
10. Investigational vaccination against C. difficile. 
11. Previous participation in a clinical trial with cadazolid. 
12. Known hypersensitivity or contraindication to any excipients of the investigational 
drug formulations, or to oxazolidinones, quinolones, or vancomycin. 
13. Women who are breastfeeding. 
14. Investigational site staff members or relatives, and Actelion employees. 


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15. Unable or unwilling to comply with all protocol requirements including study visits, 
study procedures, diary completion, medication adherence and appropriate study 
medication storage at home. 
16. Any circumstances or conditions, which, in the opinion of the investigator, may affect 
the subject’s full participation in the study, or compliance with the protocol. 
5 TREATMENTS 
5.1 Study treatments 
5.1.1 Study drugs 
Study drugs include the investigational drug cadazolid, the active comparator 
vancomycin and their matching placebos administered during the course of the study. 
5.1.2 Investigational drug (cadazolid) and matching placebo 
Oral cadazolid and its matching placebo are provided by Actelion as granules for oral 
suspension to be reconstituted prior to administration. Cadazolid is supplied at the dose of 
250 mg in an aluminum sachet, matched for content, taste and appearance (before and 
after reconstitution) between the active drug and its matching placebo. 
The inactive ingredients of the formulation are listed in the IB [Cadazolid IB]. 
The suspension must be reconstituted prior to administration, in accordance with the 
following instructions: 
1. Open the sachet and pour its content into a glass (or a cup, a beaker or a goblet)  
2. Add approximately 25 mL (about 2 tablespoons) of water to the glass. 
3. Swirl immediately by hand with the base of the glass resting on a flat horizontal 
surface until a uniform suspension is obtained.  
4. Drink the suspension. 
Repeat steps 2 to 4 once to allow appropriate rinsing of the glass. 
 
The oral suspension should be drunk within 5 min of reconstitution. Preparation and 
administration of at least the first dose of study drug by the subject must be done under 
the guidance of appropriately delegated site staff and documented in the source notes and 
CRF. If the suspension is not taken within 5 min of reconstitution, then it can be 
administered within the next 2 h after having resumed at Step 3. 
5.1.3 Comparator (vancomycin) and matching placebo 
Oral vancomycin and its matching placebo are provided as capsules. Each capsule of 
vancomycin contains 125 mg of active drug (Vancocin®, ViroPharma). Vancomycin 


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capsules have been over-encapsulated to maintain blinding. Over-encapsulation does not 
alter the dissolution of vancomycin. 
The major excipients of the formulation are: FD&C Blue No. 2, gelatin, ferric oxide red, 
ferric oxide yellow, polyethylene glycol and titanium dioxide. 
Vancomycin or its matching placebo does not require preparation; the capsule must be 
swallowed intact with or without water. Vancomycin or its matching placebo may be 
taken at the same time as the time-matched cadazolid placebo or cadazolid.  
5.1.4 Dosing scheme 
Each subject will receive blinded study medication administered orally each day; subjects 
will take doses approximately 6 hours apart (40 doses; every 6 hours for 10 days). On a 
daily schedule, this corresponds approximately to study drug doses at breakfast, lunch, 
late afternoon (dinner) and bedtime. Study drug can be taken with or without food. 
Subjects randomized to cadazolid will receive 1 sachet of reconstituted cadazolid 
suspension twice daily and 1 capsule of placebo matching vancomycin 4 times daily. 
Subjects randomized to vancomycin will receive 1 capsule of vancomycin 4 times daily 
and 1 sachet of reconstituted placebo matching cadazolid suspension twice daily. Each 
time a sachet is taken, a capsule must be taken concomitantly [see Table 2]. 
Each dose of study drug, including date/time and composition (capsule/sachet) will be 
recorded in the Study Drug Journal by the subject or the study personnel. 
Irrespective of the time of day the subject is randomized into the study, the first dose of 
study drug will include 1 sachet and 1 capsule under the guidance of site personnel. This 
will ensure that the first administration will always contain an active study drug. If study 
drug is interrupted for ≥ 1 dose (approximately 12 h or more since last dose), then it must 
be restarted with the subject taking 1 sachet and 1 capsule. 


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Table 2 
Dosing scheme 
 
Cadazolid group 
Vancomycin group 
T0 
■○ 
□● 
T0 + 6h 
○ 
● 
T0 + 12h 
■○ 
□● 
T0 + 18h 
○ 
● 
■ Sachet of cadazolid 
□ Sachet of placebo matching cadazolid 
● Capsule of vancomycin 
○ Capsule of placebo matching vancomycin  
 
5.1.5 Treatment assignment 
At the beginning of Visit 1 after the subject has signed the ICF:  
The investigator/delegate contacts the Interactive Voice Response System (IVRS) and 
obtains a subject number from the IVRS which will identify the subject throughout the 
study. Subjects are allowed to be re-screened [Section 5.1.1] if they failed eligibility and 
were not randomized. The subject number assigned during the first screening procedure 
will be retained in re-screened subjects. 
At the end of Visit 1, after having ensured that the responsible personnel/pharmacist is 
available to dispense the study drug, all eligible subjects will be assigned a randomization 
number and a treatment kit: 
• The investigator/delegate contacts the IVRS a second time after having confirmed 
that the subject fulfills all eligibility criteria. The IVRS assigns a randomization 
number to the subject, which is used to link the subject to 1 of the 2 treatment arms 
(1:1 ratio). The IVRS also specifies a treatment kit number to be assigned to the 
subject (the kit matches the treatment arm assigned by the randomization list). 
 
The randomization list is generated by an independent contract research organization 
(CRO), 
. The randomization code is generated using 
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recurrence. The randomization code is kept strictly confidential. It is accessible only to 
authorized persons who are not involved in the study conduct or final analysis of the 
study, until the time of unblinding [see Section 5.1.7]. 
5.1.6 Blinding 
This study will be performed in a double-blind fashion. The investigator and study staff, 
the subjects, the monitors, the sponsor staff (except the Clinical Trial Supply group, 
Quality Assurance-Global Quality Management, and Global Drug Safety in case of a 
suspected unexpected serious adverse reaction [SUSAR]), the CRO staff (except the 
bioanalytical laboratory in charge of analyzing cadazolid plasma concentration and the 
Independent Statistical Data Analysis Center [ISDAC] in charge of performing the 
unblinded statistical analysis for the IDMC meetings) will remain blinded to the 
treatment until study completion; see below for further details on double-blind exclusion. 
The investigational drug, the active comparator and their matching placebos are 
indistinguishable and all subject kits will be packaged in the same way. 
For the bioanalytical laboratory in charge of analyzing cadazolid plasma concentrations, 
the randomization code will reside in a secure area of the bioanalytical laboratory server, 
where only designated people will have access. As per the signed contract, the 
bioanalytical laboratory will not send any subject or drug concentration data to Actelion, 
until they are authorized by Actelion in writing at the end of the study. However, they can 
convey to the study team, any issues relating to sample collection and/or 
handling/processing (e.g., sample arrived unfrozen, sample hemolyzed) so that corrective 
actions can be taken across all sites involved in the pharmacokinetic sub-study.  
5.1.7 Unblinding  
5.1.7.1 Unblinding for final study analyses and reporting 
The randomization code will be broken and made available for the final statistical 
analysis only after study database closure in accordance with the sponsor’s standard 
operating procedures (SOPs). 
5.1.7.2 Unblinding before final analyses 
An independent statistical data analysis center (ISDAC) 
 
, not otherwise involved in the design, conduct and 
analysis of the study, will have access to the randomization code in order to prepare 
unblinded reports for review by the IDMC (for IDMC review meetings during the course 
of the trial). The randomization code will be made available to the ISDAC in accordance 
with the sponsor’s SOPs. 


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5.1.7.3 Unblinding of a Suspected Unexpected Serious Adverse Reaction (SUSAR) 
When a SUSAR is identified for a subject participating in the study, Actelion Global 
Drug Safety will request the unblinding of the treatment code for that particular subject. 
This code will not be communicated to the site staff or to the Actelion study team. 
Unblinded SUSAR information is only provided to Actelion Global Drug Safety, 
respective health authorities and Institutional Review Boards/Independent Ethics 
Committees (IRBs/IECs). SUSARs will be anonymized. 
5.1.7.4 Emergency procedure for unblinding 
The investigator and the study staff must remain blinded to the subject’s treatment 
assignment. The identity of the study drug may be revealed only if the subject 
experiences a medical event, the management of which would require knowledge of the 
blinded treatment assignment. In this case, the investigator can receive the unblinded 
randomization code for study drug dispensed through the IVRS. In these situations, the 
decision to unblind a subject’s treatment assignment resides solely with the investigator. 
Whenever possible, and if it does not interfere with (or does not delay) any decision in 
the best interest of the subject, the investigator is invited to discuss the intended code 
break with the sponsor. 
The site may contact the sponsor for any urgent question, including intended unblinding 
of treatment assignment, via the medical hotline numbers. These numbers can be found in 
the Investigator Site File (ISF), and also appear on the study drug and kit labels. 
The occurrence of any unblinding during the study must be clearly justified in the 
subject’s site file and in the CRF. The investigator must not disclose the unblinded 
treatment in the CRF or to the sponsor or its delegates. In all cases, the sponsor must be 
informed as soon as possible before or after the unblinding. 
Refer to the IVRS guidelines for complete information regarding the IVRS procedures 
for randomization, study drug assignment, and unblinding. 
5.1.8 Study drug supply 
The sponsor will supply all study drugs to the site according to local regulations.  
All drug supplies are to be used only in accordance with this protocol, and not for any 
other purpose.  
5.1.8.1 Study drug packaging and labeling 
5.1.8.1.1 Study drug packaging  
Study drugs are provided as granules in sachets and capsules in childproof blister packs 
within a treatment kit. 


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Each kit contains sachets and capsules for 10 days of treatment plus a reserve for 2 days 
of treatment: 
20 + 4 sachets of cadazolid 250 mg, granules for suspension or matching placebo. 
40 + 8 over-encapsulated capsules of vancomycin 125 mg or matching placebo. 
5.1.8.1.2 Study drug labeling 
Each sachet and each blister pack of 8 capsules are simply labeled, whereas the treatment 
kit has a label with a detachable label for dispensing purposes. The labeling complies 
with the applicable laws and regulations of each participating country.  
5.1.8.2 Study drug distribution and storage  
The study drug kit must be stored in a secure location at a temperature between 2 °C and 
25 °C / 35.6 °F and 77 °F; do not refrigerate. A temperature log is to be kept at each 
location where study drug is stored prior to subject dispensation. The adequacy of storage 
conditions should be documented. In the case of a temperature excursion, the site monitor 
must be immediately contacted. Subjects should store the medication at room 
temperature, less than 25 °C / 77 °F. 
An order to dispense study drug must be written by the physician investigator (listed on 
FDA form 1572 for US sites only and/or the delegation of authority log for all sites). The 
study drug label must be detached from the kit and placed on an Study Drug Label 
Dispensing Log. The time of study drug administration and, in the case of the suspension, 
the time of preparation if the subject is an in-patient must be recorded in the source 
documents and CRF. 
5.1.8.3 Study drug return and destruction  
On an ongoing basis and upon study completion or termination of the study, the monitor 
will prepare used and unused subject kits for return to the local depot where the sponsor 
or deputy will check drug reconciliation before destruction.  
5.1.9 Compliance with study treatment 
Study drug accountability must be performed by the study staff on the day of the visit and 
recorded on the Study Drug Dispensing and Accountability log, in order to ensure that 
the subject is compliant with study requirements. Study drug accountability is also 
recorded in the case report form (CRF) and checked by the monitor during site visits.  
Subjects are asked to return the treatment kit, including empty sachets and blister packs, 
and all unused study drug at each site visit. An accurate record of the date and amount of 
study drug dispensed to each subject must be available for inspection at any time. 
For each subject, a Study Drug Journal will be completed daily to record timing of each 
dose of study drug (sachets and capsules). This information will be utilized to reconcile 


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with study drug kits and the study drug dispensing and accountability log and for the 
study staff to enter information on study drug intake and compliance with study treatment 
in the CRF. 
5.1.10 Study drug interruption and premature discontinuation of study drug 
Temporary interruption of study treatment, including missed doses must be recorded in 
the CRF with the reason for interruption. If study drug is interrupted (≥ 1 dose or 
approximately 12 h or more since last dose), then it must be restarted with the subject 
taking 1 sachet and 1 capsule. Premature discontinuation of study drug (withdrawal from 
treatment) may happen either independently from study withdrawal or in conjunction 
with study withdrawal. 
If the subject discontinues from study treatment but remains in the study, all subsequent 
scheduled visits (telephone or on site) and collection of information (e.g., diary cards) 
will be performed according to protocol up to Visit 5.  
If the subject discontinues not only from study treatment but also does not agree to 
continue in the study, then the subject withdraws from the study [see Section 9.1].  
The reason for premature discontinuation from study drug (withdrawal from treatment), 
the decision owner (as applicable), and whether subject decision to discontinue study 
treatment does or does not include study withdrawal, must be documented in the CRF. 
Reasons for premature discontinuation are mutually exclusive and only the primary 
reason for premature discontinuation should be recorded in the CRF. 
Premature discontinuation can occur at any time during the treatment period. A subject 
who requires insertion of a feeding tube during the treatment period and who requires 
administration of study drug through the feeding tube, must discontinue study drug. If the 
subject is a treatment failure or has received an insufficient duration of therapy prior to 
premature discontinuation of the study drug (e.g., adverse event [AE]), then the study 
drug is discontinued and an alternative appropriate therapy for CDAD is initiated 
[Section 5.2.2]. 
In case of premature discontinuation, Visit 3 is performed and the subject enters the 
follow-up period. Every effort must be made to perform the Visit 3 assessments before 
initiation of alternative therapy for CDAD. Subjects prematurely discontinued from study 
drug for any reason will not be replaced. 
5.2 Previous and concomitant medications 
A previous medication is defined as a medication that was previously taken and was 
stopped prior to the first dose of study medication. A concomitant medication is defined 
as a medication that started, stopped, or was ongoing between first dose of study 
medication and Visit 5. 


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All previous (within 7 days of randomization or in the past 3 months for antibiotics and 
acid suppressing medications, see Section 7.1) and concomitant medications (including 
mandatory methods of contraception, see Section 7.1) are to be recorded in CRF (and 
subject’s file) along with the appropriate indication. 
5.2.1 Prohibited and allowed concomitant medications 
The following concomitant medications are prohibited during the study: 
• Antimicrobial treatments active against CDAD or FMT up to Visit 5 unless provided 
for clinical failure or recurrence [Section 5.2.2]:  
− Antimicrobial treatments active against CDAD include: oral vancomycin, 
metronidazole, bacitracin, fusidic acid, nitazoxanide, teicoplanin, tigecycline, 
fidaxomicin, rifampicin/rifampin or rifaximin. 
• Other medication active against CDAD including probiotics, intravenous 
immunoglobulins, and binding agents (e.g., cholestyramine) up to Visit 5. 
• Initiation of treatment with opiates after randomization up to and including 2 days 
after the EOT.  
• A change in dose/regimen resulting in an increased opiate effect up to and including 
2 days after the last dose of study drug is forbidden.  
Note: In the case of ongoing treatment with opiates at randomization, a stable 
treatment with opiates or a decrease in the dose/regimen or discontinuation of 
treatment with opiates is allowed. For equivalence between opiates see Appendix 1. 
• Anti-peristaltic medications (e.g., loperamide), kaolin or related products, pectin or 
charcoal-containing anti-diarrheals up to Visit 5. 
• Any investigational drug, antibody or vaccine to prevent or treat CDAD up to Visit 5.  
 
Notes: 
1. Proton pump inhibitors (PPIs) and H2 blockers are allowed during the study. 
2. The use of kaolin or related products, charcoal containing anti-diarrheals, or binding 
agents (e.g., cholestyramine) should be discontinued as soon as possible during the 
screening period for subjects likely to be randomized. 
5.2.2 Alternative therapy for CDAD 
In case of Clinical Failure or recurrence, an antimicrobial treatment active against CDAD 
(or FMT) should be initiated as recommended per local guidelines and/or physician 
judgment. 
Subjects who have a first occurrence of CDAD at baseline, and who experience a 
recurrence are eligible for participation for re-treatment with cadazolid [Section 8.4]. 


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6 STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoint 
Primary efficacy endpoint determination 
Daily, from randomization to Visit 5, the subject or the study personnel (e.g., when the 
subject is hospitalized) records each bowel movement and the time it is produced, and 
evaluates whether the bowel movement meets the definition of a UBM (i.e., taking the 
shape of the container in which it is produced) in a stool diary [see Section 7.2.1 for more 
information on the stool diary]. 
Subject interviews are performed face-to-face or by telephone every day starting on 
Day 2 up to Visit 4 and then twice weekly no more than 4 days apart until Visit 5 by site 
personnel to document the CDAD status of the subject and to ensure that the subject is 
collecting the information appropriately in the stool diary since the last subject interview. 
During these subject interviews, the study personnel will collect and document 
information regarding the number of UBMs (or presence or absence of > 3 UBMs if 
exact number unknown) and total number of stools for each day. Based on this 
information, ROD (ROD: ≤ 3 UBM per day for at least 2 consecutive days) or any NED 
(NED: > 3 UBMs after ROD) can be assessed [see Section 7.2.2 for more information on 
subject interviews]. 
During on-site study visits, the study personnel review the stool diary with the subject to 
ensure consistency with other source documentation, including the subject interviews. 
The study personnel ensure that the subject is collecting the information appropriately 
and reconciles information as necessary. 
On each bowel movement entry of the stool diary, every effort should be made to indicate 
whether this is a UBM or not, even if the timing of the bowel movement is unknown (in 
which case Not Known will be entered for the time). In the stool diary, reconciled stool 
diary entries are distinguished from initial subject entries. The stool diary is collected on 
an ongoing basis and stored at the site.  
After reconciliation, the investigator enters the reconciled number of UBMs and the total 
number of stools in the Daily Stool Information section of the CRF. In the event that the 
exact number of UBMs is not known but sufficient information is available to document 
the presence or absence of > 3 UBMs, then this information must be recorded. This 
section of the CRF must be filled out based on all information available to the 
investigator, i.e., recorded on the reconciled stool diary and daily subject interview. 
The full information from the reconciled stool diary (timing and consistency of each 
bowel movement) is entered in the Stool Log section of the CRF. The investigator is 


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responsible for the accuracy of stool data entered into the CRF, based on the review and 
reconciliation of source documentation. Based on the reconciled information gathered 
during daily subject interviews up to EOT + 2 days, the investigator can evaluate if the 
subject meets the ‘per-protocol’ definition of Clinical Cure and can document it at 
Visit 4 in the CRF. A worksheet to assist in the determination of the PP definition of 
clinical cure can be found in the CRF.  
At the end of the trial, the information collected in the Daily Stool Information section of 
the CRF will be used by the sponsor to determine the primary endpoint Clinical Cure (see 
definition below).  
The monitors performing source data verification ensure that the CRF entries match the 
reconciled stool diary and the documentation of the daily subject interviews.  
Definition of the primary endpoint 
Clinical Cure 
Clinical Cure is defined as: 
• ROD (≤ 3 UBMs per day for at least 2 consecutive days) on study treatment and 
maintained for 2 days after EOT 
 
AND 
• No additional antimicrobial treatment active against CDAD or FMT between first 
dose of study drug and 2 days after EOT (inclusive).  
 
ROD is determined from the number of UBMs (or if the exact number is missing from 
presence or absence of > 3 UBMs), per day recorded in the Daily Stool Information 
section of the CRF. Days are measured according to calendar days. 
Antimicrobial treatment active against CDAD or FMT is determined from concomitant 
medications/procedures CRF pages. 
Subjects who do not fulfill the requirements for Clinical Cure are considered Clinical 
Failures. 
6.1.2 Secondary efficacy endpoints 
The information collected in the Daily Stool Information section will be used to 
determine Sustained Cure. The daily timing and consistency of the stools recorded in the 
Stool Log section will be used to derive Time to ROD. 


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Sustained Cure  
Sustained Cure is defined as:  
• Clinical Cure  
AND 
• No recurrence 
 
Subjects who do not fulfill the requirements for a Sustained Cure are considered not to be 
a Sustained Cure. 
Recurrence is defined for subjects with Clinical Cure as: 
• NED: > 3 UBMs within 1 day between 3 days after EOT and Visit 5  
AND 
• Stool test showing positive C. difficile GDH and toxin test on the same stool sample 
(according to EIA tests approved by the sponsor)  
AND 
• Antimicrobial treatment active against CDAD (including participation in the 
re-treatment extension with cadazolid) or FMT started between 3 days after EOT and 
Visit 5. 
 
NED is determined from the number of UBMs, or if the exact number is missing from 
presence or absence of > 3 UBMs, per day collected in the Daily Stool Information 
section of the CRF. Days are measured according to calendar days. 
A positive stool test is determined from the corresponding unscheduled visit for NED, 
where the result of the test is recorded. 
Antimicrobial treatment active against CDAD or FMT is determined from concomitant 
medications/procedures CRF pages. 
Subjects with Clinical Failure, or with Clinical Cure and recurrence, are considered to be 
without Sustained Cure. 
Please note that recurrence, according to the same definition, is per se an exploratory 
efficacy endpoint [Section 6.1.4]. 


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Time to Resolution of Diarrhea 
Time to ROD is defined as: 
• The time (h) elapsed between the first dose of study drug  
AND 
• The time when ROD is considered achieved 
Time when ROD is considered achieved is the time of the last UBM prior to the first 
2 consecutive 24 h periods with ≤ 3 UBMs and subsequently ≤ 3 UBMs per day 
maintained up to 2 days after EOT. The 2 consecutive 24 h periods and last UBM 
date/time prior to that period is determined from the Stool Log section of the CRF. The 
condition of maintaining ≤ 3 UBMs per calendar day is determined from the Daily Stool 
Information section of the CRF.  
Absolute change from baseline in CDAD DaySyms PRO total daily score  
Absolute change from baseline in CDAD DaySyms PRO total daily score up to Day 12 
derived from the daily CDAD DaySyms PRO. 
6.1.3 Meta-analysis endpoint 
Sustained Cure in subjects with hypervirulent strains (currently defined as Strains 
027, 078, and 244) is the same as Sustained Cure defined in Section 6.1.2. 
6.1.4 Other efficacy endpoints – supportive of primary and secondary efficacy 
objectives  
Investigator’s assessment of ETR at Visit 2  
This is assessed by the investigator as improved, unchanged or worsened compared to 
baseline.  
Investigator Judgment of Clinical Response (ICR) Visit 4 
Investigator responses for ICR consist of cure, and failure. The investigator will qualify 
on which basis he/she makes the assessment: 
• Cure will be qualified by any of the following criteria (more than one criterion may 
apply): 
− Subject required no additional CDAD therapy or FMT between first dose of study 
drug up to and including 2 days after EOT. 


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− Subject had < 3 UBMs for 2 consecutive days on therapy and maintained for 
2 days after EOT. 
− Subject had a marked reduction in the number of UBMs (in the opinion of the 
investigator). 
− Subject had stabilization and improvement in CDAD signs and symptoms (other 
than diarrhea – e.g., abdominal pain, fever), or other criteria (e.g., WBC elevation 
[not due to a clear alternative etiology]).  
 
• Failure will be qualified by any of the following criteria (more than one criterion 
may apply): 
− Subject required additional CDAD therapy or FMT between first dose of study 
drug up to and including 2 days after EOT. 
− Subject did not have < 3 UBMs for 2 consecutive days on therapy and maintained 
for 2 days after EOT. 
− Subject did not have a marked reduction in the number of unformed stools (in the 
opinion of the investigator). 
− Subject had worsening of CDAD signs and symptoms (other than diarrhea – e.g., 
abdominal pain, fever), or other criteria (e.g., WBC elevation [not due to a clear 
alternative etiology]). 
 
The investigator will have the opportunity to specify any additional criterion which 
applies in the CRF. 
Investigator’s judgment of Sustained Response (ISR) at Visit 5 
Investigator responses for ISR consist of Sustained Cure and not a Sustained Cure. The 
investigator will qualify on which basis he/she makes the assessment.  
Sustained Cure will be qualified by: 
• Subject was considered a cure at the ICR 
AND 
• Subject met one or more of the following criteria: 
− Subject required no additional CDAD therapy or FMT between EOT + 3 days up 
to and including Visit 5. 
− Subject maintained ≤ 3 UBMs per day between EOT + 3 days up to and including 
Visit 5. 
− Subject maintained a marked reduction in the number of UBMs (in the opinion of 
the investigator) between EOT + 3 days up to and including Visit 5. 


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− Subject maintained the stabilization and improvement in CDAD signs and 
symptoms (other than diarrhea – e.g., abdominal pain, fever), or other criteria 
(e.g., WBC elevation [not due to a clear alternative etiology]) between 
EOT + 3 days up to and including Visit 5. 
− Subject maintained other criteria (specified in ICR response) between 
EOT + 3 days up to and including Visit 5; please specify criteria. 
 
Not a Sustained Cure will be qualified by: 
• Subject was considered a failure at the ICR. 
OR 
• Subject met one or more of the following criteria:  
− Subject required additional CDAD therapy or FMT between EOT + 3 days up to 
and including Visit 5. 
− Subject had a repeat stool test between EOT + 3 days up to and including 
Visit 5 showing positive C. difficile GDH and toxin test on the same sample 
(according to EIA tests approved by the sponsor). 
− Subject did not maintain < 3 UBMs per day between EOT + 3 days up to and 
including Visit 5. 
− Subject did not maintain a marked reduction in the number of UBMs (in the 
opinion of the investigator) between EOT +3 days up to and including Visit 5. 
− Subject did not maintain the stabilization and improvement in CDAD signs and 
symptoms (other than diarrhea – e.g., abdominal pain, fever), or other criteria 
(e.g., WBC elevation [not due to a clear alternative etiology]) between 
EOT + 3 days up to and including Visit 5. 
− Subject did not maintain other criteria (specified in ICR response) between 
EOT + 3 days up to and including Visit 5; please specify criteria. 
The investigator will have the opportunity to specify any additional criterion which 
applies in the CRF. 
Early Clinical Cure by Day 5  
Early Clinical Cure by Day 5 is defined as: 
• 
ROD by Day 5: ≤ 3 UBMs for at least 2 consecutive days prior to or including 
Day 5 and maintained up to EOT + 2 days,  
AND 
• 
No additional antimicrobial treatment active against CDAD or FMT between first 
dose of study drug and EOT + 2 days as defined in Section 6.1.1. 


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Normalization of Bowel Movements (NBM) defined as: 
• ≤ 2 bowel movements per day and no UBM on at least 2 consecutive days up to EOT 
and maintained up to 2 days after the last dose of study drug,  
AND 
• No additional antimicrobial treatment active against CDAD or FMT between 
randomization and 2 days after EOT. 
Time to return to usual stools  
• Time to return to usual stools is defined as the time (days) elapsed between the first 
dose of study drug and the first day where the stools have returned to usual for a 
subject i.e., the number of bowel movements (including UBM) per day ≤ number of 
bowel movements reported as usual by the subject and maintained for at least 
3 calendar days.  
Recurrence [Section 6.1.2] 
Recurrence can be further classified as relapse or re-infection based on microbiology 
results [see Section 7.2.5.2] 
Time to recurrence 
Defined as the time (h) elapsed between the last dose of study drug and the onset time of 
NED determined to be a recurrence. 
The information collected in the Stool Log section of the CRF are used to determine time 
to recurrence, and the information collected in the Daily Stool Information section of the 
CRF to determine all the other endpoints. 
Change from baseline in CDAD DaySyms PRO scores – supportive of the CDAD 
DaySyms PRO secondary objective: 
• Change (absolute and/or percent) from baseline in CDAD DaySyms PRO total daily 
score to each day. 
• Change from baseline (absolute and/or percent) in CDAD DaySyms PRO domain 
scores to each day. 
 


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Susceptibility of C. difficile to cadazolid, vancomycin, linezolid, moxifloxacin, 
metronidazole, and fidaxomicin. 
Change from baseline in susceptibility of C. difficile to cadazolid, vancomycin, 
linezolid and moxifloxacin in case of Clinical Failure or recurrence. Post-baseline 
MIC increases ≥ 4-fold are considered microbiologically relevant. 
Change from baseline to Visit 3 in vancomycin-resistant enterococci (VRE) count 
for vancomycin-resistant E. faecium and vancomycin-resistant E. faecalis.  
Susceptibility of VRE to cadazolid, vancomycin, linezolid, moxifloxacin, 
fidaxomicin, 
daptomycin, 
tigecycline, 
ampicillin, 
gentamicin, 
and 
quinupristin-dalfopristin 
for 
vancomycin-resistant 
E. faecium 
and 
vancomycin-resistant E. faecalis.  
6.2 Safety and tolerability endpoints 
• Deaths up to Visit 5. 
• AEs and serious adverse events (SAEs) up to Visit 5. 
• Treatment-emergent AEs (TEAEs) and SAEs up to 7 days after the EOT. 
• AEs leading to premature discontinuation of study treatment. 
• Change from baseline to Visit 3 and Visit 5 in vital signs (SBP, DBP, and HR), body 
temperature and body weight. 
• Marked abnormalities in vital signs (SBP and DBP) up to EOT + 7 days (treatment 
emergent) and up to Visit 5. 
• Change from baseline to Visit 3 and Visit 5 in ECG parameters. 
• Marked abnormalities in ECG up to EOT + 7 days (treatment-emergent) and up to 
Visit 5. 
• Change from baseline to Visit 3 and Visit 5 in hematology, coagulation, and blood 
chemistry parameters. 
• Marked abnormalities in hematology, coagulation, and blood chemistry parameters 
up to EOT + 7 days (treatment-emergent) and up to Visit 5. 
6.3 Pharmacoeconomic endpoints 
• Length of stay (days) in hospital. 
• Length of stay (days) by ward unit (i.e., general ward, step-down/intermediate unit, 
Intensive Care Unit [ICU]). 
• Re-admission/admission to the hospital after start of treatment. 
• Visit to emergency department after the start of treatment. 


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• Change 
from 
baseline 
in 
work 
productivity 
and 
activity 
impairment: 
C. difficile-associated diarrhea (WPAI:CDAD) scores. 
• WPAI:CDAD scores on absenteeism, presenteeism, work productivity loss, and 
activity impairment are assessed. 
6.4 Pharmacokinetic endpoints 
Plasma cadazolid concentrations at 2 h post-dose at Visit 3. 
7 STUDY ASSESSMENTS 
7.1 Baseline parameters 
Baseline demographics include sex, age, ethnicity, and race and are to be recorded in the 
CRF at Visit 1, including for subjects screened but not randomized. 
Medical history is to be documented at Visit 1 and recorded in the CRF.  
The following must be systematically recorded:  
• Chronic medical conditions and new acute medical conditions in the past 6 months 
• Exposure to healthcare settings in the past 3 months 
• Antibiotic exposure in the past 3 months 
• Use of acid-suppressing medications in the past 3 months 
• History of chemotherapy and immunosuppression 
• History of gastrointestinal surgery including appendectomy 
• Number of daily bowel movements (including UBM) reported as usual by the subject, 
prior to the episode of CDAD 
• Serum creatinine, prior to the episode of CDAD, if available 
• Concomitant baseline medications 
• For female subjects, presence or absence of child-bearing potential, as well as a 
situation of true abstinence from intercourse with a male partner (in this case, the 
reason should be collected in source document), or mandatory methods of 
contraception (see below) must be recorded in the CRF. 
− Condoms, diaphragm or contraceptive sponge if used in combination with a 
spermicide.  
− Intra-uterine devices.  
− Injectable contraceptive agents, levonorgestrel implants, or transdermal 
contraceptive hormone patches. If a hormonal contraceptive is chosen, it must be 
taken for at least 1 month prior to randomization. In case of oral contraception, an 
additional method must be employed, as diarrhea may affect the effectiveness of 
the oral contraceptive pill. 


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− Alternatively a sterilization method (tubal ligation or partner’s vasectomy) is 
considered acceptable. 
Baseline CDAD disease characteristics must be documented in CRF, and include: 
• First CDAD occurrence or first recurrence; documentation of the first episode, 
including treatment, dose, and dates should be collected in subjects with a first 
recurrence 
• Metronidazole Treatment Failure (MTF) 
• In-patient or out-patient status at randomization  
• Number of bowel movements, including UBMs within 24 h prior to randomization 
• Abdominal physical examination (normal/abnormal and details) 
• Severe CDAD is defined as any one of the following: 
1. Maximum core temperature recorded at baseline > 38.5 °C 
2. WBC > 15.0 × 109/L (based on Central Laboratory) 
3. Rise in serum creatinine > 50% compared to pre-CDAD diagnosis 
Note: Mild–moderate disease is considered if none of these criteria that define 
severe CDAD are satisfied. 
• Presence of pseudomembranes or histopathology classified as pseudomembranous 
colitis (for subjects having had endoscopy) 
• Presence of distension of large intestine, colonic wall thickening, including low 
attenuation mural thickening, pericolonic fat stranding, or ascites not explained by 
other causes (for subjects having had imaging) 
• Date and time of fecal sampling for C. difficile strain based on Restriction 
Endonuclease Assay (REA) type and PCR ribotype [Section 7.2.5.2]. 
7.2 Efficacy assessments 
7.2.1 Stool diary 
Stool frequency and consistency is recorded daily in a diary from randomization to 
Visit 5. The subject or the study personnel (e.g., when the subject is hospitalized) record 
each bowel movement and the time it is produced, and evaluate whether the bowel 
movement meets the definition of a UBM (i.e., taking the shape of the container in which 
it is produced). Entries made by the study personnel in the stool diary are distinguished 
from entries made by the subject. The stool diary is shown in Appendix 2.  
During on-site study visits, the study personnel review the stool diary with the subject to 
ensure consistency with source documentation including the daily subject interviews 
[Section 7.2.2]. The study personnel ensure that the subject is collecting the information 
appropriately and reconciles information as necessary in the appropriate column in the 
stool diary or an alternative document to record reconciliation (reconciled stool diary 
entries). For each bowel movement entry, every effort should be made to indicate 


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whether this is a UBM or not, even if the timing of the bowel movement is unknown (in 
which case Not Known will be entered for the time). The reconciled stool diary entry is 
collected on an ongoing basis and stored at the site following the end of subject 
participation in the study. 
• Based on this diary, several endpoints including Clinical Cure and Sustained Cure 
(Recurrence), are determined. 
• The investigator may consider the subject as treatment failure (in case of no change or 
worsening diarrhea and other signs and symptoms of CDAD) at any time during the 
treatment period. 
• The investigator evaluates ETR at Visit 2, investigator judgment of Clinical Response 
(ICR) at Visit 4, and investigator judgment of sustained Response (ISR) at Visit 5. 
The subject and the study staff can determine when a NED happens and triggers an 
unscheduled visit for recurrence; the subject must contact the site immediately and a visit 
should be scheduled within 48 hours. 
7.2.2 Subject interviews 
Subject interviews (face-to-face or by telephone every day starting from Day 2 up to 
Visit 4 and then twice weekly no more than 4 days apart until Visit 5) are performed by 
site personnel to document the status of the subject. An interview log will be provided to 
investigators/study personnel to document site communication with the subject.  
During the subject interview the following information is discussed with the subject: 
1. Date, time, and consistency of each bowel movement (BM) since last subject 
interview; 
2. Change in symptoms of CDAD since last subject interview; 
3. New concomitant medications or treatments since last subject interview;  
4. Compliance with study drug and completion of the Study Drug Journal and reminder 
to record doses taken, missed doses, and to retain the study drug containers for 
collection at the on-site visits; 
5. New AEs since last subject interview.  
During these subject interviews, the study personnel will collect and document 
information regarding each BM and can determine the number of UBMs per day and total 
number of stools per day. In the event that the exact number of UBMs is not known but 
sufficient information is available to document the presence or absence of > 3 UBMs then 
this information will be recorded in the source documentation and reconciled with the 
stool diary. Based on this information, ROD or any NED can be assessed by the 
investigator. 


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An interview log will document the dates of the interviews in the CRF and the 
information collected or documentation that each element of the subject interview was 
discussed with the subject will be recorded in the subject interview source 
documentation. This documentation will be used by the study personnel to reconcile 
information collected by subject in the stool diary [see Section 7.2.1 above]. The 
remainder of the information collected (signs and symptoms, concomitant treatment, AEs 
or compliance) must be recorded in the corresponding CRF sections. The source 
documentation of the subject interviews is stored at the site during and following the end 
of subject participation in the study. 
7.2.3 Investigator assessments 
Investigator assessments are performed at Visit 2, Visit 4 and Visit 5.  
At Visit 2 for ETR, the investigator determines the subject response based on the: 
1. Frequency and consistency of stool 
2. Signs and symptoms of CDAD 
3. Additional antimicrobial treatment active against CDAD or FMT 
  
Investigator responses consist of improved, unchanged, or worsened. 
At Visit 4, the investigator evaluates and records in the CRF if the subject fulfills the PP 
definition of Clinical Cure [as defined in Section 6.1.1] on which the investigator will 
base the management of the subject for the rest of the study. In addition, the investigator 
provides his/her own judgment of Clinical Response [ICR – see Section 6.1.4]: Clinical 
Cure and ICR consist of cure or failure. 
At Visit 5, the investigator evaluates and records in the CRF if the subject fulfills the PP 
definition of Sustained Cure [as defined in Section 6.1.2]. In addition, the investigator 
provides his/her own judgment of Sustained Response [ISR – see Section 6.1.4]: 
Sustained Cure and ISR consist of Sustained Cure and not Sustained Cure.  
These assessments must be recorded in the CRF. 
7.2.4 CDAD DaySyms PRO 
The CDAD DaySyms PRO is a new questionnaire that has been developed by the 
sponsor in accordance with the FDA Guidance for Industry on Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Label Claims [FDA 2009] to 
assess the symptoms of CDAD from a subject perspective. The items forming the CDAD 
DaySyms PRO were developed through a literature review, discussions with expert 
clinicians, an initial phase of interviews with US subjects suffering from CDAD to assess 
symptoms frequent and relevant to them, and a second phase of interviews of US and 
Canadian subjects to confirm the items in the draft instrument. Results suggest that the 


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CDAD DaySyms PRO is a comprehensive measure assessing symptoms which are 
relevant to subjects with CDAD, and that the CDAD DaySyms PRO is easy to complete 
for subjects. 
The CDAD DaySyms PRO comprises 13 items with a recall period of 24 h. The 13 items 
are:  
1. Diarrhea 
2. Feeling that you need to empty your bowels right away  
3. Needing to go to or use the bathroom more than usual  
4. Passing gas (flatulence)  
5. Abdominal cramping 
6. Abdominal pain 
7. Feeling bloated (feeling like you need to loosen your clothes)  
8. Feeling tired  
9. Lack of energy  
10. Lightheadedness  
11. Dizziness 
12. Lack of appetite  
13. Nausea.  
 
The questionnaire will be administered in a paper-and-pencil format daily. The items are 
scored on a five-scale response scale (None, Mild, Moderate, Severe, and Very Severe). 
The scoring of the scale will be established during the psychometric validation of the 
instrument [Appendix 3]. 
All subjects who personally signed the ICF (i.e., the ICF was not signed by a legally 
authorized representative) will complete the questionnaire daily from Visit 1 to Visit 4. 
These subjects must complete the CDAD DaySyms PRO by themselves without help 
from anybody else. The first completion of the CDAD DaySyms PRO will take place 
prior to randomization. From then onwards until Visit 4, the subject will complete the 
questionnaire in the evening of each day. The data from the paper forms will be 
transferred into the study database via double data entry. 
The sponsor has the right to use the CDAD DaySyms PRO in this study, as it was 
developed by Actelion. 
All translations have been carried out according to international guidelines on translations 
and linguistic validations. 


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7.2.5 Stool microbiology 
Fecal sampling for microbiology is performed at baseline for subject eligibility and to 
document the C. difficile baseline characteristics. 
Samples are also taken at Visit 3 and in case of NED (Visit 4.a, 4.b, etc.) If no stool is 
available on the day of Visit 3 or Visit 4, then a stool sample may be collected within 
24 h after the visit and brought to the study site as described above; this is not valid for 
the Visit 1 sample that must be collected prior to randomization. 
The subject will be instructed to collect the stool sample ideally within 24 h of the 
scheduled appointment or agreed upon drop-off time, and to store the sample in a 
refrigerator until departing for the study site. The subject should record the date and time 
at which the sample was produced. The samples should be delivered to the site using 
cooler bag and gel packs. 
At the study site the investigator will store two tubes containing stools from each sample 
at around −70 °C/−94 °F (in exceptional cases and after written confirmation by the 
sponsor, samples may be stored below −20 °C/−4 °F in a non-frost-free freezer), one tube 
for the microbiology laboratory and one back-up tube kept until it is later sent to the 
microbiology laboratory. Date and time at which the stool sample was produced are 
recorded on the tube labels and in the CRF. 
In case of NED, only UBMs must be collected. If the stool sample is collected at the 
subject’s place of residence, the subject should call the study site immediately to make an 
appointment or arrangements to drop the sample at the study site as soon as possible. 
The subjects will receive guidelines for fecal sampling and delivery to the study site. 
The study sites will be instructed to ship the tubes at regular intervals, on dry ice, to the 
Central Laboratory. The tubes containing stools will be stored frozen at the Central 
Laboratory 
. Investigators will not receive results 
from the central microbiology laboratories but from the sponsor after the end of the trial. 
7.2.5.1 C. difficile GDH and toxin A/B tests 
At Visit 1, a positive GDH and toxin A/B test, performed locally, is needed to document 
CDAD diagnosis and confirm subject eligibility. 
The sponsor will provide an EIA test to all sites wherever and whenever possible, 
following local regulations. This test detects glutamate dehydrogenase (GDH) antigen in 
addition to detecting toxin A and B. 


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If a GDH and toxin A/B test (using an EIA test approved by the sponsor) has been 
performed prior to screening and returned a positive result, the test should not be repeated 
as this result will document eligibility. 
If a non-approved test has been used for the diagnosis of CDAD prior to screening, then 
after the subject has signed the ICF, a GDH and toxin A/B test (using an EIA test 
approved by the sponsor) must show a positive result to confirm eligibility. 
The GDH and toxin A/B test for eligibility must be performed on the same sample of 
stool (UBM only) collected within the 72 h (48 h in case of MTF) prior to randomization. 
In case of suspected recurrence during a NED, a GDH and toxin A/B test (using an EIA 
test approved by the sponsor) must be performed on the same sample of stool (UBM 
only) to confirm recurrence. 
If the sponsor-provided test is used, then the result of the test will be recorded in the CRF 
while the lot number and expiration date of the test will be recorded in the site source 
documentation. If the sponsor-provided test is not used, then the name of the 
sponsor-approved GDH and toxin A/B test, with the results of the test, will be recorded in 
the CRF. A negative GDH or toxin A/B test result for the screening sample will exclude 
the subject from the mITT analysis set. 
7.2.5.2 C. difficile strain identification and susceptibility  
The Central Laboratory analyzes the feces received in the frozen tubes to isolate 
C. difficile at baseline and in cases of Clinical Failure or recurrence. The C. difficile 
isolates are then tested for susceptibility against cadazolid, vancomycin, linezolid, 
moxifloxacin, metronidazole, and fidaxomicin in accordance with the Clinical and 
Laboratory Standards Institute (CLSI) testing standards.  
The C. difficile isolates are shipped to specialty laboratories for identification of 
C. difficile strains (REA and PCR ribotyping) and susceptibility testing will be performed 
for all subjects, at baseline and in cases of treatment failure or recurrence. This will lead 
to identification of hypervirulent strains currently defined as PCR ribotype 027, 078, or 
244 [Freeman 2010, Lim 2014, De Almeida 2013]. New hypervirulent strains emerging 
during the course of the study may be added. Strain identification will also be used to 
differentiate relapse (C. difficile strain identical to the baseline strain) from re-infection 
(C. difficile strain different from the baseline strain) in subjects with recurrence.  
7.2.5.3 Vancomycin-resistant enterococci (VRE) quantitative culture and 
susceptibility  
The Central Laboratory analyzes the feces received in the frozen tubes to culture and 
enumerate VRE isolates (Enterococcus faecium and Enterococcus faecalis) from Visit 1 
and Visit 3 fecal specimens for all subjects. The VRE isolates are then tested for 


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susceptibility against cadazolid, vancomycin, linezolid, moxifloxacin, fidaxomicin, 
daptomycin, tigecycline, ampicillin, gentamicin, and quinupristin-dalfopristin in 
accordance with the CLSI testing standards. 
7.3 Safety and tolerability assessments 
The definitions, reporting, and follow-up of AEs, SAEs and pregnancies are described in 
Section 10.1.1. 
7.3.1 Vital signs 
BP and HR are to be measured, and recorded in the CRF, at Visit 1 (prior to 
randomization), Visit 3, unscheduled visits (if applicable), and Visit 5. 
Systolic BP (SBP) and diastolic BP (DBP) are to be measured using the same type of 
device throughout the study, the dominant arm being preferred. Measurements are to be 
recorded preferably in the supine position and after the subject has rested for 5 min or 
more. If possible, HR should be measured at the same time as BP.  
HR and BP are recorded in the CRF. Clinically relevant vital signs abnormalities, which 
meet the definition of an AE [Section 10.1.1], must be recorded by the investigator on the 
AE page of the CRF. 
Body temperature is measured or (if available in the subject medical chart) collected at 
Visit 1 (prior to randomization), Visit 3, unscheduled visits (if applicable), and Visit 5, 
and must be recorded in the CRF (in case of multiple measurements available in a day the 
maximum temperature of the day must be entered in the CRF). 
Recommended body temperature measurements are rectal, oral, ear, or axilla. Body 
temperature is recorded in the CRF. Conversion to core body temperature will be 
performed programmatically.  
Marked abnormalities in BP are defined in Appendix 4. 
7.3.2 ECG 
A standard 12-lead ECG is to be performed, at rest with the subject in the supine position 
for a 5-min period, at Visit 1 (prior to randomization) Visit 3, unscheduled visits (if 
applicable), and Visit 5. 
ECGs are read by a local cardiologist after each subject has completed the study and then 
the information is entered in the CRF. If the site is unable to identify a local cardiologist, 
ECGs will be evaluated by 
 and the information will be 
directly transferred electronically to Actelion. 


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The following quantitative variables will be measured and recorded in the CRF: PR (ms), 
QRS (ms), QT (ms), HR (beats per minute [bpm]). 
QTC (ms) will be calculated according to Bazett’s and Fridericia’s formula 
(QTcB = QT/(RR) ½ and QTcF = QT/(RR) ⅓, respectively). 
ECG findings based on the local cardiologist’s interpretation will be recorded in the ECG 
CRF page. Clinically relevant ECG findings, as evaluated by the investigator, made after 
study drug initiation, which meet the definition of an AE [Section 10.1.1], must be 
recorded on the AE page of the CRF.  
7.3.3 Weight and height 
Body weight is to be measured and recorded in the CRF at Visit 1 (prior to 
randomization), Visit 3, unscheduled visits (if applicable), and Visit 5. Height is to be 
measured and recorded in the CRF at Visit 1. Body mass index (BMI) will be derived 
from height and weight. 
7.3.4 Physical examination 
A physical examination is to be performed and recorded in the CRF at Visit 1 (prior to 
randomization), Visit 3, unscheduled visits, and Visit 5.  
Physical examination should be recorded by body system in the CRF as normal or 
abnormal. If an abnormality is found then it should be specified in the CRF page, 
describing the signs related to the abnormality (e.g., systolic murmur) not the diagnosis 
(e.g., mitral valve insufficiency). Clinically relevant findings (other than those related to 
CDAD) that are present at Visit 1 must be recorded on the Medical History CRF page. 
Clinically relevant physical exam findings made after study drug initiation, which meet 
the definition of an AE [Section 10.1.1], must be recorded by the investigator on the AE 
page of the CRF. 
7.3.5 Laboratory assessments 
7.3.5.1 Type of laboratory 
The 
 Global Central Laboratory will be used for all hematology, coagulation, and 
blood chemistry. All Central Laboratory reports will be communicated to the 
investigator. 
At the time of randomization, local laboratory results are used for checking subject 
eligibility since Central Laboratory results would not be available within the 48 h 
screening period. The local laboratory results (with the corresponding normal ranges) and 
pregnancy test will be recorded in the CRF. Laboratory parameters required at Visit 1 are 
repeated at the Central Laboratory to be used as the baseline values for safety laboratory 
endpoints specified in the protocol. Laboratory certification / reference ranges / 


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laboratory director’s Curriculum Vitae (CV) will be collected by the sponsor for all 
local laboratories providing data that are entered into the clinical and/or safety databases. 
Analysis of laboratory parameters for safety monitoring, including the routine monitoring 
of laboratory parameters and protocol mandated follow-up in case of abnormal values, is 
performed by the Central Laboratory. In specific circumstances (such as an emergency) 
the initial detection of an abnormality and/or its follow-up may be done by local 
laboratory testing. In such instances, the local laboratory results (with the corresponding 
normal ranges) will be entered in the clinical database via dedicated CRF pages; this 
includes all laboratory results associated with an unscheduled visit, as well 
as all abnormal laboratory values associated with an AE, including all follow-up results 
to document resolution. In addition, laboratory certification / laboratory director’s CV 
will be collected if not already collected as part of the baseline local laboratory 
certification. 
Clinically relevant abnormalities from Central Laboratory results (or local laboratory 
when applicable) made after study drug initiation, which meet the definition of an AE 
[Section 10.1.1], must be recorded by the investigator on the AE page of the CRF. In the 
case of a clinically significant abnormality, repeated assessments are mandatory until 
return to baseline, stabilization or until the change is no longer clinically relevant. 
Results from the Central Laboratory and local laboratories will be used for safety 
laboratory endpoints determination. With Sponsor approval, if a laboratory test is unable 
to be analyzed by the Central Laboratory for technical reason and if values have been 
obtained on the same day from a local laboratory for this laboratory test, then the local 
value will be entered in the CRF. 
7.3.5.2 Laboratory parameters 
Hematology 
• Hemoglobin, hematocrit 
• Platelet count 
• Erythrocyte count 
• Leukocyte count with differential 
 
Coagulation 
• Prothrombin time / international normalized ratio (INR) 
• Activated partial thromboplastin time (aPTT) 
 
Chemistry 
• Aminotransferases (AST/ALT), alkaline phosphatase, total and direct bilirubin 
• Creatinine, blood urea / blood urea nitrogen 


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• Sodium, potassium, chloride, calcium 
• Protein, albumin 
 
Hematology, coagulation and chemistry laboratory assessments are performed at Visit 1 
(prior to randomization), Visit 3, unscheduled visits, and Visit 5. Subjects do not need to 
fast.  
Pregnancy test 
A urine or plasma/serum pregnancy test will be performed locally at screening for 
women of childbearing potential to document eligibility prior to randomization. 
Approximately 13.2 mL of blood (i.e., 2 mL of blood for the hematology tests; 8.5 mL 
for chemistry tests, and 2.7 mL for coagulation tests) will be collected for the Central 
Laboratory tests at each visit where laboratory parameters are assessed. The date and time 
of collection of samples for laboratory tests will be recorded in the CRF. Further details 
regarding blood sampling procedures, collection and shipment of samples and reporting 
of results are described in the 
 Global Central Laboratory Manual. Definitions for 
marked laboratory abnormalities are listed in Appendix 4. Normal ranges are presented in 
Appendix 5. 
7.4 Pharmacoeconomic assessments 
7.4.1 Work Productivity and Activity Impairment Questionnaire: 
Clostridium difficile-associated diarrhea V2.0 (WPAI:CDAD) 
The WPAI:CDAD is a 6-question, patient-reported quantitative assessment of the amount 
of absenteeism, presenteeism, work productivity loss, and activity impairment 
attributable to CDAD during the previous 7 days.  
The sponsor has adapted for CDAD the specific health version of the WPAI Version 2 
which was developed by Reilly Associates [Reilly 1993; see Appendix 6]. 
All subjects who sign the ICF themselves will complete the WPAI:CDAD. The 
WPAI:CDAD will be completed by the subject at Visit 1, Visit 3 and Visit 5. These 
subjects must complete the WPAI:CDAD by themselves without help from anybody else.  
It is recommended that at Visit 3 and Visit 5 the WPAI:CDAD questionnaire is 
completed prior to any clinical assessments. Preferably, subjects would complete the 
WPAI:CDAD before any interaction with healthcare providers to avoid any potential bias 
or impact of interventions in their responses. 
Subjects will complete the questionnaire on a paper form. The data from the paper forms 
will be transferred into the study database via double data entry. 


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The sponsor has notified the developer about the use of the instrument in this study. No 
license is required for the administration of the instrument. 
7.4.2 Other pharmacoeconomic assessments 
Information on the subject’s total length of stay in the hospital and the length of stay in 
specific types of hospital units including general ward, step-down/intermediate care unit, 
and an ICU (in days) will be collected. 
ICU (or critical care unit) is defined as a hospital unit in which concentrated special 
equipment and specially trained personnel take care of seriously ill subjects requiring 
immediate and continuous attention. 
Step-down/intermediate care unit is defined as a transitional unit for subjects from ICU 
that provides close monitoring and provision of non-critical care. 
Information on the reason of the subject’s (re-)admission to hospital will be captured as a 
variable, differentiating between admission for CDAD and admission for other reasons. 
Information on the subject’s location (e.g., home, nursing home, specific hospital ward) 
prior to admission to hospital as well as the subject’s location upon discharge will be 
collected. 
Information on the type and number of CDAD-related procedures (FMT, 
hemi-colectomy, colectomy) will be collected. 
This information collected as described above will be used for the pharmacoeconomic 
evaluation. 
7.5 Pharmacokinetic assessments 
In a sub-population of at least 120 subjects pooled from AC-061A301 and AC-061A302, 
on Visit 3 following a sachet and capsule dose, a 3 mL blood sample will be drawn 
approximately 2 h post-dose for determination of cadazolid plasma concentrations. The 
actual time post-dose will be used in the assessment (Note: All PK blood samples taken 
up to 3 h post-dose will not be considered as protocol deviations). The time of the 
3 previous sachet/capsule doses prior to this blood sample, whether the last dose prior to 
this blood sample was taken within 1 h of consuming a meal (not a snack e.g., bag of 
crisps or a biscuit), and the time of blood sample collection should be recorded in the 
CRF.  
Approximately 3 mL of blood will be collected by direct venipuncture in an antecubital 
vein in the arm in a Monovette tube (or equivalent) containing ethylenediaminetetraacetic 
acid. Immediately following collection of the required blood volume, the tubes will be 
slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into 


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solution, and immediately cooled on ice. Within 30 min of collection, the tubes will be 
centrifuged at approximately 2000 g for 10 minutes at 2–8 °C. When a centrifuge that can 
be cooled is not available, the blood samples and the bucket of the centrifuge must be 
cooled on ice prior to centrifugation. The plasma will then be transferred into one labeled 
polypropylene tube, avoiding carry-over of erythrocytes. All samples will be stored in an 
upright position at −70 °C or lower. The actual clock time of collection of the blood 
sample will be entered in the CRF. 
Labeling 
The tubes for both collecting blood for cadazolid determination and storage of plasma 
samples will be provided along with pre-printed labels to each of the participating sites 
by the central laboratory before starting the study. They will provide fields to collect the 
following information: 
Actelion Pharmaceuticals Ltd 
AC-061A301 
Plasma 
Centre number 
Subject number 
Study day  
Date / Time collected 
Bioanalysis 
All samples from subjects on cadazolid will be analyzed by the bioanalytical laboratory. 
Twenty percent of the samples from subjects on vancomycin will be analyzed by the 
bioanalytical laboratory as negative controls. No samples should be destroyed until the 
study report is signed off. 
Cadazolid plasma concentrations will be determined using a validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) assay. The foreseen limit of 
quantification (LOQ) is 0.25 ng/mL. Concentrations will be calculated by interpolation 
from a calibration curve. Quality control samples will be analyzed throughout the study, 
and their measured concentrations will be determined between-run and overall precision 
and accuracy of the analysis. 
Shipping procedures 
The plasma samples for cadazolid determination must be shipped from the sites to the 
Central Laboratory, then to the bioanalytical laboratory on a regular basis, as agreed by 
the sponsor. The samples must be packed securely with completed shipment forms, 
(detailing what the tubes contain, subject numbers, site number and date) in polystyrene 
insulated shipping containers, together with enough dry ice to keep the package frozen 
for at least 48 h. Arrangements must be made with the regional central laboratory before 


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the site sends the sample to the Central Laboratory, then with the bioanalytical laboratory 
before the regional central laboratory sends the samples to the bioanalytical laboratory. 
8 SCHEDULE OF VISITS 
Table 1 provides an overview of the chronological sequence of the assessments. 
At each study visit, study personnel must remind women of child-bearing potential to use 
the methods of contraception defined for this study.  
Unless otherwise specified, study visits must be performed on site; however, visits at the 
subject’s place of residence may be acceptable after having received documented 
agreement from the sponsor. 
The following tasks must be carried out by a physician investigator: 
• Informed consent process 
• Specific protocol procedures including the decision on subject eligibility, laboratory 
test result interpretation (including GDH and toxin A/B test), study drug prescription 
(decision on start and discontinuation), assessment of AEs/SAEs, and ECG reading 
for the ongoing safety assessment of the subject (Note: Only ECG interpretations 
made by the local cardiologist are entered in the CRF [see Section 7.3.2]). 
• CRF/Query sign off. 
 
The physical exam and some tasks related to the informed consent process can be 
delegated to an advanced practice role (e.g., nurse practitioner) provided that this is in 
accordance with local regulations, site-specific SOPs and the person’s education and 
certification. 
8.1 Screening and Randomization / Visit 1 
The Screening Period will last for up to 48 h prior to randomization and includes: 
• After discussing the study with the investigator and after agreeing to study 
participation by signing the ICF, subjects will be assigned a subject number by the 
IVRS provider. For any subject signing an ICF, it is the responsibility of the 
investigator to obtain written informed consent prior to any screening assessment. If a 
study-specific procedure or assessment has been performed as part of routine 
assessments and the results are available prior to the signing of the ICF, such 
procedure or assessment may be used to assess eligibility and does not have to be 
repeated. In such cases, it must be clear from the source document when and for 
which reason the assessment was done prior to the signing of the informed consent. 
The subject number will identify the subject throughout the study. Subjects are 
allowed to be re-screened if they failed eligibility and were not randomized. The 


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subject number assigned during the first screening procedure will be retained in 
rescreened subjects.  
• C. difficile GDH and toxin test (approved by the sponsor). At investigational sites 
where the sponsor-approved C. difficile GDH and toxin test is not standard of care, a 
two-part ICF may be used: Section A covering the C. difficile GDH and toxin test 
only, and Section B covering the enrollment into the study. 
• Fecal sampling for microbiology 
• Recording of demographics, medical history, and disease characteristics 
• Recording of previous (within 7 days of randomization or in the past 3 months for 
antibiotics and acid suppressing medications) and concomitant medications (including 
mandatory methods of contraception) 
• Recording of body temperature (maximum value if multiple assessments), vital signs 
(BP, HR), body weight, and height 
• Physical examination 
• Hematology, coagulation, blood chemistry, and urine (or plasma/serum) pregnancy 
test for women of childbearing potential 
• 12-lead ECG 
• Completion of the CDAD DaySyms PRO diary 
• WPAI:CDAD 
• Recording of SAEs. 
 
The investigator will check all inclusion/exclusion criteria to ascertain final eligibility. 
The reasons for screening failure are documented in the IVRS system and in the CRF 
(screening information is collected for all screen failure subjects). 
After all screening assessments are done and eligibility determined, and after having 
ensured that the pharmacist is available to dispense study drug, the subject is randomized 
in the IVRS. As a result, a randomization number and a treatment kit number are 
assigned. Randomization is followed by the administration of the first dose of study drug 
(1 sachet AND 1 capsule). Preparation and administration of, at least, the first dose of 
study drug by the subject must be done by or under the guidance of the investigator or the 
study coordinator. 
Subjects are instructed on study drug administration and Study Drug Journal, prohibited 
medications and therapy, stool diary, and CDAD DaySyms PRO. They are also provided 
with the necessary kit and guidelines for feces collection, sampling, and delivery. 
Subjects are allowed to leave the study site only after the investigator has confirmed that 
their clinical status is compatible with being discharged. Subjects are reminded to contact 
the site immediately in case of an AE.  


