Conditions: Clostridium Difficile Infection
Keywords: vancomycin children cadazolid clostridium difficile associated diarrhea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
Cadazolid has demonstrated activity against a bacteria named Clostridium difficile in animal studies. The results of a first study conducted in adult patients have suggested efficacy of the new antibiotic, cadazolid, in the treatment of diarrhea caused by this bacteria. This is the first study of cadazolid in children. The overall purpose of this study is to provide reassurance on the safety and efficacy of cadazolid in children suffering from infection due to Clostridium difficile.

Detailed description:
This multicenter, study will be run into two parts. Both parts will be run in consecutive age cohorts, starting from the oldest age categories(12 to \< 18 years old) to the youngest (birth to \< 3 months).

* Part A is an open-label, dose finding part to be conducted in at least 24 subjects.
* Part B follows a randomized, assessor-blinded, parallel-group design with vancomycin used as an active comparator. Part B will be conducted in about 176 children.

In both parts, the treatment period will be 10 days and will be followed by a Follow-up period of 28-32 days.

Arms:
arm 1: Subjects from 12 years to 18 years old (exclusive) will receive cadazolid 500 mg per day for 10 days. The dose may be adjusted based on the pharmacokinetic (PK) and safety data reviewed for the first 3 subjects. arm 2: Subjects from 6 years to 12 years old (exclusive) will receive cadazolid for 10 days. The dose will depend on the PK and safety data from cohort A reviewed by the Independent Data Monitoring Committee (IDMC). arm 3: Subjects from 2 years to 6 years old (exclusive) will receive cadazolid for 10 days. The dose will depend on the PK and safety data from cohort B reviewed by the IDMC. arm 4: Subjects from 3 months to 2 years old (exclusive) will receive cadazolid for 10 days. The dose will depend on the PK and safety data from cohort C reviewed by the IDMC. arm 5: Subjects from birth to 3 months old (exclusive) will receive cadazolid for 10 days. The dose will depend on the PK and safety data from cohort D reviewed by the IDMC. arm 6: Subjects from birth to 18 years old (exclusive) will receive cadazolid for 10 days, at the dose defined in the corresponding age cohort in Part A. arm 7: Subjects from birth to 18 years old (exclusive) will receive vancomycin capsule (for subjects able to swallow) or vancomycin solution (for the others) during 10 days .

Interventions: intervention 1: Cadazolid intervention 2: Vancomycin capsule intervention 3: Vancomycin solution
Intervention descriptions: intervention 1: Granules for oral suspension to be administered twice daily intervention 2: Capsule containing 125 mg of vancomycin to be administered orally 4 times a day intervention 3: Vancomycin powder to be administered as oral solution at a dose of 40 mg/kg/day, 3 to 4 times a day

Protocol document:
Prot_000.pdf: 
NCT03105479 
Cadazolid / ACT-179811 
Clostridium difficile-associated diarrhea  
Protocol AC-061A303 
A prospective, multicenter study to investigate the pharmacokinetics, safety, and 
efficacy of cadazolid versus vancomycin in pediatric subjects with Clostridium difficile-
associated diarrhea 
 
LIST OF AMENDMENTS  
(Summary of changes) 
 
 
Document History: 
 
- Original Version 
14 July 2015 
- Global Amendments 
 
Amendment 1 (non-substantial) 
05 November 2015 
Amendment 2 (substantial) 
27 October 2016  
Amendment 3 (substantial) 
01 March 2017  
 
 
 
Confidentiality statement 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or otherwise 
disclosed without the consent of Actelion Pharmaceuticals Ltd. 
 
 
 


NCT03105479 
 
Amendment 1 (non-substantial amendment), 05 November 2015 
This amendment was made before protocol submission to any IRBs/IECs. 
 
Amendment 2 (substantial amendment), 27 October 2016 
Main reason for this Amendment: To align the global protocol with the European Medical Agency's 
decision on the cadazolid Paediatric Investigation Plan and with the FDA's requirements (as 
described below) 
 Description of change(s)  
Amended protocol sections 
Inclusion of neonates and infants below 6 months of age  
Sections 1.3, 2.1, 3.1, 3.1.1, 3.2, 
4.1, 4.2 & 4.3 
Figure 1 
The age cohort of subjects from 2 to < 12 years to be split 
into two new cohorts: subjects from 6 to < 12 years and 
from 2 to < 6 years resulting in a minor increase in sample 
size from 194 to 200 participants 
Sections 3.1.1, 3.2, 4.1 & 10.5.1 
Figure 1 
Study timelines to be shortened by enrolling subjects in Part 
B of the study as soon as dosing recommendations are 
available for respective age groups based on Part A 
Section 3.1.2 
Figure 1, Figure 3 
Addition of an Independent Data Monitoring Committee to 
review the data and make recommendations as to further 
dosing in the subsequent age cohorts or strata 
Sections 3.1.1, 3.2, 3.4 & 8.3 
Part B of the study to be blinded to an efficacy assessor 
Sections 3.1.2, 3.3.2, 5.1.5 & 
7.2.3.3 
Palatability/acceptability to be studied in all subjects 
Sections 2.4, 6.4.1, 7.4 & 10.3.5.7 
Addition of a lower strength of oral cadazolid (50 mg) 
Section 5.1.1, 5.1.3 &5.16 
Table 1 
 
