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)
Phase: PHASE3
Conditions: Clostridium Difficile Infection
Sponsor: Actelion

 
 
 
 
 
 
 
 
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 
Version 3 
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Doc No D-15.418 
 
 
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 
Version 3 
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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. 
 
 
 

Cadazolid/ACT-179811 
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 
Version 3 
22 October 2015, page 5/138 
Confidential  
EudraCT: 2013-002528-17 
Doc No D-15.418 
 
 
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 
Version 3 
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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 
Protocol AC-061A301 
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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 
Protocol AC-061A301 
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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 
Protocol AC-061A301 
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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 
Protocol AC-061A301 
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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 
Protocol AC-061A301 
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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 
SAS 9.3. Randomization is stratified by site and by CDAD first occurrence or first 

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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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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 
Confidential  
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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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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. 

Cadazolid/ACT-179811 
Clostridium difficile-associated diarrhea 
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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 
Version 3 
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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 
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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 
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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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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 
Protocol AC-061A301 
Version 3 
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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). 

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Clostridium difficile-associated diarrhea 
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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 
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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].