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8.2 Treatment period 
The treatment period starts after randomization with the administration of the first dose of 
study drug (1 sachet AND 1 capsule). Preparation and administration of, at least, the first 
dose of study drug prepared by the subject must be done under the guidance of the site 
personnel. 
The treatment period ends 10–11 days later, on the day of the last dose of study drug, 
depending on the time of the day the subject takes the first dose. If the subject is an 
out-patient or at the time of discharge from the hospital between Visit 1 and Visit 3, the 
subject receives the remainder of the treatment kit. During the entire treatment period, a 
Study Drug Journal recording study drug intake is completed daily by the subject or the 
study personnel (if hospitalized).  
Women of childbearing potential are reminded to use acceptable methods of 
contraception from Visit 1 until 7 days after study drug discontinuation; methods of 
contraception are recorded in the CRF. All subjects are interviewed face-to-face or by 
telephone every day up to Visit 4 and then twice weekly up to Visit 5. 
8.2.1 Visit 2 
Visit 2 takes place on Day 5 (or Day 6 if the visit cannot take place on Day 5) – this 
evaluation may be done at the site or by telephone, if in the investigator’s opinion, a 
face-to-face visit is not necessary. Visit 2 includes: 
• Subject interview 
• Review of stool diary and reconciliation of source documents if necessary (if on-site 
visit),  
• Verify compliance with CDAD DaySyms PRO 
• Review of Study Drug Journal (if on-site visit) 
• Investigator assessment of Early Treatment Response 
• Recording of concomitant medications, including repeated instructions on prohibited 
medications 
• Recording of AEs and SAEs 
Subjects are also provided with the necessary kit and guidelines for feces collection, 
sampling, and delivery (if on-site visit and this has not been done at Visit 1). 
Premature discontinuation of study drug including treatment failure (if there is no change 
or worsening of the subject then the investigator may consider the subject a treatment 
failure) may occur at any time during the treatment period, in particular during subject 
interviews (i.e., telephone calls) and planned visits/evaluations (i.e., Visit 2 and Visit 3). 
In case of premature discontinuation of study drug, Visit 3 is performed and the 


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follow-up period takes place as planned. Every effort must be made to perform the Visit 3 
assessments before initiation of alternative therapy for CDAD. 
8.2.2 Visit 3 
Visit 3 occurs on site between Day 8 and Day 10 while the subject is taking study drug. 
Visit 3 includes: 
• Administer WPAI:CDAD first 
• Fecal sampling for microbiology  
• Subject interview 
• Review of stool diary and reconciliation of source documents if necessary, verify 
compliance with CDAD DaySyms PRO 
• Review of Study Drug Journal 
• Physical examination and recording of body weight 
• Recording of vital signs (BP, HR) and temperature 
• Hematology, coagulation, and chemistry tests 
• 12-lead ECG 
• Recording of concomitant medications 
• Recording of AEs and SAEs 
• Provide subjects with the necessary kits for microbiology sampling during the 
Follow-up Period 
• Schedule an appointment for Visit 4 (if a face-to-face visit is necessary) and Visit 5. 
8.3 Follow-up period 
The follow-up period starts immediately after the last dose of study drug and ends 
approximately 30 days after the last dose of study drug. 
8.3.1 Visit 4 
Visit 4 occurs 2–4 days after the EOT (at site or by telephone if it is the investigator’s 
opinion that a face-to-face visit is not necessary). 
Visit 4 includes: 
• Subject interview 
• Review of stool diary and reconciliation of source documents if necessary (if on-site 
visit) 
• Verify compliance with CDAD DaySyms PRO 
• Review of Study Drug Journal (if on-site visit) 
• Recording of concomitant medications 
• Recording of AEs and SAEs 


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• Investigator’s evaluation of the subject by the per-protocol definition of Clinical Cure 
(please note a subject can only be declared a Clinical Cure when there is ROD and no 
additional CDAD therapy through EOT + 2 days). The follow-up is performed 
similarly, with the same scheduled assessments, whether the subject is assessed as 
clinically cured or not. 
• Investigator’s judgment of clinical response (ICR) 
8.3.2 Unscheduled visits for recurrence 
Unscheduled visits (Visit 4.a, 4.b, etc.) to evaluate for recurrence may occur when a 
subject experiences a NED at any time between Visit 4 and 5. Under some conditions 
[see Section 8.4], the subject may enter the re-treatment extension. Subjects cannot be 
enrolled into the re-treatment extension if Visit 5 occurs after end of treatment + 32 days. 
See below in Section 8.3.4. for information on unscheduled visits not related to NED that 
can occur at any time during the study. Unscheduled visits for recurrence may include: 
• Subject interview 
• Review of stool diary and reconciliation of source documents if necessary. 
• Review of Study Drug Journal (if Visit 4 not an on-site visit)  
• Physical examination  
• Recording of vital signs (BP, HR) and temperature 
• Hematology, coagulation, and chemistry tests 
• Recording of concomitant medications 
• GDH and toxin A/B test on the same stool sample, in case of suspected recurrence 
• Fecal sampling for microbiology (only in the subjects having recurrence) 
• Recording of AEs and SAEs. 
Note: All assessments must be performed in the case of a recurrence. 
Subject may enter the re-treatment extension with cadazolid in case of recurrence 
[see Section 8.4]. 
8.3.3 Visit 5  
Visit 5 takes place 30 ± 2 days after last dose of study drug (in case of study withdrawal, 
Visit 5 should be scheduled within 48 h [see Section 9.1] and includes: 
• Administer WPAI:CDAD first 
• Subject interview 
• Review of stool diary and reconciliation of source documents if necessary 
• Review of Study Drug Journal (if Visit 4 not an on-site visit and no episode of NED) 
• Physical examination, and recording of body weight 


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• Recording of vital signs (BP, HR) and temperature 
• Hematology, coagulation, and chemistry tests 
• 12-lead ECG 
• Recording of concomitant medications 
• Recording of CDAD related procedures (FMT, colectomy, hemi-colectomy) 
• Recording of AEs and SAEs 
• Investigator’s evaluation of the subject by the per-protocol definition of Sustained 
Cure 
• Investigator’s judgment of sustained response (ISR) 
8.3.4 Unscheduled visits 
Unscheduled visits (Visit U1, U2, etc.) unrelated to NED may occur between scheduled 
visits as described above. The date of the visit and the reason for the visit, as well as data 
related to study assessments performed at unscheduled visits will be collected in the CRF. 
8.4 Re-treatment extension with cadazolid (optional) 
Subjects who experience a NED [see Section 6.1.2] and fit with eligibility criteria, 
including a positive GDH and toxin test (performed on the same stool sample), etc., are 
invited to enter, after providing informed consent, a re-treatment extension consisting of a 
10-day treatment with cadazolid followed by an approximately 30-day follow-up period. 
The subjects will follow the same visit schedule (visits are labeled by adding ‘Re-’ in 
front of the visit number) as described in the main study protocol. The description of the 
procedures to be followed during the visits, re-treatment Visit 1 (Re-1) to re-treatment 
Visit 5 (Re-5), are identical to the corresponding visits in the main study protocol 
(Visit 1–5) that are described in Section 8.1, Section 8.2, Section 8.3, and Section 8.4, 
with the exceptions listed later in this section. The schedule of assessment for the 
re-treatment extension with cadazolid is described in Table 3. 
If the subject does not qualify for the re-treatment extension with cadazolid, an 
alternative therapy is prescribed for the recurrence and the subject remains on the original 
visit and assessment schedule. 
When a subject experiences a recurrence and participation in the re-treatment extension is 
confirmed (after the subject has signed the ICF for re-treatment and eligibility is 
confirmed), Visit 5 in the main study is not performed. Assessments that would have 
been performed as part of Visit 5 in the main study are performed as part of re-treatment 
Visit 1 (Re-1). Subjects cannot be enrolled into the re-treatment extension if Visit 5 
occurs after end of treatment + 32 days. 
Assessments performed after signing the Informed Consent for the re-treatment extension 
are recorded in the Visit Re-1 section of the CRF. Assessments performed at the NED 


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visit, prior to signing the Informed Consent for re-treatment extension and as long as they 
have been performed within 24 h of enrollment (72 h of enrollment for the fecal 
sampling), do not need to be repeated for Visit Re-1. In these cases it will be recorded on 
the applicable eCRF at visit Re-1 that the assessment was not performed (i.e., assessment 
performed and recorded at the NED visit). 
The re-treatment extension with cadazolid will involve only subjects (cadazolid or 
vancomycin) with a first occurrence of CDAD at initial study entry who experience a first 
recurrence of CDAD during the study. The subject has to fulfill the following eligibility 
criteria: 
Inclusion criteria 
1. Signed informed consent prior to any re-treatment extension-mandated procedure. 
2. Male or female ≥ 18 years of age at the screening visit. 
A non-pregnant woman of childbearing potential [as defined in Section 4.2] is 
eligible only if: 
• The absence of pregnancy is confirmed by a negative urine (or plasma/serum) 
pregnancy test at Visit Re-1 
• She agrees to use one of the methods of contraception [defined in Section 4.2] 
from Visit Re-1 until 7 days after study drug discontinuation. 
3. Subject with a diagnosis of mild–moderate or severe CDAD at Visit Re-1 with: 
• Diarrhea, defined as a change in bowel habits with > 3 UBMs, in the 24 h 
prior to enrollment into the re-treatment extension,  
AND 
• Positive C. difficile GDH and toxin A and/or B stool test, on the same sample 
collected no more than 72 h prior to enrollment using an EIA test approved by 
the sponsor. 
Exclusion criteria 
1. Any previous episode of CDAD in the 3-month period prior to initial randomization 
into the study. 
2. Fulminant or life-threatening CDAD. If in the judgment of the investigator there is a 
suspicion of fulminant or life-threatening CDAD, the presence of any of the 
following criteria during the 72 h period prior to enrollment and related to the 
fulminant or life-threatening CDAD episode excludes the potential subject from the 
re-treatment extension with cadazolid: 


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• Septic shock – Systolic BP < 90 mmHg or a mean arterial pressure < 70 mmHg in 
the absence of other causes of hypotension and that persists despite adequate fluid 
resuscitation 
• Peritonitis 
• Ileus 
• Toxic megacolon  
• Significant dehydration based on investigator judgment  
• White blood cells count > 30.0 × 109/L  
• Core body temperature > 40 °C 
3. Concurrent immediately life-threatening disease or condition (likelihood of death 
within 72 h). 
4. History of inflammatory colitides (e.g., ulcerative colitis or Crohn’s disease, 
microscopic colitis, collagenous colitis) or chronic abdominal pain or chronic 
diarrhea of any etiology, or known positive diagnostic test for enteropathogens. 
5. Vomiting or other condition that interferes with the ability to take oral medication or 
subjects with feeding tubes (i.e., when study drug would have to be given by the 
feeding tube). 
6. Antimicrobial treatment active against CDAD administered for > 24 h for the current 
episode of CDAD. 
7. Planned additional treatment with antimicrobial medication active against CDAD, 
FMT, or any forbidden concomitant medications [see Concomitant medications, 
Section 5.2].  
8. FMT, intravenous immunoglobulins, or any investigational drug to prevent or treat 
CDAD in the 1 month (or 5 half-lives in case of investigational drug, whichever is 
longer) period prior to enrollment. 
9. Treatment with monoclonal antibodies against C. difficile in the 6-month period prior 
to enrollment. 
10. Investigational vaccination against C. difficile. 
11. Previous participation in a clinical trial with cadazolid prior to initial randomization 
into the study. 
12. Known hypersensitivity or contraindication to any excipients of the investigational 
drug formulations, or to oxazolidinones or quinolones. 
13. Women who are breastfeeding. 


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14. Investigational site staff members or relatives, and Actelion employees. 
15. Unable or unwilling to comply with all protocol requirements including study visits, 
study procedures, diary completion, medication adherence, and appropriate study 
medication storage at home. 
16. Any circumstances or conditions, which, in the opinion of the investigator, may affect 
the subject’s full participation in the study, or compliance with the protocol. 
The study design including the re-treatment extension is depicted below. 
Figure 2 
Study design including re-treatment extension  
 
A subject is considered to have completed the extension and the study if re-treatment 
Visit 5 (Re-5) is performed at least 28 days after the last dose of open-label cadazolid. 
Upon eligibility, the subject number is kept. A re-treatment kit number is assigned and an 
additional 10-day treatment with cadazolid is provided. 
The study treatment is an oral administration of cadazolid 250 mg twice daily (with or 
without food): 1 sachet of reconstituted cadazolid suspension is to be taken 
approximately 12 h apart, i.e., at breakfast and late afternoon (dinner), or at lunch and 
bedtime. Randomization and blinding (or unblinding) procedures do not apply. The 
treatment duration is also 10 days until EOT when the last dose is taken.  


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Efficacy endpoints in the re-treatment extension with cadazolid are captured and 
determined in the same manner as the efficacy endpoints in the randomized blinded part 
of the study.  
AEs in the re-treatment extension with cadazolid are captured and analyzed in the same 
manner as AEs in the randomized blinded part of the study. A TEAE is any AE from 
study drug initiation until 7 days after the last dose of study drug [see Section 10.1.1]. 
AEs that started during the re-treatment extension with cadazolid screening period are 
recorded as AEs in the main study. All AEs are reported as part of the re-treatment 
extension with cadazolid after the first dose of open-label study drug. AEs ongoing at the 
time of first dose of open-label cadazolid and worsening thereafter must be reported as 
new AEs. 
All re-treatment endpoints are exploratory.  
 


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Table 3 
Visit and assessment schedule for the re-treatment extension with cadazolid 
PERIODS 
Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
- 
 
Duration 
Up to 24 hours 
10 to 11 days 
28 to 32 days 
- 
VISIT 
Number 
Re-1 
Re-2 
Re-3 
Re-4 
Re-4.a, Re-4.b,… 
Re-5 
Re-U1,  
Re-U2, … 
 
Name 
Eligibility 
Re-treatment 
kit delivery 
 
 
 
NED 
 
Unscheduled 
EVALUATION 
Time 
Day –1 to 1 
(within 24 h) 
Day 1 
Day 5  
or 6 
On site or by phone 
Day 8 to 10 
incl. Premature 
Disc. 
 
EOT + 2 to 4 days  
On site or by phone 
If applicable, in 
case of NED4 
  
EOT + 28 to 32 days
or Study Withdrawal 
If applicable 
Informed consent 
X 
 
 
 
 
 
 
 
Fecal sampling for microbiology 
X 
 
X 
 
X 
 
 
C. difficile GDH and toxin test 
within 72 h 
 
 
 
 
X 
 
 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
X 
X 
X 
X 
Body weight 
X 
 
X 
 
 
X 
X 
Vital signs / Body temperature 
X 
 
X 
X 
X 
X 
Hematology/coagulation/ 
chemistry 
X1 
 
 
X 
 
X 
X 
X 
12-lead ECG 
X  
 
X 
 
 
X 
X 
Re-treatment kit delivery 
X 
 
 
 
 
 
 
Study Drug intake  
X2 
and Study Drug Journal completion 
 
 
 
 
Stool Diary 
 
 
 
CDAD DaySyms PRO Diary 
 
 
 
 
Interview (face to face or by phone) 
Daily5 
Twice weekly 
 
Investigator assessment 
 
X 
 
X 
 
X 
 
WPAI:CDAD 
X 
 
X 
 
 
X 
 
AEs/SAEs3 
X 
X 
X 
X 
X 
X 
X 
1. Includes pregnancy test for women of childbearing potential. 2.After re-treatment kit delivery. 3. All AEs and SAEs are reported after the first dose of study drug. Between informed consent and 
first dose of study drug, AEs and SAEs are reported as part of the main study. 4. All assessments must be performed in the case of a recurrence. 5. Interviews start on Day 2. 
AE = adverse event, C-difficile = Clostridium difficile, CDAD = Clostridium difficile-associated diarrhea, ECG = electrocardiogram, EOT = end-of-treatment, GDH = glutamate dehydrogenase, 
NED = new episode of diarrhea, PRO = patient reported outcomes, SAE = serious adverse event, WPAI = work productivity and activity impairment. 


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9 STUDY COMPLETION 
All randomized subjects who received study drug must be followed up to Visit 5, whether 
or not they are prematurely discontinued from study treatment. Randomized subjects who 
do not receive a dose of study drug will complete Visit 5 as soon as possible. 
Subjects are considered to have completed the study if Visit 5 or Re-5, in case of 
re-treatment extension with cadazolid, is performed at least 28 days after last dose of 
study drug. 
9.1 Withdrawal from study 
A subject will be considered as withdrawn from the study if he/she (or the physician on 
behalf of the subject) withdraws consent to be treated and to be followed up. A subject 
who prematurely discontinues study drug is not considered as withdrawn from the study, 
and will be followed up as outlined in Section 8.3, unless the subject withdraws from the 
study. 
A subject will also be considered as withdrawn from the study if he/she dies, or is lost to 
follow-up.  
The site must take preventive measures to avoid a subject being lost to follow-up 
(i.e., document in subject’s notes and CRF different ways to contact subjects, including 
telephone number, home address, e-mail address, person to be contacted in case the 
subject cannot be reached). If the subject cannot be reached then the site must make a 
reasonable effort to contact the subject and document in subject’s notes and CRF all 
attempts. The following methods must be used: at least 3 telephone calls must be placed 
to the last available telephone number and 1 registered letter must be sent by mail to the 
last available home address. Additional methods may be acceptable if they are compliant 
with local rules/regulations (e.g., visit to the subject’s home) and respect the subject’s 
right to privacy.  
If the subject is still unreachable after all contact attempts listed above, then he/she will 
be considered to be lost to follow-up.  
9.2 End of the trial 
The end of the trial occurs when all the subjects have completed Visit 5 or Re-5 for those 
participating in the re-treatment extension with cadazolid.  
9.3 Premature termination or suspension of the study 
Actelion reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 


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If the study is prematurely suspended or terminated, then Actelion will promptly inform 
the investigators, the IRBs/IECs and health authorities as appropriate, and provide the 
reasons for the suspension or termination.  
If the study is prematurely suspended or terminated for any reason, then the investigator, 
in agreement with Actelion, must promptly inform all enrolled subjects, and ensure their 
appropriate treatment and follow-up. 
In addition, if the investigator suspends or terminates the study without prior agreement 
from Actelion, then the investigator must promptly inform Actelion and the IRB/IEC, and 
must provide Actelion and the IRB/IEC with a detailed written explanation of the 
termination or suspension. 
If the IRB/IEC suspends or terminates its approval / favorable opinion of the study, then 
the investigator must promptly notify Actelion and provide Actelion with a detailed 
written explanation of the termination or suspension. 
Any premature suspension or termination of the study must be discussed with the IDMC 
and the Steering Committee. 
9.4 Medical care of subjects after the End-of-Treatment 
When a subject is declared a Clinical Failure, or at the time of recurrence if the subject 
does not participate in the re-treatment extension with cadazolid, the investigator/delegate 
will explain to subjects what treatment / medical care would be necessary and available 
according to local practice and regulation. 
10 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
10.1 Adverse events 
10.1.1 Definitions of adverse events 
An AE is any adverse change from the subject’s baseline condition, i.e., any unfavorable 
and unintended sign, including an abnormal laboratory finding, symptom or disease, that 
occurs during the course of the study, whether or not considered related to the study drug.  
A TEAE is any AE from study drug initiation until 7 days after the last dose of study 
drug whether or not considered related to the study drug. See also Section 8.4 for AEs 
during the re-treatment extension. 
AEs include: 
• Exacerbation of a pre-existing disease. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 


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• Disease or medical condition detected or diagnosed after study drug administration 
even though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at baseline that worsen following 
the start of the study.  
• Abnormal assessments e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at baseline or worsened 
during the course of the study. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at baseline or worsened during the course 
of the study or led to dose reduction, interruption or permanent discontinuation of 
study drug.  
• Overdose, misuse and abuse of the study drug should be reported as AEs and errors 
with the study medication should be documented in the study drug log of the CRF. 
10.1.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the CRF.  
If the intensity of an AE worsens during study drug administration, only the worst 
intensity should be reported on the AE page. If the AE lessens in intensity, no change in 
the severity is required. 
The 3 categories of intensity are defined as follows: 
Mild 
The event may be noticeable to the subject. It does not influence daily activities, and 
usually does not require intervention. 
Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
Severe 
The event may cause noticeable discomfort, and usually interferes with daily activities. 
The subject may not be able to continue in the study, and treatment or intervention is 
usually needed. 
A mild, moderate, or severe AE may or may not be serious [see Section 10.3.1]. These 
terms are used to describe the intensity of a specific event. Medical judgment should be 
made on a case per case basis.  
Seriousness, rather than severity assessment, determines the regulatory reporting 
obligations. 


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10.1.3 Relationship to study drug  
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study drug, and reported as either ‘suspect’ (i.e., 
related) or ‘not suspect’ (i.e., not related). 
10.1.4 Reporting of adverse events 
All AEs occurring after study drug initiation and up to Visit 5 (30 ± 2 days after last dose 
of study drug) must be recorded on specific AE pages of the CRF. 
10.1.5 Follow-up of adverse events 
If an AE is still ongoing at the End-of-Study (EOS), then the AE must be followed until it 
is stable or no longer clinically significant. 
10.2 Serious adverse events 
10.2.1 Definitions of serious adverse events 
10.2.1.1 Serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the 
following criteria: 
• Fatal 
• Life-threatening: refers to an event in which the subject was at risk of death at the 
time of the event. It does not refer to an event that hypothetically might have caused 
death had it been more severe 
• Requiring inpatient hospitalization, or prolongation of existing hospitalization 
• Resulting in persistent or significant disability or incapacity 
• Congenital anomaly or birth defect 
• Medically significant: refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered to 
be SAEs when, based upon appropriate medical judgment, they may jeopardize the 
subject, and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions above.  
The following reasons for hospitalizations are exempt from being reported:  
• Hospitalizations for cosmetic elective surgery, or social and/or convenience reasons 
• Hospitalizations for pre-planned standard monitoring of a pre-existing disease or 
medical condition that did not worsen (e.g., hospitalization for coronary angiography 
in a subject with stable angina pectoris) 
• Hospitalizations for elective treatment of a pre-existing disease (present at baseline) 
or medical condition that did not worsen (e.g., elective hip replacement for arthritis) 


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However, complications that occur during hospitalization are AEs or SAEs (for example, 
if a complication prolongs hospitalization). 
10.2.1.2 Serious adverse events associated to study design or protocol mandated 
procedures  
An SAE is defined as related to study design or protocol-mandated procedures if it 
appears to have a reasonable possibility of a causal relationship to either the study design 
or to protocol-mandated invasive procedures. For example, a complication of an invasive 
procedure specifically required by the protocol. 
10.2.2 Reporting of serious adverse events  
10.2.2.1 During screening period  
All SAEs, occurring after signing the ICF must be reported (whether considered 
associated or not associated to study design or study-mandated procedures).  
These SAEs must be reported on an SAE form and in the CRF (AE section).  
10.2.2.2 During treatment period  
All SAEs, regardless of causal relationship, must be reported. 
These SAEs must be reported on an SAE form and in the CRF (AE section).  
10.2.2.3 During follow-up period 
All SAEs, regardless of causal relationship, which occur within 30 days after study drug 
discontinuation must be reported.  
These SAEs must be reported on an SAE form and in the CRF (AE section).  
All SAEs must be reported to the IRB/IEC according to the site-specific IRB/EC 
reporting requirements. Copies of all communication regarding SAEs/pregnancy to the 
IRB/IEC and to the sponsor must be appropriately filed in the ISF. 
10.2.3 Follow-up of serious adverse events  
SAEs still ongoing at EOS must be followed up until resolution or stabilization, or until 
the event outcome is provided (e.g., fatal outcome).  
10.2.4 After the follow-up period  
New SAEs occurring after the follow-up period must be reported to the Actelion Drug 
Safety Department within 24 h of the investigator’s knowledge of the event, only if 
considered causally related to previous exposure to the study medication by the 
investigator.  


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10.2.5 Reporting procedures 
All SAEs must be reported by the investigator to the Actelion Drug Safety Department 
within 24 h of the investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study drug received by 
the subject and irrespective whether or not this event is considered by the investigator to 
be related to study drug.  
The SAE forms must be faxed to the Actelion Drug Safety Department (contact details 
are provided on the SAE form). The investigator must complete the SAE form in English, 
and must assess the causal relationship of the event to study drug. 
Follow-up information about a previously reported SAE must also be reported within 
24 h of receiving it. The Actelion Drug Safety Department may contact the investigator 
via email and/or fax to obtain further information.  
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and 
documentation. 
10.3 Pregnancy 
10.3.1 Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy detected during study 
drug administration and up to 30 days following the last dose of study drug, must be 
reported within 24 hours of the investigator’s knowledge of the event.  
Pregnancies must be reported on the Actelion Pregnancy form and faxed to the Actelion 
Drug Safety Department (see contact details provided on the pregnancy form). 
Pregnancies must be reported on an AE page of the CRF. 
If a pregnancy is detected while on study drug, then permanent discontinuation of study 
drug must be considered. The investigator must counsel the subject and discuss the risks 
of continuing with the pregnancy and the possible effects on the fetus.  
10.3.2 Follow-up of pregnancy  
Any pregnancy must be followed to its conclusion and its outcome must be reported to 
the Actelion Drug Safety Department.  
For any ongoing pregnancy, investigator should provide follow-up information at the 
beginning of each trimester. 


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10.4 Study safety monitoring 
Blinded clinical study safety information (e.g., AEs, SAEs, laboratory values, ECGs, vital 
signs, and project-specific labs/examinations as required) is monitored and reviewed on a 
continuous basis by Actelion to ensure subjects’ safety as well as data quality. These 
activities are complementary to the IDMC’s activities, which include monitoring safety 
and efficacy data periodically in an unblinded fashion [see Section 3.3]. 
11 STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by designated CROs supervised 
by Actelion. 
A Statistical Analysis Plan (SAP) will provide full details of the analyses, data displays, 
and algorithms to be used for data derivations. Statistical analysis of pharmacokinetic 
endpoints will be described in a separate statistical analysis plan. 
For subjects entering into the re-treatment extension, only data collected prior to starting 
re-treatment with cadazolid (first re-treatment dose) will be considered for all variables 
specified below, unless specifically mentioned as in Section 8.4. For subjects entering the 
re-treatment extension with cadazolid, a similar definition will be applied to estimate the 
exploratory endpoints Clinical Cure, recurrence and Sustained Cure assessed during the 
re-treatment extension with cadazolid.  
11.1 Variables 
11.1.1 Primary variable  
CCR (%) is the variable to be analyzed for the primary endpoint Clinical Cure, as defined 
in Section 6.1.1 and will be derived by the sponsor. CCR is the proportion of subjects 
assessed as meeting the criteria for Clinical Cure, where Clinical Cure is defined for a 
subject meeting both the following: 
• ROD (≤ 3 UBMs per day for at least 2 consecutive days) on study treatment and 
maintained for 2 days after EOT  
AND 
• No additional antimicrobial treatment active against CDAD or FMT between first 
dose of study drug and 2 days after EOT (inclusive). 
ROD is determined from the number of UBMs, or if the exact number is missing, from 
presence or absence of > 3 UBMs per day recorded in the Daily Stool Information section 
of the CRF. Days are measured according to calendar days. 


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Antimicrobial treatment active against CDAD or FMT is determined from concomitant 
medication/procedure CRF pages. 
Subjects who do not fulfill the requirements for Clinical Cure are considered Clinical 
Failure. 
11.1.2 Secondary variables 
11.1.2.1 Sustained cure rate (SCR) 
SCR (%) is the variable to be analyzed for the secondary endpoint Sustained Cure [as 
defined in Section 6.1.2], and will be derived by the sponsor. SCR is the proportion of 
subjects assessed as meeting the criteria for Sustained Cure, where Sustained Cure is 
defined for each subject having Clinical Cure and no recurrence.  
Recurrence is defined for subjects with Clinical Cure as: 
• NED (> 3 UBMs on any day between 3 days after EOT and Visit 5) 
AND 
• Stool test showing positive C. difficile GDH and toxin test on the same sample 
(according to EIA tests approved by the sponsor)  
AND 
• Antimicrobial treatment active against CDAD (including participation in the 
re-treatment extension with cadazolid) or FMT started between 3 days after EOT and 
Visit 5). 
NED is determined from the number of UBMs, or if the exact number is missing from 
presence or absence of > 3 UBMs, per day collected in the Daily Stool Information 
section of the CRF. Days are measured according to calendar days. 
A positive stool test is determined from the corresponding unscheduled visit for NED, 
where the result of the test is recorded. 
Antimicrobial treatment active against CDAD or FMT is determined from concomitant 
medication/procedure CRF pages. Participation in the re-treatment extension is derived 
from enrollment into the re-treatment extension as recorded in the CRF.  
NED should precede both the positive C. difficile GDH and toxin test and antimicrobial 
treatment active against CDAD (including participation in the re-treatment extension with 
cadazolid) or FMT. To avoid temporal dissociation between NED and the positive 
C. difficile GDH and toxin test and treatment of recurrence, at least one day with 
> 3 UBMs must be present within a window of 4 days prior to (and including) either the 
date of the fecal sampling for the GDH and toxin test or the start date of antimicrobial 


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treatment active against CDAD or the date of FMT. If the date of fecal sampling or start 
date of antimicrobial treatment active against CDAD are not the same, it is enough that at 
least one of these time windows contain a day with > 3 UBMs to confirm a recurrence.  
If a subject has missing information on UBMs within the window 4 days prior to and 
including the date of fecal sample or antimicrobial treatment, the rules governing the 
handling of missing UBMs described in the SAP will be applied. 
If a fecal sample for the GDH and toxin test is taken or antimicrobial treatment active 
against CDAD is started before a NED, it will not be considered a recurrence. Fecal 
sampling for the GDH and toxin test should be prior to or on the start date of 
antimicrobial treatment or FMT. Fecal sampling for the GDH and toxin test taken 1 or 
more days after the start date of a antimicrobial treatment active against CDAD or FMT 
are not considered in determining recurrence.  
Where multiple GDH and toxin tests are performed during a period with daily number of 
UBMs > 3, the latest fecal sample for the GDH and toxin test prior to (and including) 
antimicrobial treatment is selected. Where > 3 UBMs occur on 1 or more days within the 
4 day window prior to (and including) start date of antimicrobial treatment and the most 
recent GDH or toxin test is negative and performed on a fecal sample collected prior to 
this 4 day window, the negative GDH or toxin test is not considered and the subject will 
be considered to have a recurrence. 
Subjects with Clinical Failure or with Clinical Cure and recurrence are considered to be 
without Sustained Cure.  
11.1.2.2 Time to Resolution of Diarrhea (ROD) 
Time to ROD is defined as the time (h) elapsed between the first dose of study drug and 
the time when ROD is considered achieved. 
Time when ROD is considered achieved is the time of the last UBM prior to the first 
2 consecutive 24 h periods with ≤ 3 UBMs and subsequently ≤ 3 UBMs per day 
maintained up to 2 days after EOT. The two consecutive 24 h periods and last UBM 
date/time prior that period is determined from the Stool Log section of the CRF. The 
condition of maintaining ≤ 3 UBMs per calendar day is determined based on the number 
of UBMs per day as described for Clinical Cure [Section11.1.1].  
Subjects without Clinical Cure are censored at EOT day. Similarly, subjects who have 
withdrawn from the study, died, or are lost to follow-up before EOT + 2 days are 
censored at the expected EOT day, i.e., 10 days after starting medication. This will 
constitute a right-censored observation. 


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11.1.2.3 Absolute change from baseline in CDAD DaySyms PRO total daily score  
The absolute change in CDAD DaySyms PRO total daily score will be derived as the 
difference between the post-baseline and the baseline CDAD DaySyms PRO total daily 
score for each day. Data from all available days will be used for the analysis, fitting a 
general mixed model for repeated measurements [see Section 11.3.4.3]. Comparison 
between cadazolid and vancomycin will be made up to Day 12.  
The exact definition of the CDAD DaySyms PRO total score will be determined in the 
psychometric validation of the CDAD DaySyms PRO conducted in parallel, based on a 
blinded analysis of the sub-study for psychometric validation of AC-061A301 and study 
AC-061A302. 
11.1.2.4  Other efficacy variables 
11.1.2.4.1 Investigator’s assessment of Early Treatment Response at Visit 2 
The variable is defined as the ETR as assessed by the investigator at Visit 2 as improved, 
unchanged or worsened compared to baseline. 
11.1.2.4.2 Investigator’s judgment of Clinical Response Rate (ICRR) at Visit 4 
ICRR (%) is the proportion of subjects cured at Visit 4 based on the investigator’s 
judgment of Clinical Response. 
11.1.2.4.3 Investigator’s judgment of Sustained Response Rate (ISRR) 
ISRR (%) is the proportion of subjects with a Sustained Cure at Visit 5 based on the 
investigator’s judgment of Sustained Response. 
11.1.2.4.4 Early Clinical Cure Rate (ECCR) by Day 5 
ECCR (%) is the proportion of subjects assessed as meeting the criteria for ECC by 
Day 5, where ECC is defined for a subject meeting both the following: 
• ROD by Day 5: ≤ 3 UBMs for at least 2 consecutive days prior to or including Day 5 
and maintained up to EOT + 2 days 
• No additional antimicrobial treatment active against CDAD or FMT between first 
dose of study drug and EOT + 2 days as defined in Section 6.1.1 
ROD by Day 5 is determined from the number of UBMs in the same way as for Clinical 
Cure [Section 11.1.1]. To be considered with Early Clinical Cure the subject must have 
≤ 3 UBMs per day from Day 4 up to EOT + 2 days. If the number of UBMs on one or 
more days is missing or ‘unknown’ then the subject is considered a Failure. 


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11.1.2.4.5 Normalization of Bowel Movements rate (NBMR) 
It is the proportion of subjects with NBM, where NBM is defined as: 
• ≤ 2 bowel movements per day and no UBM on at least 2 consecutive days up to EOT 
and maintained up to 2 days after last dose of study drug  
AND 
• No additional antimicrobial treatment active against CDAD or FMT between first 
dose and EOT + 2 days after EOT. 
The number of bowel movements and UBMs are determined from the Daily Stool 
Information of the CRF. 
Additional antimicrobial treatment active against CDAD or FMT is derived as defined in 
Section 11.1.1. 
11.1.2.4.6  Time to return to usual stools 
Time to return to usual stools is defined as the time (days) elapsed between the first dose 
of study drug and the first day where the stools have returned to usual for a subject, i.e., 
the number of bowel movements (including UBMs) per day ≤ number of bowel 
movements reported as usual by the subject and maintained for at least 3 calendar days. 
Number of usual bowel movements is reported by the subject at baseline and recorded in 
the CRF. Number of bowel movements per day is determined from the Daily Stool 
Information section of the CRF (where days are measured according to calendar days) 
between date of first dose up to Visit 5. 
Subjects without return to usual stools as defined above are censored at Visit 5. Subjects 
without a Visit 5 assessment who died, withdrew from the study or are lost to follow-up, 
are censored at the date of death, study withdrawal or last contact, respectively. 
11.1.2.4.7 Recurrence Rate 
Recurrence Rate (RR, %) is the proportion of subjects assessed as having a recurrence 
[see Section 11.1.2] out of subjects meeting the criteria for Clinical Cure.  
Recurrence is classified either as:  
• Relapse: Identical strains identified either by REA typing or ribotyping at new 
episode of diarrhea (Visit 4.a, 4.b, etc.) and baseline . 
• Re-infection: Different strains identified either by REA typing or ribotyping at new 
episode of diarrhea (Visit 4. a, 4.b, etc.) and baseline  


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11.1.2.4.8 Time to recurrence  
Defined for subjects meeting the criteria of recurrence as the period (h) between the time 
of the last dose of study drug and the onset time of NED determined to be recurrence. 
Onset time of NED is defined as the time of the first UBM recorded in the Stool Log of 
the CRF in the day of NED (first day with > 3 UBMs between EOT + 3 days and Visit 5 
date as recorded in the Daily Stool Information section of the CRF) determined to be 
recurrence. Subjects considered Sustained Cure, i.e., clinically cured but without 
establishment of recurrence or death, are censored at the Visit 5. Subjects who died after 
EOT + 3 days are censored at the time of death. Subjects who are lost to follow-up 
without a Visit 5, are censored at the last contact date.  
Subjects not clinically cured and not at risk for a recurrence are not considered for this 
endpoint. 
11.1.2.4.9 Change from baseline in CDAD DaySyms PRO scores 
• Absolute (and/or percent) change from Baseline in CDAD DaySyms PRO total score 
per day. 
• Absolute (and/or percent) change from baseline in each of the domain score(s) per 
day. 
11.1.2.4.10 Susceptibility of C. difficile (MIC50 and MIC90, in µg/mL) 
Susceptibility is defined as the minimum inhibitory concentration (MIC in µg/mL) of the 
test agent (cadazolid, vancomycin, linezolid, moxifloxacin, metronidazole and 
fidaxomicin) which inhibits bacterial growth: 
• At baseline 
• In case of Clinical Failure, as the MIC of C. difficile from a fecal sample collected at 
Visit 3 
• In case of Recurrence as the maximum MIC of C. difficile in fecal samples collected 
at any Visit 4.a, 4.b, etc. 
11.1.2.4.11 Change from baseline in susceptibility of C. difficile  
This variable is measured only in subjects with Clinical Failure or recurrence. It is 
defined as the relative change in MIC of cadazolid, vancomycin, linezolid and 
moxifloxacin at post-baseline compared to baseline: MIC at post-baseline / MIC at 
baseline, categorized as ≥ 4-fold decrease, 2-fold decrease, no change, 2-fold increase or 
≥ 4-fold increase. The MIC at post-baseline is defined for Clinical Failures and 
recurrence as specified in Section 11.1.2.4.10.  
11.1.2.4.12 Change from baseline to Visit 3 in VRE count  
It is defined as the difference between baseline and Visit 3 VRE counts. 


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The Central Laboratory provides density of VRE counts (log10 cfu/mL) at Visit 1 and 
Visit 3 for all subjects. VRE counts are defined as the sum of counts for isolates 
identified as vancomycin-resistant Enterococcus faecium and vancomycin-resistant 
Enterococcus faecalis. 
11.1.2.4.13 Susceptibility of VRE to cadazolid, vancomycin, linezolid, moxifloxacin, 
fidaxomicin, daptomycin, tigecycline, ampicillin, gentamicin, and 
quinupristin-dalfopristin 
Susceptibility for vancomycin-resistant E. faecium and vancomycin-resistant E. faecalis 
isolates is defined as the minimum inhibitory concentration (MIC in µg/mL) of the test 
agent (cadazolid, vancomycin, linezolid, moxifloxacin, fidaxomicin, daptomycin, 
tigecycline, ampicillin, gentamicin, and quinupristin-dalfopristin) which inhibits bacterial 
growth. 
11.1.3 Safety variables  
• Deaths up to Visit 5 
• AEs and SAEs up to Visit 5 
• TEAEs and treatment-emergent SAEs up to 7 days after EOT, day inclusive 
• AEs leading to premature discontinuation of study treatment 
• Change from baseline up to Visit 3 and Visit 5 in vital signs (SBP, DBP, and HR), 
body temperature and body weight 
• Marked abnormalities in vital signs (SBP and DBP) up to EOT + 7 days (treatment 
emergent) and up to Visit 5 
• Change from baseline in ECG parameters up to Visit 3 and Visit 5 
• Marked abnormalities in ECG up to EOT + 7 days (treatment-emergent) and up to 
Visit 5 
• Change from baseline in hematology, coagulation, and chemistry parameters up to 
Visit 3 and Visit 5 
• Marked abnormalities in hematology, coagulation and blood chemistry parameters up 
to EOT + 7 days (treatment-emergent) and up to Visit 5. 
11.1.4 Other variables  
11.1.4.1 Exposure to study drug 
• 
The duration of exposure is defined as the time elapsing between study drug 
initiation and discontinuation, inclusive. This will be determined for cadazolid and 
vancomycin for double-blind treatment and for re-treatment with cadazolid 
(open-label treatment). 
• 
The mean daily dose per subject is defined as the ratio between the total study drug 
dose taken during the treatment period and the total exposure time.  


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• 
Compliance (%) is defined as percent of doses taken out of planned doses (20 sachets 
for cadazolid, and 40 capsules for vancomycin) and determined separately for 
sachets and capsules. 
11.1.4.2 Demographic variables 
• 
Country. 
• 
Sex. 
• 
Age categories.  
• 
BMI. 
• 
Race and Ethnicity. 
• 
Severe CDAD is defined as any one of the following: 
a. Maximum core temperature recorded at baseline > 38.5 °C. 
b. WBC > 15.0 × 109/L (based on Central Laboratory). 
c. Rise in serum creatinine > 50% compared to pre-CDAD diagnosis. 
11.1.4.3 Baseline disease characteristics variables 
• 
Prior antimicrobial treatment active against CDAD. 
• 
First occurrence / first recurrence. 
• 
Initial strain of CDAD (hypervirulent or not). 
• 
In-patient or out-patient at randomization. 
• 
Baseline frequency of UBMs. 
11.1.4.4 Pharmacoeconomic variables 
11.1.4.4.1 Hospitalization 
• 
Length of stay in hospital (days) 
• 
Length of stay by ward unit (general ward, step-down/intermediate unit, ICU [days]) 
• 
Frequency of re-admissions/admissions to hospital after start of treatment 
• 
Frequency of emergency department visits after start of treatment 
11.1.4.4.2 Change from baseline in WPAI:CDAD scores 
Absolute WPAI:CDAD scores and absolute change from baseline for each WPAI:CDAD 
score at/to each visit where the WPAI:CDAD questionnaire was administered will be 
summarized. 


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WPAI:CDAD scores are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity. The 4 WPAI:CDAD scores are 
defined as follows, based on the scores Q1–Q6 of Questions 1–6: 
• 
Absenteeism: Percent work time missed due to CDAD = Q2 / (Q2+Q4) * 100 
• 
Presenteesism: Percent impairment while working due to CDAD = Q5/10 *100 
• 
Work productivity loss: Percent overall work impairment due to  
CDAD = Q2/(Q2+Q4) + [(1-Q2/(Q2+Q4)) * (Q5/10)] * 100 
• 
Activity Impairment: Percent activity impairment due to CDAD Q6/10 * 100 
11.1.4.5 Pharmacokinetic variables 
Cadazolid plasma concentration 2 h post-dose at Visit 3.  
11.1.4.6 Re-treatment extension with cadazolid variables 
Variables for the re-treatment extension with cadazolid will be defined in the same way 
as for the corresponding variables defined for the treatment and follow-up periods of the 
randomized blinded part of the study and will be defined and fully described in the SAP.  
11.2 Analysis sets 
The following analysis sets are defined. 
11.2.1 Screened analysis set (SCRAS) 
This analysis set includes all subjects screened even if they were not eligible. 
11.2.2 Full analysis set (FAS) 
The Full analysis set (FAS) includes all subjects allocated to a study treatment based on 
the randomization-assigned treatment.  
11.2.3 Modified intent-to-treat (mITT) analysis set  
The mITT analysis set includes subjects in the FAS who received at least one dose of 
study drug and had a confirmed diagnosis of CDAD; i.e., 
• > 3 UBMs in the 24 h prior to randomization. 
• Positive GDH and toxin test (EIA approved by the sponsor) on the same stool sample 
produced in the 72 h (48 h for MTFs) period prior to randomization. 
It is based on the randomization-assigned treatment.  
11.2.4 Per-protocol analysis set (PPS) 
The PPS comprises all subjects from the mITT analysis set without major protocol 
violations or conditions that might affect the evaluation of the effect of the study drug on 


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the primary endpoint. The following conditions will lead to the exclusion of a subject 
from the PP analysis: 
At study entry: 
• More than one previous episode of CDAD in the 3-month period prior to 
randomization 
• Fulminant or life threatening CDAD 
• Concurrent immediately life-threatening disease or condition 
• History of inflammatory colitides, chronic abdominal pain, or chronic diarrhea, or 
known positive diagnostic test for enteropathogens 
• Antimicrobial treatment active against CDAD > 24 h (except for MTFs) 
• Any investigational drug to prevent or treat CDAD 
During study: 
• Any prohibited concomitant medication, except treatment with antimicrobial 
medication active against CDAD or FMT or any investigational therapy to treat 
CDAD after randomization and up to and including 2 days after EOT [see 
Section 5.2] 
• Insufficient course of therapy: Subjects classified as a Clinical Failure with less than 
6 doses of cadazolid or 12 doses of vancomycin. Subjects classified as a Clinical 
Cure with less than 16 doses of cadazolid or 32 doses of vancomycin 
• Received study treatment differed from randomized study treatment 
• Subject was unblinded before Database Lock 
• Insufficient information to determine Clinical Cure 
• Positive diagnostic test for enteropathogens during treatment period. 
It is estimated that approximately 15% of the randomized subjects will not be part of the 
PPS.  
11.2.5 Hypervirulent analysis set (HVAS) 
The Hypervirulent analysis set (HVAS) includes subjects in the mITT analysis set who 
are confirmed with CDAD due to a hypervirulent strain at baseline. 
11.2.6 PRO analysis set (PROAS) 
The PRO analysis set includes subjects in the mITT analysis set who have signed the ICF 
themselves. It is based on the assigned treatment rather than the actual received 
treatment.  


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11.2.7 Safety set (SS) 
The Safety Set (SS) includes all randomized subjects who received at least one dose of 
study drug, based on the actual treatment received.  
11.2.8 Re-treatment extension with cadazolid Set (ES) 
The Re-treatment extension with cadazolid set (ES) includes all subjects enrolled in the 
re-treatment extension and received at least one dose of open-label cadazolid.  
11.2.9 Pharmacokinetic analysis set (PKS) 
This analysis set comprises all subjects who provide an evaluable plasma cadazolid 
concentration (quantifiable or BLQ) at approximately 2 h post-dose on Day 8–10 
(Visit 3). 
11.2.10 Role of the different analysis sets 
Subject disposition and study completion/discontinuation, including reason for screening 
failure, will be summarized for the SCRAS. Protocol violations, baseline demographic 
and disease characteristics, and previous/concomitant medications, will be summarized in 
the FAS. 
The main analysis of NI for the primary variable will be performed on the PPS and on the 
mITT. All other efficacy analyses will be performed on the mITT analysis set. The 
analysis of relevant secondary endpoints may be repeated on the PPS for sensitivity. 
The HVAS will be used in the meta-analysis, described in Section 11.4. The SS will be 
used for the analyses of the safety variables and treatment exposure.  
Analyses of variables based on the CDAD symptoms diary will be performed on the 
PROAS (excluding subjects who participate in the PRO sub-study). Analyses of 
WPAI:CDAD questionnaire will be performed on the PROAS. Analyses of endpoints for 
the extension treatment will be performed on the ES. Analyses of pharmacokinetic 
endpoints will be analyzed on the PKS.  
Listings will be prepared on the FAS, unless specified otherwise.  
11.2.11 Randomization and stratification 
Approximately 630 subjects will be randomized 1:1 to the 2 treatment groups 
(315 cadazolid and 315 vancomycin), to ensure that at least 536 subjects will be available 
in the PPS and 598 in the mITT analysis set. Randomization will be stratified on CDAD 
first occurrence or first recurrence and on study site, using the IVRS system. 


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11.3 Description of statistical analyses 
11.3.1 General considerations 
• Unblinding of study drug code for the data analysis will occur after database closure 
in accordance with Actelion SOPs. 
• The experimentwise significance level will be controlled at the overall two-sided 
α = 0.05 
• Covariates will include stratification factor first occurrence and first recurrence and 
geographical region. It is anticipated that the number of subjects enrolled at some 
sites may be small. Therefore the sites will be pooled considering geographical 
region, pooling first according to country of the site. Countries may be further 
combined according to geographical region to ensure sufficient patients in each strata 
for the analyses. Regions may include North America, South America, Western 
Europe, Eastern Europe, Asia. Details for the pooling of sites will be defined in the 
SAP. Other covariates/subgroups to be explored include the following anthropometric 
and baseline characteristics: sex, race, age category, baseline frequency of UBMs, 
in-patient status, initial severity of the disease, prior antimicrobial treatment active 
against CDAD, and initial strain of CDAD (hypervirulent or not). 
• AEs and medical history will be coded according to MedDRA dictionary (Version 16 
or more recent version if available). Concomitant medications will be coded 
according to the WHO drug code and the anatomic therapeutic chemical (ATC) class 
code (Version 01Mar2010 or later). 
• SAS version 9.2 or higher will be used for all the statistical analysis.  
• All analysis variables will be listed and presented in tables; variables to be presented 
in figures will be specified in the SAP. 
• Data will be listed and summarized by appropriate descriptive statistics (tables or 
figures), typically including: 
− Number of non-missing observations, number of missing observations, mean, 
standard deviation (SD), minimum, Q1, median, Q3 and maximum for continuous 
variables 
− Number of events, number of censored observations and Kaplan-Meier estimates 
of the survival function will be provided for time-to-event variables.  
− Number of non-missing observations, number of missing observations and 
frequency with percentage per category (percentages based on the sum of number 
of non-missing observations and total number of observations) for categorical 
variables.  
− For susceptibility data: Number of non-missing observations, number of missing 
observations, geometric mean, median (MIC50), 90% quantile (MIC90), 
minimum, maximum.  


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Absolute changes from baseline are defined as: post-baseline value minus baseline value, 
i.e., a positive sign indicates an increase as compared to baseline. 
A percentage change from baseline is defined as the absolute change from baseline 
divided by the baseline value (if the baseline value > 0) and then multiplied by 100. 
For susceptibility (MIC) endpoints change from baseline is defined as: post-baseline 
value divided by baseline value. 
Handling of dropouts and missing data 
This section describes the concepts to be used. Further details for handling of missing 
data and missing dates and times will be described in the SAP. Additional imputations 
methods may be specified in the SAP to assess sensitivity of analyses to the imputation 
methods used. 
In general, summaries and analyses will be based upon observed data i.e., without 
imputation of missing values; exceptions to this rule for the most important variables are 
described below. 
• Clinical Cure 
In case of death for any cause, or lost to follow-up, or study withdrawal prior to EOT + 2 
days, the subject is considered a Clinical Failure.  
• Sustained Cure 
In case of death for any cause, study withdrawal or lost to follow-up from EOT + 3 days 
and prior to EOT + 28 days, the subject is considered not a Sustained Cure.  
11.3.2 Analysis of subject disposition and study completion / withdrawal 
The number and percentage of subjects in the different analysis sets will be summarized 
and listed together with reasons for exclusion from the relevant set. The number and 
percentage of subjects screened, entered and who completed the study or withdrew 
prematurely (by reason of withdrawal) will be presented in tables and listings. Summaries 
will be presented by treatment group and overall for the SCRAS. Similarly, number and 
percentage of subjects receiving extension treatment will be presented. 
11.3.3 Analysis of the primary variable 
11.3.3.1 Hypotheses and statistical inference 
The objective of the study is met if it is demonstrated that the CCR for cadazolid (CCRc) 
is not inferior to the CCR for vancomycin (CCRv), accounting for a NI margin of 10%. 
The justification of the choice of 10% a NI margin is detailed in Appendix 7. 


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The main analysis will be done on the mITT analysis set and on the PPS: NI must be 
shown in the mITT analysis set and in the PPS to claim NI of cadazolid versus 
vancomycin. A one-sided 0.025 significance level is applied in both analysis sets. 
The null hypothesis is: 
H0(1): CCRc − CCRv ≤ −10%, 
and the alternative:  
 
H1(1): CCRc − CCRv > −10%. 
If the lower bound of a two-sided 95% CI of the difference between proportions is greater 
than −10%, the NI of cadazolid versus vancomycin for Clinical Cure will be 
demonstrated.  
The NI assessment on the mITT analysis set and the PPS will compose the first part of 
the hierarchical testing procedure [Figure 3]. 
11.3.3.2 Statistical model 
No statistical model is defined – the analysis is based on the CI of the crude difference in 
proportions. 
11.3.3.3 Main analysis 
The main analysis is carried out as described in Section 11.3.3.1. The CCR will be 
summarized per treatment group. Two-sided 95% confidence intervals (CIs) for the 
difference of cure rates will be estimated using the Wilson’s Score method for the 
difference of proportions [Newcombe 1998].  
The main analysis will be conducted on the mITT analysis set and the PPS. 
Imputation methods for the substitution of incomplete, missing, or potentially biased data 
are defined in Section 11.3.1, but will be more detailed in the SAP. 
11.3.3.4 Supportive/sensitivity analyses 
A stratified Cochran-Mantel-Haenszel analysis will be applied as supportive analysis 
stratified by first occurrence and first recurrence (IVRS) and geographical region based 
on the PPS and mITT analysis set. For the average risk difference the 
Cochran-Mantel-Haenszel estimate and corresponding CI will be derived using normal 
approximation.  
Consistency of results on CCR will be explored over different subgroups defined by 
anthropometric and baseline characteristics: first occurrence and first recurrence (IVRS), 
geographical region, sex, race, age category, baseline frequency of UBMs, in-patient 
status, initial severity of the disease, presence of prior antimicrobial treatment active 
against CDAD and initial strain of CDAD (hypervirulent or not).  
The CCR will be summarized by treatment group per subgroup with 95% CIs for the 
difference of cure rates estimated using the Wilson’s Score method [Newcombe 1998]. 


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For each anthropometric and baseline characteristic a logistic regression will be applied 
on the CCR, including the treatment group, the baseline characteristic and the interaction 
of both of them. Treatment effects in each subgroup will be reported with odds ratios 
(cadazolid/vancomycin) and 95% CI for each baseline characteristic together with the 
overall treatment effect and 95% CI, and will be presented in a Forest plot [Cuzick 2005]. 
An exploratory test for the interaction will be performed at two-sided α = 0.1.  
Any additional sensitivity analyses of the CCR will be specified in the SAP. 
11.3.4 Analysis of the secondary variables 
11.3.4.1 Sequential test strategy for secondary variables 
The analyses of the secondary analyses will be performed by implementing a hierarchical 
strategy to control the experimentwise α level [Dmitrienko 2010] as displayed in Figure 3 
with overall two-sided α = 0.05. The secondary efficacy endpoints will be tested in a 
sequential conditional manner, starting with SCR. 
Figure 3 
Hierarchical testing strategy 
Overall two-sided α = 0.05 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCR = Clinical Cure Rate; SCR = Sustained Cure Rate; ROD = Resolution of Diarrhea; 
S(t) = ROD survival function; CHG(t) = Change from BL in CDAD DaySyms Score;  
PPS = Per-protocol analysis set; mITT = modified intent-to-treat; PROAS = PRO 
analysis set. 
Change from BL in CDAD DaySyms score superiority (PROAS) 
H0(4): CHGc(t) = CHGv(t) vs H1(4): CHGc(t) ≠ CHGv(t)   
 
α 
 
SCR superiority (mITT) 
H0(2): SCRc − SCRv = 0 vs H1(2): SCRc − SCRv ≠ 0       
 
α 
Time to ROD superiority (mITT) 
H0(3): Sc(t) = Sv(t) vs H1(3): Sc(t) ≠ Sv(t)           
 
 
α 
 
CCR non-inferiority (PPS and mITT) 
H0(1): CCRc − CCRv ≤ −10% vs H1(1): CCRc − CCRv > −10%  
α 


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11.3.4.2 Hypotheses and statistical inference 
If NI for CCR is demonstrated in both PPS and mITT analysis set, the SCR will be 
hierarchically tested on the mITT analysis set at the two-sided alpha 0.05 (equivalent to 
one-sided test with alpha of 0.025).  
The null hypothesis is:  
H0(2): SCRc – SCRv = 0%,  
and the alternative:   
H1(2): SCRc – SCRv ≠ 0% 
If the lower limit of the two-sided 95% CI is greater than zero, the statistical superiority 
of cadazolid versus vancomycin in SCR will be claimed.  
If superiority of SCR is demonstrated in the mITT analysis set, the superiority of the 
secondary endpoints Time to ROD and change from baseline in CDAD DaySyms PRO 
total daily score up to Day 12 will be hierarchically tested respectively on the mITT 
analysis set and the PROAS, at the same two-sided alpha 0.05.  
For testing time to ROD the null hypothesis is: H0: Sc(t) = Sv(t) and the alternative is H1: 
Sc(t) ≠ Sv(t), where S(t) denotes the survival function.  
For testing change from baseline in CDAD DaySyms PRO score up to Day 12 the null 
hypothesis is: H0: CHGc(t) = CHGv(t) and the alternative is H1: CHGc(t) ≠ CHGv(t). 
11.3.4.3 Analysis for secondary variables 
The analyses for the secondary variables will be conducted for the mITT analysis set.  
The CI for the difference in SCR [as defined in Section 11.1.2.1] will be estimated using 
the Wilson’s score method for difference in proportions. The SCR will be summarized by 
treatment group per subgroup with 95% CIs for the difference of cure rates estimated 
using same methods and subgroups as for the main analysis.  
Additional exploratory subgroup analysis will be conducted using logistic regression as 
specified for the primary variable.  
In the hypervirulent subgroup SCR will be assessed in a meta-analysis involving studies 
AC-061A301 and AC-061A302 [see Section 11.4]. 
Analysis of Time to ROD will be conducted using a two-sided stratified log-rank test, 
including the strata first occurrence and first recurrence and geographical region. 
Kaplan-Meier estimates for the survival functions will be provided. Sensitivity analysis 
will be conducted using a stratified Cox proportional hazards model adjusting for 
covariates, Covariates as specified above will be used with first occurrence and first 
recurrence and geographical region following strata assignation from the IVRS.  


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Analysis on absolute (and percent) change from baseline in CDAD DaySyms PRO total 
daily score up to Day 12 will be conducted using the PROAS (excluding subjects who 
participate in the PRO sub-study) based on a general mixed ANCOVA model for 
repeated measurements modeling the absolute change from baseline in CDAD DaySyms 
PRO total daily scores using all available data. The model will include fixed effects terms 
for treatment and time and the interaction between treatment and time, the baseline 
CDAD DaySyms PRO total score as a covariate, and random effects of between subjects 
(within treatment) and within subjects (residual). Comparison between cadazolid and 
vancomycin will be made up to Day 12.  
As the psychometric validation of the CDAD DaySyms PRO is ongoing further 
refinements of the analysis will be required and other analyses may be specified after 
completion of the validation process. Appropriate methods will be further detailed in the 
statistical analysis plan.  
Frequency of subjects that needed antimicrobial treatment active against CDAD or FMT 
between first dose of study drug and EOT + 2 days, will be summarized by treatment 
arm. Similar summaries will be prepared for the frequency of subjects that required these 
kind of medications between EOT + 3 days and Visit 5 or participated in the cadazolid 
re-treatment extension. 
Imputation methods for the substitution of incomplete, missing, or potentially biased data 
are defined in Section 11.3.1.  
11.3.4.4 Supportive/sensitivity analyses of Sustained Cure  
A sensitivity analysis of the SCR variable as defined in Section 11.1.2.1 will be 
performed on the PPS.  
In addition, an exploratory analysis of Sustained Cure using a modified definition of 
recurrence will be performed, where modified recurrence is defined independently of a 
C. difficile stool GDH and toxin test for subjects with Clinical Cure as: 
• NED (> 3 UBMs on any day between 3 days after EOT and Visit 5) 
AND 
• Antimicrobial treatment active against CDAD (including participation in the 
re-treatment extension with cadazolid) or FMT started between 3 days after EOT and 
Visit 5). 
Subjects with Clinical Cure but without modified recurrence are considered a Modified 
Sustained Cure. All other rules, including the handling of dropouts as specified for the 
variable SCR [Section 11.1.2.1 and 11.3.1] will apply to this modified SCR. The 


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statistical analysis for this modified SCR will be performed on the mITT analyses set 
using the same methods as specified for SCR. 
Any additional sensitivity analyses of the SCR will be specified in the SAP. 
11.3.4.5 Analysis of the other efficacy variables 
Analysis for the exploratory variables will be conducted for the mITT analysis set unless 
otherwise specified. 
ICRR (%) will be analyzed in the PPS and mITT analysis set, using the same null 
hypothesis and statistical methods as for the statistical analysis of primary efficacy 
endpoint. 
ISRR (%) will be analyzed, in the mITT analysis set, using the same null hypothesis and 
statistical methods as for the statistical analysis of SCR. 
RR (%) will be analyzed in an exploratory manner, to support the reduction in recurrence 
indirectly demonstrated after showing NI on CCR and superiority on SCR. 
All the different cure rates (ICRR, ISRR, RR, NBMR, and ECCR) will be summarized 
per treatment arm. 95% CIs for the difference of cure rates will be estimated using the 
Wilson’s Score method [Newcombe 1998].  
Time to return to usual stools will be estimated by Kaplan-Meier. Time to recurrence will 
be estimated by Kaplan-Meier based on subjects clinically cured only. 
Susceptibility test results for C. difficile isolates at baseline and post-baseline visits will 
be summarized with descriptive statistics including MIC range, MIC50, MIC90, and the 
frequency of isolates at each MIC test concentration for each test agent.  
VRE counts at baseline and Visit 3, as well as changes from baseline to Visit 3 VRE 
counts, will be summarized with descriptive statistics. 
Susceptibility test results for vancomycin-resistant E. faecium and vancomycin-resistant 
E. faecalis isolates at Visit 1 and Visit 3 will be summarized including MIC range, 
MIC50, MIC90, and the frequency of isolates at each MIC test concentration for each test 
agent. 
Efficacy endpoints for the extension treatment period will be summarized on the ES, 
using descriptive statistics and frequencies, overall, and by the randomized treatment 
group. 
All other exploratory efficacy endpoints will be summarized using descriptive statistics 
using the mITT analysis set. 