Amendment 3 (substantial amendment), 01 March 2017 
Main reason for this Amendment: To address agreed changes in the response to Voluntary 
Harmonization Procedure (VHP) list of grounds for non-acceptance, dated 10 February 2017. 
The key requested modifications to the protocol included: 
Description of change(s)  
Amended protocol sections 
Classification of the study as a Phase 2/3 instead of Phase 
3, as the study includes a preliminary dose-finding part 
and a subsequent part assessing safety and efficacy 
Title page, Section 3.1 
Addition of a separate summary section of known 
potential risks and benefits for Cadazolid 
Section 1.2.3 
Updates of the exclusion criteria by adding the following 
criteria:  
- Exclusion of subjects with hypersensitivity to 
cadazolid and to any of the excipients of 
vancomycin); 
- Exclusion of subjects with mental disorders 
Section 4.4 
Clarification on the effectiveness of double-barrier 
Section 4.5.2 


NCT03105479 
 
contraception methods and on the variability of 
acceptance of such contraception measures between 
concerned countries 
To clearly indicate that patients must be discontinued 
from the study in case of recognized fulminant or life-
threatening Clostridium difficile-associated diarrhea 
Section 5.1.8, 5.2.5 & 6.1.1.2 
 
 
 


 
 
TPL-000052_v10 
 
Cadazolid / ACT-179811 
Clostridium difficile-associated diarrhea  
Protocol AC-061A303 
A prospective, multicenter study to investigate the pharmacokinetics, safety, and 
efficacy of cadazolid versus vancomycin in pediatric subjects with Clostridium 
difficile-associated diarrhea 
 
 
NCT Number: 
NCT03105479 
EudraCT Number: 
2015-004805-17 
Document version, Date: 
Final Version 4, 01 March 2017 
Document History: 
 
- Original Version 
14 July 2015 
- Global Amendments 
 
Amendment 1 
05 November 2015 (non-substantial) 
Amendment 2 
27 October 2016 (substantial) 
Amendment 3 
01 March 2017 (substantial) 
 
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-061A303 
Final Version 4 
1 March 2017, page 2/117 
Confidential 
EudraCT 2015-004805-17 
Doc No D-17.162 
 
 
SPONSOR CONTACT DETAILS 
SPONSOR 
 
ACTELION Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
 
+41 61 565 65 65 
Clinical Trial Physician  
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File 
MEDICAL HOTLINE 
Toll phone number: [number] 
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 Scientist 
 BSc  
 
Clinical Trial Statistician 
 MSc 
 
Clinical Trial Physician 
 MD, MSc 
 
Clinical Trial Pharmacologist 
 
 PhD 
 
Drug Safety Physician 
 MD 
 
 


Cadazolid / ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A303 
Final Version 4 
1 March 2017, page 3/117 
Confidential 
EudraCT 2015-004805-17 
Doc No D-17.162 
 
 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
 
CENTRAL LABORATORY 
 
 
 
CENTRAL 
RANDOMIZATION 
 
 
 
MONITORING 
 
 
 
A list of site-specific contact details for Contract Research Organizations (CROs) can be 
found in the Investigator Site File. 
 
 


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Cadazolid / ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A303 
Final Version 4 
1 March 2017, page 5/117 
Confidential 
EudraCT 2015-004805-17 
Doc No D-17.162 
 
 
INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Cadazolid / ACT-179811 
Indication 
Clostridium difficile-associated diarrhea 
Protocol number, study title 
AC-061A303, A prospective, multicenter study to investigate the pharmacokinetics, safety, and 
efficacy 
of 
cadazolid 
versus 
vancomycin 
in 
pediatric 
subjects 
with 
Clostridium 
difficile-associated diarrhea 
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 protocol deviation, including any ancillary studies or procedures performed on study 
subjects (other than those procedures necessary for the wellbeing of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and 
applicable regulations and laws. I will obtain approval by an independent ethics committee or 
institutional review board (IEC/IRB) prior to study start and signed informed consent from all 
parents/ legally designated representatives of the subjects included in this pediatric study. If an 
amendment to the protocol is necessary, I will obtain approval by an IEC/IRB and ensure 
approval by regulatory authorities has been obtained before the implementation of changes 
described in the amendment, and I will re-consent the subjects (if applicable). I will allow direct 
access to source documents and study facilities to sponsor representative(s), particularly Clinical 
Research Associate(s) (CRA[s]) and auditor(s), and agree to inspection by regulatory authorities 
or IEC/IRB representative(s). I will ensure that the study treatment(s) supplied by the sponsor 
is/are being used only as described in this protocol. I will ensure that all subjects or legally 
designated representatives have understood the nature, objectives, benefits, implications, risks 
and inconveniences for participating in this study. During the conduct of the study, I will 
constantly monitor the risk/benefit balance for an individual subject. 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 
Principal 
Investigator 
 
 
 
 
 
 