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11.3.5 Analysis of the safety variables 
The Safety analysis set will be used to perform all safety analyses. All safety data will be 
included in listings, with flags for quantitative abnormalities. 
11.3.5.1 Adverse events 
All AEs will be coded using MedDRA Version 16 or higher. TEAEs and treatment 
emergent SAEs up to 7 days after last dose of study drug will be tabulated by study 
treatment, System Organ Class (SOC) and preferred terms within each SOC: number and 
percentage of subjects who experienced (S)AEs coded with the same preferred term will 
be displayed. (S)AEs will also be tabulated by maximum intensity and relationship to 
investigational drug or comparator. 
AEs and SAEs from first dose up to Visit 5 will be summarized by treatment group, SOC 
and preferred terms within SOC. AEs leading to premature discontinuation of study 
treatment will be summarized in similar manner.  
Re-treatment extension-emergent AEs and SAEs (occurring during the re-treatment 
extension with cadazolid) will be summarized with similar tables, and based on the ES. 
Listings will be provided for all reported AEs, including SAEs. In addition, separate 
listings will be provided for SAEs, for AEs leading to premature discontinuation of study 
drug, and for AEs leading to death. 
11.3.5.2 Deaths  
AEs with outcome death will be summarized in a similar manner as described for SAEs, 
for TEAEs up to 7 days and separately for AEs up to Visit 5.  
All deaths will be summarized separated into deaths from first dose to EOT + 7 days, and 
deaths from first dose of study drug until Visit 5. Listings of all deaths will be provided. 
11.3.5.3 Vital signs  
Descriptive summary statistics by visit and study treatment will be provided for observed 
values and absolute changes from baseline in SBP, DBP, HR, body temperature and body 
weight. The number of subjects with at least one marked abnormality up to EOT + 7 days 
(treatment-emergent) and up to Visit 5 will be summarized. Treatment-emergent 
abnormality is defined as an abnormality post first dose study drug not present at 
baseline. Marked abnormalities are defined in Appendix 4. 
11.3.5.4 ECGs 
Descriptive summary statistics by visit and study treatment will be provided for observed 
values and absolute changes from baseline in numeric 12-lead ECG values (HR, PR, 
QRS, QT, QT corrected for HR on the basis of Bazett’s formula [QTcB], QT corrected 


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for HR on the basis of Fridericia’s formula [QTcF]). The number of subjects with at least 
one marked QT or QTc abnormality up to EOT + 7 days (treatment-emergent) and up to 
Visit 5 will be summarized. Treatment-emergent abnormality is defined as an 
abnormality post first dose study drug not present at baseline. Marked abnormalities are 
defined in Appendix 4. 
The number of subjects with abnormal ECG findings not present prior to start of 
treatment will be summarized. 
11.3.5.5 Hematology, coagulation and chemistry 
Descriptive summary statistics by visit and study treatment will be provided for observed 
values and absolute changes from baseline for laboratory tests (hematology, chemistry). 
Data will be displayed in Standardized International (SI) units as provided by the Central 
Laboratory. If any local laboratories are used with different normal ranges, then the 
values and their normal ranges will be normalized using the Central Laboratory values as 
a reference, and this will be detailed in the SAP. 
The number of subjects with at least one treatment-emergent abnormality and the number 
of subjects with at least one marked abnormality up to EOT + 7 days 
(treatment-emergent) and up to Visit 5 will be summarized. Treatment-emergent 
abnormality is defined as an abnormality post-first dose of study drug not present at 
baseline. 
Treatment-emergent laboratory test abnormalities will be assessed according to the 
normal ranges. Marked abnormalities are defined in Appendix 4. 
11.3.6 Analysis of other variables 
Pharmacoeconomic hospitalization variables will be summarized with descriptive 
statistics in the mITT analysis set. Variables related to the WPAI:CDAD questionnaire 
will be summarized using descriptive statistics on the PROAS. 
Cadazolid 2 h post-dose plasma concentrations at Visit 3 will be summarized using 
descriptive statistics (arithmetic mean, 95% CI of the arithmetic mean, minimum, 
maximum, median, SD, standard error (SE), and if the data allows geometric mean and 
95% CI of the geometric mean).  
11.3.7 Exposure to study drug 
The duration of exposure and mean daily dose will be tabulated using the usual location 
and scale statistics by treatment group. Compliance will be tabulated using the usual 
location and scale statistics by treatment group and separately for sachets and capsules. 
The cumulative distribution of exposure time by different class intervals (e.g., at least 


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1 day, etc.) will be tabulated to show the number and percentage of subjects in each class 
interval.  
11.3.8 Demographic and baseline characteristics 
Summaries for demographic and baseline characteristics will be performed on the FAS, 
PPS and the mITT analysis set. The variables country, sex, age categories, BMI, 
ethnicity, race, disease severity, prior antimicrobial treatment active against CDAD, 
first occurrence / first recurrence, and initial strain of CDAD (hypervirulent or not), 
in-patient at randomization, baseline frequency of UBMs, concomitant treatment with 
opiates at baseline, concomitant antibiotics for infections other than CDAD, concomitant 
treatment with PPIs will be summarized per treatment group, overall, and also only for 
the subjects presenting Clinical Cure.  
Previous and concomitant medications will be coded according to the WHO drug code 
and the ATC class code, and summarized by tabulating the number and percentages of 
subjects having received each treatment. 
Summaries of concomitant medications will also be presented separately for concomitant 
medications according to antimicrobial treatment active against CDAD, concomitant 
antibiotics for infections other than CDAD and concomitant treatment with PPIs. 
Medical history will be coded using MedDRA and summarized in a similar manner to 
AEs. 
Protocol deviations will be listed and summarized by treatment group and type of 
deviation. 
11.4 Meta-analysis 
A meta-analysis of trials AC-061A301 and AC-061A302 will be performed to assess the 
superiority of cadazolid for the SCR in the hypervirulent subgroup. The analysis will be 
performed if NI in Clinical Cure and superiority in Sustained Cure was demonstrated in 
the whole mITT analysis set within both individual trials.  
The null hypothesis is: 
H0(3): SCRc – SCRv = 0%,  
and the alternative:  
 
H1(3): SCRc – SCRv ≠ 0% 
Superiority of Sustained Cure in the hypervirulent subgroup is assessed using a 
fixed-effect meta-analysis combining the risk difference estimates from both individual 
trials using the HVAS. The analysis will be stratified by trial. A CI is derived and 
superiority test performed based on normal approximation. A separate SAP will be 
prepared for this analysis. 


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11.5 Interim analyses 
No interim analysis is planned.  
11.6 Sample size 
Approximately 630 subjects will be randomized 1:1 to the 2 treatment groups 
(315 cadazolid and 315 vancomycin).  
11.6.1 Sample size justification 
Assuming a CCR of 85% for cadazolid and vancomycin treatment groups, a power of 
90%, a type I error of 2.5% (one-sided) and an NI margin of 10%, a total sample size of 
536 (268 in each treatment group) evaluable subjects is required. Taking into account 
approximately 15% subjects not qualifying for the PPS and approximately 5% not 
qualifying for the mITT analysis set, a total of approximately 630 subjects will be 
randomized into the trial. 
Assuming 598 subjects in the mITT analysis set (approximately 95% of the randomized 
subjects) and the same assumptions on CCR as for the PPS, the power for showing NI in 
clinical cure on the mITT analysis set is 93%. The probability to be successful in both 
analysis sets is approximately 89% under the assumption of 90% of the subjects in the 
mITT analysis set qualifying for the PPS. The power for showing superiority of cadazolid 
versus vancomycin in SCR on the mITT analysis set will be 98%, with a difference in 
SCR of at least 15%, and 88% with a difference of 12%, assuming the SCRv is 60%, and 
a two-sided type I error of 0.05. The above results are derived independently of the 
primary variable and are conditional on reaching this step in the hierarchical testing 
strategy. 
It is estimated that 25% of the subjects would present a hypervirulent strain. Thus, the 
pooled analysis would be based on approximately 300 evaluable subjects (150 from each 
trial) in the mITT analysis set.  
The power for showing a superiority of at least 15% in SCR, cadazolid versus 
vancomycin, in the hypervirulent subgroup, with two-sided type I error of 0.05, is 
approximately 80%, assuming a SCR of 60% in the vancomycin group. The above results 
are derived independently of the primary and secondary variable and are conditional on 
reaching this step in the hierarchical testing strategy. 
11.6.2 Sample size sensitivity 
With a fixed sample size of 536 (268 per treatment group) the power for showing NI 
depends on the assumed CCR in the vancomycin group. Table 4 displays power 
calculations for different assumptions for the CCRs for vancomycin with equally large 
CCR in the cadazolid group, one-sided type I error of 0.025, NI margin of 10% and 
sample size of 536 as estimated for the PPS. With CCRs ranging from 80–90% the 


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resulting power ranges from 82–97%. A table like this one for the mITT analysis set 
would show, using the same assumptions, a range of estimated power slightly higher than 
for the PPS due to the higher number of subjects. Similarly, the probability to be 
successful in both the mITT analysis set and the PPS will range from approximately 
81–97% depending on the actual CCR rate in both populations. 
Table 4 
Sample size sensitivity for main analysis (PPS) 
Scenario 
CCRv  
(%) 
CCRc 
(%) 
Power 
(%) 
1 
90.0 
90.0 
97 
2 
87.5 
87.5 
94 
3 
82.5 
82.5 
86 
4 
80.0 
80.0 
82 
CCRc = clinical cure rate for cadazolid, CCRv = clinical cure rate for vancomycin, PPS = Per-protocol analysis set. 
 
Similarly, with fixed sample size, the power for showing superiority of cadazolid versus 
vancomycin in SCR depends on the SCR in the vancomycin group (SCRv) and the 
difference between the SCR in the treatment groups. Table 5 displays the power for 
showing superiority in SCR of cadazolid versus vancomycin with a fixed sample size of 
598 in the mITT analysis set, and a two-sided type I error of 5%.  
Table 5 
Sample size sensitivity for secondary variable Sustained Cure Rate 
Scenario 
SCRv  
(%) 
SCRc–SCRv 
(%) 
Power 
(%) 
1 
65.0 
15.0 
99 
2 
55.0 
15.0 
97 
3 
65.0 
12.0 
90 
4 
55.0 
12.0 
86 
SCRc = sustained cure rate cadazolid, SCRv = sustained cure rate vancomycin. 
 
11.6.3 Sample size re-estimation 
No sample size re-estimation is planned. 


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12 DATA HANDLING 
12.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness, 
legibility and timeliness of the data reported. All source documents should be completed 
in a neat, legible manner to ensure accurate interpretation of the data. Data reported in the 
electronic CRF derived from source documents must be consistent with the source 
documents. 
CRF data will be captured via electronic data capture (using the Rave system provided by 
Medidata Solutions, Inc., a web-based tool). The investigator and site staff will be trained 
to enter and edit the data via a secure network, with secure access features (username, 
password and identification – an electronic password system). A complete electronic 
audit trail will be maintained. The investigator/delegate will approve the data (i.e., 
confirm the accuracy of the data recorded) using an electronic signature (ref. to 
21 CFR Part 11). 
Entries recorded on paper (e.g., stool diary) by a subject are considered source data. The 
site staff will review and ensure completeness and readability of a subject’s entries 
recorded on paper. The site will also ensure that if any information allowing subject’s 
identification is written on the paper(s) collected, that it will not be visible when copies of 
the source data are provided to the sponsor for entry into the clinical trial database. 
Subject screening and enrollment data will be completed for all subjects (i.e., eligible and 
non-eligible) through the IVRS system and CRF. 
For each subject screened, regardless of randomization or study drug initiation, a CRF 
must be completed and signed by the investigator/delegate. This also applies to those 
subjects who fail to complete the study. If a subject withdraws from the study or 
discontinues treatment prematurely, then the reason must be noted on the CRF. 
12.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On CRFs or 
other documents submitted to Actelion, subjects must be identified only by number, and 
never by name. The investigator/delegate must keep a subject identification code list, at 
the site, showing the randomization number, the subject’s name, date of birth and address 
or any other locally accepted identifiers. Documents identifying the subjects (e.g., signed 
ICFs) must not be sent to Actelion, and must be kept in strict confidence by the 
investigator/delegate. 


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12.3 Database management and quality control 
Electronic CRFs will be used for all subjects. The investigator will have access to the site 
CRF data throughout the study. The CRF must be kept current to reflect subject status at 
any time point during the course of the study (i.e., the data should be entered in the 
system within 10 days of the subject’s visit/assessment completion). 
While entering the data, the investigator/delegate will be prompted by logical 
checks/error messages built into the web-based data entry screening performed on the 
data. Other protocol-specific validation programs will run routinely to perform more 
extensive data checks for accuracy and completeness. Additional data review will be 
processed in parallel by the sponsor to look for unexpected patterns in data and study 
monitoring. In the event that problematic data are detected, a query specifying the 
problem and requesting clarification will be issued and visible to the investigator/delegate 
via the CRF, so that the investigator/delegate can respond and clarify directly onto the 
CRF.  
The investigator/delegate must, on request, supply Actelion with any required 
background data from the study documentation or clinical records. This is particularly 
important when errors in data transcription are suspected. In the case of health authority 
queries, it is also necessary to have access to the complete study records, provided that 
subject confidentiality is protected. 
This process will continue until database closure. 
Laboratory samples will be processed through a central laboratory and specialist 
microbiology labs and the results will be sent electronically to Actelion. 
Data from local ECGs and local laboratories will be entered into the database by site staff 
(except in the case of ECG read by 
, where data will be transferred electronically to 
Actelion), and subject PRO data will be entered into the database by data management 
using double data entry. Data from the PK sub-study will be transferred electronically to 
Actelion following the database closure of both the AC-061A301 and AC-061A302 
studies. 
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate Actelion SOP. At the end of the trial, the investigator will receive the CRF of 
the subjects of her/his site (including all data changes made) on a CD-ROM or as a paper 
copy. 


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13 PROCEDURES AND GOOD CLINICAL PRACTICE 
13.1 Ethics and Good Clinical Practice 
The sponsor and investigators will ensure that the study is conducted in full compliance 
with ICH-GCP Guidelines, the principles of the ‘Declaration of Helsinki’ and with the 
laws and regulations of the country in which the research is conducted.  
13.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document provided to the 
subject (such as Subject Information Leaflet used to obtain informed consent) to an IRB 
or IEC. Approval from the committee must be obtained before starting the study, and 
must be documented in a dated letter to the investigator, clearly identifying the study, the 
documents reviewed, and the date of approval.  
Modifications made to the protocol after receipt of the approval must also be submitted as 
amendments by the investigator to the IRB/IEC in accordance with local procedures and 
regulations [see Section 13.6]. 
A list of members participating in the meeting must be provided, including the names, 
qualifications and functions of these members. If that is not possible, the attempts made 
to obtain this information along with an explanation as to why it cannot be obtained or 
disclosed must be documented in the study documentation. If a study staff member was 
present during a meeting, it must be clear that this person did not vote. 
13.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according 
to ICH-GCP guidelines and local regulations from each individual participating in this 
study and/or legally authorized representative. The investigator/delegate must explain to 
subjects that they are completely free to refuse to enter the study, or to withdraw from it 
at any time for any reason. 
The ICF will be provided in the country local language(s). 
Site staff authorized to participate in the consent process and/or to obtain consent from 
the subject and/or legal representative will be listed on Actelion Delegation of Authority 
form. A study physician must always be involved in and have oversight of the informed 
consent process.  
In sites participating in the cadazolid plasma concentration sub-study, the subject will 
have to consent to the study and will have the opportunity to consent to participating in 
the sub-study. A separate independent consent will also be needed for participation in the 
re-treatment extension study with cadazolid at the time of a NED.  


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At sites where the sponsor-approved EIA is not standard of care for the diagnosis of 
CDAD, a two-part ICF may be used: Section A covering the use of the subjects’ stool 
sample to perform the sponsor-approved EIA, and Section B covering enrollment into the 
study. The subject and/or legally authorized representative must sign, personally date and 
time (if appropriate) the ICF before any study-related procedures (i.e., any procedures 
required by the protocol) begin. If a study-specific procedure or assessment has been 
performed as part of routine assessments, meets the protocol requirements, and the results 
are available prior to the signing of the ICF, such procedure or assessment may be used to 
assess eligibility and does not have to be repeated. In such cases, it must be clear from the 
source document when and for which reason the assessment was done prior to the signing 
of the informed consent. The ICF must also be signed, personally dated and timed (if 
appropriate) by the authorized site staff listed on Actelion Delegation of Authority form. 
A copy of the signed and dated ICF is given to the subject and/or legally authorized 
representative; the original is filed in the site documentation.  
The informed consent process must be fully documented in the subject’s medical records, 
including study reference, subject number, date/time (if applicable) when the subject was 
first introduced to the Actelion clinical study, date/time (if applicable) of consent, who 
participated in the consent discussion, who consented the subject and any additional 
person present during the consent process (e.g., subject family member), copy of the 
signed ICF given to the subject/legally authorized representative. 
The subject is also given a clinical study participant card to provide information to 
medical personnel and/or health care professionals that the subject is participating in a 
clinical trial – who to contact to receive more information about the trial, and how this 
person can be reached. 
In the event that the site would like to recruit a subject who cannot read or does not 
speak or understand the ICF language, additional measures must be implemented in order 
to ensure subject rights are respected and the consent obtained is legally valid. The 
sponsor, the regulatory authorities (if applicable) and the IRB/IEC must be informed 
prior to the recruitment. The consent process (e.g., involvement of an impartial witness) 
must be fully described, submitted to, and approved by the IRB/IEC, according to 
procedures.  
The informed consent process must proceed as follows:  
• A physician investigator participates in and has oversight of the informed consent 
process (i.e., introduction of the study and consent process) 
• A physician answers medical questions, questions regarding alternatives to therapy or 
any other questions from the subject. 


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• A physician or delegated advance practice role discusses trial procedures and risks. 
• A physician or delegated advance practice role answers non-medical questions. 
• A physician or delegated advance practice role performs source documentation of the 
consent. 
• Before the subject signs the ICF, a physician verifies with the subject that all 
questions have been answered. 
13.4 Compensation to subjects and investigators 
The sponsor provides insurance in order to indemnify (with both legal and financial 
coverage) the investigator/site against claims arising from the study, except for claims 
that arise from malpractice and/or negligence. 
The compensation of the subject in the event of study-related injuries will comply with 
applicable regulations. 
13.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the approved version of the 
protocol and must not implement any violation/deviation/change from the protocol, 
except when the change involves only logistical or administrative aspects (e.g., change in 
telephone number), or in case it would be necessary to eliminate an immediate hazard to 
the subject.  
If a protocol violation occurs, the investigator/delegate will inform Actelion or its 
representative, in a timely manner. The investigator/delegate must document in the CRF 
and in the subject’s file and explain any violation/deviation/change from the approved 
protocol. Protocol violation/deviation/change must also be submitted to IRB/IEC and to 
the regulatory authority(ies), according to their requirements.  
13.6 Protocol amendment 
Any change to the protocol can only be made through a written protocol amendment 
approved by Actelion. A protocol amendment must be submitted in a timely manner (no 
more than 30 calendar days after receipt) to IRB/IEC, and regulatory authority(ies), 
according to their requirements.  
Approval must be obtained before any change can be implemented, except when the 
change involves only logistical or administrative aspects (e.g., change in telephone 
number), or in case it would be necessary to eliminate an immediate hazard to the 
subject; in this case. IRB/IEC and regulatory authority(ies) must be notified as soon as 
possible, according to their requirements, but not later than 15 calendar days. 


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13.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the 
reconstruction and evaluation of the study. A number of attributes are considered of 
universal importance to source data and the records that hold those data. These include 
that the data and records are accurate, legible, contemporaneous, original (or certified 
copy), attributable, complete, consistent, enduring and available when needed.  
These records are to be classified into two different categories of documents: 
investigator’s file, and subject clinical source documents.  
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’s requirements (e.g., as specified in the clinical study agreement), and national 
and/or international regulations, whichever would be the longest period. If the 
investigator cannot guarantee this archiving requirement at the investigational site for any 
or all of the documents, special arrangements, respecting the data confidentiality, must be 
made between the investigator and Actelion to store these documents outside the site, so 
that they can be retrieved in case of a regulatory inspection. No study document should 
be destroyed without prior written approval from Actelion. Should the investigator wish 
to assign the study records to another party, or move them to another location, Actelion 
must be notified in advance.  
Documentation of study assessments must be available in the subject medical records 
(e.g., vital signs, physical examination), including the screening procedures/assessment 
prior to enrollment. 
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 
or equivalent standard) and if the monitor has been provided personal access to verify 
consistency between electronic source data and the CRF during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the monitor could not be 
provided access to the system, the site is requested to print the complete set of source 
data needed for verification by the monitor. The print-outs must be signed and dated by 
the investigator/delegate to confirm that these certified copies are exact copies with the 
same information as the original subject’s data. The print-outs will be considered as the 
official clinical study records. In order to verify that the process the site uses to prepare 
certified copies is reliable, the monitor must be able to observe this process and confirm 
that the comparison of the source documents and the certified copy did not reveal 
inconsistencies. The monitor does not need to verify this process for all data of all 
subjects, but at least for some of them (e.g., first subject; regular check during the study 
of critical data like inclusion/exclusion criteria, endpoints for some subjects) as per 


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Actelion’s instructions. If it is not possible for the monitor to observe this process, then it 
is not possible to rely on the site’s certified copies, and therefore the site cannot be used 
for the clinical study. The printouts should be filed either with the subject medical 
records or with the subject’s CRF. 
13.8 Equipment considerations and quality requirements 
Documentation should be made available to the monitor and any potential auditor to 
verify the qualification of equipment or physical devices used to perform study 
tasks. This includes thermometers in areas where study drug is stored, freezers that store 
lab samples, and/or equipment such as ECG machines, scales, etc. used for study 
assessments. This documentation could include validation or calibration certificates and 
freezer logs, and should be filed in the ISF. It is the responsibility of the investigational 
site to maintain these documents. Only certified/calibrated equipment or validated 
systems should be used. 
13.9 Monitoring 
The monitor will contact and visit the investigational site regularly, and on request must 
be permitted to have access to trial facilities and all source documents needed to verify 
adherence to the protocol and the completeness, consistency and accuracy of the data 
being entered on the CRFs and other protocol-related documents. Actelion monitoring 
standards require full verification that informed consent has been provided, and 
verification of adherence to the inclusion/exclusion criteria, documentation of SAEs, and 
the recording of the main efficacy, safety and tolerability endpoints; this includes 
verification that source documentation relevant to the study (e.g., safety events) is 
reported in the CRFs. Additional checks of the consistency of the source data with the 
CRFs will be performed according to the study-specific monitoring plan. 
The required site personnel must be available during monitoring visits and allow 
adequate time to meet with the monitor to discuss study related issues. An initiation visit 
will be performed after the required essential documents are received at Actelion and 
before the first subject is included in the study. Monitoring visits will be conducted 
regularly; frequency will be based on subject recruitment rate and critical data collection 
times. A close-out visit will be performed for any initiated site. 
The investigator agrees to cooperate with the monitor(s) to ensure that any issues 
detected in the course of these monitoring visits are resolved. If the subject is hospitalized 
or dies in a hospital other than the study site, the investigator is responsible for contacting 
that hospital in order to document the SAE. 


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13.10 Audit  
Actelion’s Global Quality Management representative may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine 
the investigator’s adherence to ICH-GCP, the protocol, applicable regulations, and the 
sponsor’s requirements (e.g., SOPs). Prior to initiating this audit, the investigator will be 
contacted by Actelion to arrange a convenient time for the audit.  
The investigator and staff must cooperate with the auditor(s) and allow access to all study 
documentation (e.g., subject records) and facilities. 
13.11 Inspections 
Health authorities and/or IRB/IEC may also wish to conduct an inspection of Actelion’s 
clinical study (during the study or after its completion).  
Should an inspection be requested by a health authority and/or IRB/IEC, the investigator 
must inform Actelion immediately (usually via the monitor) that such a request has been 
made.  
The investigator and staff must cooperate with inspector(s) and allow access to all study 
documentation (e.g., subject records) and study facilities. 
13.12 Reporting of study results and publication  
Study results will be documented in a clinical study report that will be signed by Actelion 
representatives and the Coordinating Investigator. 
The coordinating investigator and the Steering Committee, will have the opportunity to 
review the analysis of the data and to discuss the interpretation of the study results with 
the sponsor prior to publication. 
Actelion will post results from Phase 2–4 clinical studies on Actelion’s Clinical Trial 
Register, and on external/national registries, as required by law. 
In accordance with the Good Publication Practices and ethical practice, the results of the 
study will be submitted for publication in a peer-reviewed journal. Investigators shall not 
publish data from an individual study center until after the results of the multicenter 
center are published. Study results can be submitted for presentation at a congress before 
publication in a peer-reviewed journal. 
Authorship will be determined in accordance with the International Committee of Journal 
Editors criteria, and be based on: 
• Substantial contributions to the conception and design, or acquisition of data, or 
analysis and interpretation of data  


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• Drafting of the publication or critical review for important intellectual content 
• Providing final approval of the version to be published. 
The list of authors of any publication of study results may include representatives of 
Actelion, and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted 
to Actelion for review at least 30 days prior to submission for publication or presentation. 
Upon review, Actelion may provide comments, and may also request alterations and/or 
deletions for the sole purpose of protecting its confidential information and/or patent 
rights. Neither the institution nor the investigator should permit publication during such a 
review period. 
Actelion’s Policy on Scientific Publications can be found at: 
 


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between binomial proportions based on paired data. Statistics in Medicine 
1998;17(22): 2635–50. 
[O’Brien 2007] O’Brien JA, Lahue BJ, Caro JJ, Davidson DM. The emerging infectious 
challenge of Clostridium difficile-associated disease in Massachusetts hospitals: 
clinical and economic consequences. Infect Control Hosp Epidemiol. 2007; 
Nov;28(11):1219-27. 
[Pachecho 2013] Pachecho SM, Johnson S. Important clinical advances in the 
understanding 
of 
Clostridium 
difficile 
infection. 
Curr 
Opin 
Gastroenterol. 2013 Jan;29(1):42–8. 
[Poutanen 2004] Poutanen SM, Simor AE. Clostridium difficile-associated diarrhea in 
adults. CMAJ 2004;171(1):51–8. 
[Reilly 1993] Reilly MC, Zbrozek AS, Dukes E. The validity and reproducibility of a 
work productivity and activity impairment measure. PharmacoEconomics 1993; 
4(5):353–65. 
[Tannock 2010] Tannock GW, Young W, Munro K, Byrne B, Taylor C, Emery J, et al. A 
new macrocyclic antibiotic, fidaxomicin (OPT80), causes less alteration to the 
bowel microbiota of Clostridium difficile-infected patients than does vancomycin. 
Microbiology 2010;156, 3354–59. 
[Vancomycin USPI] VANCOCIN® (Vancomycin hydrochloride capsules, USP). Package 
Insert. ViroPharma Incorporated [accessed on 2013 Aug 29]. Available from 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/050606s028lbl.pdf 
[Voelker 2010] Voelker R. Increased Clostridium difficile Virulence Demands New 
Treatment Approach. JAMA 2010 May;303(20)20:2017–19. 


Cadazolid/ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
Version 3 
22 October 2015, page 121/138 
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EudraCT: 2013-002528-17 
Doc No D-15.418 
 
 
[Weiss 2009] Weiss K. Toxin-binding treatment for Clostridium difficile: a review 
including reports of studies with tolevamer. Int J Antimicrob Agents. 2009;33(1): 
4-7. 
[Wilcox 1995] Wilcox MH, Howe R. Diarrhoea caused by Clostridium difficile: response 
time for treatment with metronidazole and vancomycin. J Antimicrob 
Chemother. 1995 Oct;36(4):673–9. 
[Zar 2007] Zar FA, Bakkanagari SR, Moorthi KMLST, Davis MB. A Comparison of 
Vancomycin 
and 
Metronidazole 
for 
the 
Treatment 
of 
Clostridium 
difﬁcile-Associated Diarrhea, Stratiﬁed by Disease Severity. Clinical Infectious 
Diseases 2007;45:302–7. 


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Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
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Doc No D-15.418 
 
 
Appendix 1 
Equivalence between opiates  
By convention, for this study, the following equivalence will be used: 
Drug 
Route 
Equianalgesic dose 
(mg) 
Duration 
(h) 
Morphine 
IM/IV/SC 
10 
3-4 
Morphine 
PO 
20-30 
3-6 
Codeine 
IM 
130 
4-6 
Codeine 
PO 
200 
4-6 
Oxycodone 
PO 
15-20 
3-6 
Hydrocodone 
PO 
30 
4-8 
Oxymorphone 
IM/IV/SC 
1 
3-6 
Oxymorphone 
PO 
15 
- 
Hydromorphone 
IM/IV/SC 
1.5 
3-4 
Hydromorphone 
PO 
7.5 
3-6 
Levorphanol 
IM/IV/SC 
2 
4-8 
Levorphanol 
PO 
4 
4-8 
Meperidine 
IM/IV 
75 
3-5 
Meperidine 
PO 
300 
3-5 
Methadone 
IM/IV/SC 
10* 
6-8 
Methadone 
PO 
20 
4-6 
Fentanyl 
IV/SC 
0.1 
0.5-1 IV; 1-2 SC 
Buprenorphine 
IV/IM 
0.3–0.4 
6 
Buprenorphine 
patch 
5–10 microgram 
7 days 
*Extremely variable with chronic dosing; e.g., conversion from oral morphine to oral methadone may range from 4 to 14:1. 


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Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
Version 3 
22 October 2015, page 123/138 
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Appendix 2 
Stool diary 
 


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Clostridium difficile-associated diarrhea 
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Appendix 3 
CDAD DaySyms PRO 
 
Instructions: These questions ask about symptoms you may have each day. Please 
complete the daily diary at about the same time every evening. 
 
For each symptom listed below, mark with an X the box that best describes the worst 
severity of that symptom during the past 24 hours. Please be sure to answer each 
question. 
 
 
None 
Mild 
Moderate 
Severe 
Very 
Severe 
1. 
Diarrhea 
 
 
 
 
 
2. 
Feeling that you needed to empty 
your bowels right away 
 
 
 
 
 
3. 
Needing to go to the bathroom 
more  
than usual 
 
 
 
 
 
4. 
Passing gas (flatulence) 
 
 
 
 
 
5. 
Abdominal cramping 
 
 
 
 
 
6. 
Abdominal pain 
 
 
 
 
 
7. 
Feeling bloated (feeling like you 
need to loosen your clothes) 
 
 
 
 
 
8. 
Feeling tired 
 
 
 
 
 
9 
Lack of Energy 
 
 
 
 
 
10. Lightheadedness 
 
 
 
 
 
11. Dizziness 
 
 
 
 
 
12. Lack of appetite 
 
 
 
 
 
13. Nausea 
 
 
 
 
 
  
 


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Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
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Appendix 4 
Definitions of marked abnormalities for safety parameters 
The following abnormalities are based on the Common Terminology Criteria for Adverse 
Events (CTCAE v4.03) – if a new version becomes available this is not implemented in 
the ongoing study but will be implemented in the following studies or in the Summary of 
Clinical Safety. Hematology, coagulation and chemistry abnormal values are defined 
based on the normal ranges from the Central Laboratory [Appendix 5].  
An abnormality is considered treatment-emergent if it was not present at baseline and if a 
worsening occurred, i.e., a shift from normal or to a higher abnormality category, as 
compared to the corresponding value at baseline. 
Safety Parameter 
LL 
LLL 
HH 
HHH 
Hematology 
 
Hemoglobin (g/L) 
< 100 
< 80 
Increase in 
(> 20 g/L) above 
ULN or above 
baseline if baseline 
is above ULN 
Increase in (> 40 g/L) 
above ULN or above 
baseline if baseline is 
above ULN 
Hematocrit (%) 
< 28% F 
< 32% M 
< 20% 
> 60% M 
> 55% F 
> 65% 
Platelet count (109 /L) < 75  
< 50 
> 600 
> 999 
Neutrophils (109 /L)  
< 1.5  
< 1.0 
 
 
Eosinophils (109 /L)  
 
 
> 5.0 
 
Lymphocyte (109 /L) 
< 0.8 
< 0.5 
> 4.9 
> 20 
WBC count (109 /L) 
< 3.0 
< 2.0 
> 20.0 
> 100.0 
Coagulation 
 
INR 
 
 
> 1.5 × ULN or  
> 1.5 × above 
baseline 
if on 
anticoagulation 
> 2.5 × ULN or 
> 2.5 × above baseline 
if on anticoagulation 
Chemistry 
 
AST (U/L) 
 
 
> 3 ULN 
> 5 ULN 
ALT (U/L) 
 
 
> 3 ULN 
> 5 ULN 
Alkaline phosphatase 
(U/L) 
 
 
> 2.5 ULN 
>5 ULN 
Total bilirubin 
(umol/L) 
 
 
> 2 ULN  
> 5 ULN 
Creatinine (umol/L) 
 
 
> 1.5 ULN or  
1.5 × baseline 
> 3 ULN or  
3.0 × baseline 
Albumin (g/L) 
< 30  
< 20 
 
 
Calcium (mmol/L) 
< 2.0  
< 1.75 
> 2.9 
> 3.1 


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Clostridium difficile-associated diarrhea 
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Potassium (mmol/L) 
< 3.2 
< 3.0 
> 5.5 
> 6.0 
Sodium (mmol/L) 
 
< 130 
> 150  
> 155  
Vital signs 
 
 
 
 
SBP (mmHg) 
SBP < 90  
or 
decrease 
> 20 from 
baseline 
 
SBP 140–159 
or 
increase > 20 from 
baseline 
SBP ≥ 160 
DBP (mmHg) 
DBP < 50  
or 
decrease 
> 10 from 
baseline 
 
DBP 90–99 
or 
increase > 10 from 
baseline 
DBP ≥ 100 
ECG 
 
 
 
 
QT, QTc (msec) 
(absolute) 
 
 
> 450 (H) 
> 480 (HH) 
 
> 500 
QT, QTc (msec) 
(change) 
 
 
> 30  
> 60 
 


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Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
Version 3 
22 October 2015, page 127/138 
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Doc No D-15.418 
 
 
Appendix 5 
Central Laboratory Normal Reference Ranges 
“The ranges below are valid at the time of protocol finalization. Any changes to these 
ranges during the course of the study will be reflected in the ranges displayed in the 
laboratory reports sent from the Central Laboratory to the investigational sites.” 
 
Parameter 
Sex 
Unit 
Normal Range 
Low 
High 
Hematology 
Hemoglobin 
M 
g/L 
130 
175 
F 
g/L 
115 
160 
Hematocrit 
M 
L/L 
0.416 
0.541 
F 
L/L 
0.364 
0.489 
Platelets 
M/F 
^109/L 
130 
400 
Erythrocytes 
M 
^1012/L 
4.50 
5.90 
F 
^1012/L 
3.80 
5.20 
Leukocytes  
M/F 
^109/L 
4.5 
11.0 
Absolute Neutrophil Count 
M/F 
^109/L 
1.8 
7.7 
Absolute Lymphocyte Count 
M/F 
^109/L 
1.0 
4.8 
Absolute Monocyte Count 
M/F 
^109/L 
0.1 
0.8 
Absolute Eosinophil Count 
M/F 
^109/L 
0.0 
0.5 
Absolute Basophil Count 
M/F 
^109/L 
0.0 
0.2 
Coagulation (Frozen Plasma) 
Protime  
M/F 
seconds 
9.4 
11.4 
INR  
M/F 
N/A 
0.90 
1.10 
aPTT  
M/F 
seconds 
24.0 
33.0 
Blood chemistry 
Aspartate aminotransferase (AST) 
M 
U/L 
14 
39 
F 
U/L 
14 
34 
Alanine aminotransferase (ALT) 
M 
U/L 
0 
44 
F 
U/L 
0 
33 
Alkaline phosphatase 
M 
U/L 
53 
129 
F 
U/L 
42 
98 


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Clostridium difficile-associated diarrhea 
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Bilirubin, total 
M/F 
umol/L 
5.1 
20.5 
Bilirubin, direct 
M/F 
umol/L 
0.0 
5.1 
Calcium 
M/F 
mmol/L 
2.15 
2.55 
Creatinine 
M 
umol/L 
62 
115 
F 
umol/L 
44 
97 
Urea 
M/F 
mmol/L 
3.2 
8.2 
Sodium 
M/F 
mmol/L 
136 
145 
Potassium 
M/F 
mmol/L 
3.5 
5.1 
Chloride 
M/F 
mmol/L 
99 
109 
Protein 
M/F 
g/L 
64 
83 
Albumin 
M/F 
g/L 
35 
52 
 


Cadazolid/ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
Version 3 
22 October 2015, page 129/138 
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Doc No D-15.418 
 
 
Appendix 6 
Work Productivity and Activity Impairment Questionnaire  
 
Clostridium difficile-associated diarrhea V2.0 (WPAI:CDAD) 
 
The following questions ask about the effect of your Clostridium difficile-associated 
diarrhea on your ability to work and perform regular activities. Please fill in the blanks or 
circle a number, as indicated. 
 
1. Are you currently employed (working for pay)?  _____ NO 
___ 
YES 
If NO, check ‘NO’ and skip to Question 6. 
 
The next questions are about the past seven days, not including today. 
 
2. During the past seven days, how many hours did you miss from work because of 
problems associated with your Clostridium-difficile associated diarrhea?  
Include hours you missed on sick days, times you went in late, left early, etc., because 
of your Clostridium-difficile associated diarrhea. Do not include time you missed to 
participate in this study. 
_____HOURS 
 
3. During the past seven days, how many hours did you miss from work because of any 
other reason, such as vacation, holidays, time off to participate in this study? 
 
_____HOURS 
 
4. During the past seven days, how many hours did you actually work? 
 
_____HOURS  
If ‘0’, skip to Question 6. 
 


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Clostridium difficile-associated diarrhea 
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Doc No D-15.418 
 
 
5. During the past seven days, how much did your Clostridium difficile-associated 
diarrhea affect your productivity while you were working?  
 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully 
as usual. If Clostridium difficile-associated diarrhea affected your work only a little, 
choose a low number. Choose a high number if Clostridium difficile-associated diarrhea 
affected your work a great deal.  
Consider only how much Clostridium difficile-associated diarrhea affected  
productivity while you were working. 
Clostridium 
difficile-associated 
diarrhea had no 
effect on my work 
 
 
 
 
 
 
 
 
 
 
 
Clostridium 
difficile-associated 
diarrhea completely 
prevented me from 
working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 


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Clostridium difficile-associated diarrhea 
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CIRCLE A NUMBER 
6. During the past seven days, how much did your Clostridium difficile-associated 
diarrhea affect your ability to do your regular daily activities, other than work at a 
job?  
 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like. If Clostridium difficile-associated diarrhea affected your 
activities only a little, choose a low number. Choose a high number if 
Clostridium difficile-associated diarrhea affected your activities a great deal.  
 
Consider only how much Clostridium-difficile associated diarrhea affected your 
ability to do your regular daily activities, other than work at a job. 
Clostridium-
difficile 
associated 
diarrhea had no 
effect on my 
daily activities 
 
 
 
 
 
 
 
 
 
 
 
Clostridium-
difficile associated 
diarrhea 
completely 
prevented me from 
doing my daily 
activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
WPAI:CDAD V2.0 (US English)  
[Reilly 1993] 


Cadazolid/ACT-179811 
Clostridium difficile-associated diarrhea 
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Version 3 
22 October 2015, page 132/138 
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Doc No D-15.418 
 
 
Appendix 7 
Justification of the non-inferiority margin 
Historical evidence to estimate the treatment effect of vancomycin against placebo is 
obtained from the results of two large randomized, double-blind, and controlled studies 
demonstrating the superiority of vancomycin over tolevamer [Louie 2007, Bouza 2008, 
Weiss 2009]. The cadazolid studies will be conducted in a similar population as the 
studies on tolevamer and the recently conducted studies to compare fidaxomicin versus 
vancomycin. Therefore, a similar 10% NI margin is justified and is consistent with the 
draft FDA Guidance for Industry Non-Inferiority Clinical Trials (Draft, March 2010), and 
the Center for Drug Evaluation and Research document as Statistical Review for the new 
drug application (NDA) of fidaxomicin (Application 201699Orig1s000). 
The FDA has used the results of these two trials to estimate vancomycin’s treatment 
effect while considering tolevamer as putative placebo. In the Statistical Review that the 
FDA has performed on the fidaxomicin Phase 3 results, additional analyses were 
performed on the two fidaxomicin trials 303 and 304, on publications by Louie  
[Louie 2006, Louie 2007], Bouza [Bouza 2008], and Weiss [Weiss 2009] and using the 
summary of the trials in clinicaltrials.gov. It included also a discussion of similarities and 
differences between the historical trials and current trials as well as a discussion of 
evidence from vancomycin placebo trials. Based on these results, the FDA considered the 
NI margin of 10% for the fidaxomicin trial as acceptable. 
The treatment effect of vancomycin was estimated based on the data from two pivotal 
trials comparing vancomycin to tolevamer and showing the superiority of vancomycin 
over tolevamer. 
Table 1 
Summary of clinical success rate of historical trials (from Louie 
[Louie 2007] and Bouza [Bouza 2008]): Intent-to-Treat analysis 1 
Study  Agent 
Clinical Cure rate  
Treatment Difference 
(95% CI)2 
Number of subjects cured/Total 
% 
301 
Tolevamer  
124/266 
46.4
4 
 
Vancomycin 
109/134 
80.7
4 
35% 
(25%, 43%) 
302 
Tolevamer  
112/268  
41.6
4 
 
Vancomycin 
101/125  
80.1
6 
39% 
(29%, 47%) 
1. Intent-to-Treat Set: includes all randomly assigned patients who received at least 1 dose of study drug, with any 
post-dosing Investigator Evaluation data. 
2. Confidence interval was derived using method recommended in Newcombe 1998 and Agresti 2000. 
CI = confidence interval. 
 


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Clostridium difficile-associated diarrhea 
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Results from the Phase 3 fidaxomicin studies and the recently completed Actelion 
Phase 2 cadazolid study (AC-061A201) support an unchanged effect of vancomycin 
across studies and time. No decrease in the efficacy of vancomycin as measured by the 
clinical cure was observed and in the Phase 2 study. In this study, cadazolid had in the 
250 mg treatment arm a higher rate of clinical cure than vancomycin on the modified 
clinical cure endpoint, which is the endpoint with the most similar definition to the 
primary endpoint used in the fidaxomicin pivotal studies.  
Table 2 
Summary of Clinical Cure rates of cadazolid and historical trials: 
mITT analysis set.  
Study  
Agent 
Clinical Cure Rate 
Treatment 
Difference 
(95% CI) 
Number of subjects 
cured / 
Total 
% 
Cure Rate 
Fidaxomicin 003 
Fidaxomicin 
255/289 
88.2 
 
Vancomycin 
258/307 
84.0 
4.2% 
(−1.4%, 9.7%) 
Cure Rate 
Fidaxomicin 004 
Fidaxomicin 
217/253 
85.8 
 
Vancomycin 
219/256 
85.5 
0.2% 
(−5.9%, 6.4%) 
Modified Cure Rate  
Cadazolid AC-061201  
Cadazolid 250 mg 
BID 
16/17 
94.1 
 
Vancomycin 
125 mg QID 
19/22 
86.4 
 
BID = twice daily; CI = confidence interval; QID = four times daily. 


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Clostridium difficile-associated diarrhea 
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The cadazolid studies will be conducted on very similar patient population to the 
fidoxamicin and the tolevamer trials, and under very similar experimental conditions. 
Important design features, including patient populations, concomitant medications, and 
endpoint assessment, for establishing the constancy assumption are outlined and 
compared in Table 3. 
Importantly, overall design characteristics are similar with all studies being international 
randomized, double-blind studies with vancomycin as the active comparator at a dose of 
125 mg every 6 hours for 10 days. All studies are contemporaneous, having been 
conducted after 2005 when the epidemic hypervirulent strain 027 was identified in North 
America. One minor difference in the primary endpoint assessment is the Actelion’s use 
of an objective, programmatic assessment of clinical cure at EOT + 2 days as opposed to 
a more subjective clinician reported outcome used in the other trials.  
Table 3 
Comparison of current studies to historical studies 
Studies 
Tolevamer 
Fidaxomicin 
Cadazolid 
AC-061A301/302 
Overall study 
design 
Randomized, double-
blind, parallel groups. 
Randomized, double-blind, 
parallel groups. 
Randomized, double-blind, 
parallel groups. 
Number of sites, 
countries 
Study 301: 91 sites in the 
US and Canada. 
Study 302: 135 sites in 
Australia, Canada, and 
Europe.  
Study 003: 75 sites in the 
US, 23 sites in Canada. 
Study 004: 30 sites  
in the US, 11 sites in 
Canada, 45 sites in Europe. 
For each study: up to 100 
centers in up to 
20 countries (planned) 
among: 
AUS, AUT, BEL, BGR, 
CAN, CHE, CHN, DEU, 
DNK, ESP, FIN, FRA, 
GBR, HUN, ITA, MEX, 
NZL, POL, ROU, SWE, 
USA. 
Treatment arms 
Vancomycin 
Tolevamer Metronidazole 
Vancomycin 
Fidaxomicin 
Vancomycin  
Cadazolid 
Randomization 
scheme 
1:2:1  
1:1  
1:1  
Total number of 
subjects 
1420 (ITT) 
1105 (mITT) 
Approximately 1280 
subjects randomized. 
Start date- 
end date  
301: March 2005 to 
February 2007. 
302: May 2005 to August 
2007.  
003: 9 May 2006 to 
21 August 2008. 
004: 19 April 2007 to 
11 December 2009. 
3rd Quarter 2013. 
4th Quarter 2015. 
Duration of 
treatment 
10 days 
10 days  
10 days  
Assessments 
Daily Assessments 
Daily Assessments 
Daily Assessments 
Test of Cure 
Day 10 
EOT to Day 12 
EOT + 2 days 


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Clostridium difficile-associated diarrhea 
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Definition of 
Clinical Cure 
Resolution of diarrhea 
(not defined in detail) and 
absence of severe 
abdominal discomfort due 
to CDAD for 2 contiguous 
days including Day 10.  
- Subjects who, in the 
opinion of the Investigator, 
require no further CDAD 
therapy 2 days after 
completion of study 
medication. 
- Subjects who have 3 or 
fewer unformed stools for 
2 consecutive days and 
remain well prior to the 
time of study medication 
discontinuation. 
- Subjects who at EOT 
have had a marked 
reduction in the number of 
unformed stools and who 
have residual and mild 
abdominal discomfort 
interpreted as recovering 
bowel, providing no new 
antiinfective CDAD 
therapy has been initiated.  
- Resolution of Diarrhea 
ROD  
(≤ 3 UBMs per day for at 
least 2 consecutive days) 
on study treatment and 
maintained for 2 days after 
EOT). 
 
Inclusion criteria 
- Adult patients 
- Acute CDAD (mild, 
moderate, or severe),  
+ Mild: 3–5 bowel 
movements per day, WBC 
less or equal to 1500/mm3 
and no abdominal pain, 
+ Moderate: 6–9 bowel 
movements per day, WBC 
1501–20000/mm3 and no, 
mild or moderate 
abdominal pain, 
+ Severe: 10 or more 
bowel movements per 
day, WBC greater or equal 
to 20001/mm3 
 and severe abdominal 
pain. 
- 1st occurrence or 
recurrent. 
- Male or female 
≥ 16 years  
- CDAD (> 3 UBMs 
within 24 hours and 
positive C. difficile toxin 
A/B test within 48 hours of 
randomization for 
metronidazole failures, or 
within 96 hours of 
randomization for subjects 
with ≤ 24 hours 
pretreatment of CDAD). 
- 1st occurrence or 
1st recurrence within 
3 months.  
- Subjects meeting CDAD 
criteria after at least a full 
3 day course of 
metronidazole. 
- Male or female 
≥ 18 years  
- CDAD (> 3 UBMs 
within 24 hours and 
positive C. difficile toxin 
A/B test within 72 hours). 
- 1st occurrence or 1st 
recurrence within 
3 months.  
- Subjects meeting CDAD 
criteria (with a positive test 
within 48 hours) after at 
least 72 hours of treatment 
with metronidazole (MTF). 


Cadazolid/ACT-179811 
Clostridium difficile-associated diarrhea 
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Doc No D-15.418 
 
 
Exclusion criteria 
Not known 
- Life-threatening or 
fulminant CDAD,  
+ septic shock,  
+ peritoneal signs,  
+ significant dehydration, 
+ systolic blood pressure < 
90mmHg, 
 + WBC count > 30000 
/mm3, 
+ body temperature 
> 40 °C. 
- Toxic megacolon. 
- Likelihood of death 
within 72 hours from any 
cause. 
- History of ulcerative 
colitis or Crohn’s disease. 
- No more than 24 hours of 
treatment with 
metronidazole and/or 
vancomycin.  
- Opiates are permitted as 
needed (PRN) as long as 
subjects taking them are on 
stable doses at the time of 
randomization and 
expected to maintain these 
doses during the treatment 
period. 
- The anticipated need to 
continue other 
antibacterials for a period 
exceeding 7 days. 
- Subjects who, in the 
opinion of the investigator, 
require other drugs to 
control diarrhea 
(e.g., loperamide) or drugs 
that could affect 
peristalsis.  
- Participation in other 
clinical research studies 
utilizing an investigational 
agent within 1 month 
- Fulminant or 
life-threatening CDAD, 
+ septic shock,  
+ peritonitis,  
+ significant dehydration,  
+ systolic blood pressure < 
90mmHg,  
+ WBC count > 
30000/mm3,  
+ body temperature 
> 40 °C, 
+ ileus,  
+ toxic megacolon. 
- Concurrent 
life-threatening disease or 
condition (likelihood of 
death within 72 hours). 
- History of ulcerative 
colitis, microscopic colitis 
or Crohn’s disease, chronic 
abdominal pain or chronic 
diarrhea of any etiology. 
- History of total 
colectomy. 
- Vomiting, inability to 
take oral medication 
(subjects with feeding 
tubes are excluded). 
- Antimicrobial treatment 
active on CDAD 
> 24 hours for the current 
episode, except MTF. 
- Planned treatment with 
prohibited concomitant 
medications: 
+ cholestyramine, fecal 
transplant, probiotics until 
Visit 5, 
+ Initiation or change in 
dose or regimen resulting 
in an increased opiate 
effect up to TOC, 
+ Anti-peristaltic 
medications, kaolin, pectin 
or charcoal-containing 


Cadazolid/ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
Version 3 
22 October 2015, page 137/138 
Confidential  
EudraCT: 2013-002528-17 
Doc No D-15.418 
 
 
before screening or within 
5 half-lives of the 
investigational agent, 
whichever was longer.  
- Previous exposure to 
fidaxomicin. 
- Subjects the investigator 
believes are inappropriate 
for the trial, e.g., subjects 
with known 
hypersensitivity to 
vancomycin. 
anti-diarrheals until EOS. 
- Fecal transplant, 
treatment with 
immunoglobulin or another 
investigational drug within 
1 month. 
- Treatment with 
monoclonal antibodies 
against Clostridium 
difficile within 6 months.  
- Investigational 
vaccination against 
Clostridium difficile. 
- Previous participation in 
a clinical trial with 
cadazolid. 
- Known hypersensitivity 
or contraindication to any 
excipients of the 
investigational drug 
formulation, to an 
oxazolidinone, a quinolone 
or to vancomycin. 
CDAD = clostridium difficile-associated diarrhea; EOS = end-of-study; EOT = end-of-treatment;  
ITT = intent-to-treat; mITT = modified intent-to-treat; MTF = metronidazole treatment failure; PRN = pro 
re nata (as necessary); ROD = resolution of diarrhea; TOC = test-of-cure; UBM = unformed bowel 
movement; WBC = white blood cell. 
As it is assumed that tolevamer response rates are similar to and no worse than placebo, 
the estimated treatment effect of vancomycin versus tolevamer presents a conservative 
estimate of the treatment effect of vancomycin versus placebo in case of a small 
treatment effect of tolevamer.  
A meta-analysis of the results using the DerSimonian and Laird approach (random effect 
model) gives an estimate of the vancomycin treatment effect of 37% with 95% CI of 
(30%, 43%). 
To account for the uncertainties in the constancy assumption, the lower CI of the 
vancomycin treatment effect estimate from the tolevamer meta-analysis of 30% is 
discounted by 10%, resulting in an estimate for the vancomycin treatment effect of 
M1 = 27% (M1 defined as the entire effect of active control assumed to be present in the 
study, see FDA 2010) . The proposed NI-margin M2 is 10% which is generally 
considered clinically acceptable to show non-inferiority in antibacterial trials (M2 is 
defined as the largest clinically acceptable difference of test drug compared to active 


Cadazolid/ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A301 
Version 3 
22 October 2015, page 138/138 
Confidential  
EudraCT: 2013-002528-17 
Doc No D-15.418 
 
 
control, see FDA 2010). This still preserves at least 60% (17%/27% = 63.0%) of the 
vancomycin treatment effect of 27%. In addition, the true treatment effect of vancomycin 
versus placebo is probably larger than the estimate, since tolevamer may have some 
limited clinical benefit. 
Therefore, taking into account all the above consideration, the proposed NI margin of 
10% will preserve more than 60% of the treatment effect of vancomycin, which is the 
minimal recommendation in [FDA 2010]. 
 

SAP_000.pdf: 
STATISTICAL ANALYSIS PLAN 
FOR CLINICAL STUDY REPORT 
AC-061A301 / AC-061A302 
Two multi-center, randomized, double-blind studies to compare the efficacy 
and safety of cadazolid versus vancomycin in subjects with 
Clostridium difficile-associated diarrhea (CDAD) 
Purpose of Analysis 
Clinical Study Report 
Investigational Drug 
Cadazolid 
NCT Numbers 
NCT01987895 & NCT01983683 
Protocol Numbers 
AC-061A301 / AC-061A302 
Document Status / Version Number 
Final Version 3 
Date 
19 May 2017 
Confidential 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or 
otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd. 


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TABLE OF CONTENTS 
1 
INTRODUCTION .......................................................................................................13 
2 
STUDY DESIGN AND FLOW ..................................................................................14 
2.1 
Study design .................................................................................................14 
2.2 
Study visit and assessment schedule ............................................................16 
3 
OBJECTIVES .............................................................................................................19 
3.1 
Primary objective ..........................................................................................19 
3.2 
Secondary objectives ....................................................................................19 
3.3 
Other objectives ............................................................................................19 
3.3.1 
Objective of the meta-analysis of AC-061A301 and 
AC-061A302 .....................................................................................19 
3.3.2 
Exploratory objective ........................................................................19 
3.3.3 
Safety objective .................................................................................19 
3.3.4 
Objective of the re-treatment extension with cadazolid ...................19 
4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................20 
4.1 
Changes related to PRO validation ...............................................................20 
4.2 
Changes to the analyses planned in the study protocol ................................20 
4.3 
Changes in the conduct of the study / data collection ..................................21 
4.3.1 
Clarification on wording ...................................................................21 
5 
DEFINITIONS OF VARIABLES ..............................................................................21 
5.1 
Screening failures .........................................................................................22 
5.1.1 
Unmet eligibility criteria ...................................................................22 
5.2 
Subject characteristics ..................................................................................23 
5.2.1 
Demographics ...................................................................................23 
5.2.2 
Baseline disease characteristics ........................................................23 
5.2.3 
Other baseline characteristics ...........................................................25 
5.2.4 
Medical history .................................................................................26 
5.2.5 
Previous and concomitant therapies .................................................27 
5.2.5.1 
Previous therapies .................................................................... 27 
5.2.5.2 
Study concomitant therapies ................................................... 27 
5.2.5.3 
Specific therapies .................................................................... 27 
5.2.6 
Procedures .........................................................................................29 
5.2.6.1 
Concomitant procedures .......................................................... 30 
5.2.6.2 
Endoscopy and imaging since first dose of study drug ........... 30 


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5.3 
Study treatment exposure and compliance ...................................................30 
5.3.1 
Exposure ...........................................................................................30 
5.3.2 
Compliance with study treatment .....................................................32 
5.3.3 
Study treatment discontinuation .......................................................32 
5.3.4 
Study treatment interruptions ............................................................32 
5.4 
Study withdrawal ..........................................................................................33 
5.5 
Efficacy variables .........................................................................................33 
5.5.1 
Primary efficacy variable: Clinical Cure ..........................................33 
5.5.1.1 
Derivation details .................................................................... 34 
5.5.1.2 
Clinical Failure ........................................................................ 36 
5.5.2 
Secondary efficacy variables ............................................................37 
5.5.2.1 
Sustained Cure ......................................................................... 37 
5.5.2.2 
Time to ROD ........................................................................... 44 
5.5.2.3 
Change from baseline in CDI-DaySyms PRO domain 
scores at Day 3 ........................................................................ 44 
5.5.3 
Other efficacy variables ....................................................................45 
5.5.3.1 
Investigator’s assessment of Early Treatment Response 
at Visit 2 .................................................................................. 45 
5.5.3.2 
Investigator’s judgment of Clinical Response at Visit 4 ......... 45 
5.5.3.3 
Investigator’s evaluation of Clinical Cure per protocol 
definition ................................................................................. 46 
5.5.3.4 
Investigator’s judgment of Sustained Response at Visit 5 ...... 46 
5.5.3.5 
Investigator’s evaluation of Sustained Cure per protocol 
definition ................................................................................. 46 
5.5.3.6 
Early Clinical Cure by Day 5 .................................................. 46 
5.5.3.7 
Normalization of bowel movements rate ................................ 46 
5.5.3.8 
Time to return to usual stools .................................................. 47 
5.5.3.9 
Recurrence rate and adjusted recurrence rate .......................... 47 
5.5.3.10 
Time to recurrence ................................................................... 48 
5.5.3.11 
Modified Sustained Cure ......................................................... 49 
5.5.3.12 
CDI-DaySyms PRO response rate at Day 3 ............................ 49 
5.5.4 
Microbiology variables .....................................................................49 
5.5.4.1 
Isolation of C. difficile ............................................................ 50 
5.5.4.2 
Typing of C. difficile ............................................................... 51 
5.5.4.3 
Susceptibility of C. difficile .................................................... 52 
5.5.4.4 
Change from baseline in susceptibility of C. difficile ............. 53 
5.5.4.5 
Isolation of vancomycin-resistant enterococci ........................ 54 
5.5.4.6 
Vancomycin-resistant enterococci quantitative culture .......... 55 
5.5.4.7 
Change from baseline in vancomycin-resistant 
enterococci quantitative culture at Visit 3 ............................... 55 


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5.5.4.8 
Susceptibility of vancomycin-resistant enterococci to 
different antibiotics .................................................................. 55 
5.5.5 
Re-treatment extension variables ......................................................56 
5.6 
Safety variables .............................................................................................56 
5.6.1 
Adverse events ..................................................................................57 
5.6.1.1 
Frequency of treatment-emergent adverse events ................... 58 
5.6.1.2 
Intensity of adverse events ...................................................... 58 
5.6.1.3 
Relationship of adverse events ................................................ 58 
5.6.2 
Deaths ...............................................................................................58 
5.6.2.1 
All deaths ................................................................................. 58 
5.6.2.2 
Adverse events with fatal outcome ......................................... 58 
5.6.3 
Serious adverse events ......................................................................58 
5.6.4 
Non-serious adverse events ..............................................................59 
5.6.5 
Adverse events leading to discontinuation of study treatment .........59 
5.6.6 
Other significant adverse events .......................................................59 
5.6.7 
Vital signs and body weight ..............................................................59 
5.6.8 
Electrocardiography ..........................................................................61 
5.6.9 
Laboratory .........................................................................................63 
5.6.10 
Other safety variables .......................................................................67 
5.7 
Quality of life variables ................................................................................67 
5.8 
Pharmacoeconomic variables .......................................................................67 
5.8.1 
Hospitalizations ................................................................................67 
5.8.2 
Change from baseline in Work Productivity and Activity 
Impairment: Clostridium difficile-associated diarrhea scores ..........68 
5.9 
Pharmacokinetic variables ............................................................................69 
6 
DEFINITION OF PROTOCOL DEVIATIONS .........................................................69 
7 
ANALYSIS SETS .......................................................................................................70 
7.1 
Definitions of analysis sets ...........................................................................70 
7.1.1 
Screened analysis set ........................................................................70 
7.1.2 
Full analysis set .................................................................................70 
7.1.3 
Modified intent-to-treat analysis set .................................................70 
7.1.4 
Per-protocol analysis set ...................................................................71 
7.1.5 
Hypervirulent analysis set .................................................................73 
7.1.6 
Patient reported outcome analysis set ...............................................73 
7.1.7 
Safety analysis set .............................................................................73 
7.1.8 
Re-treatment extension with cadazolid analysis set .........................74 
7.1.9 
Other analysis sets ............................................................................74 
7.2 
Usage of the analysis sets .............................................................................74 


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8 
DEFINITION OF SUBGROUPS ................................................................................75 
9 
GENERAL STATISTICAL METHODOLOGY ........................................................76 
9.1 
Statistical methods for binary data ...............................................................76 
9.1.1 
Confidence interval ...........................................................................76 
9.1.2 
Stratified Cochran-Mantel-Haenszel ................................................76 
9.1.3 
Logistic regression ............................................................................77 
9.2 
Statistical methods for time-to-event data ....................................................77 
9.2.1 
Time to Event and log-rank test ........................................................77 
9.2.2 
Cox proportional hazard model ........................................................78 
9.3 
ANOVA model for repeated measurements .................................................78 
10 STATISTICAL ANALYSES ......................................................................................79 
10.1 
Overall testing strategy .................................................................................79 
10.1.1 
Statistical considerations ...................................................................80 
10.2 
General rules for data presentations .............................................................81 
10.3 
Display of subject disposition, protocol deviations and analysis sets ..........82 
10.3.1 
Screening failures .............................................................................82 
10.3.2 
Subject disposition ............................................................................82 
10.3.3 
Protocol deviations ...........................................................................82 
10.3.4 
Analysis sets .....................................................................................83 
10.4 
Analyses of subject characteristics ...............................................................83 
10.4.1 
Demographics ...................................................................................83 
10.4.2 
Baseline disease characteristics ........................................................83 
10.4.3 
Other baseline characteristics ...........................................................83 
10.4.4 
Medical history .................................................................................83 
10.4.5 
Previous and concomitant therapies .................................................84 
10.4.6 
Procedures .........................................................................................84 
10.5 
Analysis of study treatment exposure and compliance.................................84 
10.5.1 
Exposure ...........................................................................................84 
10.5.2 
Compliance with study treatment .....................................................85 
10.5.3 
Study treatment discontinuation .......................................................85 
10.5.4 
Study treatment interruptions ............................................................85 
10.6 
Analysis of the primary efficacy variable .....................................................85 
10.6.1 
Hypothesis and statistical model .......................................................85 
10.6.2 
Handling of missing data ..................................................................85 
10.6.3 
Main analysis ....................................................................................86 
10.6.4 
Supportive/sensitivity analyses .........................................................86 
10.6.4.1 
Stratified Cochran-Mantel-Haenszel analysis of Clinical 
Cure rate .................................................................................. 86 


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10.6.4.2 
Analysis of Clinical Cure rate with imputation for a 
single missing day ................................................................... 87 
10.6.5 
Subgroup analyses ............................................................................87 
10.6.6 
Other analyses ...................................................................................87 
10.7 
Analysis of the secondary efficacy variables................................................88 
10.7.1 
Sustained Cure Rate ..........................................................................88 
10.7.1.1 
Hypothesis and statistical model ............................................. 88 
10.7.1.2 
Handling of missing data ......................................................... 88 
10.7.1.3 
Statistical analysis ................................................................... 88 
10.7.1.4 
Supportive/sensitivity analyses of Sustained Cure rate ........... 89 
10.7.1.5 
Subgroup analyses ................................................................... 89 
10.7.1.6 
Other analyses ......................................................................... 89 
10.7.2 
Time to resolution of diarrhea ..........................................................89 
10.7.2.1 
Hypothesis test and statistical model ....................................... 90 
10.7.2.2 
Handling of missing data ......................................................... 90 
10.7.2.3 
Statistical analysis ................................................................... 90 
10.7.2.4 
Supportive/sensitivity analysis ................................................ 90 
10.7.3 
Absolute change from baseline to Day 3 in CDI-DaySyms 
PRO domain scores ...........................................................................90 
10.7.3.1 
Hypothesis test and statistical model ....................................... 91 
10.7.3.2 
Handling of missing data ......................................................... 91 
10.7.3.3 
Statistical analysis ................................................................... 92 
10.8 
Analysis of other efficacy variables .............................................................93 
10.8.1 
Efficacy variables .............................................................................93 
10.8.1.1 
Investigator’s assessment of Early Treatment Response 
at Visit 2 .................................................................................. 93 
10.8.1.2 
Investigator’s judgment of Clinical Response at Visit 4 ......... 93 
10.8.1.3 
Investigator’s evaluation of Clinical Cure per protocol 
definition ................................................................................. 93 
10.8.1.4 
Investigator’s judgment of Sustained Response at Visit 5 ...... 93 
10.8.1.5 
Investigator’s evaluation of Sustained Cure per protocol 
definition ................................................................................. 93 
10.8.1.6 
Early Clinical Cure by Day 5 .................................................. 94 
10.8.1.7 
Normalization of Bowel Movements rate ............................... 94 
10.8.1.8 
Time to return to usual stools .................................................. 94 
10.8.1.9 
Recurrence rate and adjusted recurrence rate .......................... 94 
10.8.1.10 
Time to recurrence ................................................................... 94 
10.8.1.11 
CDI-DaySyms PRO response rates ......................................... 94 
10.8.1.12 
Comparison of absolute values of CDI-DaySyms domain 
scores versus Clinical Cure ..................................................... 95 
10.8.1.13 
Re-treatment extension variables ............................................ 95 


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10.8.2 
Analysis of microbiology variables ..................................................96 
10.8.2.1 
Isolation of C. difficile ............................................................ 96 
10.8.2.2 
Typing of C. difficile ............................................................... 96 
10.8.2.3 
Susceptibility of C. difficile .................................................... 97 
10.8.2.4 
Change from baseline in susceptibility of C. difficile ............. 98 
10.8.2.5 
Vancomycin-resistant enterococci .......................................... 98 
10.8.2.6 
Vancomycin-resistant enterococci quantitative culture .......... 98 
10.8.2.7 
Susceptibility of vancomycin-resistant enterococci ................ 98 
10.9 
Analysis of safety variables ..........................................................................99 
10.9.1 
Adverse events ..................................................................................99 
10.9.2 
Deaths, other serious adverse events ..............................................100 
10.9.2.1 
Deaths .................................................................................... 100 
10.9.2.2 
Serious adverse events ........................................................... 100 
10.9.2.3 
Adverse events leading to study treatment 
discontinuations ..................................................................... 100 
10.9.2.4 
Other significant adverse events ............................................ 101 
10.9.3 
Electrocardiography ........................................................................101 
10.9.4 
Laboratory tests ...............................................................................102 
10.9.5 
Vital signs and body weight ............................................................102 
10.9.6 
Other safety variables .....................................................................103 
10.10 
Analysis of quality of life variables ............................................................103 
10.11 
Analysis of pharmacoeconomic variables ..................................................103 
11 GENERAL DEFINITIONS AND DERIVATIONS .................................................103 
11.1 
Unit conversion ...........................................................................................103 
11.2 
Variable derivation .....................................................................................104 
11.3 
Dates, times and days .................................................................................104 
11.4 
Periods ........................................................................................................106 
11.5 
Summaries by visit .....................................................................................106 
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS .............106 
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES (TLFS) ..................109 
13.1 
Subject disposition ......................................................................................109 
13.2 
Protocol deviations .....................................................................................110 
13.3 
Subject characteristics ................................................................................110 
13.3.1 
Demographics .................................................................................110 
13.3.2 
Baseline disease characteristics ......................................................111 
13.3.3 
Other baseline characteristics .........................................................111 
13.3.4 
Medical history ...............................................................................111 
13.3.5 
Previous and concomitant therapies ...............................................112 


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13.3.6 
Specific previous and concomitant .................................................113 
13.3.7 
Procedures .......................................................................................114 
13.4 
Study treatment exposure and compliance .................................................114 
13.4.1 
Exposure .........................................................................................114 
13.4.2 
Compliance with study treatment ...................................................114 
13.4.3 
Study treatment discontinuation .....................................................115 
13.4.4 
Study treatment interruptions ..........................................................115 
13.5 
Study withdrawal ........................................................................................115 
13.6 
Primary efficacy analyses ...........................................................................116 
13.6.1 
Main analysis ..................................................................................116 
13.6.2 
Supportive/sensitivity analyses .......................................................116 
13.6.3 
Subgroup analyses ..........................................................................117 
13.6.4 
Other analyses .................................................................................117 
13.7 
Secondary efficacy analyses .......................................................................118 
13.7.1 
Further supportive/sensitivity analyses for Sustained Cure ............120 
13.8 
Other efficacy analyses ...............................................................................120 
13.9 
Safety analyses ...........................................................................................127 
13.9.1 
Adverse events ................................................................................127 
13.9.2 
Serious adverse events ....................................................................128 
13.9.3 
Adverse events by intensity or relationship to study treatment ......128 
13.9.4 
Other significant adverse events .....................................................129 
13.9.4.1 
Adverse events leading to treatment discontinuation ............ 129 
13.9.4.2 
Adverse events leading to death ............................................ 129 
13.9.5 
Deaths .............................................................................................129 
13.10 
Electrocardiography ....................................................................................130 
13.11 
Laboratory tests ..........................................................................................130 
13.12 
Vital signs and body weight .......................................................................132 
13.13 
Other safety variables .................................................................................132 
13.14 
Other evaluations ........................................................................................132 
13.14.1 
Quality of life analyses ...................................................................132 
13.14.2 
Pharmacoeconomic analyses ..........................................................133 
13.14.3 
Benefit-risk evaluations ..................................................................133 
13.14.4 
Pharmacodynamic analyses ............................................................133 
13.14.5 
Pharmacokinetic analyses ...............................................................133 
14 REFERENCES ..........................................................................................................134 
15 APPENDICES ...........................................................................................................135 
 


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LIST OF TABLES 
 
Table 1 
Visit and assessment schedule ........................................................................ 17 
Table 2 
Visit and assessment schedule for the re-treatment extension with 
cadazolid ......................................................................................................... 18 
Table 3 
Antimicrobial treatments active against CDAD ............................................. 28 
Table 4 
Reasons for Clinical Failure ............................................................................ 37 
Table 5 
Handling of missing data for the definition of recurrence .............................. 41 
Table 6 
Reasons for Not Sustained Cure ..................................................................... 43 
Table 7 
Domains and items of the CDI-DaySyms diary ........................................... 44 
Table 8 
Threshold for responders (response definition) .............................................. 49 
Table 9 
Relative changes in minimum inhibitory concentration ................................. 53 
Table 10 
Marked abnormalities in blood pressure ......................................................... 60 
Table 11 
Marked abnormalities in ECG (absolute and change) .................................... 63 
Table 12 
Examples of treatment-emergent QT/QTc marked abnormalities .................. 63 
Table 13 
Marked abnormalities in laboratory parameters ............................................. 66 
Table 14 
Overview of the different analysis sets and their usage .................................. 75 
Table 15 
Handling of missing date and time ............................................................... 107 
 
LIST OF FIGURES 
 
Figure 1 
Study design .................................................................................................... 15 
Figure 2 
Study design including re-treatment extension ............................................... 16 
Figure 3 
Derivation of Clinical Cure: Schematic overview .......................................... 34 
Figure 4 
Clinical Cure: Derivation examples ................................................................ 36 
Figure 5 
Derivation of Sustained Cure: Schematic overview ....................................... 38 
Figure 6 
Sustained Cure: Derivation examples ............................................................. 42 
Figure 7 
Hierarchical testing strategy............................................................................ 80 
 
LIST OF APPENDICES 
 
A. 
Protocol synopsis, Protocol version 3 ........................................................... 135 
B. 
Discussion and further considerations of the applied statistical methods ..... 140 
C. 
Chronic kidney disease SMQ selected preferred terms ................................ 141 
D. 
Scoring and analysis guideline for the CDI-DAYSYMS (formerly 
known as CDAD-DAYSYMS) ................................................................... 143 
E. 
Multiple imputation and tipping point analysis for CDI PRO ...................... 147 
F. 
Document history .......................................................................................... 154 


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LIST OF ABBREVIATIONS AND ACRONYMS 
AE  
Adverse event 
ALT  
Alanine aminotransferase 
AMT  
Antimicrobial treatment active against CDAD 
ANCOVA  
Analysis of covariance 
AST  
Aspartate aminotransferase 
ATC  
Anatomical therapeutic chemical 
BMI  
Body mass index 
BUN  
Blood urea nitrogen 
CC  
Clinical Cure 
CCR  
Clinical Cure Rate 
CCRc  
Clinical Cure Rate for cadazolid 
CCRv  
Clinical Cure Rate for vancomycin 
CDAD  
Clostridium difficile-associated diarrhea 
CI  
Confidence interval 
CMH  
Cochran-Mantel-Haenszel 
CRF  
Case report form 
CSR  
Clinical study report 
DBP  
Diastolic blood pressure 
ECC  
Early Clinical Cure 
ECG  
Electrocardiogram/graphy 
EIA  
Enzyme immunoassay 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ES  
Re-treatment extension with cadazolid set 
ETR  
Early Treatment Response 
FAS  
Full analysis set 
FDA  
Food and Drug Administration 
FMT  
Fecal microbiota transplant 


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GDH  
Glutamate dehydrogenase 
HR  
Heart rate 
HVAS  
Hypervirulent analysis set 
ICF  
Informed consent form 
ICU  
Intensive care unit 
INR  
International normalized ratio 
ISR  
Investigator’s judgment of Sustained Response 
IVIG  
Intravenous immunoglobulin 
IVRS  
Interactive voice response system 
LT  
Liver test 
LLN  
Lower limit of normal 
LOCF  
Last observation carried forward 
MAR  
Missing at random 
MedDRA  
Medical Dictionary for Regulatory Activities 
MIC  
Minimum inhibitory concentration 
MIC50  
Median of minimum inhibitory concentration 
MIC90  
90% quantile of minimum inhibitory concentration 
MNAR  
Missing not at random 
mITT  
Modified intent-to-treat 
MTF  
Metronidazole treatment failure 
NBM  
Normalization of bowel movements 
NED  
New episode of diarrhea 
NI  
Non-inferiority 
PCR  
Polymerase chain reaction 
PK  
Pharmacokinetic 
PPI  
Proton pump inhibitor 
PPS  
Per-protocol analysis set 
PRO  
Patient reported outcome 
PROAS  
Patient reported outcome analysis set 


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QTc  
Corrected QT 
QTcB  
QT corrected using Bazett’s formula 
QTcF  
QT corrected using Fridericia’s formula 
REA  
Restriction endonuclease assay 
ROD  
Resolution of diarrhea 
RTE  
Re-treatment end 
RTS  
Re-treatment start 
SAE  
Serious adverse event 
SAP  
Statistical analysis plan 
SAS®  
Statistical Analysis Software 
SBP  
Systolic blood pressure 
SCR  
Sustained Cure Rate 
SCRAS  
Screened analysis set 
SCRc  
Sustained Cure Rate for cadazolid 
SCRv  
Sustained Cure Rate for vancomycin 
SDTM  
Study Data Tabulation Model 
SI  
International system of units 
SMQ  
Standardised MedDRA Query 
SOC  
System organ class 
SS  
Safety set 
STS  
Study treatment start 
UBM  
Unformed bowel movement 
ULN  
Upper limit of normal 
VRE  
Vancomycin-resistant enterococci 
WBC  
White blood cells 
WHO  
World Health Organization 
WPAI  
Work productivity and activity impairment 


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1 
INTRODUCTION 
The studies AC-061A301 and AC-061A302 have identical designs, including study 
assessments and statistical methods. This statistical analysis plan (SAP) describes in 
detail the analyses and data presentation of the primary, secondary and exploratory 
endpoints for each final clinical study report (CSR).  
Outputs are prepared separately for each study. All information about subjects in the 
respective trials, including that collected during the open-label re-treatment extension 
with cadazolid, are included in the database lock and statistical analysis for the CSR. 
Separate SAPs (not described here) are developed for: 
• The meta-analysis of Sustained Cure rate in the hypervirulent subgroup, 
• Analysis of pharmacokinetic (PK) data, 
• Statistical analysis on questionnaires for the blinded analysis of content validity and 
psychometric properties planned in the patient reported outcomes (PRO) sub-study 
protocol, 
• Gut microbiome assessment,  
• Fecal cadazolid concentrations, if required. 
CDI-DaySyms PRO is a new PRO measure to assess Clostridium difficile-associated 
diarrhea (CDAD)-related symptoms in subjects with CDAD on a daily basis. The 
psychometric validation of the ‘Clostridium difficile infection (CDI) – Daily symptoms’ 
(CDI-DaySyms) PRO, was completed on 18 January 2017. The CDI-DaySyms PRO was 
previously known as the CDAD-DaySyms PRO. In order to be consistent with the 
disease description used in current medical practice and the terminology used in 
publications, the name of the questionnaire has been updated to refer to CDI rather than 
CDAD.  
This SAP has been updated to incorporate the changes to the endpoints for analyses of 
the CDI-DaySyms PRO based on the psychometric validation, as well as further 
refinements to the planned analyses of these endpoints. The algorithms for the PRO 
endpoints are described in Section 5.5.2.3.  
Source data for the analyses are provided as Statistical Analysis Software (SAS®) data 
sets according to Clinical Data Interchange Standards Consortium Study Data Tabulation 
Model (SDTM). 


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2 
STUDY DESIGN AND FLOW 
The two trials AC-061A301 and AC-061A302 have identical study designs. The only 
difference is the location of the centers participating in the studies. The protocol synopsis 
of AC-061A301 is included in Appendix A.  
2.1 Study design 
Each study is a prospective, multi-center, double-blind, double-dummy, randomized, 
parallel group, active controlled, Phase 3 study. In each study approximately 630 adult 
subjects are to be randomized to the two treatment groups: cadazolid and vancomycin 
using a 1:1 ratio, stratified by first occurrence / first recurrence of CDAD and by site 
(approximately 100 sites). 
The study consists of the following study periods: 
• Screening period lasts up to 48 hours, starting from signature of informed consent 
form (ICF) and ending with subject randomization.  
• Treatment period starts immediately after randomization with the first dose of study 
drug at the end of Visit 1 (Day 1 of the study) and ends with End-of-Treatment (EOT) 
on the day of the last dose of study drug (which is either Day 10 or Day 11 of the 
study, to account for 10 complete days of treatment). 
• Follow-up period starts immediately after the last dose of study drug and ends 
approximately 30 days after the last dose of the study drug, at Visit 5. The 
End-of-Study (EOS) is expected to occur together with Visit 5.  
Unscheduled visits may also take place during the treatment and follow-up periods. 
The study design of the main study is shown in Figure 1. 


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Figure 1 
Study design  
 
 
Randomization is stratified by (i) 1st occurrence or 1st recurrence of CDAD and (ii) by site.  
*Unless subject enters the open-label re-treatment extension with cadazolid 
EOS = End-of-Study; EOT = End-of-Treatment. 
 
The study also includes an extension phase: 
• Re-treatment extension with cadazolid: Subjects with first occurrence of CDAD at 
study entry who experience a recurrence during the study, whether they have been 
treated with cadazolid or vancomycin, may enter the re-treatment extension with 
cadazolid (after providing a specific informed consent) consisting of a 10-day 
treatment with cadazolid followed by an approximately 30-day follow-up. 
The study design including re-treatment extension is shown in Figure 2. Subjects can start 
the re-treatment extension at any time during the follow-up period of the main study once 
they have experienced a recurrence (between EOT + 3 days and EOT + 32 days). At that 
moment, the follow-up period of the main study stops and the subject continues in the 
re-treatment extension. 
Screening 
Period 
(48 h) 
Double-Blind  
Treatment Period 
(10–11 days) 
cadazolid 
vancomycin 
Follow-Up Period 
(28–32 days) 
Rando-
mization 
EOT 
EOS* 


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Figure 2 
Study design including re-treatment extension 
 
EORT = End of Re-Treatment; EOS = End-of-Study; EOT = End-of-Treatment; NED = New episode of diarrhea Visit.  
 
2.2 Study visit and assessment schedule 
Table 1 shows a schematic representation of the assessments during the study. The 
schedule of assessments performed during the re-treatment extension with cadazolid is 
summarized in Table 2.  
If a subject experiences a recurrence and participation in the re-treatment extension is 
confirmed (i.e., after the subject has signed the ICF for re-treatment and eligibility is 
confirmed), Visit 5 in the main study is not performed. Assessments that would have 
been performed as part of Visit 5 in the main study are performed as part of Re-treatment 
Visit 1 (Re-1). 
Note: Visit 1 referred to in Table 1 covers the entire screening and randomization period 
(within 48 h of randomization), followed by randomization and study treatment start. 
Similarly, Visit Re-1 referred to in Table 2 covers the entire screening for re-treatment 
period, eligibility assessment for re-treatment and re-treatment kit delivery.  
Screening 
Period 
Double- 
Blind  
Treatment 
cadazolid 
vancomycin 
Follow-Up Period 
Rando-
mization 
EOT 
EOT +30 
NED 
Re-treatment Extension 
Open-Label 
Treatment 
(10–11 days) 
cadazolid 
Open-Label  
Follow-Up Period 
(28–32 days) 
 


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Table 1 
Visit and assessment schedule 
PERIODS 
Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
- 
 
Duration 
Up to 48 hours 
10 to 11 days 
28 to 32 days 
- 
VISIT 
Number 
1 
2 
3 
4 
4.a, 4.b,… 
5 
U1, U2, … 
 
Name 
Screening 
Randomization 
 
 
 
NED 
 
Unscheduled 
EVALUATION 
Time 
Day –2 to Day 1 
(within 48 h) 
Day 1 
Day 5 or Day 6 
On site or by phone 
Day 8 to Day 10 
incl. Premature Disc. 
EOT + 2 to 4 days  
On site or by phone 
If applicable, in 
case of NED 5, 6 
EOT + 28 to 32 days  
or Study Withdrawal 
If applicable 
Informed consent 
X 
 
 
 
 
 
 
 
Fecal sampling for microbiology  
X 
 
X 
 
X 
 
 
C. difficile GDH and toxin test 
within 72 h (MTF: 48 h) 
 
 
 
 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
X 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
X 
X 
X 
X 
Body weight/height 
X1 
 
X 
 
 
X 
X 
Vital signs / Body temperature 
X1 
 
X 
X 
X 
X 
Hematology/coagulation/chemistry 
X 2 
 
X 
X 
X 
X 
12-lead ECG 
X  
 
X 
 
 
X 
X 
Randomization 
X 
 
 
 
 
 
 
Study drug 
X3 
and Study Drug Journal completion 
 
 
 
 
Stool Diary 
 
 
 
CDAD DaySyms PRO Diary 
 
 
 
 
Interview (face to face or by phone) 
Daily7 
Twice weekly 
 
Investigator assessment 
 
X 
 
X 
 
X 
 
Pharmacokinetic sample Sub-study 
 
X 
 
 
 
 
WPAI:CDAD  
X 
 
X 
 
 
X 
 
AEs/SAEs 4 
X 
X 
X 
X 
X 
X 
X 
X 
1. Height collected at Visit 1 only. 2. Includes pregnancy test for women of childbearing potential. 3. After randomization. 4. All AEs and SAEs are reported after the first dose of study drug. 
Between informed consent and first dose of study drug, only SAEs are reported. 5. Subject may enter re-treatment extension with cadazolid in case of recurrence. 6. All assessments must be 
performed in the case of a recurrence. 7. Interviews start from Day 2. 
AE = adverse event, C. difficile = Clostridium difficile, CDAD = Clostridium difficile-associated diarrhea, ECG = electrocardiogram, EOT = End-of-Treatment, GDH = glutamate dehydrogenase, 
MTF = metronidazole treatment failure, NED = new episode of diarrhea, PRO = patient reported outcomes, SAE = serious adverse event, WPAI = work productivity and activity impairment. 
 
 


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Table 2 
Visit and assessment schedule for the re-treatment extension with cadazolid 
PERIODS 
Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
- 
 
Duration 
Up to 24 hours 
10 to 11 days 
28 to 32 days 
- 
VISIT 
Number 
Re-1 
Re-2 
Re-3 
Re-4 
Re-4.a, Re-4.b,… 
Re-5 
Re-U1,  
Re-U2, … 
 
Name 
Eligibility 
Re-treatment 
kit delivery 
 
 
 
NED 
 
Unscheduled 
EVALUATION 
Time 
Day –1 to 1 
(within 24 h) 
Day 1 
Day 5  
or 6 
On site or by phone 
Day 8 to 10 
incl. Premature 
Disc. 
 
EOT + 2 to 4 days  
On site or by phone 
If applicable, in 
case of NED4 
  
EOT + 28 to 32 days
or Study Withdrawal 
If applicable 
Informed consent 
X 
 
 
 
 
 
 
 
Fecal sampling for microbiology 
X 
 
X 
 
X 
 
 
C. difficile GDH and toxin test 
within 72 h 
 
 
 
 
X 
 
 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
X 
X 
X 
X 
Body weight 
X 
 
X 
 
 
X 
X 
Vital signs / Body temperature 
X 
 
X 
X 
X 
X 
Hematology/coagulation/ 
chemistry 
X1 
 
 
X 
 
X 
X 
X 
12-lead ECG 
X  
 
X 
 
 
X 
X 
Re-treatment kit delivery 
X 
 
 
 
 
 
 
Study drug intake  
X2 
and Study Drug Journal completion 
 
 
 
 
Stool Diary 
 
 
 
CDAD DaySyms PRO Diary 
 
 
 
 
Interview (face to face or by phone) 
Daily5 
Twice weekly 
 
Investigator assessment 
 
X 
 
X 
 
X 
 
WPAI:CDAD 
X 
 
X 
 
 
X 
 
AEs/SAEs3 
X 
X 
X 
X 
X 
X 
X 
1. Includes pregnancy test for women of childbearing potential. 2.After re-treatment kit delivery. 3. All AEs and SAEs are reported after the first dose of study drug. Between informed consent and 
first dose of study drug, AEs and SAEs are reported as part of the main study. 4. All assessments must be performed in the case of a recurrence. 5. Interviews start on Day 2. 
AE = adverse event, C. difficile = Clostridium difficile, CDAD = Clostridium difficile-associated diarrhea, ECG = electrocardiogram, EOT = end-of-treatment, GDH = glutamate dehydrogenase, 
NED = new episode of diarrhea, PRO = patient reported outcomes, SAE = serious adverse event, WPAI = work productivity and activity impairment. 


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3 
OBJECTIVES 
3.1 Primary objective 
To determine whether the clinical response after 10-day oral administration of cadazolid 
is non-inferior to oral vancomycin in subjects with CDAD. 
3.2 Secondary objectives 
To determine whether oral administration of cadazolid for 10 days is superior to oral 
vancomycin in the sustained clinical response of subjects with CDAD. 
To determine whether the resolution of diarrhea (ROD) is more rapid with oral 
administration of cadazolid compared to vancomycin. 
To determine whether CDAD symptoms as reported by the subject show larger 
improvements from baseline with oral administration of cadazolid compared to 
vancomycin. 
3.3 Other objectives 
3.3.1 Objective of the meta-analysis of AC-061A301 and AC-061A302 
To determine through meta-analysis of both studies whether oral administration of 
cadazolid for 10 days is superior to vancomycin in the sustained clinical response of 
subjects with CDAD due to infection by hypervirulent C. difficile strains. 
3.3.2 Exploratory objective 
To evaluate the plasma cadazolid concentration at approximately 2 hours post-dose (PK 
sub-study). 
3.3.3 Safety objective 
To determine the safety and tolerability of an oral administration of cadazolid compared 
to vancomycin. 
3.3.4 Objective of the re-treatment extension with cadazolid 
To describe the clinical response, sustained clinical response and safety in subjects with a 
first occurrence of CDAD at study entry (cadazolid or vancomycin subjects) who 
experience a recurrence of CDAD and are re-treated with cadazolid for 10 days. 


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4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL  
4.1 Changes related to PRO validation 
It was specified in section 7.2.4 of the protocols of studies AC-061A301 and 
AC-061A302 that the CDI-DaySyms PRO questionnaire comprises 13 items. Based on 
the psychometric validation of this tool, 3 out of the 13 items have been removed 
(passing gas, dizziness, and nausea). Absolute change from baseline in CDI-DaySyms 
PRO total daily score up to Day 12 derived from the daily CDI-DaySyms PRO items is 
described as one of the secondary endpoints in the study protocols. However, derivation 
of such a total score is not supported by the psychometric validation, and therefore three 
symptom domain scores are derived: Diarrhea Symptoms, Abdominal Symptoms, and 
Systemic/Other Symptoms. These three domains are tested hierarchically, starting with 
Diarrhea Symptoms, then Abdominal Symptoms, and finally Systemic/Other Symptoms. 
The figure in section 11.3.4.1 of the protocol describing the hierarchical testing strategy 
to control the experimentwise α level is updated in Section 10.1.1 of this SAP in order to 
include the hierarchical testing of the CDI-DaySyms domain scores.  
Section 11.3.4.3 of the protocols specified that a repeated measurements ANCOVA for 
the absolute and percent change from baseline would be applied, including the baseline 
value as a covariate. In order to maximize the number of data points included in the 
analysis, an ANOVA model is fitted to all available absolute values (including baseline 
and post-baseline data up to Day 12), and treatment difference for the absolute change 
from baseline for each day is computed from the model using appropriate contrast 
statements. Consequently, the baseline value is not included as a covariate, and percent 
change from baseline analysis has been dropped.  
The change from baseline to Day 3 is identified as the primary comparison of interest 
(and used for the hierarchical testing strategy); comparisons for all other days are 
considered exploratory. Day 3 is selected as the primary comparison of interest as the 
results from the Phase 2 trial showed that time to modified resolution of diarrhea was 
48 hours after start of treatment in the cadazolid arm vs 72 hours in the vancomycin arm. 
Methods for handling missing data are further described in Section 10.7.3.2. Additional 
new responder endpoints for the CDI-DaySyms domains are also defined in 
Section 5.5.3.12. The corresponding supportive analysis of these endpoints is included in 
Section 10.8.1.11. 
4.2 Changes to the analyses planned in the study protocol 
A change in the definition of censoring for the variable ‘Time to return to usual bowel 
movements’ is applied: Subjects without a return to usual bowel movements are censored 
at the last date with known number of bowel movements. This represents a modification 
of the text included in the study protocol, which states they would be censored at Visit 5 


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or, for subjects without a Visit 5 assessment who either died, withdrew from the study or 
are lost to follow-up, would be censored at the date of death, study withdrawal or last 
contact, respectively. The rationale for this change is the following: A return to usual 
bowel movements cannot be achieved after the last recorded bowel movement 
information, i.e., the subject is no longer in the risk set. Censoring at the last recorded 
bowel movement information is therefore more appropriate and results in being more 
conservative in the assessment. 
4.3 Changes in the conduct of the study / data collection 
The following protocol amendments were performed:  
Protocol Version 2, 11 December 2014 
• Analysis of the primary endpoint (Clinical Cure) on two co-primary analysis sets (i.e., 
modified intent-to-treat [mITT] analysis set and Per-protocol analysis set [PPS]) 
instead of sequentially on PPS and mITT analysis set, following FDA advice.  
• Derivation of the variable Sustained Cure was clarified. 
Further changes included, e.g., the addition of an emerging hypervirulent C. difficile 
strain, the addition of endpoints related to susceptibility testing of C. difficile and 
vancomycin-resistant enterococci, and general clarifications of eligibility criteria. 
Protocol Version 3, 22 October 2015 
• Removal of planned interim analysis, which was to be performed after the 
randomization of the first 67% of subjects.  
Additional changes were, for example, the following: a diagnostic test for C. difficile is 
required to detect both glutamate dehydrogenase (GDH) and toxin A/B; introduction a 
two-part ICF in order to improve efficiency of the informed consent procedure; change of 
the planned duration of the trial from 23 to 40 months; allowing routine / standard-of-care 
assessments performed prior to consenting.  
Note: Only the main reasons for the protocol amendments are described. 
4.3.1 Clarification on wording 
Actelion’s templates for SAP and CSR have been updated since protocol finalization. 
The terminology used in the SAP is the one of the revised template. Changes of 
terminology comprise “medications” replaced by “therapies”, and “protocol violations” 
replaced by “protocol deviations.” 
5 
DEFINITIONS OF VARIABLES 
This section provides the definitions and sources for all variables used in the analyses, 
including specifications for the derivations. 


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General recurrent definitions (e.g., study treatment start date, baseline) or unit conversion 
are described in Section 11. 
The description of re-treatment variables and analyses are organized in this document as 
follows: Re-treatment efficacy variables and analyses are separated from the main study 
efficacy variables [Section 5.5.5] and analyses [Section 10.8.1.13] as re-treatment 
efficacy variables are not part of the hierarchical statistical testing strategy. However, 
safety and subject characteristic variables and analyses for the re-treatment extension are 
described together with their corresponding main study counterparts [Section 5 and 
Section 10] to ease description of derivation and analyses. 
5.1 Screening failures 
A subject is considered a screening failure, if the subject is recorded as screened and 
never randomized in the Interactive Voice Response System (IVRS; subjects screened 
more than once and subsequently randomized are not counted as screening failures). 
The primary reason for screening failure is documented in the randomization case report 
form (CRF; primary reason why the subject was not randomized) as ‘subject not eligible’, 
‘subject withdrew consent’, ‘adverse event’ or ‘other’. If a subject is considered a 
screening failure but no reason for screening failure is reported, the reason is categorized 
as ‘Unknown’. 
For the re-treatment extension, a subject is considered screened for re-treatment if the 
answer to the question ‘Has the subject been screened for re-treatment?’ in the CRF is 
‘Yes.’ The subject is considered a screening failure for re-treatment if he/she has signed 
the informed consent to participate but then the answer to the question ‘Has the subject 
been enrolled into the re-treatment?’ is answered ‘No.’ 
5.1.1 Unmet eligibility criteria 
Unmet eligibility criteria are defined as:  
• Inclusion criteria not met (reported as No in the CRF) and  
• Exclusion criteria met (reported as Yes in the CRF).  
The inclusion and exclusion criteria information is taken from the Screening and 
Randomization Visit. For re-screened subjects it is taken from the latest Re-screening and 
Randomization Visit. Unmet re-treatment extension eligibility criteria are defined in the 
same way and taken from the Re-1 Visit. 


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5.2 Subject characteristics 
5.2.1 Demographics 
Demographic data comprise age at screening (years; continuous and categorical), sex, 
ethnicity, race, height (cm), weight (kg) and body mass index (BMI; kg/m2; continuous 
and categorical). 
The following categories are defined for demographic variables: 
• Age (years): 18–64; 65–74; ≥ 75  
In addition, EudraCT age categories are defined as 18–64; 65–84; ≥ 85. 
• BMI (kg/m2): < 18.5; ≥ 18.5 – ≤ 25; > 25 – ≤ 30; > 30 – ≤ 40; > 40. 
• Geographical region: According to the recruitment plans, the following 
geographical regions are considered:  
– United States (301 & 302). 
– Canada (301 & 302). 
– Europe: Belgium (302 only), Croatia (302 only), Czech Republic (302 only), France 
(301 only), Germany (301 only), Greece (302 only), Hungary (302 only), Italy (301 
only), Netherlands (301 only), Poland (301 only), Romania (301 & 302), Slovakia 
(302 only), Spain (301 only), United Kingdom (302 only). 
– Rest of the World: Argentina (302 only), Australia (301 only), Brazil (301 & 302), 
Chile (302 only), Israel (302 only), Peru (301 only), South Korea (302 only). 
5.2.2 Baseline disease characteristics 
Main baseline disease characteristics include: 
• CDAD episode type strata (from IVRS) defined as baseline stratification factor 
‘First occurrence’ or ‘First recurrence’ of CDAD as recorded in the IVRS at the time 
of subject randomization. The CDAD episode type together with randomization 
number and date and time of randomization information is transferred to the CRF via 
IVRS integration (Primary form). 
• CDAD episode type reported (CRF) defined as ‘First occurrence’ or ‘First 
recurrence’ of CDAD as entered in the CRF (Demographics form). 
• Initial strain of C. difficile identified in baseline stool sample* by polymerase chain 
reaction (PCR) performed by the central laboratory is categorized as: 
– ‘Hypervirulent’ if the C. difficile strain belongs to either ribotype 027, 078 or 244 
(initial type).  


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– ‘Non-hypervirulent’ if the C. difficile strain has a PCR ribotype which is different 
from 027, 078 or 244. 
– ‘Unable to determine’ if PCR ribotype information of C. difficile at baseline is not 
available, e.g., due to missing baseline fecal sample or if C. difficile was not isolated 
in central laboratory. 
* Baseline stool sample is the last sample collected up to treatment start date (inclusive) 
with available C. difficile culture result. The sampling date is recorded on the CDAD 
Diagnosis and Microbiology Sample CRF for subjects enrolled under protocol version 3 
or later. For subjects enrolled under earlier protocol versions, the sampling date is 
collected on the Fecal Sampling CRF.  
Note: Handling of multiple samples with identical fecal sampling date/time qualifying for 
baseline is detailed in Section 5.5.4.1.  
If a new ribotype(s) is identified by external experts as a hypervirulent strain prior to 
unblinding of the data of any of the two studies, this SAP will be updated accordingly to 
include the new ribotype(s) in the hypervirulent strain definition.  
• CDAD severity at Baseline is categorized according to the definition specified in the 
protocol [see sections 1.1.1 and 7.1 of the protocol] and derived as: 
– ‘Severe’ if 
– baseline maximum core body temperature > 38.5 °C  
(Source: Vital Signs CRF), or  
– baseline white blood cell (WBC) counts > 15.0 109/L  
(Source: From central laboratory; if not available local result is used, see 
Section 5.6.9), or  
– rise in baseline serum creatinine > 50% compared to pre-CDAD diagnosis  
(Source: baseline serum creatinine is taken from central laboratory; if not 
available local result is used, see Section 5.6.9. Pre-CDAD serum creatinine is 
taken from the CDAD Related Medical History CRF at screening. Handling of 
missing pre-CDAD diagnosis is described below.) 
– ‘Mild-Moderate’ if none of the 3 criteria above for severe are met, and all 
measurements required for derivation of severity have been performed. 
– ‘Unable to determine’ if any of the measurements required for derivation of severity 
is missing for subjects not yet considered severe. 
Pre-CDAD serum creatinine values will be converted to the same units as used for the 
baseline value and, where applicable, will be normalized using the method as specified in 
Section 5.6.9. If no pre-CDAD diagnosis assessment of creatinine is available for 


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subjects without chronic kidney disease (i.e., subjects whose medical history does not 
include selected preferred terms from the Standardised MedDRA Query [SMQ] Chronic 
kidney disease [Appendix C]), the CDAD is considered severe if the baseline serum 
creatinine > 1.5 × upper limit of normal (ULN). 
Other main baseline characteristics include: 
• Time since diarrhea start date for current CDAD episode (days) is defined as the 
randomization date minus the start date of current CDAD episode + 1. 
• Time since first occurrence for subjects with first recurrence is defined as the 
randomization date minus the start date of first occurrence + 1. 
• Number of bowel movements within 24 hours prior to randomization, as 
recorded in the CRF at Screening Visit (Bowel Movement Information form).  
• Number of unformed bowel movements (UBMs) within 24 hours prior to 
randomization, as recorded in the CRF at Screening Visit (Bowel Movement 
Information form). 
Note: For the 2 variables above, the following categories are used: 0 to ≤ 3; 
> 3 to ≤ 5; > 5 to ≤ 9; and > 9. 
• Number of bowel movements per day reported as usual by the subject, as 
recorded in the CRF at Screening Visit (Bowel Movement Information form). 
• Number of UBMs per day reported as usual by the subject, as recorded in the 
CRF at Screening Visit (Bowel Movement Information form). 
Note: For the 2 variables above, the following categories are used: 0, 1, 2, 3, > 3.  
Note: For re-screened subjects, information for baseline characteristics is taken from the 
last Re-screening Visit instead of the Screening Visit.  
5.2.3 Other baseline characteristics 
Other baseline disease characteristics include: 
• Endoscopy during current CDAD episode (for subjects who have undergone 
endoscopy during the current CDAD episode as recorded at Screening Visit) 
– Visible pseudomembranes (Yes/No) 
– Histology consistent with pseudomembranous colitis (Yes/No) 
• Imaging during current CDAD episode (for subjects who have undergone 
abdominal imaging during the current CDAD episode as recorded at Screening Visit) 
– Distension of large intestine (Yes/No) 


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– Colonic wall thickening, including low attenuation mural thickening, pericolonic fat 
stranding (Yes/No) 
– Ascites not explained by other causes (Yes/No) 
• Hospitalization status at baseline categorized as: 
– ‘Outpatient’ if the response to the question ‘Is the subject an outpatient?’ is ‘Yes’, as 
recorded on the Baseline Healthcare Setting CRF. 
– ‘Inpatient’ if the response to the question ‘Is the subject an outpatient?’ is ‘No’. 
• Healthcare settings in the past three months at baseline categorized as: 
– Hospitalization (Yes/No) 
– Long-term care facility (Yes/No) 
– Chronic outpatient exposure (Yes/No) 
– Other (Yes/No) 
Include all healthcare setting information as reported on the CDAD-related Medical 
History CRF.  
• Metronidazole treatment failure (MTF) as reported on the CDAD-related Medical 
History CRF at Screening Visit (Yes/No). 
• Prior antimicrobial treatments active against CDAD within 1 week of study 
treatment start (Yes/No) taken from the Concomitant Medication CRF, see 
definition in Section 5.2.5.3.  
• History of chemotherapy and immunosuppression as reported on the 
CDAD-related Medical History CRF at Screening Visit (Yes/No). 
Note: For re-screened subjects, information for other baseline characteristics is taken 
from the last Re-screening Visit instead of the Screening Visit 
5.2.4 Medical history 
Medical history includes previous and/or concomitant diseases or diagnoses recorded in 
the Medical History CRF. Reported terms are coded using MedDRA version 19. 
Previous medical history are those diseases or diagnoses that are not ticked as ongoing 
(ongoing ‘Yes’ not ticked) on the CRF and with an end date before or equal to the study 
treatment start date. In the event of a partial end date that overlaps with first dose 
(e.g., May2013 and first dose occurred on 23May2013) or if an end date is missing, the 
medical history is considered as previous if ongoing is ticked ‘No’. All other medical 
history terms are considered concomitant. 


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5.2.5 Previous and concomitant therapies 
Therapies are collected in the Concomitant Medications CRF and terms are coded using 
the WHO drug code dictionary and the anatomical therapeutic chemical (ATC) 
classification code (version dated 1 March 2016). 
5.2.5.1 Previous therapies 
Previous therapies are those medications that were started prior to start date/time of study 
treatment with an end date/time prior to study treatment start date/time.  
In the event of a partial end date that overlaps with study treatment start date (e.g., end 
date May2013 and study treatment start occurred on 23May2013) or if an end date is 
missing, then the therapy is considered as previous if ‘Ongoing at start of treatment?’ is 
ticked ‘No’. All other therapies are considered concomitant. 
5.2.5.2 Study concomitant therapies 
Main study concomitant therapies are all the treatments that are ongoing at start of study 
treatment or initiated on or after the start date/time of study treatment first dose (from 
Study Drug Log CRF) and up to Visit 5, and prior to start of re-treatment with cadazolid 
(in the re-treatment extension). 
Main study concomitant therapies are further split into (i) main study concomitant 
therapies with onset prior to study treatment start and (ii) main study concomitant 
therapies with onset on or after study treatment start up to EOT + 7 days.  
Re-treatment concomitant therapies are all the treatments that are ongoing at start of 
re-treatment with cadazolid or initiated on or after the start date/time of first dose of 
re-treatment and up to Visit Re-5. 
5.2.5.3 Specific therapies 
Concomitant opiate treatments at baseline are those initiated before or at the first dose 
of study treatment, and with end date at or after the study treatment start date/time.  
Opiates are defined as any therapy in the Standardised Drug Grouping 1: Analgesia 
producing opioids. 
Antimicrobial treatments active against CDAD (AMT) comprise the therapies 
(standardized medication name) within the specified ATC codes (medication class code) 
and route as detailed in Table 3.  


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Table 3 
Antimicrobial treatments active against CDAD 
Medication  
(Standardized Name**) 
Medication class code 
(ATC) 
Route  
Description of 
combinations 
Vancomycin 
Vancomycin hydrochloride 
A07AA, J01XA 
Oral* 
 
Vanco Plus 
J01RA 
Oral* 
with vancomycin 
Metronidazole  
P01AB, J01XD, A02BD 
Any 
 
Metronidazole Benzoate 
J01XD 
Any 
 
Pylera 
Helidac /01327801/ 
A02BD 
Any 
with metronidazole 
Bacitracin  
J01XX, A07AX 
Any 
 
Bacitracin w/polymyxin  
J01XB 
Any 
with bacitracin 
Nebacetin /00037701/ 
A07AA 
Any 
with bacitracin 
Fusidic Acid 
J01XC 
Any 
 
Nitazoxanide 
P01AX 
Any 
 
Teicoplanin 
J01XA 
Oral* 
 
Tigecycline 
J01AA 
Any 
 
Fidaxomicin 
A07AA 
Any 
 
Rifampicin 
Rifamycin 
Rifabutin 
Rifapentine 
J04AB 
Any 
 
Rifaximin 
A07AA 
Any 
 
Rifaprim 
Rifinah 
Rifacept-3 
Levofloripine 
Risorine 
Tisobrif 
Rifater 
Kombipak II 
J04AM 
Any 
with rifampicin 
* In addition to oral administration, the administration of these products via rectal and intragastric route (or in the event 
of missing route information) will be considered as antimicrobial treatment active against CDAD. 
** Standardized medication name = Preferred name from WhoDrug Dictionary. 
ATC = anatomical therapeutic chemical; CDAD = Clostridium difficile-associated diarrhea. 
 
Prior antimicrobial treatments active against CDAD within 1 week of study 
treatment start are defined as any AMT taken in the 7 days prior to study treatment 
start. This is derived as previous medications with medication start date/time or end 
date/time between study treatment start date – 7 days (inclusive) up to study treatment 
start date/time; or main study concomitant medications with medication start date/time 


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prior to study treatment start. If start or end time is missing, evaluation is done using the 
date part only. Previous medications with missing end dates are not considered to have 
been taken within 1 week prior treatment start.   
Main study concomitant antimicrobial treatments active against CDAD are defined 
as any main study concomitant therapies [see Section 5.2.5.2] with ATC codes as defined 
in Table 3. 
Main study concomitant antibiotics for infections other than CDAD are defined as 
any main study concomitant therapies [see Section 5.2.5.2] with ATC codes equal to or 
starting with A07A, G01, J01, R02AB, S02A, with the exception of those reported as 
active against CDAD [see Table 3].  
Main study concomitant proton pump inhibitors (PPIs) and H2 blockers are defined 
as any main study concomitant therapies [see Section 5.2.5.2] with ATC codes equal to 
or starting with A02BA (H2 blockers), A02BC (PPIs), or with the ATC codes 
A02BD, B01AC, M01AE for combination therapies that include omeprazole, 
esomeprazole, pantoprazole or lansoprazole. 
Main study concomitant antimicrobial treatments active against CDAD, main study 
concomitant antibiotics for infections other than CDAD and concomitant PPIs and H2 
blockers will be considered, in addition, for the two following periods: (i) starting 
between study treatment start and EOT + 2 days (inclusive), or (ii) starting between EOT 
+ 3 days and Visit 5 (inclusive).  
The following categories will be considered in addition for efficacy analyses:  
• Concomitant antibiotics for infections other than CDAD taken from first dose to 
EOT + 2 days (yes/no)  
• Concomitant antibiotics for infections other than CDAD taken from first dose to 
Visit 5 / re-treatment (yes/no)  
Concomitant medication days: Several variables defining the number of days between a 
specific date and the start date of concomitant medication are derived using the 
definitions in Section 11.3: Concomitant medication days from first dose, from last dose, 
from first re-treatment dose, and from last re-treatment dose. 
5.2.6 Procedures 
Pre-specified CDAD-related procedures as well as any other procedures are collected in 
the Procedures CRF, where the date of procedure is reported.  
CDAD-related procedures are defined as the following pre-specified CDAD-related 
procedures: Fecal microbiota transplant (FMT), colectomy, hemicolectomy, loop 
ileostomy with colonic lavage.  


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Other procedures are coded using MedDRA version 19.  
Procedures performed before starting the study are reported in the Medical History CRF.  
5.2.6.1 Concomitant procedures 
Concomitant procedures are classified into main study procedures and re-treatment 
extension procedures.  
• Main study concomitant procedures, if the date of the procedure is between the first 
dose of the study and Visit 5, inclusive (or prior to first dose of re-treatment, if 
applicable). 
• Re-treatment extension concomitant procedures, if the date of the procedure is 
between the first dose of the re-treatment with cadazolid and Visit Re-5, inclusive. 
Procedures performed after Visit 5 or after Visit Re-5 are presented chronologically in a 
listing and, thus, not classified into a period.  
5.2.6.2 Endoscopy and imaging since first dose of study drug 
For subjects who have undergone endoscopy or abdominal imaging since first dose of 
study drug, additional information is collected for these procedures on the Endoscopy and 
Imaging CRF at Visit 5 [see Section 5.2.3]. 
5.3 Study treatment exposure and compliance 
Study treatment exposure (duration and mean daily dose) and compliance are all defined 
once for the main treatment period and again for the re-treatment period. 
5.3.1 Exposure 
Exposure to study drug is described in terms of duration and mean daily dose for active 
drug type (cadazolid or vancomycin) in the double-blind treatment period, and for 
cadazolid only for the re-treatment period (open-label treatment).  
Duration of study treatment (days) is defined per active drug type: For cadazolid it is 
the time elapsing between first treatment start date/time and last treatment end date/time 
of sachets + 12 hours, and for vancomycin it is the time elapsing between first treatment 
start date/time and last treatment end date/time of capsules + 6 hours, all divided by 
24 and rounded to the nearest 0.25 of a day.  
In the event of missing treatment end time, duration of study treatment is calculated as:  
 
Last treatment end date per drug type – treatment start date per drug type + 1 
In the event of missing or partial treatment end date, duration is missing. Duration of 
re-treatment is defined in a similar way as for cadazolid above, but based on first 


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re-treatment start date/time and last re-treatment end date/time of open-label sachets 
+ 6 hours. 
Exposure (days), i.e., treatment duration adjusted for interruptions, is defined as: 
 
Duration of study treatment (days) – Total Duration of Interruptions (days),  
where Total Duration of Interruptions is defined as the sum of Duration of Interruption 
over all interruption periods, rounded to the nearest 0.25 of a day. For a single period the 
Duration of Interruption is defined as: 
Duration of Interruption, cadazolid (h) = max{Interruption End Date/Time sachets – 
Interruption Start Date/Time sachets – 12 h , 0},  
Duration of Interruption, vancomycin (h) = max{Interruption End Date/Time capsules – 
Interruption Start Date/Time capsules – 6 h , 0}, 
where Interruption Start Date/Time is the Study Drug Log End Date/Time with 
corresponding reason for treatment end being temporarily interrupted (due to an adverse 
event [AE] or not due to an AE). Interruption End Date/Time is the next chronological 
Study Drug Log Start Date/Time after Interruption Start Date/Time for the same 
medication type (capsules or sachets).  
In the event of missing treatment start or end time, derivations are conducted based on 
days. In the event of partial or missing treatment start or end date, exposure is missing. If 
Interruption End Date/Time cannot be derived as there is no next chronological Study 
Drug Log entry the exposure is missing.  
Mean daily dose (mg) per subject is defined as the total amount of active drug taken 
divided by the duration of study treatment. 
The total number of doses taken is directly taken from the Drug Accountability CRF, 
expressed as the total number of sachets/capsules taken (as determined by the 
investigator). 
The total amount of active drug taken is defined for cadazolid as the number of sachets 
taken multiplied by 250 mg. Similarly, the total amount of active drug taken is defined 
for vancomycin as the number of capsules taken multiplied by 125 mg. If total number of 
sachets/capsules taken or the duration of study treatment is missing then mean daily dose 
is set to missing. 
Cumulative subject days exposure (days) is calculated by summing the duration of 
study treatment for all subjects having a duration of at least 0.25 days. 


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5.3.2 Compliance with study treatment 
Compliance (%) is defined as the percentage of total number of sachets/capsules taken 
as recorded in the CRF out of total number of planned doses (20 sachets and 40 capsules) 
and is determined separately for sachets and for capsules (for both active study drug and 
matching placebo study drug). If the total number of sachets/capsules taken are missing, 
compliance is set to missing.  
5.3.3 Study treatment discontinuation  
Reasons for study treatment premature discontinuation are recorded on the 
Premature Permanent Discontinuation of Study Treatment CRF.  
A subject is considered to have discontinued from the study treatment prematurely if at 
least one reason is reported, or the reason for treatment discontinuation on the Study 
Drug Log CRF is ‘premature permanent discontinuation’. 
Reasons for premature discontinuation have the following possible answers: ‘Death’, 
‘Lost to follow-up’, ‘Subject decision’ (further split into ‘Tolerability related’, ‘Efficacy 
related’, or ‘Other’), ‘Physician decision’ (further split into ‘Adverse event’, ‘Lack of 
efficacy / Treatment failure’ or ‘Other’) or ‘Sponsor decision’ (further split into ‘Study 
termination by sponsor’ or ‘Other’). An additional category would be called ‘Reason not 
provided’ for subjects where the reason is missing. 
Subjects who complete study treatment as per protocol are those with a record in the CRF 
Study Drug Log of ‘Completed as per protocol’ and who have not prematurely 
discontinued study treatment.  
The duration of an interruption period is derived as described for derivation of exposure 
in Section 5.3.1. 
Re-treatment discontinuation and corresponding reasons are recorded on the Re-treatment 
Study Drug Log CRF and are derived from this source in the same way as for the main 
study.  
5.3.4 Study treatment interruptions 
Study treatment interruptions are recorded on the Study Drug Log CRF. 
A subject is considered to have had a study treatment interruption (Yes/No) if any reason 
for treatment end is either ‘Temporarily interrupted due to an AE’ or ‘Temporarily 
interrupted not due to an AE’ (Study Drug Log CRF).  
For each subject, all study treatment interruptions with reason for interruption are 
considered.  


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Re-treatment interruptions are recorded on the Re-treatment Study Drug Log CRF and 
are derived from this source in the same way as for the main study.  
5.4 Study withdrawal 
Study withdrawal is recorded on the End of Study CRF. 
A subject is considered to have completed the study if ‘Did the subject complete the 
study?’ has been ticked as ‘Yes’. A subject is considered to have withdrawn from the 
study prematurely if ‘Did the subject complete the study?’ has been ticked as ‘No’.  
Possible reasons for withdrawal are ‘Death’, ‘Lost to follow-up’, ‘Subject decision’ 
(further split into ‘Withdrawal of consent from study participation’ or ‘Other’), 
‘Physician decision’ or ‘Sponsor decision’ (further split into ‘Study termination by 
sponsor’ or ‘Other’). An additional category would be called ‘Reason not provided’ for 
cases where the reason is missing. 
Study withdrawal is described separately for the main study and the re-treatment 
extension. Subjects are considered to have completed the main study if they have 
completed the study and were not enrolled in the re-treatment extension. Subjects are 
considered to have completed the re-treatment extension if they have completed the study 
and were enrolled in the re-treatment extension.  
Study withdrawal days: Several variables defining the number of days between a 
specific date and the date of study withdrawal are derived according to the definitions in 
Section 11.3: Study withdrawal days from first dose, study withdrawal days from last 
dose, study withdrawal days from first re-treatment dose and study withdrawal days from 
last re-treatment dose.  
5.5 Efficacy variables 
Regarding subjects who enter the re-treatment extension, only data collected prior to 
starting re-treatment with cadazolid (first re-treatment dose) are considered for all main 
study analysis variables [up to Section 5.5.4.8, inclusive], unless otherwise specified.  
For the re-treatment extension variables, only data collected after the start of re-treatment 
with cadazolid (first re-treatment dose) from subjects entering the re-treatment extension 
will be considered [see Section 5.5.5], unless otherwise specified.  
5.5.1 Primary efficacy variable: Clinical Cure 
Clinical Cure Rate (CCR; %) is the variable to be analyzed for the primary endpoint 
Clinical Cure, and is derived by the sponsor based on daily UBM information and 
concomitant medications recorded by the investigator in the CRF.  
CCR is the proportion of subjects meeting both criteria for Clinical Cure described below 
[see also Figure 3]: 


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• Resolution of diarrhea (ROD; ≤ 3 UBMs per day for at least 2 consecutive days) on 
study treatment and maintained for 2 days after EOT 
AND 
• No additional antimicrobial treatment active against CDAD (AMT) or fecal 
microbiota transplant (FMT) between first dose of study drug and 2 days after EOT 
(inclusive). 
In the event of death by any cause, or being lost to follow-up, or study withdrawal prior 
to EOT + 2 days, the subject is considered a Clinical Failure. 
Figure 3 
Derivation of Clinical Cure: Schematic overview 
 
 
AMT = antimicrobial treatment active against CDAD; FMT = fecal microbiota transplant; ROD = resolution of 
diarrhea. 
 