Cadazolid / ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A303 
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Doc No D-17.162 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .....................................................................................................6 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................13 
SUBSTANTIAL GLOBAL AMENDMENT 3 .................................................................16 
PROTOCOL SYNOPSIS AC-061A303 ............................................................................19 
PROTOCOL ......................................................................................................................34 
1 
BACKGROUND .........................................................................................................34 
1.1 
Clostridium difficile-associated diarrhea ......................................................34 
1.1.1 
Introduction .......................................................................................34 
1.1.2 
Epidemiology ....................................................................................34 
1.1.3 
Current CDAD therapies ..................................................................35 
1.2 
Study treatment(s) .........................................................................................36 
1.2.1 
Cadazolid ..........................................................................................36 
1.2.2 
Vancomycin ......................................................................................37 
1.2.3 
Summary of benefits and risks ..........................................................38 
1.3 
Purpose and rationale of the study ................................................................40 
2 
STUDY OBJECTIVES ...............................................................................................41 
2.1 
Primary objective(s) .....................................................................................41 
2.2 
Secondary objectives ....................................................................................41 
2.3 
Pharmacokinetic objectives ..........................................................................41 
2.4 
Other objectives ............................................................................................42 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................42 
3.1 
Study design .................................................................................................42 
3.1.1 
Part A ................................................................................................42 
3.1.2 
Part B ................................................................................................43 
3.1.3 
Study periods ....................................................................................45 
3.1.3.1 
Screening period (up to 48 hours) ...........................................45 
3.1.3.2 
Treatment period (10 days of treatment) .................................45 
3.1.3.3 
Follow-up period (28 to 32 days) ............................................46 
3.1.4 
Study duration ...................................................................................46 
3.2 
Study design rationale ..................................................................................46 


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3.3 
Site staff and their roles ................................................................................47 
3.3.1 
Principal investigator ........................................................................47 
3.3.2 
Clinical coordinator/study nurse .......................................................47 
3.3.3 
Blinded efficacy assessor ..................................................................47 
3.4 
Study committees .........................................................................................48 
4 
SUBJECT POPULATION ..........................................................................................48 
4.1 
Subject population description .....................................................................48 
4.2 
Rationale for the selection of the study population ......................................49 
4.3 
Inclusion criteria ...........................................................................................50 
4.4 
Exclusion criteria ..........................................................................................51 
4.5 
Criteria for female subjects of childbearing potential ..................................52 
4.5.1 
Definition of childbearing potential ..................................................52 
4.5.2 
Acceptable methods of contraception ...............................................52 
5 
TREATMENTS ..........................................................................................................53 
5.1 
Study treatment .............................................................................................53 
5.1.1 
Investigational treatment: description and rationale .........................53 
5.1.1.1 
Dosing in Part A ......................................................................53 
5.1.1.2 
Dosing in Part B ......................................................................54 
5.1.2 
Comparator: description and rationale ..............................................54 
5.1.3 
Study treatment preparation and administration ...............................54 
5.1.3.1 
Oral cadazolid suspension .......................................................55 
5.1.3.2 
Cadazolid suspension for nasogastric delivery .......................55 
5.1.3.3 
Oral vancomycin solution .......................................................55 
5.1.4 
Treatment assignment .......................................................................55 
5.1.5 
Blinding ............................................................................................56 
5.1.6 
Study treatment supply .....................................................................56 
5.1.6.1 
Study treatment packaging and labeling .................................56 
5.1.6.2 
Study treatment distribution and storage .................................57 
5.1.6.3 
Study treatment dispensing .....................................................58 
5.1.6.4 
Study treatment return and destruction ...................................58 
5.1.7 
Study treatment accountability and compliance with study 
treatment ...........................................................................................58 
5.1.8 
Premature discontinuation of study treatment ..................................59 
5.1.9 
Study treatment dose adjustments and interruptions ........................60 
5.2 
Previous and concomitant therapy ................................................................60 
5.2.1 
Definitions ........................................................................................60 
5.2.2 
Reporting of previous/concomitant therapy / auxiliary products 
in the CRF .........................................................................................61 


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5.2.3 
Allowed concomitant therapy ...........................................................61 
5.2.4 
Forbidden concomitant therapy ........................................................61 
5.2.5 
Auxiliary medicinal products / auxiliary therapy .............................62 
6 
STUDY ENDPOINTS ................................................................................................62 
6.1 
Efficacy endpoints ........................................................................................62 
6.1.1 
Primary efficacy endpoints ...............................................................62 
6.1.1.1 
Clinical Cure ............................................................................62 
6.1.1.2 
Clinical Failure ........................................................................62 
6.1.2 
Key secondary efficacy endpoints ....................................................62 
6.1.2.1 
Recurrence ...............................................................................63 
6.1.2.2 
Sustained Clinical Cure ...........................................................63 
6.1.2.3 
Time to Recurrence .................................................................63 
6.1.2.4 
Time to resolution of diarrhea .................................................63 
6.1.3 
Other efficacy endpoints ...................................................................63 
6.1.3.1 
C. difficile culture and susceptibility ......................................64 
6.1.3.2 
Vancomycin-Resistant Enterococci culture and 
susceptibility ............................................................................64 
6.1.3.3 
Change in Intestinal flora ........................................................64 
6.2 
Safety endpoints ...........................................................................................64 
6.3 
Pharmacokinetic endpoints ...........................................................................65 
6.4 
Other endpoints .............................................................................................65 
6.4.1 
Palatability and acceptability ............................................................65 
7 
STUDY ASSESSMENTS ...........................................................................................65 
7.1 
Study visits ...................................................................................................65 
7.1.1 
Screening/re-screening ......................................................................66 
7.1.2 
Unscheduled visits ............................................................................66 
7.2 
Study assessments .........................................................................................71 
7.2.1 
Demographics / Baseline parameters ................................................71 
7.2.1.1 
Medical history of special interest ...........................................71 
7.2.1.2 
Baseline CDAD disease characteristics ..................................71 
7.2.1.3 
C. difficile test to confirm subject eligibility and in case 
of Recurrence ..........................................................................72 
7.2.2 
Efficacy assessments .........................................................................72 
7.2.2.1 
Subject’s parent(s) or LAR(s) interviews ................................72 
7.2.2.2 
Site Stool Diary .......................................................................73 
7.2.2.3 
Investigator or blinded efficacy assessor assessments ............73 
7.2.3 
Stool microbiology assessments .......................................................74 
7.2.3.1 
Stool sampling for microbiology ............................................74 