5.5.1.1 Derivation details 
Clinical Cure is assessed during the period from treatment start up to EOT + 2 days, i.e., 
starting after study treatment start date/time and ending on EOT + 2 days (inclusive). 
Note: EOT is defined as the date of last double-blind drug intake. Therefore the duration 
of the assessment period varies with treatment duration.  
ROD on treatment and ROD maintained up to EOT + 2 days: A subject is considered 
to have ROD on treatment and maintained up to EOT + 2 days if he has ≤ 3 UBMs for at 
least two consecutive days up to EOT date (inclusive) and subsequently ≤ 3 UBMs 
maintained up to EOT + 2 days.  
Note: This condition is met if and only if the subject has ≤ 3 UBMs on each day within 
the 4-day interval from EOT − 1 day to EOT + 2 days. 
≤ 3 UBMs per day (derived) is considered met if: 
1. ‘Daily number of UBMs’ (Daily Stool Information CRF) is ≤ 3.  
2. ‘≤ 3’ is ticked for the question ‘Daily number of UBMs, if exact number is not 
known’ (Daily Stool Information CRF). 
ROD maintained up 
to EOT + 2 days  
AMT or FMT 
up to EOT + 2 days 
Yes 
Yes 
No 
Clinical Failure 
Clinical Cure 
No 
EOS date prior 
EOT + 2 days 
Yes 
No 


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Where both 1 and 2 above are missing (investigator response of ‘Not known’ is not 
considered as missing):  
3. ‘Check if no bowel movement today’ is ticked ‘Yes’ in the daily stool diary (Stool 
Log CRF), the number of UBMs per day is assigned 0. 
Where both 1 and 2 above are missing or unknown: 
4. ‘Daily number of bowel movements’ is ≤ 3 (Daily Stool Information CRF). 
AMT up to EOT + 2 days: Derived as any antimicrobial treatment [as defined in 
Table 3] taken after treatment start date/time and up to EOT + 2 days (inclusive). 
FMT up to EOT + 2 days: Derived as any FMT [as defined in Section 5.2.6] performed 
after study treatment start date/time and up to and including EOT + 2 days. 
Study withdrawal (EOS date) prior to EOT + 2 days: A subject is considered to have 
withdrawn from the study prior to EOT + 2 days if the EOS date recorded on the EOS 
CRF (for any EOS reason, including death, lost to follow-up, or any other withdrawal) is 
prior to EOT + 2 days. For subjects that are lost to follow-up, the last contact date is used 
as the study withdrawal date instead of the EOS date (as the EOS date, in this case, 
represents an unsuccessful contact attempt per CRF completion guidelines). 
Handling of missing data for daily number of UBMs is detailed in Section 10.6.2, 
treating subjects with missing UBM information on critical days as failures. Handling of 
missing or partial EOT date is detailed in Section 12, and Clinical Cure is then being 
evaluated based on the imputed EOT date.  


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Figure 4 
Clinical Cure: Derivation examples  
AMT = antimicrobial treatment active against CDAD; EOS = End-of-Study; EOT = End-of-Treatment; FMT = fecal 
microbiota transplant; STS = Study treatment start; UBM = unformed bowel movement. 
 
5.5.1.2 Clinical Failure 
Subjects who do not fulfill the requirements for Clinical Cure (including due to missing 
data) are considered a Clinical Failure. Reasons for Clinical Failure will be categorized as 
described in Table 4.  
 
 
 
 
 
 
 
Days from Treatment Start 
1 
2 
3 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
4 
1 
2 
3 
4 
5 
≤ 3UBMs 
> 3UBMs 
EOT 
 
Yes 
EOT 
EOT 
EOT 
EOT 
 
 
 
 
UBM critical period: EOT – 1 to EOT + 2  
AMT, FMT or EOS assessed from STS to EOT + 2 
No 
AMT 
No 
No 
EOS 
No 
FMT 
Nr. 
Clinical 
Cure 
Missing UBMs 
6 
EOT  
 
No 


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Table 4 
Reasons for Clinical Failure 
Short description 
Derivation details 
AMT or FMT up to 
EOT + 2 days  
Any additional antimicrobial treatment active against CDAD taken or 
FMT received from treatment start up to EOT + 2 days. 
No AMT or FMT up to 
EOT + 2 days: 
 
No ROD on treatment 
Subject does not have ≤ 3 UBMs per day for at least 2 consecutive 
days on treatment (i.e., from treatment start date up to EOT day 
inclusive) and not classified as ‘Missing UBMs without ROD’.* 
ROD not maintained up to 
EOT + 2 days 
≤ 3 UBMs per day for at least 2 consecutive days on treatment but 
≤ 3 UBMs per day not maintained up to EOT + 2 days and not 
classified as ‘Missing UBMs with ROD’.* 
Missing UBMs without ROD 
Any day with missing UBMs and no day with > 3 UBMs between 
EOT – 1 day and EOT + 2 days and no ≤ 3 UBMs per day for at least 
2 consecutive days on treatment.* 
Missing UBMs with ROD 
Any day with missing UBMs and no day with > 3 UBMs between 
EOT – 1 day and EOT + 2 days and ROD, i.e., ≤ 3 UBMs per day for 
at least 2 consecutive days on treatment.* 
Premature withdrawal prior to 
EOT + 2 days  
Premature study withdrawal prior to EOT + 2 days and no AMT or 
FMT received up to date of withdrawal (EOS date). 
ROD maintained up to 
withdrawal 
≤ 3 UBMs per day for at least 2 consecutive days on treatment and 
≤ 3 UBMs per day maintained up to date of withdrawal (EOS date). 
No ROD / ROD not 
maintained up to withdrawal 
Not classified as ‘ROD maintained up to withdrawal’ above.  
* For subjects without AMT or FMT or premature withdrawal prior to EOT + 2 days. 
AMT = antimicrobial treatment active against CDAD; EOS = End-of-Study; EOT = End-of-Treatment; FMT = fecal 
microbiota transplant; ROD = resolution of diarrhea; UBM = unformed bowel movement. 
 
5.5.2 Secondary efficacy variables 
5.5.2.1 Sustained Cure 
Sustained Cure Rate (SCR, %) is the variable to be analyzed for the secondary endpoint 
Sustained Cure, and is derived by the sponsor based on daily UBM information, GDH 
and toxin test results and concomitant medications recorded by the investigator in the 
CRF. SCR is the proportion of subjects assessed as meeting the criteria for Sustained 
Cure up to Visit 5 (scheduled per protocol at EOT + 30 days, with protocol window of 
28 to 32 days). 
Sustained Cure is defined as Clinical Cure AND no recurrence. 


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Recurrence is defined for subjects with Clinical Cure as: 
• New episode of diarrhea (NED): > 3 UBMs on any day between EOT + 3 days and 
Visit 5 (inclusive) 
AND 
• Stool test showing positive C. difficile GDH and toxin test on the same stool sample 
(according to enzyme immunoassay [EIA] test approved by the sponsor) 
AND 
• Antimicrobial treatment active against CDAD (AMT) including participation in the 
re-treatment extension with cadazolid or fecal microbiota transplant (FMT) started 
between EOT + 3 days and Visit 5 (inclusive). 
Subjects with Clinical Failure or with Clinical Cure followed by recurrence are 
considered not to have Sustained Cure [see Figure 5]. Thus, the denominator for rate 
estimation includes all subjects in the relevant analysis set (mITT analysis set or PPS) for 
each treatment group to ensure a comparison based on the randomized treatment group.  
Figure 5 
Derivation of Sustained Cure: Schematic overview 
 
Clinical Cure is assessed up to EOT + 2 days. Sustained Cure is assessed up to Visit 5. 
STS = Study treatment start; EOT = End of Treatment date. 
 
Clinical 
Cure 
Recurrence  
from EOT + 3 days up to Visit 5 
Yes 
No 
Not Sustained Cure 
Sustained 
Cure 
STS 
EOT + 2 
Visit 5 
(scheduled: EOT + 28 to 32) 
Yes 
Premature Study Withdrawal 
prior to EOT + 28 days and prior to Day 38 
No 
Yes 
No 
Insufficient Follow-up 
Visit 5 prior to EOT + 28 days and prior to Day 38 
Yes 
No 


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5.5.2.1.1 Derivation details 
Premature Study Withdrawal prior to EOT + 28 days and Day 38: Subjects with 
Premature Study Withdrawal according to EOS CRF, i.e., EOS reason of death by any 
cause, study withdrawal (subject decision, physician decision, sponsor decision) or being 
lost to follow-up, and with Study Withdrawal date prior to EOT + 28 days and Day 38. 
These subjects are considered not to have a Sustained Cure even if there is no recurrence 
determined. 
Study Withdrawal date is defined as the EOS date unless the subject is lost to follow-up 
then it is defined as the last contact date [for definition see Section 11.3].  
Note: The EOS date for subjects lost to follow-up relates to an unsuccessful contact 
attempt. 
Insufficient Follow-Up: Subjects with Visit 5 conducted prior to EOT + 28 days and 
Day 38 are considered to have insufficient follow-up to evaluate Sustained Cure. These 
subjects are considered not to have a Sustained Cure even if there is no recurrence 
determined. 
Recurrence: A subject is considered to have a recurrence between EOT + 3 days and 
Visit 5 if the subject satisfies all 3 criteria for recurrence in the period from EOT + 3 to 
Visit 5: (i) NED (> 3 UBMs per day), (ii) positive GDH and toxin test and (iii) AMT or 
FMT, and the criteria regarding temporal relationship of the 3 elements described below 
are met.  
Temporal relationship between NED, positive GDH/toxin test and AMT/FMT for 
recurrence evaluation: 
A NED should precede the positive C. difficile GDH and toxin test and AMT/FMT. 
Similarly the positive GDH and toxin test should precede AMT. To avoid temporal 
dissociation between a NED and a positive C. difficile GDH and toxin test and treatment 
of recurrence the following rules are implemented for evaluation of recurrence: 
• A subject is only considered to have a recurrence if there is at least 1 day with 
> 3 UBMs within a window of 4 days prior to (and including) either the GDH and 
toxin test stool sample date or the AMT start date / FMT date (handling of missing 
UBMs: see below). 
• GDH and toxin test results for stool samples taken prior to a NED are not considered. 
• AMT/FMT with start date prior to a NED are not considered. 
• GDH and toxin test results for stool samples taken after the AMT start date or FMT 
date are not considered. 


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• If multiple GDH and toxin tests are performed during a period with daily number of 
UBMs > 3, only the latest stool sample for the toxin test prior to (and including) 
AMT start date or FMT date is considered.  
• Where > 3 UBMs occur on 1 or more days within the window 4 days prior to (and 
including) AMT start date (or FMT date) and the most recent GDH and toxin test is 
negative (or positive) but performed on a stool sample collected more than 4 days 
prior to AMT start date, the GDH and toxin test is not considered and the subject will 
be considered to have a recurrence in accordance with the missing data rules specified 
in Table 5.  
NED (> 3 UBMs per day): A NED is derived from the daily number of UBMs between 
EOT + 3 and Visit 5. The number of UBMs per day is determined in the same way as for 
Clinical Cure [Section 5.5.1]. If there are several consecutive days with > 3 UBMs, NED 
is the first day.  
Note: If Visit 5 occurs after EOT + 32 days, recurrence will be determined using NED 
information from EOT + 3 days up to EOT + 32 days.  
AMT or FMT between EOT + 3 days and Visit 5: Derived as  
• any AMT [as defined in Table 3] with start date between EOT + 3 days and Visit 5, 
inclusive, or if the subject participated in the re-treatment extension with cadazolid; 
or  
• any FMT between EOT + 3 and Visit 5 with FMT recorded in the Procedures CRF 
with a date between EOT + 3 days and Visit 5, inclusive.  
A subject is considered to participate in the re-treatment extension if at least one dose of 
open-label cadazolid has been taken, as recorded on the re-treatment study drug log CRF. 
AMT start date or FMT date is the start date of the AMT intake or re-treatment start date 
or the date FMT was performed.  
Positive GDH and toxin test from EOT + 3 and Visit 5: Derived as any positive result 
of an approved GDH and toxin test (either Quik Chek Complete toxin test or any other 
pre-specified test for GDH as well as toxin) recorded in the CDAD Diagnosis and 
Microbiology Sample CRF (subjects enrolled under protocol Version 3) or Fecal 
Sampling CRF (subjects enrolled under protocol versions prior to Version 3) at Visit 4.x 
(unscheduled visit for a NED), where the corresponding stool sample has been taken 
between EOT + 3 and Visit 5, inclusive.  
Similarly, a negative GDH and toxin test is derived as any negative result of an approved 
GDH and toxin test.  


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The relevant date of a GDH and toxin test is the date the corresponding stool sample was 
taken. It will be used to determine the temporal relationship between NED, toxin test and 
AMT/FMT.  
Handling of missing data:  
If a subject receives AMT or FMT, but any of the information to determine number of 
UBMs within the relevant time window, and a GDH and toxin test, is missing, the subject 
is still considered as having a recurrence and consequently does not have a Sustained 
Cure. Details are presented below in Table 5. 
Table 5 
Handling of missing data for the definition of recurrence 
AMT or FMT 
EIA GDH and toxin test 
approved by sponsor **  
> 3 UBMs 
(window) 
Recurrence 
Yes 
Missing or not done 
> 3 
Yes  
No 
Positive  
> 3 
No 
No 
Missing or not done 
> 3 
No 
Yes 
Positive 
Missing*  
Yes 
Yes 
Negative (current episode) 
Missing*  
No 
Yes 
Missing or not done 
Missing*  
Yes 
No 
Positive 
Missing*  
No 
No 
Negative 
Missing*  
No 
No 
Missing or not done 
Missing* 
No 
Yes 
Missing or not done 
≤ 3 
No 
No 
Positive 
≤ 3 
No 
No 
Missing or not done 
≤ 3 
No 
* Missing includes subjects who have 1 or more days with ‘unknown’ or missing UBMs from EOT + 3 days to 
Visit 5/Re-1 or in the 4 days prior to (and including) the GDH and toxin test stool sample date or AMT start date or 
FMT. 
** Only GDH and toxin tests on stool samples taken prior to AMT intake or FMT are considered. 
AMT = antimicrobial treatment active against CDAD; CDAD = Clostridium difficile-associated diarrhea; EIA = 
enzyme immunoassay; EOT = End-of-Treatment; FMT = fecal microbiota transplant; GDH = glutamate 
dehydrogenase; UBM = unformed bowel movement. 
 
Handling of missing Visit 5: For subjects entering the re-treatment extension, Visit 5 is 
not performed and recurrence is assessed between EOT + 3 days and start of re-treatment. 
For subjects that have neither Visit 5 nor started re-treatment, the variables Recurrence 
and Sustained Cure are evaluated using Study Withdrawal date instead of Visit 5 date. If 
Study Withdrawal occurs after EOT + 32 days, recurrence will be determined using NED 
information from EOT + 3 days up to EOT + 32 days.  
Handling of missing or partial EOT date is detailed in Section 12, and Sustained Cure 
will be evaluated based on the imputed EOT date (earliest between scheduled EOT date, 
EOS date, and death date).  


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Figure 6 
Sustained Cure: Derivation examples  
 
AMT = antimicrobial treatment active against CDAD; EOS = End-of-Study; EOT = End-of-Treatment; FMT = fecal 
microbiota transplant; SW = study withdrawal; UBM = unformed bowel movement. 
 
Reasons for Not Sustained Cure: 
Reasons for classifying subjects as Not Sustained Cure are further categorized as 
described in Table 6.  
 
 
 
Days from EOT 
3 
1 
2 
3 
4 
5 
≤ 3 UBMs 
> 3 UBMs 
Yes 
EOT + 3 days to Visit 5/ SW 
Yes 
No 
Yes 
W 
No 
Nr. 
Sustained 
Cure 
Missing UBMs 
6 
No 
28 
25 
21 
18 
15 
12 
9 
6 
31 
+ 
- 
Positive GDH and toxin test 
Negative GDH and toxin test 
A 
V5 
AMT or FMT 
Visit 5 
W Study Withdrawal 
A 
V5 
+ 
V5 
- 
A 
V5 
+ A 
A + 
A + 
7 
9 
V5 
W 
V5 
V5 
A 
+ 
A 
No 
No 
8 
V5 
A 
Yes 


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Table 6 
Reasons for Not Sustained Cure 
Short description 
Derivation details 
Not Sustained Cure 
 
Clinical Failure 
All subjects with Clinical Failure.  
Recurrence:  
Clinical Cure with recurrence 
AMT, Positive toxin test, 
> 3 UBMs (window) 
Subjects with AMT (including re-treatment or FMT between EOT + 3 
days and Visit 5), positive toxin test (i.e., approved GDH and toxin test 
with positive result between EOT + 3 days and the earliest of Visit 5 and 
AMT intake*), and at least one day with > 3 UBMs in the 4 days prior 
to (and including) AMT intake or sampling for GDH and toxin test.  
AMT, Positive toxin test, 
missing UBM (window) 
Subjects with AMT (as above), positive toxin test (as above), and at 
least one day with missing UBMs and no day with > 3 UBMs in the 
4 days prior to (and including) AMT intake or sampling for GDH and 
toxin test. 
AMT, No toxin test, 
> 3 UBMs (window) 
Subjects with AMT (as above), no toxin test (i.e., no approved GDH and 
toxin test result between EOT + 3 days and the earliest of Visit 5 and 
AMT intake*), and at least one day with > 3 UBMs in the 4 days prior 
to (and including) AMT intake.  
AMT, No toxin test, missing 
UBM (window) 
Subjects with AMT (as above), no toxin test (as above), and at least one 
day with missing UBMs and no day with > 3 UBMs in the 4 days prior 
to (and including) AMT intake. 
Premature Study Withdrawal 
prior to EOT + 28 days and 
Day 38 
Premature Study Withdrawal prior to EOT + 28 and Day 38 for subjects 
without recurrence. [Note: Includes only subjects with Clinical Cure].  
Insufficient follow-up 
Visit 5 date prior to EOT + 28 days and Day 38 for subjects without 
recurrence and without premature study withdrawal prior to EOT + 28 
days and Day 38 [Note: Includes only subjects with Clinical Cure]. 
* Toxin test results are considered if also within 4 days prior to and including AMT start date.  
AMT = antimicrobial treatment active against CDAD; EOT = End-of-Treatment; FMT = fecal microbiota transplant; 
GDH = glutamate dehydrogenase; UBM = unformed bowel movement. 
 
Reasons for classifying subjects with Clinical Cure with no Recurrence are further 
categorized as: subjects with no AMT taken; subjects with AMT and negative GDH or 
toxin test in window 4 days prior to (and including) AMT intake; and subjects with AMT, 
positive toxin test but ≤ 3 UBM on all days in the 4 days prior to (and including) AMT 
intake.  


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5.5.2.2 Time to ROD 
Time to ROD is defined as the time (h) elapsed between the first dose of study drug and 
the time when ROD is considered achieved. 
Time when ROD is considered achieved is the time of the last UBM prior to the first 
two consecutive 24 h periods with ≤ 3 UBM with subsequent maintenance of ≤ 3 UBMs 
per day up until EOT + 2. The condition of maintaining ≤ 3 UBMs per calendar day is 
determined based on the number of UBMs per day as derived for Clinical Cure 
[Section 5.5.1]. If this last UBM is prior to the first dose of study treatment, the time of 
ROD is considered equal to the date and time of first dose + 1 min and hence time to 
ROD is set to 1 min. 
Using the above criteria, the date and time when ROD is achieved is defined for subjects 
with ROD on study treatment and maintained up to EOT + 2 days, using the information 
from the Stool Log CRF or, if missing, is taken from the presence of > 3 UBMs in the 
Daily Stool Information CRF. 
If that daily UBM count is also missing or ‘unknown’ in the Daily Stool Information 
CRF, the subject is considered to have had > 3 UBMs on that day (i.e., ROD did not 
occur). If the timing of UBM is missing in the Stool Log CRF, the time when ROD is 
achieved is imputed as 23:59.  
Subjects without Clinical Cure are censored at EOT. Similarly, subjects who have 
withdrawn from the study, died, or are lost to follow-up before EOT + 2 days or have 
prematurely discontinued treatment are censored at the expected EOT day, i.e., 10 days 
after starting medication. This constitutes a right-censored observation. 
5.5.2.3 Change from baseline in CDI-DaySyms PRO domain scores at Day 3 
The CDI-DaySyms PRO has 10 items, from which three domain scores are derived: 
Table 7 
Domains and items of the CDI-DaySyms diary 
Domain scores 
Items 
Diarrhea Symptoms 
1. Diarrhea   
 
2. Feeling a need to empty bowels 
 
3. Needing to go to the bathroom 
Abdominal Symptoms 
4. Abdominal cramping 
 
5. Abdominal pain 
 
6. Feeling bloated 
Systemic/Other Symptoms 
7. Feeling tired 
 
8. Lack of Energy 
 
9. Lightheadedness 
 
10. Lack of appetite 
 


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Each item is scored on a 5-point Likert scale, with possible responses: “None”, “Mild”, 
“Moderate”, “Severe” and “Very Severe”. These responses are converted to numeric 
values, where None = 0, Mild = 1, Moderate = 2, Severe = 3 and Very Severe = 4. 
The domain score for each day is calculated as the mean of the non-missing responses for 
that domain on that day.  
If two adjacent responses (e.g., “mild”, “moderate”) are recorded by a subject for the 
same item on the same day, then the response is set to the worst case for this item, e.g., 
“moderate”. Any other cases of multiple responses, such as more than two responses or 
non-adjacent responses (e.g., “none”, “moderate”), are set to missing [see Appendix D].  
For the Diarrhea Symptoms domain, a score is always calculated if item 1 “Diarrhea” is 
available. Otherwise, the domain scores are only calculated if more than 50% of items for 
a domain are available on a day. As a sensitivity analysis, the Diarrhea Symptoms 
domain score is re-derived using this 50% rule, i.e., the score is only calculated if more 
than 50% of the items are available. 
The domain scores are calculated at each time point (i.e., for each day) from Day 1 
(baseline) to Day 12. The three domains are evaluated in a hierarchical manner, starting 
with Diarrhea Symptoms, then Abdominal Symptoms, and finally Systemic/Other 
Symptoms. 
5.5.3 Other efficacy variables 
5.5.3.1 Investigator’s assessment of Early Treatment Response at Visit 2 
The variable Early Treatment Response (ETR) is the ETR as assessed by the investigator 
at Visit 2 as improved, unchanged or worsened compared to baseline. It is taken from the 
Investigator Assessment of Early Treatment Response CRF. 
ETR rate (%) is the proportion of subjects considered to have ETR assessed as 
‘improved’. Subjects with missing assessment are considered as not improved for the 
analysis. 
5.5.3.2 Investigator’s judgment of Clinical Response at Visit 4 
The variable Investigator’s judgment of Clinical Response (ICR) is the ICR as assessed 
by the investigator at Visit 4 as Cure or Failure. It is taken from the CRF ‘Investigator 
judgment of Clinical Response (ICR)’. Reasons for assessing the ICR as cure or failure 
are taken from the answers in the same CRF. 
ICR rate (%) is the proportion of subjects with ICR assessed as cured. Subjects with 
missing assessment are considered as not cured for the analysis.  


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5.5.3.3 Investigator’s evaluation of Clinical Cure per protocol definition 
The variable Investigator’s evaluation of Clinical Cure per protocol (ICC) definition is 
taken from the Investigator evaluation of Clinical Cure per protocol definition CRF.  
5.5.3.4 Investigator’s judgment of Sustained Response at Visit 5 
The variable Investigator’s judgment of Sustained Response (ISR) is defined as the ISR 
as assessed by the investigator at Visit 5/Re-1 as Sustained Cure or Not Sustained Cure. It 
is taken from the Investigator judgment of Sustained Response CRF. Reasons for 
assessing the ISR as sustained cure or not sustained cure are taken from the same CRF. 
Subjects with missing assessment are considered as having ‘Not Sustained Cure’ for the 
analysis. 
ISR rate (%) is the proportion of subjects with ISR assessed as Sustained Cure at 
Visit 5/Re-1. 
5.5.3.5 Investigator’s evaluation of Sustained Cure per protocol definition 
The variable Investigator’s evaluation of Sustained Cure per protocol definition is taken 
from the Investigator evaluation of Sustained Cure per protocol definition CRF.  
5.5.3.6 Early Clinical Cure by Day 5 
Early Clinical Cure (ECC) rate (%) is the proportion of subjects assessed as meeting the 
criteria for ECC by Day 5, where the criteria for ECC is defined for a subject meeting 
both the following criteria: 
• ROD by Day 5: ≤ 3 UBMs per day for at least 2 consecutive days prior to or 
including Day 5 and maintained for 2 days after EOT 
AND 
• No additional AMT or FMT between first dose of study drug and 2 days after EOT 
(inclusive). 
ROD by Day 5 is determined from the number of UBMs per day in the same way as for 
Clinical Cure [Section 5.5.1]. To be considered as having Early Clinical Cure the subject 
must have ≤ 3 UBMs per day from Day 4 up to EOT + 2 days. If the number of UBMs on 
one or more days is missing or ‘unknown’ then the subject is considered a Failure. 
5.5.3.7 Normalization of bowel movements rate 
Normalization of bowel movements (NBM) rate is the proportion of subjects with NBM, 
where NBM is defined as: 
• ≤ 2 bowel movements per day and no UBM on at least 2 consecutive days up to EOT 
and maintained up to 2 days after last dose of study drug 


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AND 
• No additional AMT or FMT between first dose of study drug and 2 days after EOT 
(inclusive). 
The number of bowel movements and UBMs are determined from the Daily Stool 
Information CRF. Subjects with missing assessments are considered as not having had 
NBM for the analysis. 
5.5.3.8 Time to return to usual stools 
Time to return to usual stools is defined as the time (days) elapsed between the first dose 
of study drug and the first day where the stools have returned to usual for a subject, 
i.e., the number of bowel movements (including UBMs) per day ≤ number of bowel 
movements reported as usual by the subject and maintained for at least 3 calendar days. 
The number of usual bowel movements is reported by the subject at baseline and 
recorded in the CRF. Number of bowel movements per day is determined from the Daily 
Stool Information CRF (where days are measured according to calendar days) between 
date of first dose up to Visit 5 / re-treatment start date. If the number of bowel 
movements is missing but ‘Check if no bowel movement today’ is ticked ‘Yes’ (Stool 
Log CRF) the number of bowel movements per day is assigned 0 (unless ‘Daily number 
of UBMs’ entered by investigator is ‘exact number not known’).  
For subjects that have neither Visit 5 nor started re-treatment, the Study Withdrawal date 
is used instead of Visit 5 date in the derivation. 
Subjects without a return to usual stools are censored at the last date with known number 
of bowel movements (within Daily Stool Information CRF). Subjects without any day 
with known number of bowel movements are censored at study treatment start date.  
5.5.3.9 Recurrence rate and adjusted recurrence rate 
Recurrence rate (%) is the proportion of subjects assessed as having a recurrence [see 
definition in Section 5.5.2.1] out of subjects meeting the criteria for Clinical Cure. It is 
defined as: 
Recurrence rate (%) = 100 * 
Number of subjects with Recurrence
Number of subjects with Clinical Cure 
The Adjusted Recurrence Rate is the proportion of subjects assessed as having a 
recurrence out of subjects in the analysis set. It is defined as: 
Adjusted Recurrence Rate (%) = 100 * 
Number of subjects with Recurrence
Number of subjects in analysis set  
The following relationship exists between the two measures:  
Adjusted Recurrence Rate (%) = Recurrence Rate (%) * Clinical Cure Rate (%). 


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Recurrence rate estimates are accompanied by the proportion of subjects with recurrence 
in the analysis set. 
Recurrence is classified either as relapse or re-infection [Section 5.5.4.2]. 
5.5.3.10 Time to recurrence 
If a subject meets the criteria for recurrence then time to recurrence is determined. It is 
defined as the period (h) between the time of the last dose of study drug and the onset of 
the NED determined to be a recurrence.  
NED determined to be a recurrence is defined by a day with > 3 UBMs within the time 
window 4 days prior to (and including) AMT intake (or FMT date) or positive GDH and 
toxin test [see Section 5.5.2.1.1]. The date when the NED started is the first day with > 3 
UBMs in the time window. If this falls on the first day of the window, previous days are 
assessed for > 3 UBMs to determine the onset date of that NED. The period of interest is 
between EOT + 3 days and Visit 5 / re-treatment start date. 
Onset time of the NED is defined as the time of the first UBM recorded in the Stool Log 
CRF on the NED onset date. 
If NED information is missing (no day with > 3 UBMs in the time window), onset 
date/time is defined as either the date and time of positive EIA GDH and toxin test 
approved by the sponsor, or the start of AMT or FMT, or the start of re-treatment, 
whichever is earliest, between EOT + 3 days and Visit 5. Days with missing or not 
known UBMs are not considered for determining the onset date in derivations above. 
Subjects considered as having Sustained Cure, i.e., clinically cured and without 
establishment of recurrence or death, are censored at their Visit 5 date. Subjects who died 
after EOT + 3 days are censored at the date/time of death. Subjects without establishment 
of recurrence who are lost to follow-up without a Visit 5, are censored at the last contact 
date [see Section 11.3], and subjects without recurrence who have insufficient follow-up 
are censored at their Visit 5 date. If time (NED onset time or EOT time) is not available 
then time is imputed as 00:00. 
Subjects not clinically cured (and therefore not at risk for a recurrence) are not considered 
for this endpoint. 
If Visit 5 is missing it is replaced with the study withdrawal date in derivations (for 
subjects starting re-treatment it is replaced with the re-treatment start date).  


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5.5.3.11 Modified Sustained Cure 
Modified Sustained Cure is defined using the following modified definition of recurrence 
(independent of a C. difficile stool positive GDH and toxin test) for subjects with Clinical 
Cure. Modified recurrence is defined as follows: 
• NED (> 3 UBMs on any day between EOT + 3 days and Visit 5) 
AND 
• AMT (including participation in the re-treatment extension with cadazolid) or FMT 
started between EOT + 3 days and Visit 5). 
Subjects with Clinical Cure but without modified recurrence are considered to have a 
Modified Sustained Cure.  
All rules, including the handling of insufficient follow-up and missing data as specified 
for the variable SCR [Section 5.5.2.1], will apply to this modified SCR. 
5.5.3.12 CDI-DaySyms PRO response rate at Day 3 
Response Rate (%) = 100 * 
Number of subjects meeting response threshold
Number of subjects in analysis set
 
A responder to treatment is defined as a subject with an observed change from baseline in 
domain score below a predefined threshold for each domain, as described in Table 8. See 
the scoring and analysis guideline in Appendix D for more details of this definition.  
Change from baseline is derived as [value post-baseline] – [value at baseline], where 
baseline is the value recorded at Day 1. A negative value for change from baseline 
corresponds to a reduction in domain score, i.e., an improvement. Subjects with missing 
values at baseline or at Day 3 are considered to be non-responders.  
Table 8 
Threshold for responders (response definition) 
Domain Score 
Threshold 
Diarrhea Symptoms 
−1.00 
Abdominal Symptoms 
−0.80 
Other/Systemic Symptoms 
−0.70 
 
5.5.4 Microbiology variables 
Baseline is defined for microbiology variables as the last sample taken up to treatment 
start date (inclusive) with available result.  


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5.5.4.1 Isolation of C. difficile 
Isolation of C. difficile isolates by the central laboratory via culturing is planned to be 
performed per protocol at Visit 1, at Visit 3 for subjects considered Clinical Failure, and 
at Visit 4.x for subjects considered a Recurrence.  
A subject is defined as presenting: 
– a C. difficile isolate at the time point under consideration if C. difficile was isolated by 
the central laboratory from any stool sample corresponding to that time point 
(C. difficile culture result available with outcome ‘Isolated’), 
– no C. difficile isolate at that time point if C. difficile was not isolated by the central 
laboratory in all stool samples corresponding to that time point (C. difficile culture 
result available with outcome ‘Not isolated’).  
It is defined at the following time points: 
• Baseline, defined as the last sample taken (fecal sampling date/time) up to treatment 
start date (inclusive) with available C. difficile culture result, 
• Visit 3,  
• Visit 4.x, it is considered recovered if it was recovered in any stool sample collected 
at any Visit 4.a, 4.b, etc., or at Visit Re-1.  
The following definitions are considered: 
Baseline C. difficile isolate is defined as the C. difficile isolate from the baseline fecal 
sample (see baseline definition above for identifying the sample).  
Handling of multiple C. difficile isolates: In the unplanned event that multiple 
C. difficile isolates from different stool samples are present with identical fecal sampling 
date/time (e.g., due to unplanned testing of back-up samples), the isolate cultured earliest 
is considered for determining baseline. The isolate cultured earliest is identified by the 
earliest test or plating date/time or, if identical, by the lowest laboratory identifier number 
(MBREFID). All isolates for a subject and time point with duplicated fecal sampling 
date/time but not cultured earliest are flagged as repeats. 
Note: It is anticipated that the central laboratory may identify up to 2 phenotypically 
distinct C. difficile isolates from a small minority (i.e., < 1%) of stool specimens. Data on 
phenotypically distinct isolates from a single stool specimen (and single C. difficile 
culture) will be entered separately into the database. In these exceptional cases the 
results from isolate 2 will not be included in summary tables and figures, but will be 
included in listings. This applies also to all further C. difficile microbiology variables 
including typing and susceptibility variables. Isolate 2 data are identified in the data 
transfer specification by MBTEST variables ending with ‘ISOLATE 2’.  


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5.5.4.2 Typing of C. difficile 
C. difficile isolates are identified by using PCR ribotyping and restriction endonuclease 
assay (REA) typing information provided by the central laboratory.  
5.5.4.2.1 Ribotyping of C. difficile 
• Ribotype of a C. difficile isolate is the so-called ‘ribotype initial type’ provided by 
the central laboratory. Further ribotype information variables include the ribotype 
subtype and ribotype comments.  
• Hypervirulent ribotypes are those ribotype initial types belonging to the 
hypervirulent strains [see also Section 5.2.2]: 027, 244, 078. 
• Baseline ribotype, defined as the ribotyping result (initial type) from the baseline 
C. difficile isolate. 
• Ribotype as compared to baseline: comparison of ribotype information from 
post-baseline isolate against the baseline C. difficile isolate. They are defined as 
having: 
– Different ribotypes, in the event of different ribotype information at baseline vs 
post-baseline, i.e., either different initial type or subtype. 
– Identical ribotypes, in the event of matching ribotype information at baseline and 
post-baseline, i.e., identical initial type or initial types “AC-UNK” with identical 
subtype.  
5.5.4.2.2 REA typing of C. difficile 
• REA group of a C. difficile isolate is the so-called ‘REA initial group’ provided by 
the central laboratory. Further REA type variables include the ‘REA consistency’ (to 
be interpreted together with laboratory isolate number) and ‘REA comments’.  
• REA groups of special interest of a C. difficile isolate are the following REA initial 
groups: BI and BK group. Note: It is anticipated that BI group is equivalent to 
ribotypes 027 and 244, and BK group is equivalent to ribotype 078.  
• Baseline REA group, defined as the REA typing result (REA initial group) from the 
baseline C. difficile isolate. 
• REA type as compared to baseline: comparison of REA type information from 
post-baseline isolate against the baseline isolate. They are defined as having: 
– Identical REA groups, in the event of identical REA profiles: 
REA initial group is identical and samples have been identified as matching by 
the laboratory (either REA consistency is “Matches xxx” where “xxx” laboratory 
sample number [MRL ID] of the baseline isolate; or REA consistency contains a 
subtype [e.g., “Y6”] that is identical to the baseline subtype). 


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– Different REA groups, in the event of different REA profiles: 
Either REA initial group differs or REA consistency differs for subjects with 
identical REA initial group, i.e., samples have not been identified as matching by 
the laboratory (REA consistency is “Matches xxx, yyy, zzz, …” where none of 
“xxx”, “yyy”, “zzz”, … match the laboratory sample number [MRL ID] of the 
baseline isolate; or REA consistency contains a subtype [e.g., Y6] that differs 
from the baseline subtype).  
Notes: REA consistency of “None seen” does not reflect a subtype, and cannot be 
considered a confirmation that the REA profile differs from any other REA 
profile in the study. Therefore, the comparison of two isolates with identical REA 
initial group but REA consistency of “None seen” is considered undetermined.  
5.5.4.2.3 Relapse and Re-infection  
Subjects with Recurrence are classified either as: 
• Relapse: Identical C. difficile strain identified either by REA typing or ribotyping at 
new episode of diarrhea and baseline, i.e., subjects with identical ribotypes and 
identical REA groups as per definitions above, at (all) new episode of diarrhea visit(s) 
as compared to baseline.  
OR 
• Re-infection: Different C. difficile strains identified either by REA typing or 
ribotyping at (any) new episode of diarrhea and baseline, i.e., subjects with either 
different ribotype or different REA group at (any) new episode of diarrhea visit(s) as 
compared to baseline. 
New episode of diarrhea visit(s), Visit 4.x, are defined as: Visit 4.a, 4.b, etc., and 
Visit Re-1. Repeat isolates with identical fecal sampling date/time as defined in 
Section 5.5.4.1 are included in the derivation of relapse and re-infection.  
Handling of missing typing information: A subject with Recurrence is considered to be 
undetermined for Relapse and Re-infection if no C. difficile typing information is 
available at baseline or at (any) new episode of diarrhea visit(s). If typing information is 
missing for one of the two typing methods only, the classification is performed using the 
available typing information at baseline and at Visit 4.x, i.e., the subject is considered a 
Relapse if the available C. difficile typing information is identical, a Re-infection if the 
available typing information is different, and undetermined if the available typing 
comparison is undetermined.  
5.5.4.3 Susceptibility of C. difficile 
Susceptibility of C. difficile to different antibiotics is determined at the central laboratory 
for each C. difficile isolate by the minimum inhibitory concentration (MIC; in µg/mL) of 


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the test agent (i.e., cadazolid, vancomycin, linezolid, moxifloxacin, metronidazole and 
fidaxomicin) which inhibits bacterial growth. Per protocol it is planned to be evaluated at 
Visit 1, for Clinical Failures at Visit 3, and for Recurrences at Visit 4.x if C. difficile was 
isolated [see Section 5.5.4.1].  
Susceptibility of C. difficile to each of the test agents is the MIC (µg/mL) reported by the 
central laboratory and is defined at the following time points: 
• Baseline, defined as the MIC result from the baseline C. difficile isolate. 
• Visit 3. 
• Visit 4.x, the maximum MIC of C. difficile in stool samples collected at any Visit 4.a, 
4.b, etc., or Visit Re-1. 
• Maximum post-baseline result, maximum MIC of C. difficile during main study. 
Handling of multiple C. difficile isolates: In the event of multiple post-baseline isolates at 
a time point, the highest MIC is considered for analysis. At baseline the MIC of the 
baseline C. difficile isolate is considered. 
Note: The MIC values will be provided using categories such as: ≤ 0.03, 0.06, 0.12, 0.25, 
0.5, 1, 2, 4, 8, 16, 32, > 32. The range of tested MIC depends on the test agent.  
5.5.4.4 Change from baseline in susceptibility of C. difficile 
This variable is defined as the relative change in MIC of cadazolid, vancomycin, 
linezolid, fidaxomicin, metronidazole, and moxifloxacin at post-baseline compared to 
baseline using the following ratio: MIC at post-baseline / MIC at Baseline. MIC 
classified as > × µg/mL, will be treated as belonging to the next highest dilution, i.e., 
2 × µg/mL (e.g., > 32 will be treated as 64), for the purpose of computing the ratio. The 
change from baseline is grouped into the categories described below in Table 9.  
Table 9 
Relative changes in minimum inhibitory concentration 
Category 
Example Changes (µg/mL) 
≥ 4-fold decrease 
e.g., decrease from 16 to 4, or from > 32 to 16, or 16 to 2, or 
> 32 to 8 
2-fold decrease 
e.g., decrease 8 to 4, or from > 32 to 32, or 0.06 to ≤ 0.03  
No MIC change 
No change, e.g., from 8 to 8 
2-fold increase 
e.g., increase from 4 to 8, or from 32 to > 32, or ≤ 0.03 to 0.06 
≥ 4-fold increase 
e.g., increase from 4 to 16, or from 16 to > 32, or ≤ 0.03 to 
0.125 
MIC = minimum inhibitory concentration. 


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5.5.4.4.1 Antibiogram comparison to baseline 
Defined as antibiogram comparison of post-baseline isolate with the baseline isolate. Two 
C. difficile isolates are considered to have: 
• Different antibiograms, in the event of a ≥ 4-fold MIC difference of C. difficile in two 
unrelated test agents, i.e.,  
– ≥ 4-fold MIC difference in at least one cadazolid related agent (cadazolid, 
linezolid, moxifloxacin)  
AND 
– ≥ 4-fold MIC difference in at least one cadazolid nonrelated agent (vancomycin, 
metronidazole, fidaxomicin) 
• Similar antibiograms, if susceptibility of C. difficile information for both isolates is 
available (for at least one agent per group) and they are not considered to have 
different antibiograms.  
5.5.4.5 Isolation of vancomycin-resistant enterococci 
Isolation of vancomycin-resistant enterococci (VRE; central laboratory) is performed by 
the central laboratory at baseline and at Visit 3.  
Baseline is defined as the last fecal sample (fecal sampling date/time) taken up to 
treatment start date (inclusive) with available VRE isolation result (i.e., VRE-positive or 
VRE-negative), see also note below.  
A subject is defined at a time point to be: 
• ‘VRE-positive’ where vancomycin-resistant enterococci were present in any test 
sample corresponding to that time point: 
Any VRE type (vancomycin-resistant Enterococcus faecium, vancomycin-resistant 
Enterococcus faecium 
2nd 
colony 
morphology, 
vancomycin-resistant 
Enterococcus faecalis, 
vancomycin-resistant 
Enterococcus faecalis 
2nd 
colony 
morphology, or vancomycin-resistant Enterococcus not E. faecium and not 
E. faecalis) with outcome “Isolated” or with recorded quantitative counts.  
• ‘VRE-negative’ where vancomycin-resistant enterococci were not present in all test 
samples corresponding to that time point: 
Vancomycin-resistant Enterococcus with outcome “No isolated”.  
Handling of multiple test samples at a time point: If multiple test samples (different 
MBREFID) with identical fecal sampling date/time are available at a time point then the 
sample for analysis or determining the baseline VRE test sample is identified in the 
following hierarchy: (i) prefer VRE-positive samples over VRE-negative samples, 


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(ii) select earliest test sample (test sample with earliest testing date/time), or if identical 
testing date/time, use the lowest laboratory identifier number MBREFID. This approach 
also applies to all variables related to VRE defined in the following Sections 5.5.4.6 to 
5.5.4.8.  
Rationale: This situation is not expected as per protocol and may only arise in rare case of 
unplanned testing of e.g., back-up samples. 
5.5.4.6 Vancomycin-resistant enterococci quantitative culture  
The central laboratory provides the density of VRE counts (log10 cfu/mL) at baseline and 
Visit 3 for all subjects with quantifiable VRE counts by VRE type.  
Total VRE counts (log10 cfu/mL) per test sample are defined as the log10 of the sum of 
counts (x cfu/mL = 10^{x log10 cfu/mL}) for isolates identified as: vancomycin-resistant 
Enterococcus faecium, vancomycin-resistant Enterococcus faecalis and vancomycin-
resistant Enterococcus not E. faecium and not E. faecalis, including also second colony 
morphology counts.  
Total VRE counts for subjects considered VRE-negative at a time point, i.e., with no 
VRE present, are imputed for the analysis with a Total VRE count of 0 log10 cfu/mL 
(= 1 cfu/mL). This approach allows allocation of a suitable VRE count value to subjects 
with no VRE present.  
Total VRE counts and VRE counts per VRE type are considered at baseline and Visit 3. 
Baseline VRE count is defined as VRE count from the baseline VRE test sample [see 
Section 5.5.4.5]. Note: A quantitative VRE assessment includes all VRE types assessed 
within the same test sample, i.e., for assessing total counts VRE types should not be 
selected from different test samples (different MBREFIDs). 
5.5.4.7 Change from baseline in vancomycin-resistant enterococci quantitative 
culture at Visit 3 
This is defined as the difference between the Visit 3 and baseline total VRE counts 
(log10 cfu/mL). It is derived including imputed total VRE counts.  
5.5.4.8 Susceptibility of vancomycin-resistant enterococci to different antibiotics  
Susceptibility of VRE performed by the central laboratory is defined as the MIC (µg/mL) 
of the test agents (cadazolid, vancomycin, linezolid, moxifloxacin, fidaxomicin, 
daptomycin, tigecycline, ampicillin, gentamicin, and quinupristin-dalfopristin).  
It is determined at baseline and by visit per isolate type: VRE faecium (first and second 
colony), VRE faecalis (first and second colony) and VRE not faecium not faecalis; and 
for any type (first colony) as the highest MIC of VRE faecium, VRE faecalis, or VRE not 
faecium not faecalis (first colony only). Change from baseline in susceptibility of VRE is 
defined as described in Table 9 for change from baseline in susceptibility of C. difficile. 


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5.5.5 Re-treatment extension variables 
Primary and relevant secondary efficacy variables for the re-treatment extension with 
cadazolid are defined in the same way as the corresponding variables described above for 
the main double-blind part of the study with the appropriate change in dates or periods or 
interest. 
Re-treatment Clinical Cure: 
In the re-treatment extension, resolution of diarrhea is determined on re-treatment and 
maintained up to End of Re-treatment + 2 days. The algorithm is the same as the one 
described in Section 5.5.1, but using the information reported during the re-treatment 
with cadazolid. 
Recurrence after re-treatment: 
Recurrence is defined as for the main treatment period but using End of 
Re-treatment + 3 days and the Re-5 visit. For re-treated subjects with missing Re-5 visit, 
evaluation is based on Study Withdrawal date instead of Re-5 visit date. 
Re-treatment Sustained Cure: 
Sustained Cure is defined as Clinical Cure in the re-treatment extension period and no 
recurrence during the follow-up period up to Visit Re-5. For re-treated subjects with 
missing Re-5 visit, evaluation is based on Study Withdrawal date instead of Re-5 visit 
date.  
In the event of death by any cause, premature study withdrawal or being lost to 
follow-up, from End of Re-treatment + 2 days and prior to End of Re-treatment + 28 
days, and premature study withdrawal prior to 38 days from first re-treatment dose, the 
subject is considered not to have a Sustained Cure in the re-treatment extension period.  
Re-treatment microbiology variables: 
Microbiology variables during re-treatment are defined identically to those defined for 
the main study but using re-treatment baseline instead of baseline, and Visit Re-3 and 
Visit Re-4.x instead of Visit 3 and Visit 4.x respectively.  
Re-treatment Baseline for microbiology variables is defined based on the last sample 
taken up to re-treatment start date (inclusive) with available result. Only samples after 
EOT are considered. 
5.6 Safety variables 
Safety variables are defined in this section for the main study (double-blind part and 
follow-up) and for the open-label re-treatment extension.  


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Main study safety variables for subjects who enter the re-treatment extension, are 
considering information from study treatment start up to re-treatment start. Re-treatment 
extension safety variables consider information collected after re-treatment start.  
The period defining treatment-emergent events is defined for this study from study 
treatment start up to EOT + 7 days.  
Similarly the period defining re-treatment emergent events is defined from open-label 
re-treatment start up to End of Re-treatment + 7 days.  
In addition the period from study treatment start up to Visit 5 is used for main study 
safety displays. Visit 5 is planned to be conducted between EOT + 28 and EOT + 32 
days. It is the last visit conducted during the main study follow-up period and is expected 
to be the EOS date. In the event of missing Visit 5, information up to EOS is considered.  
Similar re-treatment extension displays are prepared from re-treatment start up to 
Visit Re-5, which is scheduled to be conducted between End of Re-treatment + 28 and 
+ 32 days and is expected to be the EOS date for re-treated subjects.  
5.6.1 Adverse events 
An AE is any event reported by the investigator on the Adverse Event CRF. All AEs are 
coded using MedDRA version 19. Each preferred term is counted as an event. 
AEs are classified according to the period of occurrence of the event. Events are 
considered to be: 
• Main study adverse events: where the start date/time of the event is from the first 
dose date/time of intake of study treatment up until Visit 5 (inclusive) or prior to the 
first dose of re-treatment with cadazolid. 
• Treatment-emergent adverse events: where the start date/time of the event is from 
the first dose date/time of intake of study treatment up to EOT + 7 days (inclusive) or 
prior to the first dose of the re-treatment period (if before EOT + 7 days).  
• Re-treatment extension adverse events: where the start date/time of the event is 
from the first dose date/time of starting re-treatment with cadazolid up until 
Visit Re-5 (inclusive). 
• Re-treatment-emergent adverse events: where the start date/time of the event is 
from the first dose intake of re-treatment up to the End of Re-treatment + 7 days 
(inclusive). 
In the event of missing or incomplete dates/times, the rules described in Section 12 are 
applied.  


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Several variables defining the number of days between a specific date and the onset date 
of an AE are derived according to definitions in Section 11.3: AE days from first dose, 
AE days from last dose, AE days from first re-treatment dose, and AE days from last 
re-treatment dose. The AE duration is defined as AE end date minus AE onset date + 1.  
5.6.1.1 Frequency of treatment-emergent adverse events 
Treatment-emergent AEs reported more than once for one subject within a specified time 
period are counted in the frequency table once. 
5.6.1.2 Intensity of adverse events 
The intensity of an AE is defined as mild, moderate or severe.  
AEs reported more than once (as qualified by the same preferred term) for a subject 
within a specified time period but with different intensities are counted only once, with 
the worst reported intensity, in the corresponding analysis. If intensity is missing, the 
event is considered severe. 
5.6.1.3 Relationship of adverse events 
Relationship to study treatment is defined as ‘related’ or ‘not related’. An event is 
considered related if the response to the question ‘Is there a reasonable possibility that the 
Adverse Event was related to the use of study drug?’ is answered ‘Yes’. 
For AEs reported more than once (as qualified by the same preferred term) for a subject 
within a specified time period, the worst relationship reported is taken. Adverse events 
with missing relationship are considered in any analysis as related. 
5.6.2 Deaths 
Death days from first dose and death days from last dose are derived using the definitions 
in Section 11.3 with respect to the date of the death. 
5.6.2.1 All deaths 
Death information is taken from the Death CRF. The primary cause of death is reported 
on the same form. 
5.6.2.2 Adverse events with fatal outcome 
AEs with an outcome reported as ‘death’ are considered as AEs with fatal outcome. 
5.6.3 Serious adverse events 
An AE is considered serious if the investigator ticked ‘Yes’ on the question ‘Serious?’ of 
the Adverse Event CRF. AEs with seriousness criteria missing are considered in any 
analysis as serious AEs. 


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5.6.4 Non-serious adverse events 
An AE is considered non-serious if it is not a serious adverse event. 
5.6.5 Adverse events leading to discontinuation of study treatment 
These are AEs with ‘Action taken with study drug’ recorded as ‘permanently 
discontinued’ on the Adverse Event CRF. 
5.6.6 Other significant adverse events 
No other significant adverse events are defined. If, based on the safety reviews, a signal 
of a potential safety issue is identified, the SAP will either be amended or an addendum 
written to define the rules to identify the events of interest. 
5.6.7 Vital signs and body weight 
Vital signs, comprising systolic blood pressure (SBP), diastolic blood pressure (DBP), 
heart rate (HR), body temperature and body weight are collected on the Vital Signs CRF, 
scheduled at Visits 1, 3, 4.x (excluding body weight), 5, Re-1, Re-3 and Re-5. 
The following variables are defined: 
• Baseline: The last vital sign assessment (per type) before the date and time of first 
dose intake of double-blind treatment. (Assessment types: blood pressure and heart 
rate, temperature, body weight, height.) 
• Re-treatment Baseline: The last vital sign assessment before the date and time of 
first dose intake of re-treatment with cadazolid. Only assessments after EOT are 
considered. 
• Change from baseline in SBP, DBP, HR, body weight and temperature: Absolute 
difference in these measurements between the visit and the baseline.  
• Change from re-treatment baseline in SBP, DBP, HR, body weight and 
temperature: Defined for visits during re-treatment extension as the absolute 
difference in these measurements between the visit and the re-treatment baseline. 
• Marked abnormalities in SBP and DBP: Defined in Table 10. 
• Treatment-emergent marked abnormalities in SBP and DBP: Any marked 
abnormality not present at baseline or if a worsening occurred, as compared to the 
corresponding value at baseline (e.g., change from no marked abnormality to any 
marked abnormality, from HH to LL or from HH to HHH). The worst abnormality is 
considered in each direction separately (Low and High). The time window of interest 
is from after the first intake of study treatment up to EOT + 7 days (inclusive) or first 
drug intake of the re-treatment period (if applicable), whichever occurs first.  


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• Re-treatment-emergent marked abnormalities in SBP and DBP: Defined as for 
treatment-emergent marked abnormalities, except the time window is from after the 
first drug intake of the re-treatment period up to End of Re-treatment + 7 days 
(inclusive). The re-treatment baseline is used to determine worsening during the 
re-treatment emergent period. 
• Main study marked abnormalities in SBP and DBP up to Visit 5: Main study 
marked abnormalities are defined as for treatment-emergent marked abnormalities 
above, except the time window of interest is from after the first drug intake up to 
Visit 5 (inclusive) or first drug intake of the re-treatment period (if applicable).  
• Re-treatment extension marked abnormalities in SBP and DBP up to Visit Re-5: 
Defined as above, except the time window of interest is after the first drug intake of 
re-treatment up to Visit Re-5. The re-treatment baseline is used for worsening during 
the re-treatment extension. 
• Vital signs days: Vital signs days from first dose is derived according to definition in 
Section 11.3 with respect to the assessment date. 
Position of the body at the moment of the vital signs measurement will not be taken into 
account in these definitions as the protocol allows measurement of BP in different 
positions. If SBP and DBP are taken in a different position at a post-baseline visit than at 
the baseline visit, the change from baseline will be derived irrespective of the position.  
Body temperature may be measured in different locations (rectal, oral, ear, axilla) in °C 
or °F. Conversion rules are provided in Section 11.1. 
Table 10 
Marked abnormalities in blood pressure 
Blood pressure 
LL 
LLL 
HH 
HHH 
SBP (mmHg) 
SBP < 90  
or 
decrease > 20 from baseline 
- 
SBP 140–159 
or 
increase > 20 from baseline 
SBP ≥ 160 
DBP (mmHg) 
DBP < 50  
or 
decrease > 10 from baseline 
- 
DBP 90–99 
or 
increase > 10 from baseline 
DBP ≥ 100 
Normal limits: 90 ≤ SBP < 140, 50 ≤ DBP < 90 
DBP = diastolic blood pressure, SBP = systolic blood pressure. 
 


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5.6.8 Electrocardiography 
ECGs are scheduled at Visits 1, 3, 5, Re-1, Re-3 and Re-5, and outcomes are recorded 
either on the local ECG forms of the CRF if assessed at the site, or provided by the 
central ECG provider electronically.  
The following ECG parameters are considered: PR (ms), QRS (ms), QT (ms), HR (bpm), 
RR (s), QTcB (ms) and QTcF (ms).  
Local ECG parameters are recorded in the CRF, apart from the QTc parameters which 
are automatically derived in the CRF. If QTcB (ms) or QTcF (ms) for local ECG 
assessments are missing they are derived using the following formulae:  
QTcB (ms) = QT (ms)/RRder1/2, where RRder is 60/HR (bpm). 
QTcF (ms) = QT (ms)/ RRder1/3, where RRder is 60/HR (bpm). 
Qualitative ECG abnormalities (findings) are recorded in the CRF or provided from the 
central ECG provider. The standardized coded terms (EGSTRESC) are considered.  
The following variables are defined: 
• Baseline: The last ECG assessment before date and time of first dose intake of 
double-blind treatment. (An ECG assessment includes all ECG parameters 
determined at the same collection date/time.)  
• Changes from baseline in ECG parameters: The absolute difference between the 
visit and the baseline for each ECG parameter (HR, PR, QT, QRS, QTcB, QTcF).  
• Re-treatment baseline: The last ECG assessment before date and time of first dose 
intake of re-treatment with cadazolid. Only assessments after EOT are considered. 
• Changes from re-treatment baseline in ECG parameters: Defined for visits during 
re-treatment extension as the absolute difference between the visit and the 
re-treatment baseline for each ECG parameter (HR, PR, QT, QRS, QTcB, QTcF). 
• Treatment-emergent marked abnormalities (change) in QT/QTc: A change is 
defined as an increase from baseline in QT, QTcB or QTcF, which is > 30 ms (HH), 
or by an increase from baseline > 60 ms (HHH). It is considered treatment-emergent 
if it occurred after first dose intake up until EOT + 7 days (inclusive) or first drug 
intake of the re-treatment period (if applicable), whichever occurs first.  
• Re-treatment-emergent marked abnormalities (change) in QT/QTc: Defined as 
above except the time window is after the first drug intake of re-treatment up to End 
of Re-treatment + 7 days, and the increases are determined from the re-treatment 
baseline. 


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• Treatment-emergent QT/QTc marked abnormalities (absolute): There are three 
different categories of abnormalities for QT/QTc (QTcB or QTcF) values; they are 
defined as: QT/QTc > 450 ms (H), > 480 ms (HH), or > 500 ms (HHH). An 
abnormality is considered treatment-emergent if it occurred after first dose intake of 
study treatment up until EOT + 7 days (inclusive, or first drug intake of the 
re-treatment if applicable), and it worsened from baseline, i.e., a change from no 
marked abnormality to HH or HHH, or from HH to HHH. The worst abnormality is 
used for analysis. Examples for treatment-emergent abnormalities for QT/QTc are 
given in Table 12. In order to allow appropriate interpretation of overall incidence of 
abnormalities > 450 ms, the marked abnormalities are presented cumulatively, e.g., a 
QTc value of 501 ms is reported in > 450 ms (H), > 480 ms (HH) and > 500 ms 
(HHH) categories. 
• Re-treatment-emergent QT/QTc marked abnormalities (absolute): Defined as 
above, except the time window is after the first drug intake of re-treatment up to End 
of Re-treatment + 7 days (inclusive). The re-treatment baseline is used to determine 
worsening during re-treatment. 
• Treatment-emergent qualitative ECG abnormalities (findings): defined as a 
finding that was not present at baseline and where the ECG interpretation is 
abnormal. It is considered treatment-emergent if it occurred after first dose intake up 
until EOT + 7 days (inclusive) or first drug intake of re-treatment (if applicable), 
whichever occurs first.  
• Re-treatment-emergent qualitative ECG abnormalities (findings): Defined as 
above, except the time window is after the first drug intake of re-treatment up to End 
of Re-treatment + 7 days, and the increases are determined from the re-treatment 
baseline. 
• Main study QT/QTc marked abnormalities (absolute and change): Defined as for 
treatment-emergent QT/QTc marked abnormalities except the time window is after 
the first dose of treatment intake up until Visit 5 (or first dose of re-treatment if 
applicable). 
• Main study qualitative ECG abnormalities (findings): Defined as for 
treatment-emergent qualitative ECG abnormalities except the time window is after 
first dose intake of treatment up until Visit 5 (or first dose of re-treatment if 
applicable). 
• Re-treatment QT/QTc marked abnormalities (absolute and change): Defined as 
above, except the time window is after the first drug intake of the re-treatment up to 
Visit Re-5, and baseline is the re-treatment baseline. 


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• Re-treatment qualitative ECG abnormalities (findings): Defined as above, except 
the time window is after the first drug intake of the re-treatment up to Visit Re-5, and 
baseline is the re-treatment baseline. 
• ECG days: ECG days from first dose is derived according to the definition in 
Section 11.3 with respect to the assessment date. 
Note: If both central and local ECG readings are available at a time point, only the 
central ECG reading is taken into account for displays in tables and figures. All 
measurements will be displayed in listings.  
Table 11 
Marked abnormalities in ECG (absolute and change) 
Parameter 
LL 
LLL 
H 
HH 
HHH 
QT/ QTc (ms) (absolute) 
 
 
> 450 
> 480 
> 500 
QT/ QTc (ms) (change) 
 
 
 
> 30 
> 60 
QTc = corrected QT. 
 