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Clostridium difficile-associated diarrhea 
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7.2.3.2 
C. difficile strain identification and susceptibility ..................74 
7.2.3.3 
VRE quantitative culture and susceptibility ............................75 
7.2.3.4 
Intestinal flora analysis ............................................................75 
7.2.4 
Safety assessments ............................................................................75 
7.2.4.1 
Vital signs ................................................................................76 
7.2.4.2 
Weight and height ...................................................................76 
7.2.4.3 
Physical examination ...............................................................76 
7.2.5 
Laboratory assessments ....................................................................77 
7.2.5.1 
Type of laboratory ...................................................................77 
7.2.5.2 
Laboratory tests .......................................................................78 
7.2.5.3 
Blood samples .........................................................................79 
7.3 
Pharmacokinetic assessments .......................................................................79 
7.3.1 
Blood samples for PK assessments ...................................................79 
7.3.1.1 
Timing .....................................................................................79 
7.3.1.2 
Collection ................................................................................79 
7.3.1.3 
Labeling ...................................................................................80 
7.3.1.4 
Shipping procedures ................................................................80 
7.3.1.5 
Bioanalysis ..............................................................................80 
7.3.1.6 
Determination of pharmacokinetic parameters .......................80 
7.3.2 
Fecal samples for PK testing ............................................................81 
7.3.2.1 
Timing .....................................................................................81 
7.3.2.2 
Collection ................................................................................81 
7.3.2.3 
Labeling ...................................................................................81 
7.3.2.4 
Shipping procedures ................................................................82 
7.3.2.5 
Bioanalysis ..............................................................................82 
7.4 
Palatability and acceptability of study treatment ..........................................82 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................83 
8.1 
Study completion as per protocol .................................................................83 
8.2 
Premature withdrawal from study ................................................................83 
8.3 
Premature termination or suspension of the study ........................................84 
8.4 
Medical care of subjects after study completion/withdrawal from 
study ..............................................................................................................85 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................85 
9.1 
Adverse events ..............................................................................................85 
9.1.1 
Definitions of adverse events ............................................................85 
9.1.2 
Intensity of adverse events ................................................................86 
9.1.3 
Relationship to study treatment ........................................................87 


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Clostridium difficile-associated diarrhea 
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9.1.4 
Reporting of adverse events ..............................................................87 
9.1.5 
Follow-up of adverse events .............................................................87 
9.2 
Serious adverse events ..................................................................................87 
9.2.1 
Definition of serious adverse events .................................................87 
9.2.2 
Reporting of serious adverse events .................................................88 
9.2.3 
Follow-up of serious adverse events .................................................88 
9.2.4 
After the 28 to 32-day Follow-up period ..........................................88 
9.2.5 
Reporting procedures ........................................................................88 
9.3 
Pregnancy .....................................................................................................89 
9.3.1 
Reporting of pregnancy ....................................................................89 
9.3.2 
Follow-up of pregnancy ....................................................................90 
9.4 
Study safety monitoring ................................................................................90 
10 STATISTICAL METHODS .......................................................................................90 
10.1 
Analysis sets .................................................................................................90 
10.1.1 
Screened Analysis Set .......................................................................90 
10.1.2 
Full Analysis Set ...............................................................................90 
10.1.3 
Modified ITT Analysis Set ...............................................................91 
10.1.4 
Per-protocol Analysis Set .................................................................91 
10.1.5 
Safety Set ..........................................................................................91 
10.1.6 
PK Sets ..............................................................................................91 
10.1.7 
Usage of the analysis sets .................................................................91 
10.2 
Variables .......................................................................................................92 
10.2.1 
Efficacy variable(s) ...........................................................................92 
10.2.1.1 
Clinical Cure ............................................................................92 
10.2.1.2 
Recurrence ...............................................................................92 
10.2.1.3 
Sustained Clinical Cure ...........................................................93 
10.2.1.4 
Time to Recurrence .................................................................93 
10.2.1.5 
Time to Resolution of Diarrhea ...............................................93 
10.2.1.6 
Other efficacy variables ...........................................................94 
10.2.1.7 
Susceptibility of VRE ..............................................................95 
10.2.1.8 
Change in intestinal flora composition from baseline up 
to EOS .....................................................................................95 
10.2.2 
Safety variables .................................................................................95 
10.2.3 
PK variables ......................................................................................96 
10.2.4 
Other variables ..................................................................................96 
10.2.4.1 
Treatment exposure and compliance .......................................96 
10.2.4.2 
Demographic variables ............................................................96 
10.2.4.3 
Baseline disease characteristics ...............................................96 
10.2.4.4 
Palatability and acceptability ...................................................97 


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10.3 
Description of statistical analyses .................................................................97 
10.3.1 
Overall testing strategy .....................................................................97 
10.3.2 
Analysis of efficacy variables ...........................................................98 
10.3.2.1 
Hypotheses and statistical model ............................................98 
10.3.2.2 
Handling of missing data .........................................................98 
10.3.2.3 
Main analysis ...........................................................................98 
10.3.2.4 
Subgroup analyses ...................................................................99 
10.3.2.5 
Analysis of the other efficacy variables ..................................99 
10.3.3 
Analysis of the safety variable(s) ....................................................100 
10.3.3.1 
Adverse events ......................................................................100 
10.3.3.2 
Deaths ....................................................................................100 
10.3.3.3 
Vital signs, body weight, and body temperature ...................100 
10.3.3.4 
Laboratory values ..................................................................100 
10.3.3.5 
Treatment exposure and compliance .....................................101 
10.3.4 
Analysis of PK parameters .............................................................101 
10.3.4.1 
Part A .....................................................................................101 
10.3.4.2 
Part B .....................................................................................102 
10.3.5 
Analysis of other variable(s) ...........................................................102 
10.3.5.1 
Subject disposition ................................................................102 
10.3.5.2 
Demographic characteristics .................................................102 
10.3.5.3 
Baseline disease characteristics .............................................102 
10.3.5.4 
Previous and concomitant medications .................................103 
10.3.5.5 
Medical history ......................................................................103 
10.3.5.6 
Protocol deviations ................................................................103 
10.3.5.7 
Palatability and acceptability .................................................103 
10.4 
Interim analyses ..........................................................................................103 
10.5 
Sample size .................................................................................................103 
10.5.1 
Sample size justification .................................................................103 
11 DATA HANDLING ..................................................................................................104 
11.1 
Data collection ............................................................................................104 
11.2 
Maintenance of data confidentiality ...........................................................104 
11.3 
Database management and quality control .................................................104 
12 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................105 
12.1 
Ethics and Good Clinical Practice ..............................................................105 
12.2 
Independent Ethics Committee / Institutional Review Board ....................105 
12.3 
Informed consent ........................................................................................106 
12.4 
Compensation to subjects and investigators ...............................................106 
12.5 
Protocol adherence/compliance ..................................................................107 


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12.6 
Protocol amendments .................................................................................107 
12.7 
Essential documents and retention of documents .......................................107 
12.8 
Monitoring ..................................................................................................108 
12.9 
Investigator site file ....................................................................................109 
12.10 
Audit ...........................................................................................................109 
12.11 
Inspections ..................................................................................................110 
12.12 
Reporting of study results and publication .................................................110 
13 REFERENCES ..........................................................................................................112 
14 APPENDICES ...........................................................................................................117 
 
LIST OF TABLES 
 
Table 1 
Anticipated starting dosing regimen based on weight categories for 
subjects < 12 years ........................................................................................54 
Table 2 
Visit and assessment schedule (PART A) ....................................................67 
Table 3 
Visit and assessment schedule (PART B) ....................................................69 
 
LIST OF FIGURES 
 
Figure 1 
Flow of recruitment ......................................................................................44 
Figure 2 
Study design of Part A ..................................................................................45 
Figure 3 
Study design of Part B ..................................................................................45 
Figure 4 
5-point facial hedonic scale ..........................................................................82 
 
LIST OF APPENDICES 
 
Appendix 1 Equivalence between opiates ......................................................................117 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
AE  
Adverse event 
AUCτ  
Area under the concentration-time curve from zero to time t 
b.i.d.  
Twice daily 
BMI  
Body mass index 
BP  
Blood pressure 
bpm  
Beats per minute 
CCR  
Clinical Cure Rate 
CDAD  
Clostridium difficile-associated diarrhea 
CDC  
Center for Disease Control 
CDI  
C. difficile infection 
CFR  
Code of Federal Regulations 
CI  
Confidence interval 
CL  
Confidence limit 
CLSI  
Clinical and Laboratory Standards Institute 
Cmax  
Maximum plasma concentration 
CRA  
Clinical Research Associate 
CRF  
Case report form - paper or electronic 
CRO  
Contract Research Organization 
CV  
Coefficient of variation 
DBP  
Diastolic blood pressure 
EDTA  
Ethylene diamine tetraacetic acid 
EIA  
Enzyme Immuno-Assay 
EMA  
European Medicines Agency 
EMLA  
Eutectic Mixture of Lidocaine and Prilocaine 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ESCMID  
European Society of Clinical Microbiology and Infectious 
Diseases 
FAS  
Full Analysis Set 
FDA  
Food and Drug Administration 


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FMT  
Fecal microbiota transplant 
FSFV  
First subject-First visit 
GCP  
Good Clinical Practice 
GDH  
Glutamate Dehydrogenase 
HR  
Heart rate 
i.v.  
Intravenous 
IB  
Investigator’s Brochure 
ICF  
Informed Consent Form 
ICH  
International Council for Harmonisation 
IDMC  
Independent Data Monitoring Committee 
IDSA  
Infectious Diseases Society of America 
IEC  
Independent Ethics Committee 
IMP  
Investigational Medicinal Product 
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
ISF  
Investigator Site File 
LAR  
Legally Authorized Representative 
LC-MS/MS  
Liquid chromatography-tandem mass spectrometry 
LOQ  
Limit of quantification 
LSLV  
Last subject-Last visit 
MedDRA  
Medical Dictionary for Regulatory Activities 
MIC  
Minimal inhibitory concentration 
MIC50  
MIC required to inhibit the growth of 50% of organisms 
MIC90  
MIC required to inhibit the growth of 90% of organisms 
mITT  
Modified intent-to-treat 
MTF  
Metronadizole treatment failure 
NAAT  
Nucleic Acid Amplification Test 
NED  
New episode of diarrhea 
PBPK  
Physiologically Based Pharmacokinetic 
PCR  
Polymerase chain reaction 
PI  
Principal investigator 