Table 12 
Examples of treatment-emergent QT/QTc marked abnormalities 
Treatment-emergent (Yes, No) 
 
 
Category/Threshold 
Baseline 
Post-baseline 
H 
HH 
HHH 
449 ms 
451 ms 
Yes  
No 
No 
455 ms 
469 ms 
No 
No 
No 
455 ms 
481 ms 
Yes 
Yes 
No 
455 ms 
501 ms 
Yes 
Yes 
Yes 
Note: Treatment-emergent QT/QTc marked abnormalities are presented in a cumulative way.  
 
5.6.9 Laboratory 
Laboratory parameters (hematology, coagulation and chemistry) are collected on the 
central or local laboratory CRF. Assessments are performed at Visits 1, 3, 4.x, 5, Re-1, 
Re-3, Re-5 and unscheduled visits. 
The following parameters are considered: 
• Hematology: Hemoglobin, hematocrit, platelets, erythrocytes, WBC counts (or 
leukocytes), neutrophils, lymphocytes, monocytes, eosinophils, basophils. 
• Coagulation: Prothrombin time, international normalized ratio (INR), activated 
partial thromboplastin time. 


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• Chemistry: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase, total bilirubin, direct bilirubin, creatinine, urea / blood urea 
nitrogen (BUN), sodium, potassium, chloride, calcium, protein, albumin. 
All parameters are considered in SI units and results are taken from the central laboratory 
CRF. Manual differentials (neutrophils, lymphocytes, monocytes, eosinophils, basophils) 
are used where automated ones are not provided by the central laboratory. Pre-CDAD 
diagnosis assessment of creatinine is not included in the analyses of laboratory variables 
[Section 10.9.4] as this laboratory test is historical and not performed as part of the study. 
If, for a visit, no central laboratory result is available, but a local laboratory result is 
recorded on the same date, the local laboratory result is used. If the normal ranges differ 
between local and central laboratory, only for graphics or tables with average values, the 
local laboratory value (Yloc) and their normal ranges (LLNloc, ULNloc) are normalized as 
Ynorm using the central laboratory normal ranges (LLN, ULN) as follows: 
Y𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛= 𝐿𝐿𝐿𝐿𝐿𝐿+ ( Y𝑙𝑙𝑙𝑙𝑙𝑙 − LLN𝑙𝑙𝑙𝑙𝑙𝑙 ) 
( ULN𝑙𝑙𝑙𝑙𝑙𝑙− LLN𝑙𝑙𝑙𝑙𝑙𝑙 ) ∗(ULN −LLN) 
 
If the value is negative after normalization, zero will be assigned.  
When determining marked abnormalities, all assessments, including unscheduled and 
local laboratory results, are considered. Marked abnormalities for local laboratory results 
are derived based on the non-normalized results except where change from baseline is 
used (hemoglobin when assessing HH and HHH, INR for subjects on anticoagulation, 
and creatinine when assessing if > multiple of baseline). The central laboratory provides 
BUN and not urea. However urea may be reported by the local laboratories in rare cases 
of unscheduled visits. For deriving marked abnormalities in BUN, local laboratory urea 
results are considered as BUN with conversion factor 1 (mmol/L).  
The following variables are defined for each parameter separately: 
• Baseline: The last assessment before date and time of first dose intake of study 
treatment. 
• Re-treatment Baseline: The last assessment before date and time of first dose intake 
of study re-treatment. Only assessments after EOT are considered. 
• Change from baseline: The absolute difference between the visit and the baseline 
values.  
• Change from re-treatment baseline: Defined for visits during re-treatment 
extension as the absolute difference between the visit and the re-treatment baseline 
values.  


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• Marked abnormalities in laboratory parameters are defined in Table 13. 
• Treatment-emergent laboratory marked abnormalities: Any marked abnormality 
not present at baseline if a worsening occurred as compared to the corresponding 
value at baseline (e.g., from no marked abnormality to any marked abnormality, from 
LL to LLL or from HH to HHH). The worst abnormality is considered in each 
direction separately (Low and High). The time window of interest is after the first 
drug intake up to EOT + 7 days (inclusive) or first drug intake of the re-treatment (if 
applicable), whichever occurs first. 
• Re-treatment-emergent laboratory marked abnormalities: Defined as for 
treatment-emergent abnormalities, except the time window is after the first drug 
intake of the re-treatment period up to End of Re-treatment + 7 days (inclusive). 
Worsening is compared to the re-treatment baseline. 
• Main study marked abnormalities up to Visit 5: Defined as for treatment-emergent 
marked abnormalities, except the time window of interest is from the first drug intake 
up to Visit 5 (or first drug intake of the re-treatment, whichever occurs first). 
• Re-treatment extension marked abnormalities up to Visit Re-5: As above, except 
the time window is after the first drug intake of re-treatment up to Visit Re-5 
(inclusive). Worsening is compared to the re-treatment baseline. 
• Laboratory days: Laboratory days from first dose and laboratory days from last dose 
are derived according to the definition in Section 11.3 with respect to the assessment 
date. 


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Table 13 
Marked abnormalities in laboratory parameters 
Safety Parameter 
LL 
LLL 
HH 
HHH 
Hematology 
 
Hemoglobin (g/L) 
< 100 
< 80 
Increase (> 20 g/L) 
above ULN or above 
baseline if baseline is 
above ULN 
Increase (> 40 g/L) 
above ULN or above 
baseline if baseline is 
above ULN 
Hematocrit (%) 
< 28% F 
< 32% M 
< 20% 
> 60% M 
> 55% F 
> 65% 
Platelet count (109/L) 
< 75  
< 50 
> 600 
> 999 
Neutrophils (109/L)  
< 1.5  
< 1.0 
 
 
Eosinophils (109/L)  
 
 
> 5.0 
 
Lymphocyte (109/L) 
< 0.8 
< 0.5 
> 4.9 
> 20 
WBC count (109/L) 
< 3.0 
< 2.0 
> 20.0 
> 100.0 
Coagulation 
 
INR 
 
 
> 1.5 × ULN if not on 
anticoagulation or  
> 1.5 × above baseline 
if on anticoagulation 
> 2.5 × ULN if not on 
anticoagulation or 
> 2.5 × above baseline 
if on anticoagulation 
Chemistry 
 
AST (U/L) 
 
 
> 3 × ULN 
> 5 × ULN 
ALT (U/L) 
 
 
> 3 × ULN 
> 5 × ULN 
Alkaline phosphatase (U/L) 
 
 
> 2.5 × ULN 
> 5 × ULN 
Total bilirubin (µmol/L) 
 
 
> 2 × ULN  
> 5 × ULN 
BUN / UREA (mmol/L) 
 
 
> 2.5 × ULN  
> 5 × ULN 
Creatinine (µmol/L) 
 
 
> 1.5 × ULN or  
> 1.5 × baseline if 
baseline is above ULN 
> 3 × ULN or  
> 3 × baseline if baseline 
is above ULN 
Albumin (g/L) 
< 30  
< 20 
 
 
Calcium (mmol/L) 
< 2.0  
< 1.75 
> 2.9 
> 3.1 
Potassium (mmol/L) 
< 3.2 
< 3.0 
> 5.5 
> 6.0 
Sodium (mmol/L) 
 
< 130 
> 150  
> 155  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; INR = international 
normalized ratio; ULN = upper limit of normal; WBC = white blood cell. 
 
For INR, a subject is considered to be on anticoagulation if the subject took 
antithrombotic agent (ATC codes B01A) and date of INR assessment is on or after start 
of anticoagulation therapy. 
• Main study elevated liver test (LT): Any LT abnormality occurring after the first 
drug intake up to Visit 5 (inclusive) or prior to first drug intake of the re-treatment (if 
applicable). The abnormalities are categorized as: 
– ALT ≥ 3, 5, 8, 10 and 20 × ULN, and also for AST separately. 


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– ALT or AST ≥ 3, 5, 8, 10 and 20 × ULN. 
– TBIL ≥ 2 × ULN. 
– ALT or AST ≥ 3× ULN and TBIL ≥ 2× ULN (at the same time as ALT or AST). 
– ALT or AST ≥ 3 × ULN and TBIL ≥ 2 × ULN and ALP < 2 × ULN (at the same time 
as ALT or AST). 
LT abnormalities for local laboratory results are derived based on the non-normalized 
results. 
Note: Laboratory results recorded as ‘< xxxʼ (or similar with ≤, >, or ≥) will be 
considered as ‘xxx’ for analysis, e.g., a result for ALT of ‘< 1’ is considered as 1 for the 
analysis.  
5.6.10 Other safety variables 
Other safety variables include all physical examinations recorded on the Physical 
Examination CRF. 
5.7 Quality of life variables 
Not applicable. 
5.8 Pharmacoeconomic variables  
5.8.1 Hospitalizations 
Hospitalizations data are collected in the Hospitalizations CRF. Hospitalization/hospital 
includes general ward, step-down/intermediate unit, or intensive care unit (ICU). The 
reason for hospitalization is collected (“CDAD” and “Other”). Duration and frequency of 
admissions are derived from study first dose up to Visit 5 (or re-treatment start date). 
• Length of stay in hospital (days) is derived for each hospitalization as the period 
between the date of admission and the date of discharge, and is defined as Date of 
discharge – Date of admission + 1. The overall stay includes all hospitalizations for a 
subject, excluding hospitalization days prior to first dose.  
• Length of stay by ward unit (general ward, step-down/intermediate unit, ICU 
[days]) is derived in the same way as the overall length of stay in hospital above but 
separately for each ward unit. 
• Frequency of re-admissions/admissions to hospital after start of treatment is 
defined as the number of times that the subject has been admitted/re-admitted to 
hospital from first dose of study treatment until Visit 5 (or first dose of re-treatment 
for subject re-treated), as reported on the Hospitalization CRF. Re-admission is 
defined as a new admission to hospital following subject discharge home (where 
home includes ‘home’, ‘rehab facility or nursing home’ or ‘other’) for the previous 


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admission to hospital (i.e., admitted to general ward, step-down/intermediate unit or 
ICU). For subjects already hospitalized at first dose and discharged home during the 
study, the number of re-admissions are counted. For subjects not hospitalized at first 
dose, the first admission and later re-admissions are counted. 
• Frequency of emergency department visits after start of treatment is defined as the 
number of times that the subject has been admitted to an emergency room in a 
hospital, from first dose of study treatment up until Visit 5, as reported on the 
Hospitalization CRF. 
For hospitalizations with reason for hospitalization as ‘CDAD’ the endpoints above are 
derived in the same way.  
Note: If the Visit 5 or re-treatment start date occurs during a hospitalization period the 
length of stay is derived up to Visit 5 date or up to re-treatment start date, respectively, 
instead of up to discharge date. If “Was the subject discharged” is answered “No” the 
EOS date is used instead of the discharge date for derivations.  
The same endpoints for the re-treatment extension are produced, except the time window 
of interest is from first dose of re-treatment until Visit Re-5.  
5.8.2 Change from baseline in Work Productivity and Activity Impairment: 
Clostridium difficile-associated diarrhea scores 
Work productivity and activity impairment: Clostridium difficile-associated diarrhea 
(WPAI:CDAD) scores are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity. The four WPAI:CDAD scores are 
defined as follows, based on the scores Q1–Q6 of Questions 1–6: 
• Absenteeism: Percent work time missed due to CDAD = Q2 / (Q2 + Q4) * 100 
• Presenteeism: Percent impairment while working due to CDAD = Q5 / 10 *100 
• Work productivity loss: Percent overall work impairment due to CDAD = {Q2 / (Q2 
+ Q4) + [(1–Q2 / (Q2 + Q4)) * (Q5 / 10)]} * 100 
• Activity impairment: Percent activity impairment due to CDAD = Q6 / 10 * 100 
Note: Questions 2–5 are only to be filled for subjects currently employed. Therefore the 
scores Absenteeism, Presenteeism, Work productivity loss are only defined for subjects 
currently employed (subjects with Question 1 “Are you currently employed” answered 
with “Yes”). 
Baseline is defined as the score at the screening visit. Change from baseline is the 
absolute difference between the visit and the baseline.  


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Note: For re-screened subjects baseline is defined as the last (highest visit label) 
screening/re-screening visit with at least one non-missing WPAI:CDAD question 
answered.  
Re-treatment baseline is defined as the Re-1 visit score. Change from re-treatment 
baseline is the absolute difference between the visit and the re-treatment baseline. 
Scoring: Handling of missing or inconsistent data 
The following rules for handling of missing or inconsistent data are implemented as 
described in the section “Coding Rules for Self-Administration” by Reilly Associates 
[Reilly Associates 2002].  
• Employment status (Q1): 
If Q1 = ‘YES’ or Q1 = ‘NO’ or ‘missing’ and hours missed (Q2) or hours worked 
(Q4) > 0, then subjects is considered employed.  
If Q1 = ‘missing’ and hours missed (Q2) and hours worked (Q4) = 0, then considered 
not employed (i.e., Q1 considered No). 
• Hours missed (Q2) and hours worked (Q4)  
If hours worked (Q4) = 0, then productivity while at work (Q5) is not applicable and 
considered as missing. 
If subject enters a range of hours for (Q2 or Q4), use the midpoint. 
If a subject is considered employed but hours missed (Q2) is missing then impute as 
zero.  
• Productivity Questions (Q5 and Q6)  
If for one question, two responses are provided, enter the midpoint and round to 
nearest integer. 
Missing response after applying the above scoring 
WPAI scores cannot be calculated if there is a missing response to one or more 
corresponding individual questions. 
5.9 Pharmacokinetic variables 
The definition of pharmacokinetic variables, including the definition of a valid PK 
sample is detailed in the PK SAP. 
6 
DEFINITION OF PROTOCOL DEVIATIONS 
This section refers to all protocol deviations as recorded in the database following the 
specifications provided in the protocol violations code list. 


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Protocol deviation PV104 ‘Received kit different from kit assigned by IVRS’ will be 
classified to ‘Incorrect kit received: treatment received different from assigned treatment’ 
(PV1041) or ‘Incorrect kit received: assigned treatment received’ (PV1042). 
Subsequently the codes PV1041 or PV1042 instead of PV104 will be considered as 
protocol deviation.  
Protocol deviations are categorized while being entered into the database into the 
following categories as specified in the protocol violations code list:  
• Main study, re-treatment extension or sub-study protocol deviations. 
Main study protocol deviations are those with protocol deviation code starting with 
‘PV’ followed by a number. Re-treatment extension protocol deviations are those 
with protocol deviation code starting with ‘PVR’ followed by a number. Protocol 
deviations related to sub-studies are those with protocol deviation code starting with 
PVK (PK sub-study), PVM (microbiome sub-study) or PVP (PRO validation sub-
study). 
• Time point protocol deviation occurred. 
Main study (including sub-study) protocol deviations are classified as occurring 
before randomization, after randomization, or before or after randomization.  
Similarly, re-treatment extension protocol deviations are classified as occurring 
before enrollment, after enrollment, or before or after enrollment.  
• Important protocol deviations (Yes/No). 
7 
ANALYSIS SETS  
7.1 Definitions of analysis sets 
7.1.1 Screened analysis set 
The Screened analysis set (SCRAS) includes all subjects screened even if they were not 
eligible. 
7.1.2 Full analysis set 
The Full analysis set (FAS) includes all subjects assigned to a study treatment based on 
the randomization-assigned treatment. Subjects are evaluated according to the study 
treatment to which they were assigned. 
7.1.3 Modified intent-to-treat analysis set 
The mITT analysis set includes subjects in the FAS who received at least one dose of 
study drug and had a confirmed diagnosis of CDAD.  
Diagnosis of CDAD is confirmed if both the following conditions are met:  


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• More than 3 UBMs in the 24 h prior to randomization,  
• Positive C. difficile GDH and toxin test (EIA approved by the sponsor) on the sample 
produced in the 72 h (48 h for MTFs) period prior to randomization. 
More than 3 UBMs in the 24 h prior to randomization is determined from the Screening 
CRF as defined at the end of Section 5.2.2; if this is missing then the subject is 
considered to have more than 3 UBMs if the Inclusion Criteria CRF item 3a ‘Diarrhea, 
defined as a change in bowel habits with > 3 UBM, in the 24 hours prior to 
randomization’ is not equal to ‘No’. 
A positive GDH and toxin test is determined by a positive result of an approved GDH 
and toxin test (either the Quik Chek Complete toxin test or any other pre-specified test 
for GDH as well as toxin) recorded in the CDAD Diagnosis and Microbiology Sample 
CRF [older CRF versions: Fecal Sampling CRF] at screening. The positive C. difficile 
GDH and toxin A and/or B stool test should be performed on a sample collected within 
72 h (48 h for MTFs) prior to or on randomization date.  
Subjects are evaluated according to the study treatment to which they were assigned. 
Reasons for exclusion from the mITT analysis set are classed into the following 
categories: (1) ‘Study drug not taken’; (2) ‘≤ 3 UBMs within 24 h prior to 
Randomization’; (3) ‘No approved positive diagnostic test’, i.e., no positive GDH and 
toxin test (approved by the sponsor) within 72 h (48 h for MTFs) prior to or on 
randomization day. 
7.1.4 Per-protocol analysis set  
The PPS comprises all subjects from the mITT analysis set without conditions that might 
affect the evaluation of the effect of the study drug on the primary variable. The 
following conditions lead to the exclusion of a subject from the PPS: 
At study entry: 
• More than one previous episode of CDAD in the 3-month period prior to 
randomization (Protocol deviation code PV013). 
• Fulminant or life-threatening CDAD (Protocol deviation code PV014). 
• Concurrent immediately life-threatening disease or condition (Protocol deviation code 
PV015). 
• History of inflammatory colitides, chronic abdominal pain, chronic diarrhea, or 
known positive diagnostic test for enteropathogens (Protocol deviation code PV016 
or PV016_V2). Positive diagnostic test for enteropathogens at study entry for subjects 
enrolled under protocol Version 1 are determined by blinded clinical review and 
mapped to the DS SDTM domain. 


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• AMT > 24 h, except for MTFs (Protocol deviation code PV017). 
• Any investigational drug to prevent or treat CDAD (Protocol deviation code PV018: 
FMT, intravenous immunoglobulin [IVIG] or any investigational drug to prevent or 
treat CDAD within 1 month prior to randomization; PV019: Monoclonal Ab against 
C. difficile within 6 months prior to randomization; and PV020: Vaccine against 
C. difficile). 
During study: 
• Any prohibited concomitant medication (except AMT or FMT or any investigational 
drug to treat CDAD) after randomization up to EOT + 2 days inclusive. Prohibited 
medications active against CDAD will lead to exclusion of a subject from the PPS as 
follows:  
1. Any use of IVIG or any investigational drug, antibodies or vaccine to prevent 
CDAD (PV119A). 
2. Other medication active against CDAD including probiotics and binding agents 
(e.g., cholestyramine) where duration is > 24 h, or consecutive or non-consecutive 
number of doses greater than what would be used in a 24 h period (PV119B). 
3. Initiation of treatment with opiates or a change in dose/regimen resulting in an 
increased opiate effect where duration is > 24 h, or initiation or increase in dose of 
opiates corresponding to a consecutive or non-consecutive number of doses 
greater than what would be used in a 24-h period, between randomization and 
EOT + 2 days inclusive (PV118B). Initiation or increase in dose of opiates for 
≤ 24 h from EOT –1 day to EOT + 2 days (PV118A).  
4. Anti-peristaltic medications (e.g., loperamide), kaolin or related products, pectin 
or charcoal-containing anti-diarrheals where duration is > 24 h, or consecutive or 
non-consecutive number of doses greater than what would be used in a 24 h 
period (PV121B). Any anti-peristaltic medications (e.g., loperamide), kaolin or 
related products, pectin or charcoal-containing anti-diarrheals taken from  
EOT –1 day to EOT + 2 days (PV121A).  
5. Use of one or more doses for more than one prohibited medication (PV122B: Use 
of ≥ 1 dose of > 1 forbidden medication [opiates, probiotics, IVIG, binding 
agents, anti-peristaltic medications, kaolin, pectin, or charcoal]). 
• Insufficient course of therapy: Subjects classified as a Clinical Failure with fewer 
than 6 doses of cadazolid or 12 doses of vancomycin taken. Subjects classified as a 
Clinical Cure with fewer than 16 doses of cadazolid or 32 doses of vancomycin taken 
(from Drug Accountability CRF).  


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• Positive diagnostic test for enteropathogens during treatment period. Positive 
diagnostic test for enteropathogens during treatment period is determined by blinded 
clinical review and mapped to the Subject Status SDTM domain. 
• Received study treatment differed from randomized study treatment (PV1041).  
[Note: PV104 is classified according to whether the received treatment is different 
from (PV1041) or the same as (PV1042) treatment assigned. This is determined after 
unblinding.] 
• Subject was unblinded before Database Lock (Source: PV103 [Unblinding for a 
reason not related to managing a clinical event] or from the DS SDTM domain 
[Unblinding of investigator or clinical trial team]; Note: Does not include unblinding 
as per process for managing SUSARs). 
• Insufficient information to determine Clinical Cure, i.e., subjects  
– with missing daily stool information on any day between EOT –1 and EOT + 2 
days, not otherwise documented as Clinical Failures (without information about 
AMT or FMT between Day 1 and EOT + 2 days, no day with > 3 UBMs between 
EOT –1 and EOT + 2 days). 
– lost to follow-up or study withdrawal prior to EOT + 2 days, not otherwise 
documented as Clinical Failures (no AMT or FMT between Day 1 and EOT + 2 
days, no day with > 3 UBMs between EOT –1 and EOT + 2 days). 
Subjects are evaluated according to the study drug to which they were assigned. 
The protocol deviation codes listed above are based on the most recent version of the PV 
code list.  
7.1.5 Hypervirulent analysis set 
The Hypervirulent analysis set (HVAS) comprises subjects in the mITT analysis set who 
are confirmed to have CDAD due to an infection by a hypervirulent strain at baseline, as 
defined in Section 5.2.2. 
7.1.6 Patient reported outcome analysis set 
The PRO analysis set (PROAS) includes all subjects from the mITT analysis set who 
have signed the ICF themselves (as recorded in Informed Consent CRF for the main 
study).  
It is based on the assigned treatment rather than the actual treatment received. 
7.1.7 Safety analysis set  
The Safety set (SS) includes all randomized subjects who received at least one dose of 
study drug (as recorded on the Study Drug Log CRF) and is analyzed based on the actual 
treatment received. 


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7.1.8 Re-treatment extension with cadazolid analysis set 
The re-treatment extension with cadazolid set (ES) includes all subjects enrolled in the 
re-treatment extension who received at least one dose of re-treatment study drug 
(open-label cadazolid) as recorded on the re-treatment Study Drug Log CRF. 
Tables on the re-treatment extension set will display results overall (Total cadazolid 
open-label) as well as by treatment arm during double-blind treatment (based on the 
actual treatment received, unless otherwise mentioned).  
7.1.9 Other analysis sets  
The definition of the Pharmacokinetic analysis set is detailed in the PK SAP. 
The number of subjects from the FAS that participate in the PK sub-study, the PRO 
psychometric sub-study and in the microbiome sub-study is determined from the CRF 
‘Sub-studies’. 
7.2 Usage of the analysis sets 
Screening failures, including reasons for screening failure, are summarized using the 
SCRAS.  
Subject disposition and study completion/withdrawal, including reason for withdrawal, 
and protocol deviations are summarized using the FAS.  
Baseline demographics and disease characteristics are summarized using the mITT and 
PPS. Previous/concomitant medications and medical history are summarized for the 
mITT. Treatment exposure is summarized using the SS and mITT. 
For efficacy, the main, supportive, sensitivity and subgroup analyses of Clinical Cure are 
performed on the PPS and on the mITT. All other efficacy analyses are performed on the 
mITT and on the PPS for the most relevant secondary endpoints, except: 
• Meta-analysis, performed on the HVAS.  
• CDI DaySyms analysis, performed on the PROAS (excluding subjects participating 
in the PRO sub-study). 
• WPAI:CDAD analysis, performed on the PROAS. 
The SS is used for the analyses of all safety variables (main study). 
Listings are prepared using the FAS, unless otherwise specified. 
All analysis of re-treatment period data are performed using the ES. 
Table 14 below provides an overview of the analysis set usage for the main variables of 
the study. 


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Table 14 
Overview of the different analysis sets and their usage 
Analyses/Data Displays 
SCRAS 
FAS 
mITT 
PPS 
SS 
ES 
Inclusion/exclusion criteria 
 
 
 
 
 
 
Disposition 
 
 
 
 
 
 
Demographic characteristics 
 
 
 
 
 
 
Baseline disease characteristics 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
Previous and concomitant therapies 
 
 
 
 
 
 
Subgroup analyses 
 
 
 
 
 
 
Treatment exposure & compliance 
 
 
 
 
 
 
Protocol deviations 
 
 
 
 
 
 
Efficacy: Primary endpoint 
 
 
 
 
 
 
Efficacy: Secondary endpoints 
 
 
 
* 
 
 
Efficacy: Other endpoints (unless 
otherwise specified) 
 
 
 
** 
 
 
Safety endpoints 
 
 
 
 
 
 
Subject listings 
 
 
 
 
 
 
Screening failures listing of reasons for 
failure 
 
 
 
 
 
 
* Only on the most relevant secondary endpoints. ** Investigator’s judgment of Clinical Cure only. 
ES = Re-treatment extension with cadazolid set; FAS = Full analysis set; mITT = modified intent-to-treat; PPS = 
Per-protocol analysis set; SCRAS = Screened analysis set; SS = Safety set. 
 
8 
DEFINITION OF SUBGROUPS 
Subgroups based on the following variables are considered for the analysis of Clinical 
Cure (primary endpoint) and Sustained Cure (secondary endpoint): 
Baseline subgroups: 
• CDAD episode type strata (from IVRS): first occurrence / first recurrence 
• Geographical region (US, Canada, Europe, Rest of the World) 
• Sex: female versus male 
• Race: white, black or african american, other  
• Age categories (years): 18–64; 65–74; ≥ 75  
• Baseline frequency of UBMs: > 3 to ≤ 5; > 5 to ≤ 9; and > 9 


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• Inpatient/outpatient status  
• CDAD severity at baseline: Mild-Moderate or Severe 
• Prior AMT within 1 week of study treatment start: yes/no [see Section 5.2.5.3] 
• Initial strain of C. difficile: hypervirulent versus non-hypervirulent 
• BMI categories: < 18.5; ≥ 18.5 – ≤ 25; > 25 – ≤ 30; > 30 – ≤ 40; > 40 
• MTF at baseline: yes/no 
If the number of subjects in a category is small, the category might be combined with a 
contiguous category e.g., if the number of subjects with BMI > 40 is small, the category 
is combined with the BMI > 30 to ≤ 40 category, or e.g., if number of subjects for a 
geographical region is small, then US and Canada is combined to North America and 
Europe and Rest of the World to Non North America. 
9 
GENERAL STATISTICAL METHODOLOGY 
This section describes in general terms the statistical models and methods applied. 
9.1 Statistical methods for binary data 
9.1.1 Confidence interval 
Confidence intervals (CIs) for single proportions are estimated using the Wilson score 
method using the following SAS code: 
proc freq data=; 
tables resp /binomial(Wilson) alpha=0.05; run; 
 
CIs for the difference between two proportions are estimated using the Wilson score 
method. 
For the Wilson score method, the confidence intervals of the differences in proportions 
are derived by adding the following statement CL=(NEWCOMBE). 
9.1.2 Stratified Cochran-Mantel-Haenszel 
Stratified differences in proportions are estimated by weighted average of the 
stratum-specific differences in proportions. Using similar notation as above, if ‘s’ is the 
total number of stratum and ‘j’ a subscript representing the stratum, we have: 
dadj =
෍
wj × dj
𝑠𝑠
𝑗𝑗=1
෍
wj
𝑠𝑠
𝑗𝑗=1
 


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Where dj is the difference in proportions in stratum j, and wj is the weight assigned to 
stratum j. 
The variance of the stratified difference in proportions is: 
Var(dadj) =
෍
wj
2 × Var(dj)
𝑠𝑠
𝑗𝑗=1
(෍
wj
𝑠𝑠
𝑗𝑗=1
)2
 
The confidence interval is obtained as dadj ± zα/2 * se(dadj). 
Cochran-Mantel-Haenszel (CMH) weights are used: wj = (n1j * n2j / (n1j + n2j) where n 
represents the number of subjects in each treatment group within each stratum ‘j’. 
9.1.3 Logistic regression 
For a binary outcome, a logistic regression model including treatment, a baseline 
covariate, and the interaction between the treatment and the covariate is considered. 
Specifically, the model with the structure below is used:  
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(𝑝𝑝)~
ε
β
β
β
β
+
×
×
+
×
+
×
+
COVAR
TREAT
COVAR
TREAT
3
2
1
0
 
 
The SAS code for this model is as follows: 
proc logistic data=aa order=data; 
 class treat(ref=‘Vancomycin’) covar(ref=“reference category”); 
model resp(event=‘1’) = covar treat covar*treat /alpha=0.05; 
oddsratio “Treatment” treat /cl=wald; 
run; 
9.2 Statistical methods for time-to-event data 
The analysis of time-to-event data are conducted using Kaplan-Meier estimates of events 
over time (including graphical representation), stratified log-rank test and Cox 
proportional hazard model. 
9.2.1 Time to Event and log-rank test 
Estimates of the event rate are obtained for each treatment group using the Kaplan-Meier 
method as implemented in SAS Proc Lifetest. The graphical representation follows the 
recommendations from Pocock [Pocock 2002]. Two-sided CIs at specific time points are 
constructed, with confidence limits calculated using Greenwood’s formula for the 
estimate of the standard error. Median time to event (as well as 25th and 75th percentiles) 
for each group are provided with the corresponding two-sided CIs calculated using the 
method of Brookmeyer [Brookmeyer 1982]. 


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The stratified log-rank test is conducted with SAS Proc Lifetest where the STRATA 
statement includes the strata variables (CDAD type and geographical region) and the 
GROUP option includes the treatment variable (treat). The TIME statement includes a 
variable with times to event (time) and an indicator variable for right censoring (censor) 
with 1 representing censoring. 
Proc lifetest data= method=KM;  
   time survtime*censor(1); 
   strata CDADTYPE  REGION / group=treat diff=control(“Vancomycin”); 
run; 
9.2.2 Cox proportional hazard model 
SAS Proc Phreg is used to estimate the hazard ratio, the p-value associated with the 
treatment effect hazard ratio and the CI of the hazard ratio (using Wald-based methods). 
The Cox regression model can be implemented using the following code:  
Proc phreg data =; 
  class treat (ref=‘Vancomycin’)  
        strat_1 (ref = ‘reference category’)…; 
  model TimeTo*censor(1)= treat /risklimits ties=exact; 
  strata CDADTYPE  REGION; 
run; 
 
An investigation into the assumption of proportional hazards for treatment is performed 
informally using a plot of the complementary log-log of the survival against the log of 
time (for each group). If the hazards are proportional, the lines should be approximately 
parallel. A plot of the Schoenfeld residuals against time and log(time) is also constructed, 
including a Loess curve [Collett 1994]. Departure from a horizontal line indicates 
violations of the proportional hazard assumption. A test of a non-zero slope is also 
derived based on traditional linear regression model. Since certain types of 
non-proportionality are not detected by the test, both the test and the plot are used to 
assess the non-proportionality assumption. 
9.3 ANOVA model for repeated measurements 
A general mixed analysis of variance (ANOVA) model for repeated measurements 
(linear mixed effects model) with unstructured covariance structure is considered. The 
model is applied to absolute values from Day 1 (baseline) to Day 12 during the main 
study. The model includes fixed effects for treatment, time, and the interaction between 
treatment and time, and subject as a random effect. The comparisons between treatments 
for the change from baseline to Days 2–12 are computed using estimate statements. The 
change from baseline to Day 3 is the primary comparison of interest and that considered 
for the hierarchical testing strategy [see Section 10.1]. The SAS code below includes 
examples for Day 3 and Day 12.  


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The SAS code for this model is as follows: 
Proc mixed data=;  
   class subject treatment time; 
   model score = treatment*time / noint DDFM = KR solution; 
   repeated time /subject=subject type=un; 
   lsmeans treatment*time; 
 example for Day 3 
  estimate “Treatment effect at Day 3” treatment * time -1 0 1 0 0 0 0 0 0 0 0 0 
                                                                                         1 0  -1 0 0 0 0 0 0 0 0 0/CL; 
 example for Day 12 
   estimate “Treatment effect at Day 12” treatment * time -1 0 0 0 0 0 0 0 0 0 0 1 
                                                                                           1 0 0 0 0 0 0 0 0 0 0  -1/CL; 
 run; 
 
Sensitivity analyses for missing data imputation is performed using a standard multiple 
imputation approach under the Missing At Random (MAR) assumption. The robustness 
of the MAR assumption is further investigated via a tipping point approach. See 
Section 10.7.3 and Appendix E. 
A similar model is applied for the comparison of absolute values of CDI-DaySyms 
domain scores versus Clinical Cure. The model includes fixed effects for Clinical Cure 
(CC) response, time, and the interaction between CC response and time, and subject as a 
random effect. The comparisons between CC response for the absolute values at Days 1–
12 are computed using estimate statements.  
Example SAS code for this model is as follows: 
Proc mixed data=;  
   class subject cc time; 
   model score = cc*time / noint DDFM = KR solution; 
   repeated time /subject=subject type=un; 
   lsmeans cc*time; 
example for Day 3 
   estimate “Clinical Cure effect at Day 3” cc * time 0 0 1 0 0 0 0 0 0 0 0 0 
                                                                                   0 0 -1 0 0 0 0 0 0 0 0 0/CL; 
run; 
 
10 STATISTICAL ANALYSES 
10.1 Overall testing strategy 
This section describes the overall testing strategy and the statistical techniques used to 
deal with multiplicity issues related to: 


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• Multiple endpoints including primary endpoint of Clinical Cure and secondary 
variables which may become additional claims. 
10.1.1 Statistical considerations 
The overall α is at 0.05 two-sided level (or 0.025 one-sided). 
No interim analysis is conducted: The analysis of the primary endpoint is conducted at 
the overall α level of 0.05 two-sided level (or 0.025 one-sided). 
The analyses of the secondary endpoints are performed by implementing a hierarchical 
strategy to control the experiment-wise α level [Dmitrienko 2010] [see Figure 7] with 
overall two-sided α = 0.05. The secondary efficacy endpoints are tested in a sequential 
conditional manner, starting with SCR. 
Figure 7 
Hierarchical testing strategy 
 
CCR = Clinical Cure Rate; CCRc = Clinical Cure Rate for cadazolid; CCRv = Clinical Cure Rate for vancomycin; 
SCR= Sustained Cure Rate; SCRc = Sustained Cure Rate for cadazolid; SCRv = Sustained Cure Rate for 
vancomycin; ROD = Resolution of diarrhea; S(t) = ROD survival function; CHGdia(t) = Change from baseline in 
CDI-DaySyms Diarrhea Domain Score; CHGabd(t) = Change from baseline in CDI-DaySyms Abdominal Domain 
Score; CHGsys(t) = Change from baseline in CDI-DaySyms Systemic/Other Domain Score; mITT = modified 
CCR NI - Co-primary populations - PPS and mITT
H0
(1): CCRc-CCRv ≤ -10% vs. H1
(1): CCRc-CCRv > -10%
SCR superiority - mITT
H0
(2): SCRc-SCRv = 0% vs. H1
(2): SCRc-SCRv ≠ 0%
Time to ROD superiority - mITT
H0
(3): Sc(t) = Sv(t) vs. H1
(3): Sc(t) ≠ Sv(t)
Change from baseline in CDI DaySyms PRO - PROAS1, tested in 
hierarchical order of importance
H0
(4): CHGdia_c(t) = CHGdia_v(t) vs. H1
(4): CHGdia_c(t)≠ CHGdia_v(t)
H0
(5): CHGabd_c(t) = CHGabd_v(t) vs. H1
(5): CHGabd_c(t)≠ CHGabd_v(t)
H0
(6): CHGsys_c(t) = CHGsys_v(t) vs. H1
(6): CHGsys_c(t)≠ CHGsys_v(t)


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intent-to-treat; NI = Non-inferiority; PPS = Per-protocol analysis set; PROAS1= Patient reported outcome analysis 
set (excluding subjects participating in the PRO sub-study). 
 
10.2 General rules for data presentations 
This section describes the general rules applied for all data displays, unless otherwise 
specified in each corresponding section. Standard Guiding Rules and Principles and 
standard outputs are followed where applicable. 
SAS version 9.3 is used for the preparation of all tables, listings and figures. Listings are 
sorted by treatment group, subject number (includes sorting by country and center) and 
timing (dates and/or visits as applicable). For analyses performed on multiple analysis 
sets, only one listing containing all analyzed subjects is presented. Names of outputs have 
a suffix that indicates the analysis set (e.g., _SAF for Safety set). 
Data are listed and summarized using appropriate descriptive statistics: 
• Number of non-missing observations, mean, standard deviation, minimum, Q1, 
median, Q3 and maximum for continuous variables. 
• Number of events, number of censored observations and Kaplan-Meier estimates of 
the survival function for time-to-event variables. 
• Number of non-missing observations, and frequency with percentage per category for 
categorical variables. Denominators for percentages are the number of subjects in the 
pertinent analysis set and treatment group, unless otherwise specified. 
• For susceptibility data: number of non-missing observations, geometric mean, MIC50 
(concentration which inhibits growth of ≥ 50% of isolates, i.e., median of MICs), 
MIC90 (concentration which inhibits growth of ≥ 90% of isolates, i.e., 90% quantile 
of MICs), minimum and maximum. 
Absolute changes from baseline are defined as: post-baseline value minus baseline value, 
i.e., a positive sign indicates an increase compared to baseline. 
A percentage change from baseline is defined as the absolute change from baseline 
divided by the baseline value (if the baseline value is > 0) and then multiplied by 100. 
For susceptibility (MIC) endpoints, change from baseline is defined as described in 
Table 9. 
In tables, column labels are ‘Cadazolid’ and ‘Vancomycin’. The cadazolid group is 
displayed in the first column, vancomycin in the second and a total column (including 
both treatment groups) is added in some tables as specified later on. 
In tables for the re-treatment extension column labels are ‘Cadazolid / Cadazolid OL’, 
‘Vancomycin / Cadazolid OL’, and ‘Total Cadazolid OL’.  


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10.3 Display of subject disposition, protocol deviations and analysis sets 
10.3.1 Screening failures 
The number of subjects screened, re-screened and reasons for screening failure are 
summarized for the SCRAS in a table and in a listing. For subjects that fail screening 
more than once, only the reason of the last failure is reported in the summary table. All 
reasons for screening failure are included in the listing.  
The number and percentage of subjects with 1 or more unmet eligibility criterion are 
presented overall and per criterion for the subjects failing screening.  
All subjects with unmet eligibility criteria are listed. Subjects randomized with unmet 
criteria are flagged in the listing.  
10.3.2 Subject disposition 
The number of subjects randomized, treated, completed treatment, completed the main 
study enrolled in re-treatment extension, re-treated, completed re-treatment, completed 
the re-treatment extension are all summarized by treatment group and overall for the 
FAS. 
Subjects prematurely withdrawn from study with reasons for premature study withdrawal 
are summarized separately. Disposition is presented overall and separately by study 
withdrawal occurring during the main study and the re-treatment extension for the FAS. 
Subject disposition variables are listed. 
Subjects randomization is also summarized by geographical region, country and site. 
10.3.3 Protocol deviations 
All main study protocol deviations as well as important main study protocol deviations 
are summarized by categories, per treatment group and overall.  
Similar summaries are prepared for all re-treatment extension protocol deviations and 
important re-treatment extension protocol deviations. 
Protocol deviations coded to “Other—Not considered a protocol violation by Actelion” 
(PV 298 and PVR298) are not included in the summaries. Also protocol deviations coded 
to sub-categories (e.g., PV118A and PV118B) are not included in the summaries as only 
the high level codes (PV with number and no letter suffix, e.g., PV118) are included to 
avoid double-counting.  
Main study protocol deviations occurring before or after randomization are summarized 
together with the protocol deviations after randomization. Similarly for the re-treatment 
extension protocol deviations occurring before or after enrollment are summarized 
together with protocol deviations after enrollment.  


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A listing of all main study and re-treatment protocol deviations is provided. 
10.3.4 Analysis sets 
The number and percentage of subjects in each analysis set as well as the number of 
subjects in the PROAS excluding subjects in the PRO validation sub-study are 
summarized in a table, per treatment group and overall. 
Reasons for excluding subjects from the mITT analysis set and PPS are listed and 
summarized in a table. 
Subjects participating in the PRO validation sub-study, the PK sub-study and the 
microbiome sub-study are summarized by treatment group and overall. 
10.4 Analyses of subject characteristics 
10.4.1 Demographics 
Demographic characteristics [defined in Section 5.2.1] are summarized using descriptive 
statistics for continuous and categorical data using the mITT, PPS and the ES. EudraCT 
age categories are summarized separately for the SS. One listing is produced, for the 
FAS. Tables are presented by treatment group and overall.  
10.4.2 Baseline disease characteristics 
Main baseline disease characteristics [defined in Section 5.2.2] are summarized by 
treatment group and overall using descriptive statistics for categorical data for the mITT 
and PPS. Listings are presented for the FAS. Separate tables are presented on the mITT 
and PPS for main disease characteristics.  
CDAD episode type strata (from IVRS) and CDAD episode type reported in the CRF are 
cross-tabulated using frequencies and percentages on the mITT. 
10.4.3 Other baseline characteristics 
Other baseline diseases characteristics [defined in Section 5.2.3] are summarized 
similarly to baseline disease characteristics for the mITT and PPS. 
10.4.4 Medical history 
Previous and concomitant medical histories [defined in Section 5.2.4] are summarized 
separately, by treatment group and overall, by tabulating the number and percentages of 
subjects who had/have each disease/diagnosis (by system organ class [SOC] and 
preferred term) using the mITT. One listing is produced for the FAS including the 
variable ‘Days from first dose of treatment’. Number and percentages of subjects having 
had at least one medical history term are presented by SOC and individual preferred term 
within each SOC.  


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SOCs are sorted by descending order of frequency. If the frequencies of SOCs are the 
same, alphabetical order is used. The same rule applies for preferred terms within SOC. 
10.4.5 Previous and concomitant therapies 
Number and percentages of subjects having taken at least one treatment are presented by 
ATC class (level 4) and individual preferred term within each ATC class. All summaries 
are tabulated by ATC class, and individual preferred terms within each ATC class, for the 
mITT. ATC classes are sorted by descending order of frequency. If the frequencies of 
ATC class are the same, alphabetical order is used. The same rule applies for preferred 
terms within ATC class. For study reporting purposes, all previous and 
study-concomitant therapies are reported in the subject listings.  
Previous therapies [Section 5.2.5.1], main study concomitant therapies [Section 5.2.5.2], 
main study concomitant therapies with onset prior to study treatment start and main study 
concomitant therapies with onset on or after study treatment start up to EOT + 7 days 
[Section 5.2.5.2] are summarized separately, by treatment group and overall, using 
descriptive statistics for categorical data. A subject listing of previous and concomitant 
medications is provided. A separate listing of re-treatment concomitant therapies on the 
ES is provided.  
Specific therapies are summarized per treatment group and overall, by type of therapy 
and preferred term. Specific main study concomitant therapies starting on or after study 
treatment start and up to EOT + 2 days and on or after EOT + 3 days and up to Visit 5 are 
summarized in a similar way. Specific therapies are flagged in the listing of all therapies.  
10.4.6 Procedures 
Main study concomitant procedures [described in Section 5.2.6.1] separated into 
CDAD-related procedures and other procedures are summarized using descriptive 
statistics for categorical data using the mITT. One listing for all procedures is produced 
for the FAS and one listing for endoscopy and imaging.  
10.5 Analysis of study treatment exposure and compliance 
10.5.1 Exposure 
Exposure characteristics for active double-blind treatment [defined in Section 5.3.1] are 
summarized per treatment group using descriptive statistics for continuous and 
categorical data, for the mITT analysis set and the SS for the main treatment period. The 
cumulative distribution of double-blind treatment exposure time by class intervals (1 day) 
is tabulated. Exposure to open-label re-treatment is summarized using the ES. One listing 
is produced for the FAS. 


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10.5.2 Compliance with study treatment 
Compliance for double-blind treatment [defined in Section 5.3.2] is summarized for both 
active study drug and placebo matching study drug per treatment group using descriptive 
statistics for continuous and categorical data, for the mITT analysis set for the 
double-blind treatment period. Compliance for open-label treatment is summarized using 
the ES. Compliance is listed in the exposure listing. 
10.5.3 Study treatment discontinuation  
Study treatment discontinuation variables [defined in Section 5.3.3] are summarized per 
treatment group, for the main study treatment using the SS and the mITT analysis set 
using number and percentages of subjects. Summaries for the mITT are performed only if 
more than 5% of subjects in the SS in any treatment group do not qualify for the mITT 
analysis set. Summaries on the SS are repeated using planned treatment instead of actual 
treatment received if actual treatment received differs from planned treatment for at least 
one subject. A listing is produced for the FAS. A separate listing of study treatment 
discontinuation variables for re-treatment are listed for the ES. 
10.5.4 Study treatment interruptions 
Subjects with study treatment interruption and corresponding reasons for interruption(s) 
[defined in Section 5.3.4] are summarized per treatment group for the main study 
treatment period using the number and percentages of subjects with at least one 
interruption on the SS. Multiple reasons for interruptions of the same type are only 
counted once per subject. One listing is produced using the FAS, also including data for 
re-treatment period interruptions. 
10.6 Analysis of the primary efficacy variable 
This section describes the analysis of the primary efficacy endpoint (i.e., CCR), as 
defined in Section 5.5.1. 
The objective is to demonstrate that the CCR for cadazolid (CCRc) is not inferior to the 
CCR of vancomycin (CCRv), accounting for a non-inferiority (NI) margin of 10%. 
The justification for the choice of 10% as NI is detailed in the study protocol. 
10.6.1 Hypothesis and statistical model 
The null hypothesis is: 
H0: CCRc–CCRv ≤ –10% 
and the alternative is:  
H1: CCRc–CCRv > –10% 
10.6.2 Handling of missing data 
Main analyses 
As described in Section 5.5.1, all subjects who do not fulfill the requirements for Clinical 
Cure are considered as Clinical Failure. 


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If one or more days between EOT –1 day to EOT + 2 days have missing or ‘unknown’ 
UBM information then the subject is considered a Clinical Failure. 
Sensitivity analyses 
A sensitivity analysis of handling missing or ‘unknown’ UBM information for Clinical 
Cure in the mITT analyses set will be conducted using the following: 
• If the number of UBMs on any one day between EOT –1 day to EOT + 2 days is 
missing or ‘unknown’ and the subject has ≤ 3 UBMs on all other days between 
EOT –1 day to EOT + 2 days, then it will be imputed with ≤ 3 UBMs, otherwise it 
will be considered > 3 UBMs. Clinical Cure is then derived as described in 
Section 5.5.1 based on this imputation.  
10.6.3 Main analysis 
Two main analyses are performed on the primary endpoint, one using the PPS and one 
using the mITT analysis set (‘co-primary populations’). No statistical model is defined; 
the main analyses are based on CI of the crude difference in proportions. 
A one-sided 0.025 significance level (equivalent to two-sided alpha of 0.05) is applied to 
test the primary hypothesis in both analysis sets.  
The NI assessment on the mITT analysis set and the PPS compose the first part of the 
hierarchical testing procedure [see Figure 7]. 
If the lower limit of the 95% CI is above –10%, for both the mITT population and the PP 
population, the NI of cadazolid versus vancomycin for CCR is claimed. 
The CCR is summarized by treatment group, including the number of subjects with and 
without a Clinical Cure. The CI for the difference in CCR is estimated using the Wilson 
score CI for the difference in proportions [Newcombe 1998] as described in 
Section 9.1.1. Imputation methods for the substitution of incomplete or missing data are 
defined in Section 10.6.2. 
For the mITT analysis set and the PPS separately, the number and percentage of subjects 
not being classified as Clinical Cure (i.e., Clinical Failure) and the reason(s) for Clinical 
Failure [as listed in Section 5.5.1] are summarized descriptively. A subject may have 
more than one reason for Clinical Failure, therefore the reasons and combination of 
reasons are summarized so that they are mutually exclusive.  
10.6.4 Supportive/sensitivity analyses 
10.6.4.1 Stratified Cochran-Mantel-Haenszel analysis of Clinical Cure rate 
A stratified CMH analysis of CCR is applied as a supportive analysis, stratified by first 
occurrence / first recurrence (IVRS) and geographical region using the PPS and mITT 
analysis set. In addition, the stratified analysis is repeated for each stratification factor 


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separately. For the average risk difference, the CMH estimate and corresponding CI is 
derived using normal approximation.  
If there are small numbers per strata, the categories for geographical region (US, Canada, 
Europe, Rest of the World) are pooled, e.g., combining US and Canada to North 
America, and Europe and Rest of the World to Non-North America.  
10.6.4.2 Analysis of Clinical Cure rate with imputation for a single missing day 
A sensitivity analysis is conducted as for the main analysis [Section 10.6.3], applying 
imputation for a single missing day in the Daily Stool Information CRF between  
EOT –1 day to EOT + 2 days, as described in Section 10.6.2. 
10.6.5 Subgroup analyses 
Consistency of CCR results is explored over the different subgroups defined in Section 8. 
A table will summarize the frequency of subjects per treatment group in each subgroup 
category for the mITT analysis set and the PPS.  
The CCR is summarized by treatment group per subgroup, with 95% CI of the difference 
in cure rates estimated using the Wilson Score method [Newcombe 1998]. Homogeneity 
per subgroup variable of the differences in proportions of CCR is assessed based on a 
Cochran’s type homogeneity chi-square test. Treatment effects (difference in proportion) 
overall and within subgroups are presented in a Forest plot.  
For each subgroup, a logistic regression is applied on the CCR, including the treatment 
group, the baseline characteristic and the interaction of both of them. Treatment effects in 
each subgroup are reported with odds ratios (cadazolid/vancomycin) and corresponding 
95% Wald CI. An exploratory test of interaction is performed comparing against 
two-sided 1% level to adjust for multiplicity. Treatment effects (odds ratios) overall and 
within subgroups are presented in a Forest plot [Cuzick 2005]. 
10.6.6 Other analyses 
Clinical Cure by concomitant therapy will be assessed as follows: 
A table will summarize the frequency of subjects with Clinical Cure per treatment group 
by ‘concomitant antibiotics for infections other than CDAD taken from first dose to EOT 
+ 2 days’ (yes/no) for the mITT analysis set together with difference in proportions and 
corresponding 95% Wilson score CIs.  
Clinical Cure by country is summarized descriptively by treatment group in the mITT 
analysis set using frequencies and percentages and corresponding 95% Wilson score CIs.  
Clinical Cure rates by MIC level are summarized descriptively as detailed in 
Section 10.8.2.3. 


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10.7 Analysis of the secondary efficacy variables 
The analyses for the secondary variables are conducted using the mITT analysis set.  
10.7.1 Sustained Cure Rate 
10.7.1.1 Hypothesis and statistical model  
If NI for CCR is demonstrated in both the PPS and the mITT analysis set, the SCR is 
hierarchically tested on the mITT analysis set [see Figure 7] at the two-sided 5% alpha 
level. 
The objective is to demonstrate that the SCR for cadazolid (SCRc) is superior to the SCR 
for vancomycin (SCRv). 
The null hypothesis is: 
H0: SCRc – SCRv = 0% 
and the alternative is:  
H1: SCRc – SCRv ≠ 0%. 
10.7.1.2 Handling of missing data  
Main analyses 
As described in Section 5.5.2.1, all subjects who do not fulfill the requirements for 
Sustained Cure are considered as not having Sustained Cure. Handling of missing UBMs 
and EIA GDH and toxin test approved by the sponsor is described in Section 5.5.2.1 and 
Table 5.  
Sensitivity analyses 
A sensitivity analysis will be conducted considering subjects with Visit 5 prior to 
EOT + 25 days and Day 35 as not sustained cure due to insufficient follow-up. The 
definition of Sustained Cure and handling of missing data as described Section 5.5.2.1 is 
used, apart from the following: 
• Subjects with Clinical Cure and no recurrence according to the definition in 
Section 5.5.2.1 that have a Visit 5 prior to EOT + 25 days and Day 35 are considered 
not Sustained Cure for this sensitivity analysis (as opposed to the definition in 
Section 5.5.2.1 considering subjects sustained cure if Visit 5 is after or on EOT + 28 
days or Day 38). If Visit 5 is missing and the subject was not re-treated the Study 
Withdrawal date instead of the Visit 5 date is used in the definition above. 
10.7.1.3 Statistical analysis 
The main statistical analysis of SCR is conducted on the mITT analysis set using the 
definition of SCR as in Section 5.5.2.1.  
Data are summarized in a similar way as for the primary endpoint analysis. The CI for the 
difference in SCR is estimated using the Wilson score CI method for difference in 
proportions. 


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If the lower limit of the CI is greater than zero, the superiority of cadazolid versus 
vancomycin in SCR is claimed. 
The number and percentage of subjects not classified as having Sustained Cure and the 
reasons for not being classified as having Sustained Cure [as listed in Table 6] are 
summarized descriptively. 
10.7.1.4 Supportive/sensitivity analyses of Sustained Cure rate 
The following sensitivity/exploratory analyses will be performed: 
The analysis of SCR described above [Section 10.7.1.3] is repeated on the PPS for 
sensitivity. 
A sensitivity analysis of Sustained Cure, applying handling of insufficient follow-up 
according to Section 10.7.1.2 (considering subjects with Visit 5 prior to EOT + 25 days 
or Day 35 as not having Sustained Cure due to insufficient follow-up), is conducted as for 
the main analysis [Section 10.7.1.3]. 
An exploratory analysis of Modified Sustained Cure [Section 5.5.3.11] will be performed 
on the mITT analysis set. The statistical analysis for this modified SCR will use the same 
methods as for SCR [Section 10.7.1.3]. 
10.7.1.5 Subgroup analyses 
The same subgroup analysis performed for the primary endpoint CCR [see 
Section 10.6.5] is conducted for SCR. 
Of note, the hypervirulent subgroup is primarily assessed in a meta-analysis involving 
both AC-061A301 and AC-061A302 studies, as described in the separate meta-analysis 
SAP. 
10.7.1.6 Other analyses 
Sustained Cure by concomitant therapy will be assessed as follows: 
A table will summarize the frequency of subjects with Sustained Cure per treatment 
group by ‘concomitant antibiotics for infections other than CDAD taken from first dose 
to Visit 5 / re-treatment’ (yes/no) for the mITT analysis set. 
Sustained Cure by country is summarized descriptively by treatment group in the mITT 
analysis set using frequencies and percentages and corresponding 95% Wilson score CIs.  
10.7.2 Time to resolution of diarrhea 
Time to ROD is hierarchically tested on the mITT analysis set [see Figure 7] at the 
two-sided 5% alpha level. 


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The objective is to demonstrate that the time to ROD for cadazolid is shorter than the 
time to ROD for vancomycin. 
10.7.2.1 Hypothesis test and statistical model 
The null hypothesis is: 
H0: Sc(t) = Sv(t) 
and the alternative is:  
H1: Sc(t) ≠ Sv(t) 
10.7.2.2 Handling of missing data 
See Section 5.5.2.2.  
10.7.2.3 Statistical analysis 
Analysis of time to ROD is conducted using a two-sided stratified log-rank test, including 
the strata first occurrence / first recurrence and geographical region (or region variable 
with pooled categories as described in Section 10.6.4.1 in the event of too small strata). 
Kaplan-Meier estimates of the survival functions are produced using upward estimates. 
Data are summarized in a table including Kaplan-Meier estimates at each day up to 
Day 10 (including CIs), median (as well as 25th and 75th percentiles) together with CIs 
and the log-rank summary statistics. 
A graphical display presenting a plot going upward is also presented overall and within 
each stratum including CIs at specific time points. 
10.7.2.4 Supportive/sensitivity analysis 
The statistical analyses for time to ROD [Section 10.7.2.3] are repeated on the PPS for 
sensitivity. An additional sensitivity analysis is conducted on the mITT analysis set using 
a stratified Cox proportional hazard model stratified by CDAD episode type (following 
strata assignation from the IVRS) and geographical region (or region variable with 
collapsed categories as described in Section 10.6.4.1 in the event of too small strata). 
10.7.3 Absolute change from baseline to Day 3 in CDI-DaySyms PRO domain 
scores 
The CDI-DaySyms PRO domain scores can be considered as quasi-continuous, and are 
therefore analyzed using methods for continuous data.  
The three CDI-DaySyms PRO domain scores are hierarchically tested on the PROAS 
(excluding subjects participating in the PRO validation sub-study) as described in 
Figure 7, at the two-sided 5% alpha level. The three domains are evaluated in a 
hierarchical manner, starting with Diarrhea Symptoms, then Abdominal Symptoms, and 
finally Systemic/Other Symptoms. The absolute change from baseline to Day 3 is the 
primary comparison of interest and that considered for the hierarchical testing strategy. 
Comparisons for other time points from Days 2–12 are also presented as exploratory 
analyses.  


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The objective is to demonstrate that the change (improvement) from baseline at Day 3 in 
each domain score is greater in the cadazolid group compared to the vancomycin group. 
10.7.3.1 Hypothesis test and statistical model 
The null hypothesis is: 
H0: CHGc(t) = CHGv(t) 
and the alternative is:  
H1: CHGc(t) ≠ CHGv(t) 
An ANOVA model for repeated measurements is applied to absolute values from Day 1 
(baseline) to Day 12 during the main study. The model includes fixed effects for 
treatment, time, and the interaction between treatment and time, and subject as a random 
effect. Assumption for this model is that missing data are MAR. The comparisons 
between treatments for the change from baseline at each time point are estimated from 
this model. 
10.7.3.2 Handling of missing data 
The main analysis models the CDI-DaySyms PRO domain scores over time using all 
available data from baseline (Day 1) to Day 12 as described in Section 9.3 under the 
MAR assumption. No imputation of missing values is performed. 
Possible reasons for missing data: 
• Early dropout (Premature study withdrawal with reason other than death – data 
missing from EOS date or last contact date onwards); 
• Death (Premature study withdrawal with reason death – data missing from EOS date 
onwards); 
• Other reasons (Not classified in any of the two categories above). 
To assess the pattern of missing data, the number and proportion of subjects with missing 
data for each domain score at each time point will be summarized overall, and by reason 
for missing data as defined above.  
Two sensitivity analyses for handling of missing data are performed using imputation 
methods: 
Multiple Imputation Method 
First, standard multiple imputation of the outcome variables (CDI-DaySyms PRO domain 
scores) under the MAR assumption is applied using PROC MI, using covariates 
constructed from the corresponding sets of preceding variables (treatment). Imputation of 
intermittent missing values is applied in a first step. In a second step, missing values after 
dropout are imputed. The resulting imputed datasets are analyzed using the model 
described in Section 9.3, and the results of these analyses are pooled using PROC 
MIANALYZE. 