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PK  
Pharmacokinetic 
PKS  
Pharmacokinetic Set 
PPS  
Per-protocol Set 
q.i.d  
Four times a day  
ROD  
Resolution of Diarrhea 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SAS  
Statistical Analysis Software 
SBP  
Systolic blood pressure 
SCR  
Sustained Cure Rate 
SD  
Standard deviation 
SE  
Standard error 
SHEA  
Society for Healthcare Epidemiology of America 
SI  
Standardized International 
SIV  
Site initiation visit 
SOC  
System organ class 
SOP  
Standard operating procedure 
SS  
Safety Set 
tmax  
Time to Cmax 
UBM  
Unformed bowel movement 
USPI  
US Prescribing Information 
VHP  
Voluntary Harmonisation Procedure 
VRE  
Vancomycin-resistant enterococci 
WHO  
World Health Organization 


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SUBSTANTIAL GLOBAL AMENDMENT 3 
Amendment rationale 
This amendment applies to global protocol AC-061A303 Version 3 dated 27 October 
2016. The resulting amended global protocol is Version 4 dated 1 March 2017. 
The main reason for this amendment is to address agreed changes in the responses to 
Voluntary Harmonisation Procedure (VHP) list of grounds for non-acceptance, dated 
10 February 2017. 
The key requested modifications to the protocol include: 
• The classification of the study, as the study includes a preliminary dose-finding part 
and a subsequent part assessing safety and efficacy. 
• The addition of a separate summary section of known potential risks and benefits for 
cadazolid, for the investigator to form his/her own opinion about the benefit/risks to 
the patient in the current trial. 
• Updates of the exclusion criteria (i.e., exclusion of subjects with hypersensitivity to 
cadazolid and to any of the excipients of vancomycin) for safety purposes. 
• The exclusion of subjects with mental disorders, as this population is even more 
vulnerable in children. 
• The clarification on the effectiveness of double-barrier contraception methods and on 
the variability of acceptance of such contraception measures between concerned 
countries. 
• Updates on the section ‘Premature discontinuation of study treatment’ to clearly 
indicate that patients must be discontinued from the study in case of recognized 
fulminant or life-threatening Clostridium difficile-associated diarrhea, and to add 
clarifications on the statements. 
Not related to VHP requests, some clarifications have been made regarding the 
dispensation of vancomycin oral solution, clarifications regarding some microbiology 
tests have been added, minor clarifications and inconsistencies have been addressed and 
some administrative changes have been updated. 
Changes to the protocol 
Two versions of the amended protocol will be prepared: 1) a clean version and 2) a Word 
comparison document, showing deletions and insertions in comparison to the previous 
protocol version. 


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Amended protocol sections 
The main sections of the protocol affected by this amendment are listed below. Where 
applicable, the same changes have also been made to the corresponding sections of the 
protocol synopsis: 
1.2.3 
Summary of benefits and risks 
2.4 
Other objectives 
3.1 
Study design 
3.1.3.3 Follow-up period (28 to 32 days) 
3.2 
Study design rationale 
4.1 
Subject population description 
4.4 
Exclusion criteria 
4.5.2 
Acceptable methods of contraception 
5.1.1.1 Dosing in Part A 
5.1.6.3 Study treatment dispensing 
5.1.8 
Premature discontinuation of study treatment 
5.2.5  
Auxiliary medicinal products / auxiliary therapy 
6.1.3.1 C. difficile culture and susceptibility 
6.1.3.2 Vancomycin-Resistant Enterococci culture and susceptibility 
6.1.3.3  Change in Intestinal flora 
6.4.1 
Palatability and acceptability 
7.2.1.3 C. difficile test to confirm subject eligibility and in case of Recurrence 
7.2.2.2 Site Stool Diary 
7.2.3.1 Stool sampling for microbiology 
7.2.3.2 C. difficile test in case of suspected Recurrence (removed) 
7.2.3.2 C. difficile strain identification and susceptibility 
7.2.3.3 VRE quantitative culture and susceptibility 


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7.2.3.4 Intestinal flora analysis 
7.2.5. 
Laboratory assessments 
9.2.5 
Reporting procedures 
10.2.1.6 Other efficacy variables 
10.2.1.7 Susceptibility of VRE 
10.2.1.8 Change in intestinal flora composition from baseline up to EOS 
10.3.2.5 Analysis of the other efficacy variables 
12.12 
Reporting of study results and publication 
 
 
Summary of previous amendments 
Amendment 
Date 
Main reason(s) 
1 
5-Nov-2015 
Correct the EudraCT number 
2 
27-Oct-2016 
To align the global protocol with the cadazolid 
Paediatric 
Investigation 
Plan 
(PIP) 
European 
Medicines Agency’s (EMA) decision and to align 
with FDA requirements 