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Second, to assess the robustness of the MAR assumption, a tipping point approach is 
applied, whereby the impact of missing data on the conclusions is assessed. The tipping 
points are defined to be the particular setting for the missing data values that would 
change the study’s conclusions. Multiple imputation under the Missing Not At Random 
(MNAR) assumption is applied by searching for a tipping point by using “shift” 
approaches until the MAR inferences change from significance to non-significance, or 
vice-versa. The shifts are applied to the mean for the non-completers in the cadazolid 
treatment arm.  
These analyses are performed in SAS 9.4 by an independent expert consultant 
 
. Full details can be found in Appendix E.  
Single Imputation Method 
All missing post-baseline values are imputed with the last non-missing value available 
(last observation carried forward [LOCF] approach). As CDI-DaySyms symptoms are 
expected to improve over time in both active treatment groups when subjects achieve 
clinical cure, LOCF could be considered as a conservative single imputation method in 
that situation. 
The latest available value prior to the missing value is imputed for any given missing data 
point. For example, if a subject has missing values at Day 4 and Day 7, but all other 
values are present, then the Day 4 value will be imputed with the Day 3 value, and the 
Day 7 value will be imputed with the Day 6 value. Missing baseline values are not 
imputed.  
The results imputed are analyzed using the same model as described in Section 9.3. 
10.7.3.3 Statistical analysis 
For each CDI-DaySyms PRO domain score, the absolute values and changes from 
baseline are summarized descriptively by treatment group and time point. A box-plot is 
created for each domain score by treatment group and time point, displaying mean, 
median, Q1, Q3, and minimum and maximum. 
Analysis of absolute change from baseline in each CDI-DaySyms PRO domain score at 
Day 3 is conducted using the PROAS (excluding subjects participating in the PRO 
validation sub-study) based on a general mixed ANOVA model for repeated 
measurements modeling the absolute CDI-DaySyms PRO domain score values using all 
available data up to Day 12. The model is described in Section 9.3.  
The main comparison between treatment groups (cadazolid – vancomycin) is made for 
change from baseline to Day 3. If the upper limit of the two-sided 95% CI for treatment 
difference for change from baseline in CDI-DaySyms PRO domain score at Day 3 is 


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below zero, then statistically significant superiority of cadazolid versus vancomycin is 
claimed.  
The treatment difference for change from baseline to all other days up to Day 12, derived 
from the model as described above is also presented. These comparisons are considered 
exploratory.  
The least square means model estimates and associated 95% CI for all time points are 
plotted by treatment group and time point for each domain score. 
10.8 Analysis of other efficacy variables 
Analyses for the exploratory variables are conducted on the mITT analysis set unless 
otherwise specified. Statistical comparisons are performed at the two-sided alpha 5% 
level for exploratory purposes. 
10.8.1 Efficacy variables 
10.8.1.1 Investigator’s assessment of Early Treatment Response at Visit 2 
Summaries are presented per treatment, with difference in rates and corresponding CIs 
estimated using the Wilson score method. 
10.8.1.2 Investigator’s judgment of Clinical Response at Visit 4 
Summaries are presented per treatment group, with difference in rates and corresponding 
CIs estimated using the Wilson score method. 
This analysis is performed on the mITT analysis set and the PPS. 
The reasons for assessing the subject as cure or failure are summarized using frequencies 
and percentages on the mITT analysis set.  
10.8.1.3 Investigator’s evaluation of Clinical Cure per protocol definition 
The information is listed. 
10.8.1.4 Investigator’s judgment of Sustained Response at Visit 5 
Summaries are presented per treatment group, with difference in rates and corresponding 
CIs estimated using the Wilson score method. 
The reasons for assessing the subject as cure and failure are summarized using 
frequencies and percentages on the mITT analysis set.  
10.8.1.5 Investigator’s evaluation of Sustained Cure per protocol definition 
The information is listed.  


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10.8.1.6 Early Clinical Cure by Day 5 
Summaries are presented per treatment group, with difference in rates and corresponding 
CIs estimated using the Wilson score method. 
10.8.1.7 Normalization of Bowel Movements rate 
Summaries are presented per treatment group, with difference in rates and corresponding 
CIs estimated using the Wilson score method. 
10.8.1.8 Time to return to usual stools 
Summaries are presented per treatment group using the Kaplan-Meier method. 
10.8.1.9 Recurrence rate and adjusted recurrence rate 
Recurrence rates (recurrence out of subjects with Clinical Cure) are summarized 
descriptively with 95% CI of individual treatment group rates estimated using the Wilson 
method. No CI of the difference is provided. This endpoint is not statistically compared 
because it would be a biased comparison since the numbers of cured subjects in both 
treatment groups are expected to be different, and these populations could not have the 
same characteristics in both treatment groups. Summaries are accompanied by summaries 
of subjects with recurrence out of the analysis set using frequencies, proportions and 95% 
Wilson CI of proportions.  
Adjusted recurrence rate (recurrence out of subjects in the analysis set) will be 
summarized with identical methods as for the recurrence rate. 
Recurrence classifications (Relapse and Re-infection) are summarized descriptively. 
Recurrence is also summarized by subgroups. 
10.8.1.10 
Time to recurrence 
This endpoint is analyzed using the same statistical methods as for the main statistical 
analysis of time to ROD [see Section 10.7.2.3]. Only subjects with Clinical Cure are 
considered in the analysis. It is summarized per treatment group, but not statistically 
compared because it would be a biased comparison. 
10.8.1.11 
CDI-DaySyms PRO response rates 
CDI-DaySyms response status is computed for each domain using data as entered [see 
Section 5.5.3.12]. No imputation of missing scores is performed prior to deriving 
response status. Subjects with missing values at baseline or at Day 3 are considered to be 
non-responders. Response rates at Day 3 are summarized descriptively for each domain 
together with 95% CI of individual treatment group rates estimated using the Wilson 
method [Newcombe 1998] as described in Section 9.1.1. The treatment difference in 
proportions and corresponding 95% Wilson score CIs are also presented. 


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10.8.1.12 
Comparison of absolute values of CDI-DaySyms domain scores versus 
Clinical Cure  
To compare the CDI-DaySyms PRO to CC response (Clinical Cure vs Clinical Failure), a 
general mixed ANOVA model for repeated measurements is applied to the absolute CDI-
DaySyms PRO values for each domain score using all available data up to Day 12. The 
model includes CC response, time and the interaction between CC response and time as 
fixed effects, and subject as a random effect. The model is as described in Section 9.3. 
The difference in absolute values of the domain score between subjects with CC and 
clinical failure for each time point at Days 1 (Baseline), 3, 7 and 12 is presented, together 
with the corresponding 95% CIs. 
Example of estimate statements for the SAS code (to be done for Days 1 (Baseline), 3, 7 
and 12): 
/*Day 3:*/ 
   estimate “CC Effect at Day 3” CC * time 0 0 –1 0 0 0 0 0 0 0 0 0 
 
0 0   1 0 0 0 0 0 0 0 0 0/CL; 
… 
 
/*Day 12:*/ 
   estimate “CC effect at Day 12” CC * time 0 0 0 0 0 0 0 0 0 0 0 –1 
 
0 0 0 0 0 0 0 0 0 0 0   1/CL; 
 
Descriptive statistics for absolute values of each domain score are presented in a 
summary table by CC response and time point. A box-plot is created by CC response, 
displaying mean, median, Q1, Q3, and minimum and maximum. 
The same analysis is repeated for each treatment group separately. 
10.8.1.13 
Re-treatment extension variables 
Unless otherwise specified, all summaries are provided by randomized treatment group 
and overall, using the ES. 
Clinical Cure, Sustained Cure: 
The number and percentage of subjects with the event of interest are summarized 
together with the 95% CI of the estimates of the difference using the Wilson score 
method. 
Recurrence Rate: 
The number and percentage of subjects with the event of interest, out of the re-treated 
subjects who presented clinical cure during the re-treatment period, is summarized per 
treatment group together with the respective 95% CI. 


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Adjusted Recurrence Rate: 
The number and percentage of subjects with the event of interest, out of the re-treated 
subjects, is summarized per treatment group together with the respective 95% CI. 
10.8.2 Analysis of microbiology variables 
10.8.2.1 Isolation of C. difficile 
Subjects with C. difficile isolate are summarized using frequencies and percentages. 
Denominator for percentages are number of subjects with any sample analyzed for 
C. difficile in central laboratory at the time point. The following displays will be 
prepared: 
• Subjects with C. difficile isolate at baseline. Overall, by geographical region, and by 
Clinical Cure outcome in the mITT and PPS; by treatment group and overall. 
• Subjects with C. difficile isolate by visit (Baseline, Visit 3 and Visit 4.x) in the mITT, 
by treatment group. 
• Subjects with C. difficile isolate for Clinical Failures (Baseline and Visit 3) and 
Recurrences (Baseline and Visit 4.x) in the mITT and PPS by treatment group. 
As described in Section 5.5.3.12, subjects with multiple new episode of diarrhea visits 
(i.e., Visit 4.a, 4.b, etc.) are considered to have a C. difficile isolate at Visit 4.x if 
C. difficile was isolated at any of these visits. 
10.8.2.2 Typing of C. difficile 
C. difficile strains are summarized using frequencies and percentages on the mITT and 
PPS. The denominator for deriving percentages is the number of subjects with 
non-missing result. The following displays will be prepared: 
• C. difficile strains for baseline isolates based on PCR ribotyping (i.e., ribotype initial 
type) by treatment group and overall. 
• C. difficile strains for baseline isolates based on REA typing (i.e., REA initial group) 
by treatment group and overall. 
• Hypervirulent ribotypes [see definition in Section 5.5.4.2.1] and REA groups of 
specific interest [see definition in Section 5.5.4.2.2] for baseline isolates are 
summarized overall, by geographical region (by treatment group and overall), by 
country and are cross tabulated. 
Furthermore, subjects with Relapse or Re-infection are summarized by treatment group 
using frequencies and percentages. The denominator for deriving percentages is the 
number of subjects with Clinical Cure, but also the percentages out of subjects in the 
mITT analysis set will be presented.  


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Typing information for all C. difficile isolates are listed.  
10.8.2.3 Susceptibility of C. difficile  
Susceptibility test results for C. difficile isolates will be summarized using MIC summary 
statistics (MIC range, MIC50, MIC90) and MIC frequency distribution (frequency of 
isolates at each MIC test concentration). The following displays will be prepared: 
• Susceptibility of C. difficile to each test agent (i.e., cadazolid, vancomycin, linezolid, 
moxifloxacin, metronidazole and fidaxomicin) at baseline and post-baseline (highest 
MIC) using MIC summary statistics and MIC frequency distribution by treatment 
group and overall in the mITT and PPS. 
• Susceptibility of C. difficile to cadazolid, vancomycin, linezolid and moxifloxacin for 
Clinical Failures at baseline and Visit 3 and for Recurrences at baseline and Visit 4.x 
using MIC summary statistics and MIC frequency distribution by treatment group in 
the mITT and PPS. 
• Susceptibility of C. difficile to each test agent at baseline. Overall and by Clinical 
Cure Outcome using MIC summary statistics by treatment group in the mITT and 
PPS. 
• Susceptibility of C. difficile to each test agent at baseline in subjects with 
hypervirulent strain. Overall and by Clinical Cure Outcome using MIC summary 
statistics and overall using MIC frequency distribution by treatment group in the 
mITT and PPS. 
• Susceptibility of C. difficile to each test agent at baseline in subjects with REA group 
of special interest. Overall and by Clinical Cure Outcome using MIC summary 
statistics by treatment group in the mITT and PPS. 
• Susceptibility of C. difficile to each test agent at baseline by geographical region 
using MIC summary statistics by treatment group in the mITT and PPS. 
Note: MIC50 and MIC90 values are derived and presented when MICs for at least 
10 isolates are present.  
Graphical displays of MIC frequency distributions of susceptibility of C. difficile to each 
test agent at baseline in the mITT will be presented.  
Clinical Cure (frequencies and percentages) will be summarized by baseline C. difficile 
MIC level to cadazolid, vancomycin, linezolid, moxifloxacin, overall and separately for 
subjects with hypervirulent and non-hypervirulent strain at baseline using the mITT and 
PPS. 
A listing of susceptibility of C. difficile will be prepared on the FAS.  


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10.8.2.4 Change from baseline in susceptibility of C. difficile 
Frequencies (number of subjects and percentages) are displayed by treatment group, 
using the mITT analysis set and PPS, for the categories of change from baseline [see 
Table 9] in the susceptibility of C. difficile to cadazolid, vancomycin, linezolid, 
fidaxomicin, metronidazole and moxifloxacin for Clinical Failures at Visit 3 and for 
Recurrences at Visit 4.x. A similar display will be prepared on change from baseline to 
highest post-baseline result. 
For subjects with ≥ 4-fold increase in C. difficile, MIC from baseline for any 
post-baseline isolate for cadazolid, linezolid or moxifloxacin separate sub-listings of 
C. difficile susceptibility information by antibiotic (cadazolid, linezolid, moxifloxacin) 
will be prepared. Samples with different ribotypes, different REA types and different 
antibiogram as compared to baseline as well as Clinical Response (Clinical Failure, 
Recurrence) will be flagged.  
10.8.2.5 Vancomycin-resistant enterococci  
Frequencies and percentages of subjects considered VRE-positive and VRE-negative at 
each visit as well as the following shifts from baseline to Visit 3 are displayed:  
• VRE Gain (or Colonization) = Visit 1 VRE-negative to Visit 3 VRE-positive  
• VRE Loss (or De-colonization) = Visit 1 VRE-positive to Visit 3 VRE-negative  
• VRE Uncolonized = Visit 1 VRE-negative and Visit 3 VRE-negative 
• VRE Colonized = Visit 1 VRE-positive and Visit 3 VRE-positive  
Summaries are presented using the mITT. 
10.8.2.6 Vancomycin-resistant enterococci quantitative culture  
Total VRE counts (cfu/mL) at baseline and Visit 3, as well as changes from baseline to 
Visit 3, are summarized by treatment group with descriptive statistics for subjects in 
whom VRE results at baseline are VRE-positive. 
Note: For VRE-positive subjects at baseline who are VRE-negative at Visit 3, the imputed 
Total VRE count of 0 log10 cfu/mL is used for analysis at Visit 3 [see Section 5.5.4.6].  
10.8.2.7 
Susceptibility of vancomycin-resistant enterococci 
Susceptibility test results for VRE (E. faecium; E. faecalis; Not E. faecium, not E. 
faecalis) isolates at baseline and Visit 3 will be summarized by VRE species (i.e., 
separately for E. faecium [first colony], and E. faecalis [first colony]) using MIC 
summary statistics (MIC range, MIC50, MIC90) to each test agent in the mITT.  


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Change from baseline in susceptibility of VRE for cadazolid, linezolid and moxifloxacin 
will be summarized by VRE species (i.e., separately for E. faecium [first colony] and 
E. faecalis [first colony]) with frequencies and percentages of subjects using the mITT. 
MIC50 and MIC90 values are derived and presented when MICs for at least 10 isolates are 
present. 
VRE isolation, quantitative culture and susceptibility are also listed.  
10.9 Analysis of safety variables 
Safety summaries are prepared using the SS or ES according to the period of interest 
(main study or re-treatment extension, respectively). 
10.9.1 Adverse events 
All AEs captured in the database are reported in the subject listings.  
AEs are summarized by presenting, per treatment group, the number and percentage of 
subjects having any AE, having an AE in each primary SOC, and having each individual 
AE (preferred term).  
The following summaries are considered: 
• Treatment-emergent AEs (up to EOT + 7) 
• Main study AEs (up to Visit 5) 
• Re-treatment-emergent AEs (up to End of Re-treatment + 7) 
• Re-treatment extension AEs (up to Visit Re-5) 
In addition, treatment-emergent AEs and re-treatment-emergent AEs are also tabulated 
by maximum intensity. Treatment-emergent AEs are also tabulated for those related to 
study treatment. One summary table of treatment-emergent AEs by preferred term 
together sorted by absolute percent different between cadazolid and vancomycin is 
prepared.  
Treatment-emergent AEs are also summarized using preferred terms only, ordered by 
incidence of subjects with events in the cadazolid group. 
Non-serious AEs are summarized separately as: 
• Non-serious frequent treatment-emergent AEs 
• Non-serious frequent re-treatment-emergent AEs  
Frequent AEs are those occurring in ≥ 5% of subjects in at least one treatment group. 


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Non-serious frequent treatment-emergent AEs and non-serious frequent re-treatment AEs 
are summarized by treatment group presenting the number and percentage of subjects 
having any such AE and having each individual AE (preferred term), together with the 
number of events overall and per individual AE (preferred term) with the event rate 
(number of events out of total events).  
A separate listing is provided comprising all AEs per treatment group.  
10.9.2 Deaths, other serious adverse events 
10.9.2.1 Deaths 
AEs with fatal outcome are summarized in a similar manner as described for AEs.  
The number and percentage of subjects who died are summarized per treatment group, 
including the reported causes of death. A summary table is provided for all deaths overall 
and split by time windows after the first treatment intake up to Visit 5 (inclusive), after 
first treatment intake up to EOT + 7 days, after the first re-treatment intake up to 
Visit Re-5 (inclusive) out of subjects in the ES. A separate listing including all deaths is 
provided.  
10.9.2.2 Serious adverse events 
Serious adverse events (SAEs) are summarized separately by SOC and preferred term as: 
• Treatment-emergent SAEs (up to EOT + 7) 
• Main study SAEs (up to Visit 5) 
• Treatment-emergent SAEs related to study drug (up to EOT + 7) 
• Treatment-emergent SAEs with fatal outcome (up to EOT + 7) 
• Re-treatment-emergent SAEs (up to End of Re-treatment + 7) 
• Re-treatment extension SAEs (up to Visit Re-5) 
A separate listing is provided comprising all SAEs per treatment group for the FAS, and 
listing of re-treatment emergent SAEs for the ES.  
In addition, treatment-emergent SAEs are summarized using preferred terms only, 
ordered by incidence of subjects with events in the cadazolid group. 
For treatment-emergent SAEs, the number of events, and event rate overall and per 
preferred term will be summarized in addition.  
10.9.2.3 Adverse events leading to study treatment discontinuations 
AEs leading to study treatment discontinuation are summarized for the main study (by 
SOC and PT, and by PT) and re-treatment extension (by SOC and PT). 


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A separate listing including all AEs leading to study treatment discontinuation and 
re-treatment discontinuation is provided. 
10.9.2.4 Other significant adverse events 
Not applicable. 
10.9.3 Electrocardiography 
Descriptive summary statistics by visit and study treatment are provided for observed 
values and absolute changes from baseline (changes from re-treatment baseline during 
the re-treatment extension). Values from unscheduled visits, and from Visits 4.a, 4.b, etc. 
[exception, see Section 11.5] are not included in these summaries, but are included in the 
listings and in the summaries for marked abnormalities and treatment-emergent marked 
abnormalities.  
The number and percentage of subjects with at least one study QT or QTc marked 
abnormality (absolute and change) or treatment-emergent QT or QTc marked 
abnormality (absolute and change) are summarized by treatment group together with 95% 
CIs for proportions (Wilson score method). The number and percent of subjects with at 
least one marked abnormality are also presented separately for each parameter by 
category together with 95% CIs. If a subject assessment qualifies for more than one 
category of a marked abnormality then the worst case is taken into account. 
The number and percentage of subjects with ECG qualitative abnormalities (findings) 
and treatment-emergent finding are summarized by treatment group.  
The denominator for percentages is the number of subjects with at least one post-baseline 
assessment. 
Re-treatment-emergent QT or QTc marked abnormalities up to End of Re-treatment + 7 
days and Re-treatment-emergent qualitative ECG abnormalities up to End of 
Re-treatment + 7 days are presented in a similar way. 
Summary statistics are calculated for ECG parameters for absolute values and changes 
from baseline to each visit (changes from re-treatment baseline during the re-treatment 
extension). 
All ECG data including QTc parameters are listed by treatment group and subject. All 
marked abnormalities are flagged and qualitative abnormalities (as reported by the 
investigator on the CRF ECG pages) are listed. 
All ECG data are also presented in one single listing. 


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10.9.4 Laboratory tests 
Descriptive summary statistics by visit and study treatment group are provided for 
observed values and absolute changes from baseline (changes from re-treatment baseline 
during the re-treatment extension). Data are displayed in SI units as provided by the 
central laboratory (local laboratory data are normalized if no central laboratory data are 
available for the same time point). Values from unscheduled visits, and from Visits 4.a, 
4.b, etc. [exception, see Section 11.5] are not included in these summaries, but are 
included in the listings and in the summaries for marked abnormalities and 
treatment-emergent marked abnormalities.  
Summaries for WBC differential count are performed only on the absolute counts and not 
on the percentages. 
The number of subjects with at least one marked laboratory abnormality is summarized 
by treatment group. 
In addition, the number of subjects with treatment-emergent marked laboratory 
abnormalities is summarized by treatment group.  
Shifts from baseline to worst post-baseline abnormality category up to Visit 5 are 
summarized with frequencies of subjects and percentages per category of shift. 
Categories considered are LLL, LL, L (L = below LLN), normal (between LLN and 
ULN), H (H = above ULN), HH, HHH. For baseline the category Missing is considered 
as well. Subjects experiencing a worsening from baseline in two different directions (e.g., 
going from normal at baseline once to H and once to L post-baseline) are counted in both 
directions.  
The denominator for percentages is the number of subjects with at least one post-baseline 
assessment. 
Re-treatment-emergent marked abnormalities up to End of Re-treatment + 7 days are 
presented in a similar way. 
All data are also presented in one single listing. All abnormalities and marked 
abnormalities including those at baseline are flagged in the listings. 
10.9.5 Vital signs and body weight 
Descriptive summary statistics by visit and study treatment group are provided for 
observed values and changes from baseline (changes from re-treatment baseline during 
the re-treatment extension) for SBP and DBP, for HR, for body weight, and for core body 
temperature. Values from unscheduled visits, and from Visits 4.a, 4.b, etc. [exception, see 
Section 11.5] are not included in these summaries, but are included in the listings and in 
the summaries for marked abnormalities and treatment-emergent marked abnormalities.  


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The number and percent of subjects with at least one blood pressure marked abnormality 
is summarized by treatment group. 
In addition, the number of subjects with treatment-emergent blood pressure marked 
abnormalities is summarized by treatment group. 
The denominator for percentages is the number of subjects with at least one post-baseline 
vital sign assessment. 
Re-treatment-emergent marked abnormalities up to End of Re-treatment + 7 days are 
presented in a similar way. 
All data are also presented in one single listing, all marked abnormalities including those 
at baseline are flagged in the listings. 
10.9.6 Other safety variables 
Physical abnormalities including abdominal examination abnormalities are presented in 
one single listing. 
10.10 Analysis of quality of life variables 
Not applicable, analyses related to CDI-DaySyms PRO are described in Section 10.7.3, 
and Sections 10.8.1.11 and 10.8.1.12. 
10.11 Analysis of pharmacoeconomic variables 
WPAI scores and number of subjects currently employed by visit during the main study 
are summarized per treatment group. Hospitalizations are summarized by treatment group 
overall and separately for hospitalization situation (yes/no) at the time of first dose and 
separately for those with reason for hospitalization recorded as CDAD. 
Number and percentage of subjects by frequency of admissions/re-admissions are 
summarized by treatment group and by reason for hospitalization. 
Descriptive summary statistics by visit and study treatment group are provided for 
observed values for the treatment period. All data are also presented in one single listing. 
11 GENERAL DEFINITIONS AND DERIVATIONS 
11.1 Unit conversion 
Height (cm) = height (in) * 2.54 
Weight (kg) = weight (lbs) * 0.4536 
Temperature (°C) = (Temperature (°F) – 32) * 5 / 9 
Core Temperature (°C) = Temperature (rectal; °C) 


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Core Temperature (°C) = Temperature (oral; °C) + 0.6 
Core Temperature (°C) = Temperature (ear; °C) 
Core Temperature (°C) = Temperature (axilla; °C) + 1.2 
Core Temperature (°C) = Temperature (forehead[temporal]; °C) + 1.2 
11.2 Variable derivation 
BMI (kg/m2) = weight (kg) / (height (cm) / 100)2 
Absolute change from baseline is defined as post-baseline value minus baseline value, 
i.e., a positive sign indicates an increase as compared to baseline. 
A percentage (relative) change from baseline is defined as the absolute change from 
baseline divided by the baseline value (if the baseline value is > 0) and then multiplied by 
100. 
For susceptibility (MIC) endpoints, change from baseline is defined as post-baseline 
value divided by baseline value. 
11.3 Dates, times and days 
Baseline is defined as the last non-missing assessment before date and time of first dose 
intake of double-blind treatment. 
Randomization date/time is taken directly from the primary form of the CRF (integrated 
from IVRS system). 
Study treatment start (STS) is defined as the date/time of first (double-blind) study 
drug intake. It is the earliest treatment start date/time recorded on the Study Drug Log 
CRF. 
Study treatment end (STE) is defined as the date/time of last (double-blind) study drug 
intake. It is the latest treatment end date/time recorded on the Study Drug Log CRF. 
Re-treatment Baseline is defined as the last non-missing assessment before date and 
time of first dose intake of open-label re-treatment with cadazolid. Only assessments after 
EOT are considered. 
Re-treatment start (RTS) is defined as the date/time of the first open-label study drug 
intake. It is the earliest treatment start date/time recorded on the re-treatment Study Drug 
Log CRF. 
End-of-Treatment (EOT / Main period) is the date of last double-blind drug intake. It 
is the latest treatment end date recorded on the Study Drug Log CRF. 


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Re-treatment end (RTE) is defined as the date/time of last open-label drug intake. It is 
the latest treatment end date/time recorded on the re-treatment Study Drug Log CRF. 
End of Re-treatment (EORT) is the date of last open-label drug intake. It is the latest 
treatment end date recorded on the re-treatment Study Drug Log CRF. 
End-of-Study (EOS) date is taken directly from the End of Study page of the CRF. 
Last contact date for subjects lost to follow up is defined as the latest date up to the 
end of study date amongst the following dates: visit dates, dates of laboratory blood 
samples taken, stool samples, physical examination / vital signs / ECG assessment date, 
AE onset and end dates, therapies start and stop dates, treatment intake, and dates with 
daily stool information. The end of study date itself is not considered as the date relates to 
an unsuccessful contact attempt. Dates completed by subjects, i.e., for patient-reported 
outcomes, are also not considered as it may contain impossible, spurious or partial dates 
and are not subject to cleaning.  
Study Day (Day) refers to the number of days elapsed since STS date plus 1 (e.g., Day 1 
is the day of STS). For dates prior to STS, study day is the negative number of days 
elapsed between the date under consideration and the day of STS. Therefore, the study 
day is always different from 0. 
Days from first dose are estimated for several assessments, including AE onset, AE end, 
study withdrawal, treatment interruptions, End-of-Treatment, concomitant medication 
start day and concomitant medication end day. It refers to the number of days between 
the occurrence of the specific event and the STS and plus 1 if the event occurs from the 
day of STS onwards, and plus 0 otherwise. It is a negative value if the event occurred up 
until the day before STS, and a positive value if occurs from the day of STS.  
Days from last dose are estimated for several assessments, including AE onset, 
concomitant medication start day, and study withdrawal. It refers to the number of days 
between the occurrence of the specific event and the date of EOT. It is a positive value if 
it occurs from the day after EOT and not defined otherwise.  
Days from first re-treatment dose are estimated for several assessments, including AE 
onset, AE end, study withdrawal, re-treatment interruptions, End of Re-treatment, 
concomitant medication start day and concomitant medication end day. It refers to the 
number of days between the occurrence of the specific event and the RTS plus 1. It is a 
positive value if it occurs from the day of RTS onwards. 
Days from last re-treatment dose are estimated for several assessments, including AE 
onset, concomitant medication start day, and study withdrawal. It refers to the number of 
days between the occurrence of the specific event and the date of RTE. It is a positive 
value if occurs from the day after RTE and not defined otherwise. 


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11.4 Periods 
For variables assessed up to Visit 5 use the date of Visit 5 as upper limit for the 
considered period. In the event of missing Visit 5, use the re-treatment start date (if 
available) otherwise the EOS date in the main study as the upper limit for the considered 
period.  
Similarly, for variables assessed in time periods up to Visit Re-5 use the date of 
Visit Re-5 as upper limit for the considered period. In the event of missing Visit Re-5 use 
the EOS date in the re-treatment extension as the upper limit for the considered period. 
11.5 Summaries by visit 
Summaries by visit are presented for Baseline, Visit 3, Visit 5 (or Visit Re-1 for subjects 
re-treated), Visit Re-1, Visit Re-3 and Visit Re-5. For subjects re-treated who do not have 
the assessment performed at Visit Re-1, the last Visit 4.x assessment performed prior to 
re-treatment are included in the summaries for the Re-1 visit if Visit 4.x is within 
24 hours of re-treatment. Otherwise it is considered to be missing for Visit Re-1.  
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS 
Missing parts for specific dates/times are imputed with acceptable non-missing values as 
described in Table 15. 
In the following, ‘lower limit’ and ‘upper limit’ refer to the minimum or maximum, 
respectively, of a possible date. For example, if the day is missing, the lowest limit is the 
first day of the given month and the upper limit is the last day of the given month. If the 
day and month are missing, the lower limit refers to the first day of the given year and the 
upper limit to the last day of the given year. The earliest and the latest dates refer to the 
first or last date, respectively, when ordered in sequence.  
In addition, a review of the available data is performed, and if the classification of an AE 
or a medication cannot be performed programmatically (e.g., partial start date of event, 
with treatment and re-treatment start date occurring the same month as the event), a query 
is raised for the investigator to provide more details on the timing of the event. Based on 
the response of the investigator, a flag ‘Assigned to re-treatment’ might then be filled in 
by Actelion in the database (flag is hidden to the investigator). 
The imputed EOT date is used in assigning safety events and assessments to the 
treatment-emergent period and used for deriving efficacy endpoints with definitions 
requiring EOT date. It is not considered for derivation of exposure variables.  


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Table 15 
Handling of missing date and time 
Type of date/time 
Date/time is incomplete 
Date/time is missing 
AE resolution date 
Use the upper limit. 
No approximation made; the AE is 
considered as ongoing in the analysis. 
AE resolution 
time 
A partially entered time is not allowed. Value is 
considered to be missing. 
Taken as ‘23:59’ if the corresponding 
AE resolution date is not missing, 
otherwise no replacement. 
AE onset date 
If the end date of the AE is before start of study 
treatment, then the earliest between study treatment 
start date –1 and the end date of AE is used. 
If the end date of the AE is not before the start of study 
treatment, and if the study treatment start falls in the 
range of possible dates, and if ‘Assign to re-treatment’ 
is not ticked, then the study treatment start date is used. 
If the end date of the AE is not before re-treatment 
start, and if the re-treatment start falls in the range of 
possible dates, and if ‘Assign to re-treatment’ is ticked, 
then the re-treatment start date is used. 
In all the other cases, the lower limit is used. 
If ‘Assign to re-treatment’ is not ticked, 
use the date of resolution of the AE or 
the date of start of study treatment, 
whichever is earlier. 
If ‘Assign to re-treatment’ is ticked, 
use the date of resolution of the AE or 
the date of re-treatment start, 
whichever is earlier. 
AE onset time 
A partially entered time is not allowed. Value is 
considered to be missing. 
If the AE onset date is equal to the 
study treatment start date, then the 
study treatment start time is used.  
If the AE onset date is equal to the 
re-treatment start date, then the study 
re-treatment start time is used.  
Otherwise, it is taken as ‘00:00’ 
AE onset time 
A partially entered time is not allowed. Value is 
considered to be missing. 
If the AE onset date is equal to the 
study treatment start date, then the 
study treatment start time is used.  
If the AE onset date is equal to the 
re-treatment start date, then the study 
re-treatment start time is used.  
Otherwise, it is taken as ‘00:00’ 
Concomitant 
medication start 
date 
If the end date of the concomitant medication is not 
before re-treatment start, and the re-treatment start date 
falls in the range of possible dates, and ‘Assign to 
retreatment’ has been ticked in the CRF, then the 
re-treatment start date is used (e.g., conmed start date 
May2014 and re-treatment start date 15May2014).  
In all other cases, the lower limit is used. 
No replacement is made. If ‘Assign to 
re-treatment’ has not been ticked in the 
CRF then the medication is considered 
to have started before the screening. 
If ‘Assign to re-treatment’ has been 
ticked in the CRF then the re-treatment 
start date is used. 


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Type of date/time 
Date/time is incomplete 
Date/time is missing 
Concomitant 
medication start 
time 
A partially entered time is not allowed. Value is 
considered to be missing. 
If the medication start date is equal to 
the study treatment start date and 
‘Ongoing at treatment start’ is ticked 
‘No’ and the medication end is after 
study treatment start then study 
treatment start time + 1 is used.  
If ‘Assign to re-treatment’ has been 
ticked the re-treatment start time is 
used. 
Otherwise ‘00:00’ is used.  
Concomitant 
medication end 
date 
The upper limit unless the medication started prior to 
study treatment start and ‘Ongoing at start of 
treatment?’ is ticked ‘No’ or the medication was 
recorded on the First Occurrence CRF, and the study 
treatment start falls in the range of possible dates then 
it is not replaced but considered a previous medication. 
No replacement; the treatment is 
considered as ongoing unless the 
medication started prior to study 
treatment start and ‘Ongoing at start of 
treatment?’ is ticked ‘No’ or the 
medication was recorded on the First 
Occurrence CRF, then it is considered 
a previous medication. 
Lab, ECG, vital 
signs assessment 
start time 
Partial time is not allowed. Value will be considered to 
be missing. 
Replace with ‘00:00’ 
Treatment start 
time missing  
Partial time is not allowed. Value will be considered to 
be missing. 
Replace with randomization time + 1 
min if randomization occurred on the 
same day, otherwise impute 00:00.  
Re-treatment start 
time missing 
Partial time is not allowed. Value will be considered to 
be missing. 
Replace with 00:00. 
EOT date 
Earliest between treatment start date + 10 days 
(Day 11), the upper limit, EOS date and Death date. 
Earliest between treatment start date + 
10 days (Day 11), EOS date and Death 
date. 
End of 
Re-treatment date 
Earliest between re-treatment start date + 10 days 
(Re-treatment Day 11), the upper limit, EOS date and 
Death date.  
Earliest between re-treatment start date 
+ 10 days (Day 11), EOS date and 
Death date. 
AE = adverse event, ECG = electrocardiogram, EOT = end-of-treatment date 
 


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13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES (TLFS) 
13.1 Subject disposition  
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 1.1 
T 
Reasons for screening failures (including unmet eligibility criteria) 
SCRAS 
L 1.1a 
L 
Screening failures 
SCRAS 
L 1.1b 
L 
Re-treatment extension screening failures 
FAS 
L 1.2a 
L 
Unmet eligibility criteria  
SCRAS 
L 1.2b 
L  
Unmet re-treatment extension eligibility criteria 
FAS 
T 1.2a 
T 
Disposition of subjects 
FAS 
T 1.2b 
T 
Disposition of subjects in re-treatment extension 
[FAS subset of subjects enrolled in re-treatment extension] 
FAS  
L 1.3 
L 
Disposition of subjects  
FAS 
T 1.3 
T 
Subjects by geographical region, country and site  
FAS 
T 1.4 
T 
Subjects by geographical region, country and site  
mITT 
T 1.5 
T 
Overview of analysis sets  
FAS 
T 1.6 
T 
Reasons for exclusion from the mITT and Per-protocol analysis sets 
FAS 
T 1.7 
T 
Participation in PRO validation, PK and gut microbiome sub-
studies 
FAS 
L 1.4 
L 
Exclusion from mITT analysis set 
FAS 
L 1.5 
L 
Exclusion from Per-protocol analysis set 
FAS 
L 1.6 
L 
Listing of randomized subjects and participation in analysis sets 
FAS 
L 1.7 
L 
Listing of subject unblinding 
FAS 
* T = Summary table, L = Listing, F = Figure. 
 


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13.2 Protocol deviations 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 2.1 
T 
All main study protocol deviations  
FAS 
T 2.2 
T 
Important main study protocol deviations 
FAS 
T 2.3 
T 
All re-treatment extension protocol deviations 
ES 
T 2.4 
T 
Important re-treatment extension protocol deviations 
ES 
L 2.1 
L 
All protocol deviations 
SCRAS 
L 2.2 
L 
Listing of other protocol deviations 
SCRAS 
* T = Summary table, L = Listing. 
 
13.3 Subject characteristics 
13.3.1 Demographics 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 3.1 
T 
Demographic characteristics  
mITT 
T 3.2 
T 
Demographic characteristics  
PPS 
T 3.3 
T 
Demographic characteristics of subjects who entered the re-
treatment extension 
ES 
T 3.4 
T 
EudraCT age categories 
SS 
L 3.1 
L 
Demographics 
FAS 
* T = Summary table, L = Listing, F = Figure. 
 


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13.3.2 Baseline disease characteristics 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 3.5 
T 
Main baseline disease characteristics  
mITT 
T 3.6 
T 
Main baseline disease characteristics  
PPS 
T 3.7 
T 
Other main baseline disease characteristics 
mITT 
T 3.8 
T 
Other main baseline disease characteristics 
PPS 
T 3.9 
T 
CDAD episode type IVRS stratification vs CRF actual type  
mITT 
L 3.2a 
L 
Baseline disease characteristics 
FAS 
L 3.2b 
L 
Baseline disease severity 
FAS 
* T = Summary table, L = Listing, F = Figure. 
 
13.3.3 Other baseline characteristics 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 3.10 
T 
Other baseline disease characteristics  
mITT 
T 3.11 
T 
Other baseline disease characteristics  
PPS 
L 3.3 
L 
Other baseline disease characteristics 
FAS 
* T = Summary table, L = Listing. 
 
13.3.4 Medical history  
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 3.12 
T 
Previous medical history by system organ class and preferred term 
mITT 
T 3.13 
T 
Ongoing medical conditions by system organ class and preferred 
term 
mITT 
L 3.4 
L 
Medical history 
FAS 
* T = Summary table, L = Listing. 
 


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13.3.5 Previous and concomitant therapies 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 3.14 
T 
Previous therapies by anatomical therapeutic chemical class and 
preferred term 
mITT 
T 3.15a 
T 
Main study concomitant therapies by anatomical therapeutic 
chemical class and preferred term 
mITT 
T 3.15b 
T 
Main study concomitant therapies with onset prior to study 
treatment start by anatomical therapeutic chemical class (ATC) and 
preferred term 
mITT 
T 3.15c 
T 
Main study concomitant therapies starting between study treatment 
start and EOT + 7 days by anatomical therapeutic chemical class 
(ATC) and preferred term 
mITT 
L 3.5 
L 
Previous and concomitant therapies 
FAS 
L 3.6 
L 
Re-treatment concomitant therapies  
ES 
* T = Summary table, L = Listing. 
 


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13.3.6 Specific previous and concomitant  
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 3.16 
T 
Prior antimicrobial treatments active against CDAD within 1 week 
of study treatment start by anatomical therapeutic chemical 
preferred term 
mITT 
T 3.17 
T 
Concomitant opiate treatments at Baseline by anatomical 
therapeutic chemical preferred term  
mITT 
T 3.18 
T 
Main study concomitant antimicrobial treatment active against 
CDAD by anatomical therapeutic chemical preferred term up to 
Visit 5 
mITT 
T 3.19 
T 
Main study concomitant antimicrobial treatment active against 
CDAD by anatomical therapeutic chemical preferred term starting 
between study treatment start and EOT + 2 days 
mITT 
T 3.20 
T 
Main study concomitant antimicrobial treatment active against 
CDAD by anatomical therapeutic chemical preferred term starting 
between EOT + 3 days and Visit 5 
mITT 
T 3.21 
T 
Main study concomitant antibiotics for infections other than 
CDAD by anatomical therapeutic chemical preferred term up to 
Visit 5 
mITT 
T 3.22 
T 
Main study concomitant antibiotics for infections other than 
CDAD by anatomical therapeutic chemical preferred term starting 
between study treatment start and EOT + 2 days. 
mITT 
T 3.23 
T 
Main study concomitant antibiotics for infections other than 
CDAD by anatomical therapeutic chemical preferred term starting 
between EOT + 3 days and Visit 5 
mITT 
T 3.24 
T 
Main study concomitant proton pump inhibitors and H2 blockers 
by anatomical therapeutic chemical preferred term up to Visit 5 
mITT 
T 3.25 
T 
Main study concomitant proton pump inhibitors and H2 blockers 
by anatomical therapeutic chemical preferred term starting between 
study treatment start and EOT + 2 days. 
mITT 
T 3.26 
T 
Main study concomitant proton pump inhibitors and H2 blockers 
by anatomical therapeutic chemical preferred term starting between 
EOT + 3 days and Visit 5 
mITT 
* T = Summary table. 
 


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13.3.7 Procedures 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 3.27 
T 
Main study concomitant procedures  
[Note: By CDAD-related procedures and Others.] 
mITT 
L 3.7 
L 
All procedures 
FAS 
L 3.8 
L  
Endoscopy and imaging 
FAS 
* T = Summary table, L = Listing. 
 
 
13.4 Study treatment exposure and compliance 
13.4.1 Exposure 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 4.1 
T 
Treatment exposure according to treatment received 
SS 
T 4.2 
T 
Treatment exposure according to treatment planned 
mITT** 
T 4.3 
T 
Re-treatment exposure (open-label cadazolid) 
ES 
L 4.1a 
L 
Exposure 
FAS 
* T = Summary table, L = Listing. 
** Not done if mITT analysis set differs from SS by ≤ 5% 
 
 
13.4.2 Compliance with study treatment 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 4.4 
T 
Compliance 
mITT** 
T 4.5 
T 
Compliance with re-treatment (open-label cadazolid) 
ES 
L 4.1b 
L 
Compliance 
FAS 
* T = Summary table. 
** Not done if mITT analysis set differs from SS by ≤ 5% 
 
 
 
 
 


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13.4.3 Study treatment discontinuation  
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 4.6a 
T 
Reasons for premature discontinuation of main study treatment  
SS 
T 4.6b 
T 
Reasons for premature discontinuation of main study treatment 
according to treatment planned 
[Present according to “planned treatment” not according to actual 
treatment received]  
SS 
T 4.7 
T 
Reasons for premature discontinuation of main study treatment 
mITT** 
L 4.2 
L 
Premature study treatment discontinuation 
FAS 
L 4.3 
L 
Premature re-treatment discontinuation 
ES 
* T = Summary table, L = Listing.  
** Not done if mITT analysis set differs from SS by ≤ 5% 
 
 
13.4.4 Study treatment interruptions 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 4.8 
T 
Reasons for temporary interruption in study treatment  
SS 
* T = Summary table, L = Listing. 
Reasons for temporary interruptions are listed in the exposure listing.  
 
 
13.5 Study withdrawal 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 5.1 
T 
Reasons for premature study withdrawal  
FAS 
T 5.2 
T 
Reasons for premature study withdrawal from the re-treatment 
extension 
[Denominator = subjects enrolled in re-treatment extension] 
FAS 
L 5.1 
L 
Premature study withdrawal 
FAS 
* T = Summary table, L = Listing. 
 


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13.6 Primary efficacy analyses 
13.6.1 Main analysis 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 6.1 
T 
Clinical Cure  
mITT 
F 6.1  
F 
Clinical Cure and Sustained Cure 
[Includes Clinical Cure on mITT, Clinical Cure on PPS, Sustained 
Cure on mITT] 
mITT 
T 6.2 
T 
Clinical Cure  
PPS 
T 6.3 
T 
Reasons for Clinical Failure 
mITT 
T 6.4 
T 
Reasons for Clinical Failure 
PPS 
L 6.1 
L 
Clinical Cure 
FAS 
L 6.2 
L 
Daily Stool information and further efficacy data 
FAS 
* T = Summary table, L = Listing, F = Figure. 
 
13.6.2 Supportive/sensitivity analyses 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 6.5 
T 
Clinical Cure – Stratified analysis 
mITT 
T 6.6 
T 
Clinical Cure – Stratified analysis  
PPS 
T 6.7 
T 
Clinical Cure – Sensitivity analysis imputing missing day 
mITT 
L 6.3 
L 
Sensitivity variables for Clinical Cure and Sustained Cure in 
subjects with at least one sensitivity variable differing from main 
endpoint   
FAS 
* T = Summary table; L = Listing. 
 


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13.6.3 Subgroup analyses 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 6.8 
T 
Clinical Cure – Subgroup analysis  
mITT 
T 6.9 
T 
Clinical Cure – Subgroup analysis 
PPS 
F 6.3 
F 
Clinical Cure – Forest plot of subgroups (difference in proportions) 
mITT 
F 6.4 
F 
Clinical Cure – Forest plot of subgroups (difference in proportions) 
PPS 
T 6.10 
T 
Clinical Cure – Logistic regression for subgroup analyses 
mITT 
F 6.5 
F 
Clinical Cure – Forest plot of subgroups (odds ratios) 
mITT 
T 6.11 
T 
Clinical Cure – Logistic regression for subgroup analyses 
PPS 
F 6.6 
F 
Clinical Cure – Forest plot of subgroups (odds ratios) 
PPS 
* T = Summary table, F = Figure. 
 
13.6.4 Other analyses 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 6.14 
T 
Clinical Cure by concomitant antibiotics for infections other than 
CDAD from first dose to EOT + 2 days  
mITT 
T 6.15 
T 
Clinical Cure by concomitant antibiotics for infections other than 
CDAD from first dose to EOT + 2 days 
PPS 
T 6.16 
T 
Clinical Cure by country 
mITT 
F 6.7 
F 
Clinical Cure by country 
mITT 
* T = Summary table, F = Figure. 
 


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13.7 Secondary efficacy analyses 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 7.1 
T 
Sustained Cure  
mITT 
T 7.2 
T 
Sustained Cure  
PPS 
F 7.1 
F 
Sustained Cure  
mITT 
T 7.3 
T 
Reasons for being classified as not Sustained Cure 
mITT 
T 7.4 
T 
Sustained Cure – Subgroup analysis  
mITT 
F 7.2 
F 
Sustained Cure – Forest plot of subgroups (difference in 
proportions) 
mITT 
T 7.5 
T 
Sustained Cure by concomitant antibiotics for infections other than 
CDAD from first dose to Visit 5 / Re-treatment 
mITT 
T 7.6 
T 
Sustained Cure – Logistic regression for subgroup analyses 
mITT 
F 7.3 
F 
Sustained Cure – Forest plot of subgroups (odds ratios)  
mITT 
T 7.7 
T 
Sustained Cure by Country 
mITT 
F 7.4 
F 
Sustained Cure by Country 
mITT 
L 7.1 
L 
Sustained Cure 
FAS 
T 7.8 
T 
Time to resolution of diarrhea analysis 
mITT 
T 7.9 
T 
Time to resolution of diarrhea analysis 
PPS 
T 7.10 
T 
Time to resolution of diarrhea: Kaplan-Meier estimates 
mITT 
T 7.11 
T 
Time to resolution of diarrhea: Kaplan-Meier estimates 
PPS 
T 7.12 
T 
Time to resolution of diarrhea: Kaplan-Meier estimates by stratum 
mITT 
F 7.5 
F 
Time to Resolution of Diarrhea: Kaplan-Meier Curve 
mITT 
F 7.6 
F 
Time to Resolution of Diarrhea: Kaplan-Meier Curve 
PPS 
F 7.7 
F 
Time to resolution of diarrhea within stratum: Kaplan-Meier curve 
mITT 
L 7.2 
L 
Time to resolution of diarrhea (ROD) 
FAS 
T 7.13 
T 
Absolute and change from baseline values for CDI-DaySyms 
domain scores by time point 
PROAS1 


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Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
F 7.8 
F 
Box-plot of absolute values for CDI-DaySyms by domain score and 
time point 
PROAS1 
T 7.14 
T 
Number and proportion of subjects with missing CDI-DaySyms 
scores, by domain score and time point 
PROAS1 
T 7.15 
T 
Statistical analysis (ANOVA) of CDI-DaySyms domain scores  
PROAS1 
F 7.9 
F 
LS mean estimates and 95% CI for CDI-DaySyms domain scores by 
time point 
PROAS1 
T 7.16 
T 
Statistical analysis (ANOVA) of CDI-DaySyms diarrhea domain 
score - sensitivity analysis with 50% missing data rule applied  
PROAS1 
T 7.17 
T 
Statistical analysis (ANOVA) of CDI-DaySyms domain scores - 
multiple imputation with MAR sensitivity analysis 
PROAS1 
T 7.18 
T 
Statistical analysis (ANOVA) of CDI-DaySyms domain scores - 
tipping point imputation sensitivity analysis 
PROAS1 
T 7.19 
T 
Statistical analysis (ANOVA) of CDI-DaySyms domain scores - 
LOCF imputation sensitivity analysis 
PROAS1 
T 7.20 
T 
CDI-DaySyms domain score response rates at Day 3   
PROAS1 
T 7.21 
T 
Absolute values of CDI-DaySyms domain scores by CC response 
and time point  
PROAS1 
T 7.22 
T 
Absolute values of CDI-DaySyms domain scores by CC response,  
time point and treatment group  
PROAS1 
T 7.23 
T 
Statistical analysis (ANOVA) of CDI-DaySyms domain scores vs 
CC response 
PROAS1 
T 7.24 
T 
Statistical analysis (ANOVA) of CDI-DaySyms domain scores vs 
CC response, by treatment group  
PROAS1 
F 7.10 
F 
Box-plot of absolute values of CDI DaySyms domain scores by CC 
response and time point 
PROAS1 
F 7.11 
F 
Box-plot of absolute values of CDI DaySyms domain scores by CC 
response, time point and treatment group 
PROAS1 
L 7.3 
L 
CDI-DaySyms individual items data (main study and re-treatment) 
FAS 


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Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
L 7.4 
L 
CDI-DaySyms domain scores and change from baseline (main 
study) 
FAS 
L 7.5 
L 
CDI-DaySyms responder status at Day 3, by domain (main study) 
FAS 
* T = Summary table, L = Listing, F = Figure.  
1. Excluding subjects in the PRO sub-study. 
 
13.7.1 Further supportive/sensitivity analyses for Sustained Cure 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 7.25 
T 
Sustained Cure – Sensitivity analysis reducing minimum follow-up 
period required to EOT + 25 days 
mITT 
T 7.26 
T 
Reasons for being classified as not Sustained Cure – Sensitivity 
analysis reducing minimum follow-up period required to EOT + 25 
days 
mITT 
T 7.27 
T 
Modified Sustained Cure 
mITT 
T 7.28 
T 
Modified recurrence 
mITT 
* T = Summary table. 
 
13.8 Other efficacy analyses 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 8.1 
T 
Investigator judgment of early treatment response (ETR) at Visit 2  
mITT 
T 8.2a 
T 
Investigator judgment of clinical response (ICR) at Visit 4 
mITT 
T 8.2b 
T 
Reasons for investigator judgment of clinical response (ICR) at 
Visit 4 
mITT 
T 8.3 
T 
Investigator judgment of clinical response (ICR) at Visit 4 
PPS 
T 8.4a 
T 
Investigator assessment of sustained response (ISR) at Visit 5 
mITT 
T 8.4b 
T 
Reasons for investigator judgment of sustained response (ISR) at 
Visit 5 
mITT 
T 8.5 
T 
Early clinical cure (ECC) by Day 5 
mITT 
T 8.6 
T 
Normalization of bowel movements rate 
mITT 


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Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 8.7 
T 
Time to return to usual stools 
mITT 
F 8.1 
F 
Time to return to usual stools: Kaplan-Meier curve 
mITT 
T 8.8 
T 
Recurrence rate and adjusted recurrence rate 
mITT 
T 8.9 
T 
Recurrence rate and adjusted recurrence rate 
PPS 
T 8.10 
T 
Recurrence rate – Subgroup 
mITT 
T 8.11 
T 
Time to Recurrence for subjects with Clinical Cure 
mITT 
F 8.2 
F 
Time to Recurrence for subjects with Clinical Cure: Kaplan-Meier 
curve 
mITT 
T 8.12a 
T 
Subjects with C. difficile isolate at baseline: Overall, by 
geographical region, and by Clinical Cure Outcome  
[showing frequencies and percentages by treatment group and 
overall] 
mITT 
T 8.12b 
T 
Subjects with C. difficile isolate at baseline: Overall, by 
geographical region, and by Clinical Cure Outcome 
[showing frequencies and percentages by treatment group and 
overall] 
PPS 
T 8.13 
T 
Subjects with C. difficile isolate by visit during main study 
mITT 
T 8.14a 
T 
Subjects with C. difficile isolate by visit for Clinical Failures 
(Baseline and Visit 3) and Recurrences (Baseline and Visit 4.x) 
mITT 
T 8.14b 
T 
Subjects with C. difficile isolate by visit for Clinical Failures 
(Baseline and Visit 3) and Recurrences (Baseline and Visit 4.x) 
PPS 
T 8.15a 
T 
C. difficile strains for baseline isolates based on PCR ribotyping 
and REA typing  
[by treatment group and overall] 
mITT 
T 8.15b 
T 
C. difficile strains for baseline isolates based on PCR ribotyping 
and REA typing  
[by treatment group and overall] 
PPS 
T 8.16a 
T 
Hypervirulent ribotypes at baseline. Overall, by geographical 
region and by country 
[by treatment group and total overall] 
mITT 
T 8.16b 
T 
REA groups of special interest at baseline. Overall, by geographical 
region and by country 
[by treatment group and total overall] 
mITT 


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Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 8.16c 
T 
Hypervirulent ribotypes at baseline. Overall, by geographical 
region and by country 
[by treatment group and total overall] 
PPS 
T 8.16d 
T 
REA groups of special interest at baseline. Overall, by geographical 
region and by country 
[by treatment group and total overall] 
PPS 
T 8.17 
T 
Hypervirulent ribotypes vs REA groups of special interest at 
baseline. Overall and by geographical region 
[cross tabulated by treatment group and total overall] 
mITT 
T 8.18a 
T 
Relapse and re-infection  
[by treatment group] 
mITT 
T 8.18b 
T 
Relapse and re-infection  
[by treatment group] 
PPS 
T 8.19a 
T 
Susceptibility of C. difficile to each test agent at baseline and post-
baseline (highest MIC). MIC summary statistics. 
[by treatment group and total; test agents = cadazolid, vancomycin, 
linezolid, moxifloxacin, metronidazole and fidaxomicin] 
mITT 
T 8.19b 
T 
Susceptibility of C. difficile to each test agent at baseline and post-
baseline (highest MIC). MIC summary statistics. 
[by treatment group and total; test agents = cadazolid, vancomycin, 
linezolid, moxifloxacin, metronidazole and fidaxomicin] 
PPS 
T 8.20a 
T 
Susceptibility of C. difficile to cadazolid, vancomycin, linezolid and 
moxifloxacin by visit for Clinical Failures (baseline and Visit 3) 
and Recurrences (baseline and Visit 4.x). MIC summary statistics. 
[by treatment group] 
mITT 
T 8.20b 
T 
Susceptibility of C. difficile to cadazolid, vancomycin, linezolid and 
moxifloxacin by visit for Clinical Failures (baseline and Visit 3) 
and Recurrences (baseline and Visit 4.x). MIC summary statistics. 
[by treatment group] 
PPS 
T 8.21 
T 
Susceptibility of C. difficile to each test agent at baseline. MIC 
summary statistics overall and by Clinical Cure outcome. 
[by treatment group and overall] 
mITT 
T 8.21 
T 
Susceptibility of C. difficile to each test agent at baseline. MIC 
summary statistics overall and by Clinical Cure outcome. 
[by treatment group and overall] 
PPS 


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Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 8.22a 
T 
Susceptibility of C. difficile to each test agent at baseline in subjects 
with hypervirulent strain. MIC summary statistics overall and by 
Clinical Cure outcome.  
[by treatment group and overall] 
mITT/PPS 
T 8.22b 
T 
Susceptibility of C. difficile to each test agent at baseline in subjects 
with hypervirulent strain. MIC summary statistics overall and by 
Clinical Cure outcome.  
[by treatment group and overall] 
PPS 
T 8.23a 
T 
Susceptibility of C. difficile to each test agent at baseline. MIC 
summary statistics by geographical region. 
[by treatment group and overall] 
mITT 
T 8.23b 
T 
Susceptibility of C. difficile to each test agent at baseline. MIC 
summary statistics by geographical region. 
[by treatment group and overall] 
PPS 
T 8.24a 
T 
Susceptibility of C. difficile to each test agent at baseline and post-
baseline (highest MIC). MIC frequency distribution 
[by treatment group] 
mITT 
T 8.24b 
T 
Susceptibility of C. difficile to each test agent at baseline and post-
baseline (highest MIC). MIC frequency distribution 
[by treatment group] 
PPS 
F 8.3 
F 
Susceptibility of C. difficile to each test agent at baseline. MIC 
frequency distribution. 
[by treatment group] 
mITT 
T 8.25a 
T 
Susceptibility of C. difficile to cadazolid, vancomycin, linezolid, 
and moxifloxacin for Clinical Failures at baseline and Visit 3. MIC 
frequency distribution. 
[by treatment group] 
mITT 
T 8.25b 
T 
Susceptibility of C. difficile to cadazolid, vancomycin, linezolid, 
and moxifloxacin for Clinical Failures at baseline and Visit 3. MIC 
frequency distribution. 
[by treatment group] 
PPS 
T 8.37a 
T 
Susceptibility of C. difficile to each test agent at baseline in subjects 
with hypervirulent strain. MIC frequency distribution 
[by treatment group] 
mITT 


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Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 8.37b 
T 
Susceptibility of C. difficile to each test agent at baseline in subjects 
with hypervirulent strain. MIC frequency distribution 
[by treatment group] 
PPS 
T 8.38a 
T 
Susceptibility of C. difficile to each test agent at baseline in subjects 
with REA group of special interest. MIC (µg/mL) summary 
statistics overall and by Clinical Cure outcome 
mITT 
T 8.38b 
T 
Susceptibility of C. difficile to each test agent at baseline in subjects 
with REA group of special interest. MIC (µg/mL) summary 
statistics overall and by Clinical Cure outcome 
PPS 
T 8.26a 
T 
Susceptibility of C. difficile to cadazolid, vancomycin, linezolid, 
and moxifloxacin for Recurrences at baseline and Visit 4.x. MIC 
frequency distribution. 
[by treatment group] 
mITT 
T 8.26b 
T 
Susceptibility of C. difficile to cadazolid, vancomycin, linezolid, 
and moxifloxacin for Recurrences at baseline and Visit 4.x. MIC 
frequency distribution. 
[by treatment group] 
PPS 
T 8.27a 
T 
Clinical Cure Rates by baseline C. difficile MIC level to each test 
agent. Overall and by Hypervirulent Strain.  
[by treatment group] 
mITT 
T 8.27b 
T 
Clinical Cure Rates by baseline C. difficile MIC level to each test 
agent. Overall and by Hypervirulent Strain.  
[by treatment group] 
PPS 
T 8.28a 
T 
Susceptibility of C. difficile to each test agent: Change from 
baseline for Clinical Failures to Visit 3 and for Recurrences to 
Visit 4.x. Frequencies for different levels of changes.  
[by treatment group] 
mITT  
T 8.28b 
T 
Susceptibility of C. difficile to each test agent: Change from 
baseline for Clinical Failures to Visit 3 and for Recurrences to 
Visit 4.x. Frequencies for different levels of changes.  
[by treatment group] 
PPS  
T 8.29 
T 
Susceptibility of C. difficile to each test agent: Change from 
baseline to highest post-baseline result. Frequencies for different 
levels of changes.  
[by treatment group] 
mITT 


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Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 8.30 
T 
Vancomycin-resistant enterococci (VRE): Subjects with isolates at 
baseline and Visit 3 and shifts from baseline.  
[by treatment group] 
mITT 
T 8.31 
T 
Total vancomycin-resistant enterococci (VRE) counts (log10 
cfu/ml) in VRE-positive subjects at baseline. Absolute values and 
change from baseline to Visit 3.  
[by treatment group] 
mITT 
T 8.32 
T 
Susceptibility of vancomycin-resistant enterococci (VRE) to each 
test agent at baseline and Visit 3. MIC summary statistics by VRE 
species  
[by treatment group; test agents = cadazolid, vancomycin, linezolid, 
moxifloxacin, fidaxomicin, daptomycin, tigecycline, ampicillin, 
gentamicin, and quinupristin-dalfopristin; VRE species = 
E. faecium (first colony), and E. faecalis (first colony)] 
mITT 
T 8.33 
T 
Susceptibility of vancomycin-resistant enterococci (VRE) to 
cadazolid, linezolid, and moxifloxacin: Change from baseline to 
Visit 3 by VRE species  
[by treatment group, VRE species = E. faecium (first colony), and 
E. faecalis (first colony)]  
mITT 
L 8.1 
L 
Investigator judgment of efficacy  
FAS 
L 8.2a 
L 
C. difficile isolation and typing 
FAS 
L 8.2b 
L 
C. difficile isolate 2 culture and typing 
FAS 
L 8.3a 
L 
Susceptibility of C. difficile to different antibiotics 
FAS 
L 8.3b 
L 
Susceptibility of C. difficile isolate 2 to different antibiotics 
FAS 
L 8.4 
L 
Susceptibility of C. difficile to cadazolid for subjects with ≥ 4-fold 
MIC increase to cadazolid 
FAS 
L 8.5 
L 
Susceptibility of C. difficile to linezolid for subjects with ≥ 4-fold 
MIC increase to linezolid 
FAS 
L 8.6 
L 
Susceptibility of C. difficile to moxifloxacin for subjects with 
≥ 4-fold MIC increase to moxifloxacin 
FAS 
L 8.7 
L 
Vancomycin-resistant enterococci culture  
FAS 
L 8.8 
L 
Vancomycin-resistant enterococci susceptibility to different 
antibiotics 
FAS 
L 8.9 
L 
Investigator judgment of efficacy 
FAS 


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Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
L 8.10 
L 
Cure reasons for investigator judgment of clinical response (ICR) 
during main study and re-treatment extension 
FAS 
L 8.11 
L 
Failure reasons for investigator judgment of clinical response (ICR) 
during main study and re-treatment extension 
FAS 
L 8.12 
L 
Cure reasons for investigator judgment of sustained response (ISR) 
during main study and re-treatment extension 
FAS 
L 8.13 
L 
Failure reasons for investigator judgment of sustained response 
(ISR) during main study and re-treatment extension  
FAS 
L 8.14 
L 
Other efficacy variables – main study 
FAS 
T 8.34 
T 
Re-treatment Clinical Cure  
ES 
T 8.35 
T 
Re-treatment Sustained Cure  
ES 
T 8.36 
T 
Re-treatment recurrence and adjusted recurrence 
ES 
L 8.15 
L 
Re-treatment Clinical Cure 
ES 
L 8.16 
L 
Re-treatment Sustained Cure 
ES 
L 8.17 
L 
Re-treatment investigator judgment of efficacy 
ES 
* T = Summary table, L = Listing, F = Figure. 
 