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PROTOCOL SYNOPSIS AC-061A303 
TITLE 
A 
prospective, 
multicenter 
study 
to 
investigate 
the 
pharmacokinetics, safety, and efficacy of cadazolid versus 
vancomycin 
in 
pediatric 
subjects 
with 
Clostridium 
difficile-associated diarrhea. 
OBJECTIVES 
Primary objectives 
The primary objective of Part A is to determine the cadazolid 
dose in children from birth to < 18 years of age by investigating 
the 
safety, 
efficacy, 
and 
the 
systemic 
and 
fecal 
pharmacokinetics (PK). 
The primary objective of Part B is to assess the safety and 
efficacy of cadazolid in children from birth to < 18 years of age 
as compared with vancomycin. 
Secondary objectives 
Secondary objectives of Part A are to assess the efficacy of 
cadazolid in terms of Clinical Cure, Sustained Clinical Cure, 
and Recurrence. 
Secondary objectives of Part B are to assess the efficacy of 
cadazolid in terms of Sustained Clinical Cure, Recurrence, time 
to Recurrence, and time to resolution of diarrhea (ROD) as 
compared to vancomycin. 
PK and other objectives 
PK and other objectives are described in Section 2.3 and 
Section 2.4. 
DESIGN 
Prospective, multicenter Phase 2/3 study in children from birth 
to < 18 years of age with Clostridium difficile-associated 
diarrhea (CDAD). 
The study consists of two parts. In each part, the treatment 
period will consist of 10 days of treatment followed by a 28 to 
32-day Follow-up period. 
Part A is a multicenter, open-label, dose-finding part, for which 
safety, PK and efficacy will be investigated in pediatric subjects 
treated with cadazolid twice daily (b.i.d.) for 10 days. 
At least 24 subjects will be enrolled sequentially by descending 


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cohort age.  
Three adolescent subjects aged 12 to < 18 years will be enrolled 
first.  
After these adolescent subjects have completed Part A, 
enrolment will be temporarily put on hold and safety, PK and 
efficacy data will be reviewed by an Independent Data 
Monitoring Committee (IDMC) before 3 children aged 6 to 
< 12 years will be enrolled. Another 3 adolescent subjects will be 
enrolled to have an adequate sample size for PK assessments in 
this cohort. 
This approach allows the IDMC to review the data and 
make recommendations as to further dosing. Details are 
described in the IDMC charter. 
After these first 3 children aged 6 to < 12 years have completed 
Part A, enrolment in that cohort will be temporarily put on hold 
and safety, PK and efficacy data will be reviewed by the IDMC 
before 3 children aged 2 to < 6 years will be enrolled. 
After the first 3 children aged 2 to < 6 years have completed 
Part A, enrolment in that cohort will be temporarily put on hold 
and safety, PK and efficacy data will be reviewed by the IDMC 
before 3 infants aged 3 months to < 2 years will be enrolled. 
If the IDMC requires additional data to conclude on a 
dosing recommendation, an additional 3 children aged 6 
to < 12 years and/or 2 to < 6 years may be enrolled. 
After the 3 infants aged 3 months to < 2 years have completed 
Part A, enrolment in that cohort will be temporarily put on hold 
and safety, PK and efficacy data will be reviewed by the IDMC 
before 3 subjects aged from birth to < 3 months will be 
enrolled. Another 3 infants aged 3 months to < 2 years will be 
enrolled to collect adequate PK and safety data in this cohort. 
The final 3 subjects aged from birth to < 3 months will be 
enrolled after safety, PK and efficacy data of the first subjects 
of the same age have been reviewed by the IDMC. 
The flow of recruitment is displayed in Figure 1. The study 
design of Part A is depicted in Figure 2. 
Part 
B 
is 
multicenter, 
randomized, 
assessor-blinded, 


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parallel-group, active-controlled for which safety and efficacy 
data will be investigated in pediatric subjects treated with 
cadazolid b.i.d. or vancomycin for 10 days. At least 
176 subjects will be randomized in a 3:1 ratio to cadazolid or 
vancomycin. The randomization will be stratified by age 
stratum. 
Part B will be initiated when: 
• Data review from the 6 adolescents in Part A is complete 
and a dosing recommendation for adolescents is available 
AND 
• Safety and efficacy results from the 2 adult Phase 3 studies 
(AC-061A301 and AC-061A302) have been analyzed. 
Randomization in each subsequent stratum will start when a 
dosing recommendation from the corresponding age group is 
available based on Part A. 
PERIODS 
There will be three periods in Parts A and B. 
Screening Period (up to 48 hours): 
Starts with the signature of the Informed Consent Form (ICF) 
and ends before the subject’s enrolment in Part A or 
randomization in Part B (within 48 h of the signature of the 
ICF) on Day 1. 
Treatment Period (10 days of treatment): 
Starts on Day 1 with the first dose of study treatment once the 
subject is enrolled in Part A or randomized in Part B and ends 
on the day of the last dose of study treatment (End-of-Treatment 
[EOT]). 
The EOT visit will take place at Visit 3 on Day 10 or earlier in 
case of premature permanent discontinuation of study treatment. 
See Footnote 1 in Table 2 (Part A) or Footnote 1 in Table 3 
(Part B), for special situations.  
Follow-up Period (28 to 32 days): 
Starts after the last dose of study treatment and ends between 
Day 38 and Day 42 (Visit 5). The End-of-Study (EOS) visit will 
take place at Visit 5.  