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13.9 Safety analyses 
13.9.1 Adverse events 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 9.1 
T 
Overview of treatment-emergent adverse events (AE) up to EOT + 
7 days 
SS # 
T 9.2 
T 
Treatment-emergent adverse events (AE) by system organ class and 
preferred term up to EOT + 7 days 
SS 
T 9.3 
T 
Treatment-emergent adverse events (AE) by preferred term up to 
EOT + 7 days 
SS 
T 9.4 
T 
Treatment-emergent adverse events (AE) by preferred term up to 
EOT + 7 days sorted by risk difference between cadazolid and 
vancomycin 
SS 
T 9.5 
T 
Main study adverse events (AE) by system organ class and 
preferred term up to Visit 5  
SS 
T 9.6 
T 
Occurrence of non-serious frequent treatment-emergent adverse 
events (AE) up to EOT + 7 days 
SS # 
T 9.7 
T 
Overview of re-treatment-emergent adverse events (AE) up to End 
of Re-treatment + 7 days 
ES # 
T 9.8 
T 
Re-treatment-emergent adverse events (AE) by system organ class 
and preferred term up to End of Re-treatment + 7 days 
ES 
T 9.9 
T 
Re-treatment extension adverse events (AE) by system organ class 
and preferred term up to Visit Re-5 
ES 
T 9.10 
T 
Occurrence of non-serious frequent re-treatment-emergent adverse 
events (AE) up to End of Re-treatment + 7 days 
ES # 
L 9.1 
L 
Listing of all adverse events (AE) 
FAS 
* T = Summary table, L = Listing. # EudraCT required. 
 


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13.9.2 Serious adverse events 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 9.11 
T 
Treatment-emergent serious adverse events (SAE) by system organ 
class and preferred term up to EOT + 7 days 
SS 
T 9.12 
T 
Treatment-emergent serious adverse events (SAE) by preferred 
term up to EOT + 7 days 
SS 
T 9.13 
T 
Main study serious adverse events (SAE) by system organ class and 
preferred term up to Visit 5 
SS 
T 9.14 
T 
Occurrence of treatment-emergent serious adverse events (SAE) up 
to EOT + 7 days 
SS # 
T 9.15 
T 
Re-treatment-emergent serious adverse events (SAE) by system 
organ class and preferred term up to End of Re-treatment + 7 days 
ES 
T 9.16 
T 
Re-treatment extension serious adverse events (SAE) by system 
organ class and preferred term up to Visit Re-5 
ES 
L 9.2 
L 
Listing of all serious adverse events (SAE)  
FAS 
L 9.3 
L 
Listing of re-treatment-emergent serious adverse events up to End 
of Re-treatment + 7 days 
ES # 
* T = Summary table, L = Listing. # EudraCT required. 
 
13.9.3 Adverse events by intensity or relationship to study treatment 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 9.16 
T 
Treatment-emergent adverse events (AE) by maximum intensity up 
to EOT + 7 days 
SS 
T 9.17 
T 
Re-treatment-emergent adverse events (AE) by maximum intensity 
up to End of Re-treatment + 7 days 
ES 
T 9.18 
T 
Treatment-emergent adverse events (AE) related to study treatment 
by system organ class and preferred term up to EOT + 7 days 
SS 
L 9.4 
L 
Listing of treatment-emergent serious adverse events (SAE) related 
to study treatment 
SS #  
T = Summary table, L = Listing. # EudraCT required. 
 


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13.9.4 Other significant adverse events 
13.9.4.1 Adverse events leading to treatment discontinuation 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 9.19 
T 
Treatment-emergent adverse events (AE) leading to premature 
discontinuation of study treatment by system organ class and 
preferred term  
SS 
T 9.20 
T 
Treatment-emergent adverse events (AE) leading to premature 
discontinuation of study treatment by preferred term  
SS 
T 9.21 
T 
Re-treatment-emergent adverse events (AE) leading to premature 
discontinuation of study treatment by system organ class and 
preferred term 
ES 
L 9.5 
L 
Listing of adverse events (AE) leading to premature discontinuation 
of study treatment 
FAS 
* T = Summary table, L = Listing. 
 
13.9.4.2 Adverse events leading to death 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 9.22 
T 
Treatment-emergent adverse events (AE) with fatal outcome by 
system organ class and preferred term up to EOT + 7 days 
SS 
T 9.23 
T 
Main study adverse events (AE) with fatal outcome by system 
organ class and preferred term up to Visit 5 
SS 
T 9.24 
T 
Treatment-emergent serious adverse events (SAE) with fatal 
outcome by system organ class and preferred term up to EOT + 7 
days 
SS # 
L 9.6 
L 
Listing of adverse events (AE) with fatal outcome 
FAS 
* T = Summary table, L = Listing. # EudraCT required. 
 
13.9.5 Deaths 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 9.25 
T 
Primary cause of death. Overall and by period  
SS 
L 9.6 
L 
Deaths 
FAS 
* T = Summary table, L= Listing. 


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13.10 Electrocardiography 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 10.1a 
T 
ECGs: Absolute values and changes from baseline by visit during 
main study 
SS 
T 10.1b 
T 
ECGs: Absolute values and changes from baseline by visit during 
re-treatment extension 
ES 
T 10.2 
T 
Treatment-emergent QT or QTc marked abnormalities up to EOT + 
7 days 
SS 
T 10.3 
T 
Re-treatment-emergent QT or QTc marked abnormalities up to End 
of Re-treatment + 7 days 
ES 
T 10.4 
T 
Main study QT or QTc marked abnormalities up to Visit 5 
SS 
T 10.5 
T 
Treatment-emergent qualitative ECG abnormalities up to EOT + 7 
days 
SS 
T 10.6 
T 
Re-treatment-emergent qualitative ECG abnormalities up to End of 
Re-treatment + 7 days 
ES 
T 10.7 
T 
Main study qualitative ECG abnormalities up to Visit 5 
SS 
L 10.1 
L 
ECG data 
FAS 
L 10.2 
L  
ECG findings 
FAS 
* T = Summary table, L = Listing. 
 
13.11 Laboratory tests 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 11.1a 
T 
Hematology: Absolute values and changes from baseline by visit 
during main study 
SS 
T 11.1b 
T 
Hematology: Absolute values and changes from baseline by visit 
during re-treatment extension 
ES 
T 11.2a 
T 
Coagulation: Absolute values and changes from baseline by visit 
during main study 
SS 
T 11.2b 
T 
Coagulation: Absolute values and changes from baseline by visit 
during re-treatment extension 
ES 


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Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 11.3a 
T 
Chemistry: Absolute values and changes from baseline by visit 
during main study 
SS 
T 11.3b 
T 
Chemistry: Absolute values and changes from baseline by visit 
during re-treatment extension 
ES 
T 11.4 
T 
Hematology: Treatment-emergent marked laboratory 
abnormalities up to EOT + 7 days 
SS 
T 11.5 
T 
Hematology: Re-treatment-emergent marked laboratory 
abnormalities up to End of Re-treatment + 7 days 
ES 
T 11.6 
T 
Hematology: Main study marked laboratory abnormalities up to 
Visit 5 
SS 
T 11.7 
T 
Coagulation: Treatment-emergent marked laboratory 
abnormalities up to EOT + 7 days 
SS 
T 11.8 
T 
Coagulation: Re-treatment-emergent marked laboratory 
abnormalities up to End of Re-treatment + 7 days  
ES 
T 11.9 
T 
Coagulation: Main study marked laboratory abnormalities up to 
Visit 5 
SS 
T 11.10 
T 
Chemistry: Treatment-emergent marked laboratory abnormalities 
up to EOT + 7 days 
SS 
T 11.11 
T 
Chemistry: Re-treatment-emergent marked laboratory 
abnormalities up to End of Re-treatment + 7 days  
ES 
T 11.12 
T 
Chemistry: Main study marked laboratory abnormalities up to 
Visit 5 
SS 
T 11.13 
T 
Hematology: Marked abnormalities shift from baseline to Visit 5 
SS 
T 11.14 
T 
Coagulation: Marked abnormalities shift from baseline to Visit 5 
SS 
T 11.15 
T 
Chemistry: Marked abnormalities shift from baseline to Visit 5 
SS 
T 11.16 
T 
Main study elevated liver tests up to Visit 5 
SS 
T 11.17 
T 
Hematology, Coagulation and Chemistry marked abnormality 
ranges  
- 
L 11.1 
L 
Hematology laboratory data 
FAS 


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Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
L 11.2 
L 
Chemistry and Coagulation laboratory data 
FAS 
* T = Summary table, L = Listing. 
 
13.12 Vital signs and body weight 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 12.1a 
T 
Vital signs absolute values and changes from baseline by visit 
during main study 
SS 
T 12.1b 
T 
Vital signs absolute values and changes from baseline by visit 
during re-treatment extension 
ES 
T 12.2 
T 
Treatment-emergent blood pressure marked abnormalities up to 
EOT + 7 days 
SS 
T 12.3 
T 
Re-treatment-emergent blood pressure marked abnormalities up to 
End of Re-treatment + 7 days 
ES 
T 12.4 
T 
Main study blood pressure marked abnormalities up to Visit 5 
SS 
L 12.1 
L 
Vital signs 
FAS 
L 12.1 
L 
Body temperature 
FAS 
* T = Summary table, L = Listing. 
 
13.13 Other safety variables 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
L 13.1 
L 
Physical and abdominal examination 
FAS 
* L = Listing. 
 
13.14 Other evaluations 
13.14.1 Quality of life analyses 
Not applicable. 


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13.14.2 Pharmacoeconomic analyses 
Number 
Dis-
play* 
Title (Description) 
Analysis 
set(s) 
T 14.1 
T 
Duration of hospitalization in main study by baseline 
hospitalization status 
mITT 
T 14.2 
T 
Frequency of hospitalization admission/re-admissions during main 
study by baseline hospitalization status 
mITT 
T 14.3 
T 
Duration of hospitalization during re-treatment extension  
ES 
T 14.4 
T 
Frequency of hospitalization admission/re-admissions by 
hospitalization status at baseline 
ES 
L 14.1 
L 
Hospitalization data 
FAS 
T 14.5 
T 
Work productivity and activity impairment (WPAI:CDAD) 
Subjects currently employed by visit 
PROAS 
T 14.6 
T 
Work productivity and activity impairment (WPAI:CDAD) scores 
by visit 
PROAS 
L 14.2 
L 
Work productivity and activity impairment for C. difficile 
associated diarrhea (WPAI:CDAD) data 
FAS 
* T = Summary table, L = Listing. 
 
 
13.14.3 Benefit-risk evaluations 
Not applicable. 
13.14.4 Pharmacodynamic analyses 
Not applicable. 
13.14.5 Pharmacokinetic analyses 
Not applicable. 
 


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14 REFERENCES 
[Brookmeyer 1982] Brookmeyer R, Crowley JA. CI for the median survival time. 
Biometrics. 1982;38:29-41. 
[Collett 1994] Collett D. Modelling survival data in medical research. London: 
Chapman & Hall; 1994. 
[Cuzick 2005] Cuzick J. Forest plots and the interpretation of subgroups. The Lancet. 
2005;365(9467):1308. 
[Dmitrienko 2010] Dmitrienko A, Tamhane AC, Bretz F. Multiple testing problems in 
pharmaceutical statistics. CRC Press; 2010. 
[Newcombe 1998] Newcombe RG. Improved confidence intervals for the difference 
between binomial proportions based on paired data. Statistics in Medicine. 
1998;17(22):2635-50. 
[Pocock 2002] Pocock SJ, Clayton TC, Altman DG. Survival plots of time-to-event 
outcomes in clinical trials: good practice and pitfalls. The Lancet 2002;359:1686-9. 
[Reilly Associates 2002]  WPAI coding; Coding Rules for Self-Administration, 
http://www.reillyassociates.net/WPAI_Coding.html,  Margaret Reilly Associates, 
Inc, 2002, Downloaded 21Nov2016.  
 


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15 APPENDICES 
A. 
Protocol synopsis, Protocol version 3 
Below, only the protocol synopsis for AC-061A301 is displayed. The protocol synopsis 
for protocol AC-061A302 is identical to the synopsis of AC-061A301 apart from the 
study number (see protocol AC-061A302) and thus is not displayed in this SAP.  
TITLE 
AC-061A301, A multi-center, randomized, double-blind study 
to compare the efficacy and safety of cadazolid versus 
vancomycin in subjects with Clostridium difficile-associated 
diarrhea (CDAD). 
MAIN OBJECTIVES 
Primary objective 
To determine whether the clinical response after 10-day oral 
administration of cadazolid is non-inferior to oral vancomycin 
in subjects with CDAD. 
Secondary objectives 
To determine whether oral administration of cadazolid for 
10 days is superior to oral vancomycin in the sustained clinical 
response of subjects with CDAD. 
To determine whether the resolution of diarrhea (ROD) is 
more rapid with oral administration of cadazolid compared to 
vancomycin. 
To determine whether CDAD symptoms, as reported by the 
subject, show larger improvements from baseline with oral 
administration of cadazolid compared to vancomycin. 
Meta-analysis objective 
To determine whether oral administration of cadazolid for 
10 days is superior to oral vancomycin in the sustained clinical 
response of subjects with CDAD due to hypervirulent strains. 
Safety objective 
To determine safety and tolerability of an oral administration 
of cadazolid compared to vancomycin. 
Exploratory objectives are described in the core protocol. 
DESIGN 
See Section 3 [protocol] 
Prospective, 
multi-center, 
double-blind, 
double-dummy, 
randomized, parallel group, active controlled Phase 3 study 
PERIODS  
See Section 3 [protocol] 
Screening Period starts with the signature of the informed 
consent form (ICF) and ends with subject randomization 


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(within 48 hours of the signature of the ICF). 
Treatment Period starts after randomization, with the first 
dose of study drug, and ends on the day of the last dose of 
study drug (EOT) 10 days later. 
Follow-up Period starts after the last dose of study drug and 
ends approximately 30 days after the last dose of study drug 
(Visit 5).  
Re-treatment extension with cadazolid: Subjects who 
experience a recurrence and provide consent may enter a 
re-treatment extension with cadazolid consisting of a 
10-day treatment of cadazolid followed by an approximately 
30-day follow-up period. 
Subject participation in the study will be up to 44 days; up to 
88 days for subjects participating in the re-treatment extension 
with cadazolid. 
PLANNED DURATION 
Approximately 40 months.  
SITES / COUNTRIES  
Approximately 100 sites in approximately 20 countries. 
SUBJECTS / GROUPS 
Approximately 630 subjects will be randomized to cadazolid 
or vancomycin by Interactive Voice Response System (IVRS), 
ratio 1:1, stratified by first occurrence or first recurrence and 
by site. 
KEY INCLUSION 
CRITERIA  
See Section 4.2 [protocol] 
Signed Informed Consent. 
Male or female ≥ 18 years of age. 
Females of childbearing potential must agree to use an 
adequate and reliable method of contraception. 
Subject with a diagnosis of mild-moderate or severe CDAD 
(first occurrence or first recurrence within 3 months) with: 
Diarrhea: a change in bowel habits with > 3 unformed bowel 
movements (UBMs) within 24 hours prior to randomization,  
AND 
Positive C. difficile GDH and toxin test (by enzyme 
immunoassay approved by the sponsor) on the same stool 
sample produced within 72 hours prior to randomization. 
KEY EXCLUSION 
CRITERIA  
See Section 4.3 [protocol] 
More than one previous episode of CDAD in the 3-month 
period prior to randomization. 
Evidence of life-threatening or fulminant CDAD. 


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Likelihood of death within 72 hours from any cause. 
History of inflammatory colitides, chronic abdominal pain, or 
chronic diarrhea, or known positive diagnostic test for 
enteropathogens. 
Inability to take oral medication, or subjects with feeding 
tubes (i.e., when study drug would have to be given by a 
feeding tube).  
Antimicrobial treatment active against CDAD administered 
for > 24 hours except for metronidazole treatment failures 
(MTF). 
Planned treatment with forbidden concomitant medications.  
Fecal microbiota transplant (FMT), immunoglobulin therapy, 
and investigational drug to prevent or treat CDAD within 
1 month prior to randomization 
Monoclonal antibodies against C. difficile within 6 months 
prior to randomization.  
Previous vaccination against C. difficile.  
Previous participation in a clinical trial with cadazolid. 
Known hypersensitivity or contraindication to study drugs, 
oxazolidinones, or quinolones. 
Females who are breastfeeding. 
Investigational site staff members or relatives, and Actelion 
employees. 
Unable or unwilling to comply with all protocol requirements. 
STUDY TREATMENTS  
See Section 5.1 [protocol] 
Investigational drug 
Cadazolid 250 mg or matching placebo granules for oral 
suspension twice daily with or without food. 
Comparator 
Oral vancomycin 125 mg or matching placebo capsules 
4 times daily with or without food. 
CONCOMITANT 
MEDICATIONS  
See Section 5.2 [protocol] 
Prohibited medications 
Antimicrobial treatment active against CDAD and FMT up to 
Visit 5 unless provided for clinical failure or recurrence. 
Other medication active against CDAD (e.g., cholestyramine, 
probiotics) up to Visit 5. 
Initiation of treatment with opiates or change in dose or 
regimen resulting in an increased opiate effect up to 2 days 
after EOT. 


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Anti-peristaltic medications, kaolin, pectin and charcoal 
containing anti-diarrheals up to Visit 5. 
ENDPOINTS  
See Section 6.1 [protocol] 
Primary endpoint 
Clinical Cure defined as: 
• Resolution of Diarrhea (ROD: ≤ 3 UBMs per day for at 
least 2 consecutive days) on study treatment, maintained 
for 2 days after EOT  
AND 
• No additional antimicrobial treatment active against 
CDAD or FMT between first dose and 2 days after EOT 
(inclusive). 
Secondary endpoints 
Sustained Cure defined as:  
• Clinical Cure  
AND 
• No Recurrence 
 
Recurrence is defined for subjects with Clinical Cure as:  
• New episode of diarrhea (NED: > 3 UBMs within 
1 day) occurring between 3 days after EOT and Visit 5 
AND 
• Positive C. difficile GDH and toxin stool test on the 
same stool sample 
AND 
• Antimicrobial treatment active against CDAD or FMT 
started between 3 days after EOT and Visit 5 (or 
participation in the re-treatment extension with cadazolid). 
Time to ROD, defined as: 
 
• The time (h) elapsed between the first dose of study drug 
and the time when ROD is considered achieved. 
Absolute change from baseline in CDAD DaySyms Patient 
Reported Outcomes (PRO). 
CDAD DaySyms total daily score change from baseline up to 
Day 12. 
Meta-analysis endpoint 
• Sustained Cure (as defined above) in hypervirulent strains 
(currently defined as Strains 027, 078, and 244). 
Additional endpoints are described in the core protocol. 


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ASSESSMENTS 
Refer to the schedule of assessments. 
STATISTICAL 
METHODOLOGY  
See Section 11 [protocol] 
Sample Size: Assuming a Clinical Cure Rate (CCR) of 85% 
in the Per-protocol analysis set (PPS) for cadazolid and 
vancomycin treatment groups, a power of 90%, a fixed type I 
error of 2.5% (one-sided), and a non-inferiority (NI) margin of 
10%, a total sample size of 536 (268 in each treatment group) 
evaluable subjects is required in the PPS. Taking into account 
approximately 15% of subjects not qualifying for the per-
protocol (PP) population, approximately 630 subjects will be 
randomized into the trial. As approximately 95% of the 
randomized subjects are assumed to qualify for the modified 
intent-to-treat (mITT) analysis set (598 subjects), the power 
for demonstrating non-inferiority in clinical cure on this 
population is higher than 90%.  
Main efficacy analysis. Clinical Cure Rate (CCR, %) is the 
variable to be analyzed for the primary endpoint. The aim is to 
demonstrate that the CCR for cadazolid (CCRc) is not inferior 
to the CCR for vancomycin (CCRv), accounting for a NI 
margin of 10%. NI in CCR of cadazolid against vancomycin 
will be assessed based on the difference between proportions 
in CCRc and CCRv. The null hypothesis is:  
H0(1): CCRc − CCRv ≤ −10%  
versus the alternative hypothesis:  
H1(1): CCRc − CCRv > −10%.  
The main analysis will be on the mITT analysis set and on the 
PPS. NI is claimed if it is demonstrated on both analysis sets, 
by a one-sided 0.025 significance level, using the lower bound 
of the two-sided 95% confidence interval (CI) of the 
difference between proportions. 
Secondary efficacy analysis: If NI for CCR is demonstrated 
in both analysis sets, mITT and PPS, the superiority of 
cadazolid on the secondary endpoint Sustained Cure Rate 
(SCR) will be tested on the mITT analysis set at the two-sided 
alpha 0.05. If the lower limit of the two-sided 95% CI is 
greater than zero, the statistical superiority of cadazolid versus 
vancomycin in SCR will be established. After this is 
demonstrated, the superiority in time to ROD (shorter median 


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time) will be tested. If demonstrated, then the superiority in 
the CDAD DaySyms scores changes from baseline will be 
tested. This full hierarchical testing strategy is used to control 
the experimentwise α level at 0.05. 
Meta-analysis: A meta-analysis of this trial and the similar 
Phase 3 trial AC-061A302 will be utilized for the assessment 
of cadazolid superiority in the Sustained Cure of subjects with 
CDAD due to hypervirulent strains. 
Safety analysis: Treatment-emergent adverse events and 
serious adverse events will be summarized per treatment arm 
and overall, by frequency, intensity and relationship to study 
medication. Other safety variables, such as laboratory 
assessments, vital signs and ECGs will be summarized. 
STUDY COMMITTEES 
Steering Committee, Independent Data Monitoring Committee 
SUB-STUDIES 
As part of this protocol, at selected sites and in subjects who 
consent to participate, the plasma concentrations of cadazolid 
will be analyzed. 
In addition, the following sub-studies, independent from the 
core study protocol and at selected sites in subjects who 
consent to participate (through an informed consent separate 
from the main protocol informed consent), will be performed 
according to stand-alone protocols: 
• Psychometric validation of CDAD DaySyms PRO 
• Gut 
microbiome 
assessment 
and 
fecal 
cadazolid 
concentrations. 
 
 
 
 
B. 
Discussion and further considerations of the applied statistical methods  
Not applicable. 


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C. 
Chronic kidney disease SMQ selected preferred terms 
Narrow A Artificial kidney device user 
10053699 
Narrow A Azotaemia 
10003885 
 Narrow A End stage renal disease 
10077512 
 Broad 
A Autoimmune nephritis 
10077087 
Broad 
A Blood creatinine abnormal 
10005481 
Broad 
A Blood creatinine increased 
10005483 
Broad 
A Bloody peritoneal effluent 
10067442 
 Broad 
A C3 glomerulopathy 
10077827 
Broad 
A Calciphylaxis 
10051714 
Broad 
A Chronic allograft nephropathy 
10063209 
Narrow A Coma uraemic 
10010082 
Broad 
A Creatinine renal clearance abnormal 
10068447 
Broad 
A Creatinine renal clearance decreased 
10011372 
Narrow A Diabetic end stage renal disease 
10012660 
Narrow A Dialysis 
10061105 
Broad 
A Dialysis amyloidosis 
10064553 
Narrow A Dialysis device insertion 
10059015 
Broad 
A Dialysis disequilibrium syndrome 
10059256 
Broad 
A Dialysis related complication 
10071946 
Broad 
A Diffuse mesangial sclerosis 
10054832 
Broad 
A Effective peritoneal surface area increased 
10068883 
Broad 
A Extensive interdialytic weight gain 
10068800 
Broad 
A Glomerular filtration rate abnormal 
10018356 
Broad 
A Glomerular filtration rate decreased 
10018358 
Narrow A Glomerulonephritis chronic 
10018367 
Broad 
A Glomerulonephritis rapidly progressive 
10018378 
Narrow A Haemodialysis 
10018875 
Broad 
A Haemodialysis complication 
10070476 
Broad 
A Haemodialysis-induced symptom 
10059268 
Narrow A Haemofiltration 
10053090 
Broad 
A Haemolytic uraemic syndrome 
10018932 
 Broad 
A Haemorrhagic fever with renal syndrome 
10075015 
Narrow A Hepatorenal failure 
10019845 
Narrow A High turnover osteopathy 
10062624 
Broad 
A Hypercreatininaemia 
10062747 
Narrow A Hyperparathyroidism secondary 
10020708 
 Broad 
A IgM nephropathy 
10077209 


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Broad 
A Intradialytic parenteral nutrition 
10074739 
Narrow A Low turnover osteopathy 
10063000 
Narrow A Nephrogenic anaemia 
10058116 
Narrow A Nephrogenic systemic fibrosis 
10067467 
 Broad 
A Obstructive nephropathy 
10077862 
Narrow A Oedema due to renal disease 
10049630 
 Broad 
A Paraneoplastic glomerulonephritis 
10076749 
Narrow A Pericarditis uraemic 
10034498 
Broad 
A Peritoneal cloudy effluent 
10067011 
Narrow A Peritoneal dialysis 
10034660 
Broad 
A Peritoneal dialysis complication 
10067594 
Broad 
A Peritoneal effluent abnormal 
10069638 
Broad 
A Peritoneal effluent erythrocyte count increased 
10067301 
Broad 
A Peritoneal effluent leukocyte count increased 
10067300 
Broad 
A Peritoneal equilibration test abnormal 
10072490 
Broad 
A Peritoneal fluid analysis abnormal 
10059524 
Broad 
A Peritoneal fluid protein abnormal 
10069000 
Broad 
A Peritoneal fluid protein increased 
10068998 
Broad 
A Peritoneal permeability increased 
10070442 
Narrow A Renal and liver transplant 
10052279 
Narrow A Renal and pancreas transplant 
10052278 
Broad 
A Renal atrophy 
10038381 
Narrow A Renal failure 
10038435 
Narrow A Chronic kidney disease 
10038444 
Narrow A Renal osteodystrophy 
10038489 
Narrow A Renal replacement therapy 
10074746 
Narrow A Renal rickets 
10038519 
Narrow A Renal transplant 
10038533 
Broad 
A Ultrafiltration failure 
10069568 
Narrow A Uraemia odour 
10056609 
Narrow A Uraemic acidosis 
10046324 
 Narrow A Uraemic myopathy 
10077910 
Narrow A Uraemic encephalopathy 
10046326 
Narrow A Uraemic gastropathy 
10063709 
Narrow A Uraemic neuropathy 
10046328 
Narrow A Uraemic pruritus 
10060875 
Broad 
A Urea renal clearance decreased 
10046358 
Narrow A Uridrosis 
10067863 


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D. 
Scoring and analysis guideline for the CDI-DAYSYMS (formerly 
known as CDAD-DAYSYMS) 
The CDI-DaySyms, formerly known as the CDAD-DaySyms, has been designed to 
capture patient-reported symptoms of Clostridium difficile infections.  
It has been developed for use in a diverse CDI patient population, and can be applied in 
clinical trial settings as well as in clinical practice. 
1 
CDI-DAYSYMS SCORING 
The final CDI-DaySyms includes 10 items distributed across three domains: Diarrhea 
Symptoms, Abdominal Symptoms, and Systemic/Other Symptoms [see Table 1].  
Table 1 
Domains and items of the CDI-DaySyms diary 
Domains and Items 
Diarrhea Symptoms 
 1. Diarrhea   
 2. Feeling a need to empty bowels   
 3. Needing to go to the bathroom  
Abdominal Symptoms 
 4. Abdominal cramping   
 5. Abdominal pain   
 6. Feeling bloated  
Systemic/Other Symptoms 
 7. Feeling tired   
 8. Lack of Energy   
 9. Lightheadedness   
 10. Lack of appetite   
 
For each item, the subject assesses daily his/her symptom severity by choosing one 
response on a 5-point Likert scale. Responses are converted to numerical values as 
follows: 
0 = no symptoms  
1 = mild symptoms 
2 = moderate symptoms 
3 = severe symptoms   
4 = very severe symptoms 
Non-missing scores of all items in a given domain are summed per day and the mean of 
the non-missing items is then taken; this defines the domain score. This domain score is 
the value to be analyzed and interpreted. 


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The minimum score for each domain is zero, and the maximum score is 4. Domains are 
scored on a daily basis. 
The three domains should be evaluated or tested in a hierarchical manner, starting with 
Diarrhea Symptoms, then Abdominal Symptoms, and finally Systemic/Other Symptoms.  
2 
HANDLING OF MISSING OR INCONSISTENT VALUES 
Considering the CDI-DaySyms® is completed with pen-and-paper, it is possible that 
some item responses may be missing, and similarly, it is possible that subjects select 
more than one response for a given item. Rules for adequately handling such situations in 
the statistical analysis are as described below. 
Missing values 
Diarrhea Symptoms domain  
• If item 1 (diarrhea) is available, then a domain score will always be calculated, 
including in cases where both item 2 (feeling a need to empty bowels) and 3 (needing 
to go to the bathroom) are missing. 
• Otherwise, if greater than 50% of items are missing (i.e., at least 2 out of 3 items), 
then the domain will be marked as missing, except in the case that only item 1 is 
available as specified above. 
Abdominal Symptoms Domain  
• If greater than 50% of abdominal symptom items are missing (i.e., at least 2 out of 3 
items), the domain will be marked as missing. 
Systemic/Other Symptoms Domain 
• If greater than 50% of systemic/other symptom items are missing (i.e., at least 3 out 
of 4 items), the domain will be marked as missing. 
Multiple responses per item 
In the event of two contiguous/adjacent responses to one of the items (e.g., moderate and 
severe), the worst of the values (i.e., the more severe one) will be selected for analysis. If 
an item has two non-contiguous/non-adjacent responses recorded (e.g., mild and severe) 
or more than two responses marked, the response to the item will be set to missing. 
3 
ANALYSIS GUIDELINES 
3.1 
Endpoints 
The effect of treatment on each of the three CDI-DaySyms® domains has to be assessed 
separately, as there is no total score.  


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It is recommended to assess response to treatment early on, as this is reflective of clinical 
practice. 
Recommended endpoints include:  
• Absolute change from baseline  
• Percentage of subjects meeting the response to treatment threshold 
• Percentage of subjects meeting the upper boundary of clinically meaningful 
improvement range  
• Time to response 
• Area under the curve (AUC) from baseline  
A responder to treatment is defined as a subject with an observed change from baseline 
below a predefined threshold for each domain, as described in Table 2. A negative value 
for change from baseline corresponds to a reduction in domain score, i.e., an 
improvement. The responder threshold was derived based on Day 3 data – using mainly 
distribution-based methods.  
Table 2 
Threshold for response definition 
Parameter 
Threshold* 
Diarrhea Symptoms 
–1.00 
Abdominal Symptoms 
–0.80 
Other/Systemic Symptoms 
–0.70 
Note: * Threshold is defined based on the absolute change from baseline, where change from baseline is 
calculated as: value post-baseline – value at baseline.  
The responder threshold is the lower boundary of the clinically meaningful improvement 
range for each domain, as described in Table 3. 
Table 3 
Clinically meaningful improvement 
Parameter 
Range* 
Diarrhea Symptoms 
–1.00 to –0.55  
Abdominal Symptoms 
–0.80 to –0.55 
Other/Systemic Symptoms 
–0.70 to –0.50 
Note: * The lower boundary of the clinically meaningful improvement range is referred to as the responder 
threshold.   Clinically meaningful improvement ranges are based on changes from baseline, where change 
from baseline is defined as: value post-baseline – value at baseline. 
The time to response is defined as the number of days from first study drug 
administration to achieving responder status.  


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3.2 
Additional considerations 
Sensitivity analysis will be conducted applying the 50% imputation rule also for the 
diarrhea domain: if greater than 50% of diarrhea symptom items are missing (i.e., at least 
2 out of 3 items), then the domain will be marked as missing. 
 
 


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E. 
Multiple imputation and tipping point analysis for CDI PRO 
1 
INCOMPLETE DATA 
Incomplete data are ubiquitous, especially in longitudinal data in human subjects. Rubin 
[Rubin 1976] and Little and Rubin [Little 1987, Chapter 6] distinguished between three 
missing value mechanisms: (1) missing completely at random (MCAR), when 
missingness is independent of both unobserved and observed data; (2) missing at random 
(MAR), when, conditional on the observed data, missingness is independent of the 
unobserved measurements; and (3) missingness not at random (MNAR), when neither 
MCAR nor MAR applies.  
A promising and now commonly used method is multiple imputation [Little 1987, 
Molenberghs 2007, van Buuren 2007, Carpenter 2013]. Multiple imputation usually 
assumes that the data are MAR. The MAR assumption cannot be verified, because the 
missing values are not observed yet would be needed for a satisfactory verification. For a 
study that assumes MAR, the sensitivity of inferences to departures from the MAR 
assumption should be evaluated. One way is by performing a sensitivity analysis under 
the MNAR assumption, imputing the missing values under a plausible MNAR scenario, 
and then compare the results to inferences under MAR. If the sensitivity analysis results 
lead to different conclusions than the primary results, then the conclusion is that the 
incomplete data have the potential to undo the primary analysis.  
2 
IMPUTATION METHODS FOR SENSITIVITY ANALYSES 
In this section, the methods to handle missing data that are used in this study, especially 
regarding multiple imputation as sensitivity analysis, will be reviewed. The main 
procedure in the SAS software for analyzing the methods mentioned are also described in 
this section. The full SAS codes, also involving the data manipulation steps and analysis 
programs, are presented in this appendix. 
Standard multiple imputation (under MAR) 
Standard multiple imputation will be applied as a first sensitivity analysis. Multiple 
imputation is essentially an iterative form of stochastic imputation and usually assumes 
that the data are MAR. That is, for a variable Y, the probability that an observation is 
missing depends only on the observed values of other variables and/or on (previously) 
observed values of the same outcome Y, but not on the unobserved values of Y. Multiple 
imputation inference involves three distinct phases: (1) The missing data are filled in m 
times to generate m complete data sets, (2) The m complete data sets are analyzed by 
using standard procedures and (3) The results from the m complete data sets are 
combined to yield pooled inferences.  
We will apply the method by using Proc MI (SAS 9.4). The MI procedure is a multiple 
imputation procedure that creates multiple imputed data sets for incomplete 


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p-dimensional multivariate data (possibly resulting from longitudinal data). It uses 
methods that incorporate appropriate variability across the m imputations (i.e., by 
drawing from the predictive distribution of unobserved values for a given patient, given 
observed information on the same patient). The imputation method is chosen based on the 
patterns of missingness (monotone, or also involving non-monotone missingness) in the 
data and the type of the imputed variable (continuous, binary, etc.).  
In the CDI-DaySyms® PRO analysis, the variable that needs to be imputed is the outcome 
CDI-DaySyms® SCORES for each domain separately, a quasi-continuous variable. This 
variable is imputed sequentially using covariates constructed from the corresponding sets 
of preceding variables, in this case: TREATMENT (cadazolid and vancomycin), and 
other possible covariates, if any. Also, the entire outcome vector of SCORES across 
measurement TIME (daily basis) is included. However, the SCORES variable has a non-
monotone missingness pattern across TIME.  
The MI procedure (SAS 9.4) with m the predetermined number of imputations is applied 
to fill in m-times the intermittent missing data for each subject across TIME. Evidently, 
the missingness after dropout, at this stage, is kept un-imputed. This procedure leads to m 
monotonized sets of data. 
proc mi data=dat12 seed=4321 simple nimpute=10 
round=1 out=dat_mon; 
mcmc impute = monotone; 
var TIME1-TIME12; 
by TREATMENT; 
run; 
The missingness due to drop out of the m monotonized dataset is then subjected to 
multiple imputation with the MI procedure (SAS 9.4) for number of imputation equal to 
one. This is because the stochastic nature of the imputation has already been taken care of 
in the first step. Evidently, also here, the imputations are drawn stochastically. This 
procedure finally leads to m complete data.  
proc mi data= dat_mon nimpute=1 out=mi_mvn seed=4321 simple; 
var TIME1-TIME12; 
by TREATMENT; 
monotone method=reg; 
run;  
The m complete data sets are analyzed separately by using standard procedures.  
proc mixed data=mi_mvn method=reml; 
class SUBJECTID TREATMENT TIME; 
model SCORES= TREATMENT* TIME / ddfm=kenwardroger solution; 


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repeated TIME / type=toeph subject= SUBJECTID; 
by _imputation_; 
estimate ‘treatment effect at day 3’  
  TREATMENT* TIME -1 0  1 0 0 0 0 0 0 0 0 0  
                                           1 0   -1 0 0 0 0 0 0 0 0 0 / CL;    
ods output SolutionF=a_mvn1; 
ods output Estimates=a_mvn_estimates1; 
run; 
The pooled inference by combining results from the m analyses is done by using the 
MIANALYZE procedure (SAS 9.4).  
proc mianalyze parms(classvar=full)=a_mvn1; 
class TREATMENT TIME; 
modeleffects TREATMENT* TIME; 
run; 
 
proc mianalyze data = a_mvn_estimates1; 
  modeleffects estimate; 
  stderr stderr; 
run; 
Sensitivity analysis approach under Missing Not At Random assumption  
Sensitivity analysis toward departures from the MAR assumption is considered. We 
implement sensitivity analysis under the MNAR assumption. Under the MNAR 
assumption, the probability that the value of Y is missing for an observation can also 
depend on the unobserved value of Y, in addition to dependence on observed 
information. This multiple imputation method is based on the pattern-mixture model 
approach [Molenberghs 2007, Carpenter 2013]. By using pattern-mixture models, there is 
chronic under-identification because the predictive distribution within a pattern is by 
definition not observable. Little [Little 1993] proposed the use of identifying restrictions; 
inestimable parameters of the incomplete patterns are set equal to the function of 
parameters describing the distribution of the other, more complete patterns, i.e., the 
predictive distribution is identified from what is available.  
In general, assume there are 𝑡𝑡= 1, … , 𝑛𝑛= 𝑇𝑇 patterns. The dropout patterns, with the 
complete data density is given by: 
𝑓𝑓𝑡𝑡(𝑦𝑦1, . . , 𝑦𝑦𝑇𝑇) = 𝑓𝑓𝑡𝑡(𝑦𝑦1, . . , 𝑦𝑦𝑡𝑡)𝑓𝑓𝑡𝑡(𝑦𝑦𝑡𝑡+1, . . , 𝑦𝑦𝑇𝑇|𝑦𝑦1, . . , 𝑦𝑦𝑡𝑡) 
(1) 
 
The first factor is identified from observed data. The second factor is unobservable, hence 
identifying restrictions need to be applied. One can base identification on all patterns for 
which a given component, 𝑦𝑦𝑠𝑠, is identified:  


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𝑓𝑓𝑡𝑡(𝑦𝑦𝑠𝑠|𝑦𝑦1, . . , 𝑦𝑦𝑠𝑠−1) = ෍𝜔𝜔𝑠𝑠𝑠𝑠𝑓𝑓𝑗𝑗(𝑦𝑦𝑠𝑠|𝑦𝑦1, . . , 𝑦𝑦𝑠𝑠−1) , 𝑠𝑠= 𝑡𝑡+ 1, … , 𝑇𝑇.
𝑇𝑇
𝑗𝑗=𝑠𝑠
 
 
(2) 
 
In the MI procedure (SAS 9.4), the MNAR statement imputes missing values by using, 
among others, the pattern-mixture model approach, assuming the missing data are 
MNAR.  
Sensitivity analysis with a tipping point approach  
A “tipping-point” analysis, first introduced in Yan et al. [Yan 2009] consists of assessing 
the impact of missing data on the conclusions of a study. Yan et al. [Yan 2009] defined 
the tipping points of a study to be the particular setting for the missing data values that 
would change the study’s conclusions and presented a simple way to display this 
information. In this study we apply sensitivity analysis based upon multiple imputations 
under the MNAR assumption by searching for a tipping point by using “shift” approaches 
until the MAR inferences change from significance to non-significance, or vice versa.  
The SAS code is as follows: 
%macro midata( data=, smin=, smax=, sinc=, out=); 
data &out; 
set _null_; 
run; 
/*------------ # of shift values ------------*/ 
%let ncase= %sysevalf( (&smax-&smin)/&sinc, ceil ); 
/*------- Imputed data for each shift -------*/ 
%do jc=0 %to &ncase; 
%let sj= %sysevalf( &smin + &jc * &sinc); 
 
proc mi data= &data nimpute=1 out=outmi seed=4321; 
var TIME1-TIME12; 
class TREATMENT; 
by TREATMENT; 
monotone method=reg; 
mnar adjust( TIME1/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
mnar adjust( TIME2/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
mnar adjust( TIME3/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
mnar adjust( TIME4/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
mnar adjust( TIME5/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
mnar adjust( TIME6/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
mnar adjust( TIME7/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
mnar adjust( TIME8/ shift=&sj adjustobs=(TREATMENT=‘1’)); 


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mnar adjust( TIME9/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
mnar adjust( TIME10/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
mnar adjust( TIME11/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
mnar adjust( TIME12/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
run; 
 
data outmi; 
set outmi; 
Shift= &sj; 
run; 
data &out; 
set &out outmi; 
run; 
%end; 
%mend midata; 
 
%midata( data=dat_mon, smin=-2, smax=2, sinc=1, out=OutX); 
Tipping point analysis with adjusted “shift” statement applied to Day 3 (the time of 
interest) only has also been considered: 
%macro midata( data=, smin=, smax=, sinc=, out=); 
data &out; 
set _null_; 
run; 
/*------------ # of shift values ------------*/ 
%let ncase= %sysevalf( (&smax-&smin)/&sinc, ceil ); 
/*------- Imputed data for each shift -------*/ 
%do jc=0 %to &ncase; 
%let sj= %sysevalf( &smin + &jc * &sinc); 
 
proc mi data= &data nimpute=1 out=outmi seed=4321; 
var TIME1-TIME12; 
class TREATMENT; 
by TREATMENT; 
monotone method=reg; 
mnar adjust( TIME3/ shift=&sj adjustobs=(TREATMENT=‘1’)); 
run; 
 
data outmi; 
set outmi; 
Shift= &sj; 


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run; 
data &out; 
set &out outmi; 
run; 
%end; 
%mend midata; 
 
%midata( data=dat_mon, smin=-2, smax=2, sinc=1, out=OutX_12); 
 
 


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3 
REFERENCES 
[Carpenter 2013] Carpenter JR, Kenward MG. Multiple Imputation and Its Application, 
New York: John Wiley & Sons; 2013.  
[Little 1993] Little RJA. Pattern-Mixture Models for Multivariate Incomplete Data, J Am 
Stat Assoc. 1993;88:125–34. 
[Little 1987] Little RJA, Rubin DB. Statistical Analysis with Missing Data, John Wiley 
& Sons, New York; 1987. 
[Molenberghs 2007] Molenberghs G, Kenward MG. Missing Data in Clinical Studies, 
New York: John Wiley & Sons; 2007. 
[Rubin 1976] Rubin DB. Inference and Missing Data. Biometrika. 1976;63;581–92. 
[van Buuren 2007] van Buuren S. Multiple Imputation of Discrete and Continuous Data 
by Fully Conditional Specification. Stat Methods Med Res. 2007;16:219–42. 
[Yan 2009] Yan X, Lee S, Li N. Missing data handling methods in medical device 
clinical trials, J Biopharm Stat. 2009;19(6):1085-98. 
 
 


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F. 
Document history 
Version 
Effective Date 
Reason 
1.0 
11-Dec-2014 
New 
2.0 
7-Jun-2016 
Update according to protocol version 3 including 
removal of interim analysis, updates of study 
design and schedule of assessments, updates 
according to MedDRA 19.0 and WHODrug 
Dictionary version dated 1 March 2016, definition 
of geographical region updated to avoid small 
regions, summary of reasons for ICR and ISR 
added, description of derivation of clinical cure 
and sustained cure improved, sensitivity analyses 
for Clinical Cure and Sustained Cure added, 
stratified efficacy analyses: alternative strategy in 
the event of small strata described, variables and 
analyses based on clinical evaluation by Actelion 
Clinical Team and modified clinical cure removed, 
efficacy analyses by country added, censoring date 
time to return to usual bowel movements updated, 
days from first dose corrected, microbiology 
variables clarified, microbiology analyses updated 
wording updated to match standard table shells, 
EudraCT required outputs added, re-treatment 
safety tables up to Visit Re-5 reduced.  
3.0 
19-May-2017 
CDI-DaySyms variables (3 domain scores instead 
of 1 total score) and analysis updated following 
PRO 
validation, 
handling 
of 
duplicate 
microbiology assessments added and consequently 
definition of baseline isolates clarified.  
Editorial updates to output titles, listings split as 
per programming requirements. Clarifications to 
the following derivations: ≤ 3 UBMs in event of 
missing 
daily 
stool 
information, 
temporal 
association of toxin test to AMT, time to 
recurrence derivation, ECG and vital signs 
baseline definitions, insufficient information to 
determine Clinical Cure. WPAI scoring further 
detailed in line with questionnaire guidelines, 
Sustained cure sensitivity analysis (follow-up until 


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EOT + 25 days) aligned throughout document 
with section 10.7.1.2, main study concomitant 
medications tables added, imputation for missing 
start 
time 
added, 
physical 
and 
abdominal 
examination 
results 
only 
listed, 
clarified 
re-treatment extension displays are on received not 
planned double-blind treatment, Liver test displays 
aligned with guidelines (category ≥ 1 × ULN for 
AST and ALT removed). 
 


 
 
 
 
AMENDMENT TO STATISTICAL ANALYSIS PLAN  
FOR CLINICAL STUDY REPORT 
AC-061A301 / AC-061A302 
Two multi-center, randomized, double-blind studies to compare the efficacy  
and safety of cadazolid versus vancomycin in subjects with  
Clostridium difficile-associated diarrhea (CDAD) 
 
 
 
 
Purpose of Analysis 
Clinical Study Report 
Investigational Drug 
Cadazolid 
Protocol Numbers 
AC-061A301 / AC-061A302 
Actelion Document Number 
D-17.297 
Document Status / Version Number 
Amendment to Final SAP for CSR 
 
Date 
19 May 2017 
 
Author 
 Trial Statistician  
Reviewer 
 Trial Statistician  
Reviewer 
 Project Statistician 
Reviewer 
 Clinical Science Program Head 
Reviewer 
 Clinical Trial Scientist 
Reviewer 
 Life Cycle Leader 
Reviewer 
 Lead Statistical Programmer 
 
 
 
 
 
 
 
Confidential 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or otherwise disclosed 
without the consent of Actelion Pharmaceuticals Ltd. 


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TABLE OF CONTENTS 
1 
OVERVIEW ..................................................................................................................4 
1.1 
Overview of site 
 enrollment and participation in substudies.................4 
2 
RATIONALE FOR SAP AMENDMENT ....................................................................4 
3 
CHANGES TO STATISTICAL ANALYSES PLANNED ..........................................5 
3.1 
Changes to the definitions of analysis sets .....................................................5 
3.1.1 
Analysis sets excluding subjects from site 
 ................................5 
3.1.2 
Analysis sets including subjects from site 
 .................................6 
3.2 
Sensitivity analyses including site 
.........................................................6 
3.2.1 
Subject disposition and analysis sets ..................................................6 
3.2.2 
Efficacy analyses ................................................................................6 
3.2.3 
Safety analyses ....................................................................................7 
3.3 
Presentation of listings ....................................................................................7 
4 
LIST OF ADDITIONAL SUMMARY TABLES FOR SENSITIVITY 
ANALYSES ..................................................................................................................8 
4.1 
Subject disposition (including site 
) .......................................................8 
4.2 
Efficacy analyses (including site 
) ..........................................................8 
4.3 
Safety analyses (including site 
) .............................................................8 
4.3.1 
Adverse events ....................................................................................8 
5 
REFERENCES ..............................................................................................................9 
6 
APPENDICES ...............................................................................................................9 
 
LIST OF TABLES 
 
Table 1 
Overview of analysis sets and their usage ........................................................ 5 
 
LIST OF APPENDICES 
 
A. 
Document history .............................................................................................. 9 
  
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
AE  
Adverse event 
AR  
All randomized set 
CDAD  
Clostridium difficile-associated diarrhea 
CSR  
Clinical study report 
EOT  
End-of-Treatment 
FDA  
Food and Drug Administration 
FAS  
Full analysis set 
ISE  
Integrated Summary of Efficacy 
ISS  
Integrated Summary of Safety 
amITT  
amended modified intent-to-treat 
PRO  
Patient reported outcome 
PPS  
Per protocol set  
PK  
Pharmacokinetic 
SAP  
Statistical analysis plan 
SCRAS  
Screened analyses set 
SDTM  
Study Data Tabulation Model 
aSS  
amended Safety set 


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1 
OVERVIEW 
This amendment applies to the statistical analysis plan (SAP) Version 3 dated 
19 May 2017 [D-17.273] for the clinical study reports (CSR) for studies AC-061A301 
and AC-061A302 (referred to hereafter as the CSR SAP). 
 
The reason for the amendment is to describe, in detail, changes to the analyses and 
presentation of results decided by Actelion before data unblinding and, following 
identification of potential scientific misconduct with relevant findings related to data 
integrity at site 
 in study AC-061A302 (letter sent to FDA Office of Compliance, 
dated 2 May 2017). 
 
The CSR SAP Version 3 details analyses which apply to both studies, however this 
amendment concerns only the analyses that are to be conducted on study AC-061A302, 
and does not affect the analyses of study AC-061A301 (with the exception of listings, as 
described in Section 3.3).  
1.1 Overview of site 
enrollment and participation in substudies 
Site 
 screened 
 subjects, of which 22 were randomized 
 
 
 
 
 
 
 
2 
RATIONALE FOR SAP AMENDMENT  
During an unannounced for-cause audit of site 
 
, 
 Actelion concluded that 
data integrity for site 
 cannot be guaranteed. Therefore, Actelion decided that all 
data from site 
 will be excluded from the statistical analyses of study AC-061A302, 
as described in this amendment to the CSR SAP [Section 3]. Sensitivity analyses will be 
performed to evaluate the impact of excluding this site from the analyses of AC-061A302 
[Section 3.2].   
In addition, data from site 
 will also be excluded from all statistical analyses 
involving pooling of data from study AC-061A302, including meta-analyses, 
microbiome, summary of clinical efficacy and summary of clinical safety. Separate 
amendments are not required for the meta-analysis SAP, microbiome SAP, ISE SAP or 
ISS SAP as these SAPs refer to the CSR SAP (and analysis sets) which will exclude all 
subjects from site 
 [Section 3.1.1]. Instead, these SAPs will have a minor revision to 
add reference to this amendment. 


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The subjects from site 
 will be flagged in an SDTM supplemental dataset and this 
flag will be used in the derivation of analysis sets to exclude site 
 and to allow 
sensitivity analyses to the exclusion of this site.  
All data from site 
will remain in the study datasets and will be presented in listings. 
As the PK sub-study and PRO psychometric validation sub-study do not include subjects 
from site 
, the analyses of these substudies are not affected. 
3 
CHANGES TO STATISTICAL ANALYSES PLANNED  
3.1 Changes to the definitions of analysis sets  
Changes to the definitions of the analysis sets (per CSR SAP Version 3, section 7) and 
their usage are described below and summarized in Table 1. 
Table 1 
Overview of analysis sets and their usage 
Excluding subjects from site 
 ----------------------- 
Including subjects from site 
 
Analysis set                                                      Usage 
Analysis set 
Usage 
 
 
Screened analysis set (SCRAS) 
T, L 
Full analysis set (FAS) 
All randomized set (AR) 
Ts*, L 
Modified intent-to-treat (mITT) analysis set  
amended mITT (amITT) 
 
Ts* 
Per-protocol set (PPS) 
 
 
Hypervirulent analysis set (HVAS) 
 
 
Patient reported outcome analysis set 
(PROAS) 
 
 
Safety analysis set (SS) 
amended SS (aSS) 
Ts** 
Re-treatment extension with cadazolid 
analysis set (ES) 
 
 
T = table for all analyses described in CSR SAP version 3; F = Figure for all analyses described in CSR SAP version 3; 
TS = table for sensitivity analyses for the amendment; *only for the primary endpoint and most relevant secondary 
endpoint:  **only for most relevant safety endpoints; L = listings including all subjects  
 
3.1.1 Analysis sets excluding subjects from site 
 
Analysis sets [as listed in Table 1] will exclude subjects from site 
. This change will 
be implemented to each analysis set for the purpose of excluding data for site 
from 
all statistical analyses (tables and figures) of study AC-061A302. Although the content of 
these analysis sets for AC-061A302 will be reduced by excluding the subjects from site 
T
&
F 


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, the names of these analysis sets are retained in order to maintain consistency across 
both studies (AC-061A301 and AC-061A302) in the presentation of tables and figures.     
3.1.2 Analysis sets including subjects from site 
 
Three additional analysis sets are defined, including subjects from site 
, for the 
purpose of performing some sensitivity analyses for AC-061A302: 
• amended modified intent-to-treat (amITT) analysis set 
• amended safety set (aSS)  
• all randomized (AR) set:  includes all randomized subjects 
The names for the amended analysis sets are chosen as they are only implemented for a 
few sensitivity analyses in the AC-061A302 study and to differentiate them from analysis 
sets excluding site 
 defined in Section 3.1.1. The AR set will also be used to produce 
the listings as defined in Section 3.3. 
An amended PPS, including subjects from site 
, was not considered as the findings 
related to data integrity are expected to affect the evaluation of the efficacy (per CSR 
SAP section 7.1.4) and thus would already lead to exclusion from such an analysis set.  
Note there is no change to the screened analysis set (SCRAS) definition and its usage.  
3.2 Sensitivity analyses including site 
 
Sensitivity analysis to the exclusion of site 
 from the analyses of AC-061A302 will 
be performed. The following sensitivity analyses, including subjects from site 
, are 
selected for the purpose of describing the disposition of all randomized subjects in 
AC-061A302, to evaluate the impact on efficacy using the primary endpoint and most 
relevant secondary endpoint, and to confirm overall safety using the most relevant safety 
endpoints.  
3.2.1 Subject disposition and analysis sets 
The number of subjects randomized, treated, completing treatment, and completing the 
main study and enrolled in the re-treatment extension are all summarized by treatment 
group and overall per CSR SAP section 10.3.2 for the AR set. 
The number and percentage of subjects in the amITT and aSS are summarized per CSR 
SAP section 10.3.4 for the AR set.  
3.2.2 Efficacy analyses  
The main analysis of the primary efficacy endpoint Clinical Cure (CSR SAP 
section 10.6.3) and the main analysis of the secondary efficacy endpoint Sustained Cure 
(CSR SAP section 10.7.1.3) are repeated for the amITT. 


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3.2.3 Safety analyses 
Treatment-emergent AEs (up to End of Treatment [EOT] + 7 days) will be summarized 
by system organ class and preferred term per CSR SAP section 10.9.1 for the aSS.   
An overview of treatment-emergent AEs (up to EOT + 7 days) will be presented for the 
aSS including subjects with at least one of the following; AE, SAE, AE leading to study 
drug discontinuation or AE with fatal outcome. 
3.3 Presentation of listings 
In order that data from site 
 will still be presented in the listings for the CSR of 
AC-061A302, all subject listings that were planned to be presented on the FAS per CSR 
SAP Version 3 (table 14, section 10 and section 13) will be changed to be presented on 
all randomized subjects (AR set) for both studies (AC-061A301 and AC-061A302) to 
maintain consistency in the presentation of listings and for efficiencies in programming 
activities.  
Note that a few subject listings (screening failures, unmet eligibility criteria and protocol 
deviations), and one table for summary of screening failures performed on screened 
subjects, are not changed and are presented using the SCRAS including site 
.   
 
 


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4 
LIST OF ADDITIONAL SUMMARY TABLES FOR SENSITIVITY 
ANALYSES 
The table number corresponds to the corresponding table number in the CSR SAP 
section 13. 
4.1 Subject disposition (including site 
 
Table 
Number 
Display* 
Title (Description) 
Analysis 
set(s) 
T 1.2a 
T 
Disposition of subjects 
AR 
T 1.5 
T 
Overview of analysis sets  
AR 
* T = Summary table 
 
4.2 Efficacy analyses (including site 
) 
Table 
Number 
Display* 
Title (Description) 
Analysis 
set(s) 
T 6.1 
T 
Clinical Cure  
amITT 
T 7.1 
T 
Sustained Cure  
amITT 
* T = Summary table 
 
4.3 Safety analyses (including site 
) 
4.3.1 Adverse events 
Table 
Number 
Display* 
Title (Description) 
Analysis 
set(s) 
T 9.1 
T 
Overview of treatment-emergent adverse events (AE) up to EOT + 
7 days 
aSS 
T 9.2 
T 
Treatment-emergent adverse events (AE) by system organ class and 
preferred term up to EOT + 7 days 
aSS 
* T = Summary table 
 
 


Cadazolid (ACT-179811) 
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Doc No D-17.297  
 
5 
REFERENCES 
[D-15.416] A multi-center sub-study to validate the CDAD-DaySyms (Clostridium 
difficile-associated diarrhea – Daily Symptoms) PRO in subjects with CDAD 
participating in study AC-061A301 or AC-061A302. Validation Sub-study protocol 
version 3. Actelion Pharmaceuticals Ltd; 30 November 2015. 
[D-15.544] AC-061A302: A multi-center, randomized, double-blind study to compare the 
efficacy and safety of cadazolid versus vancomycin in subjects with Clostridium 
difficile-associated diarrhea (CDAD). Global Protocol Version 3. Actelion 
Pharmaceuticals Ltd; 22 October 2015. 
[D-16.411] A multi-center sub-study to assess the effects of cadazolid versus vancomycin 
on the composition of intestinal microbiota of subjects with Clostridium difficile-
associated diarrhea (CDAD) participating in study AC-061A301 or AC-061A302. 
Gut microbiome sub-study protocol Version 2. Actelion Pharmaceuticals Ltd; 
22 August 2016. 
[D-17.273] Statistical Analysis Plan for Clinical Study Report AC-061A301 / 
AC-061A302: Two multi-center, randomized, double-blind studies to compare the 
efficacy and safety of cadazolid versus vancomycin in subjects with Clostridium 
difficile-associated diarrhea (CDAD). Version 3. Actelion Pharmaceuticals Ltd; 19 
May 2017. 
 
6 
APPENDICES  
A. 
Document history 
Version 
Effective Date 
Reason 
1.0 
19 May 2017 
New