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Subject participation in the study will be up to 44 days. 
PLANNED DURATION 
The overall planned study duration is an estimated 48 months 
from First Subject First Visit (FSFV) in Part A to Last Subject 
Last Visit (LSLV) in Part B. 
SITE(S) 
/ COUNTRY(IES) 
Approximately 70 sites in 20 countries, including the US, 
Canada, and Europe. 
SUBJECTS / GROUPS 
Overall, at least 200 subjects will be enrolled:  
Approximately 156 subjects treated with cadazolid (at least 
24 subjects in Part A and approximately 132 subjects in Part B), 
and approximately 44 subjects treated with vancomycin (in 
Part B). This corresponds to 176 randomized (3:1) in Part B. 
Part A: 
At least 24 subjects will be enrolled in five age cohorts: 
• Cohort A: From 12 to < 18 years (at least 6 subjects)  
• Cohort B: From 6 to < 12 years (at least 3 subjects; 
3 additional subjects may be added to this cohort if 
recommended by the IDMC) 
• Cohort C: From 2 to < 6 years (at least 3 subjects; 
3 additional subjects may be added to this cohort if 
recommended by the IDMC) 
• Cohort D: From 3 months to < 2 years (at least 6 subjects) 
• Cohort E: From birth to < 3 months (at least 6 subjects) 
Subjects who discontinue the treatment before the PK sampling 
day will be replaced within the same cohort. 
Part B: 
At least 176 subjects will be randomized in a 3:1 ratio to 
cadazolid or vancomycin. Randomization will be stratified by 
age stratum: 
• Stratum F: From 12 to < 18 years (at least 20 subjects)  
• Straum G: From 6 to < 12 years (at least 30 subjects) 
• Stratum H: From 2 to < 6 years (at least 30 subjects) 
• Stratum I: From 3 months to < 2 years (at least 20 subjects) 
• Stratum J: From birth to < 3 months (no minimum number) 


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INCLUSION CRITERIA 
Parts A and B: 
1. Signed informed consent by parents or legally authorized 
representatives (LAR) and assent by the child according to 
local requirements prior to initiation of any study-mandated 
procedure. 
2. Male or female from birth to < 18 years. 
3. A female of childbearing potential is eligible only if the 
following applies: 
a. Negative pregnancy test at Screening. 
b. Agreement to undertake another pregnancy test 28−32 
days after the last dose of study treatment. 
c. Agreement to use an adequate method of birth control 
described in Section 4.5 from Screening up to at least 
30 days after study treatment discontinuation. 
4. Subject is diagnosed with CDAD. As a minimum there must 
be a positive detection, within 72 h prior to enrolment/ 
randomization, of either  
a. Enzyme 
Immuno-Assay 
(EIA) 
for 
glutamate 
dehydrogenase (GDH) plus EIA toxin A/B in stool or 
b. EIA for GDH plus Nucleic Acid Amplification Test/ 
Polymerase Chain Reaction for toxin A/B in stool or 
c. Positive cell cytotoxicity assay or 
d. Toxigenic culture 
and: 
e. For subjects from birth to < 2 years: Watery diarrhea 
within 
the 
48 
h 
period 
prior 
to 
enrolment/ 
randomization. 
f. For subjects from 2 years to < 18 years: ≥ 3 unformed 
bowel movements (UBMs) in a 24 h period within the 
48 h period prior to enrolment/randomization. 
EXCLUSION CRITERIA 
Parts A and B: 
1. Positive Rotavirus test for subjects < 5 years. 
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 enrolment/ 
randomization 
and 
related 
to 
the 
fulminant 
or 
life-threatening CDAD episode excludes the potential 
subject from the study:  


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a. Septic shock based on the investigator judgment 
b. Peritonitis 
c. Ileus 
d. Toxic megacolon 
e. Significant dehydration based on investigator judgment 
f. White blood cells count > 30.0 109/L 
g. Core body temperature > 40 °C 
3. More than one previous episode of CDAD in the 3-month 
period prior to enrolment/randomization. 
4. Antimicrobial treatment active against CDAD administered 
within 24 h prior to Screening except for metronidazole 
treatment failures (MTF). 
5. Subjects with body weight < 3 kg. 
6. Life expectancy less than 30 days from any cause. 
7. Inflammatory bowel disease, chronic abdominal pain, or 
chronic diarrhea of any etiology. 
8. Planned treatment with forbidden concomitant medications. 
9. Fecal microbiota transplant (FMT), immunoglobulin 
therapy, or any investigational drug to prevent or treat 
CDAD within 1 month period (or 5 half-lives in case of 
investigational drug, whichever is longer) prior to 
enrolment/randomization.  
10. Subject has received an investigational therapy within 
1 month prior to enrolment/randomization except primary 
therapy for cancer with non-novel mechanisms of action and 
that do not affect the assessment of diarrhea.  
11. Monoclonal antibodies against C. difficile within 6 months 
prior to enrolment/randomization. 
12. Previous vaccination against C. difficile. 
13. Known hypersensitivity or contraindication to cadazolid, 
oxazolidinones, quinolones, or drugs of the same class, or 
any of their excipients. 
14. Females who are breastfeeding, or pregnant or planning to 
become pregnant during the study. 
15. 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.  
16. Known mental disorders. 
 


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Part B: 
All listed above exclusion criteria and the following additional 
exclusion criteria: 
17. Known hypersensitivity or contraindication to vancomycin 
or any of its excipients. 
18. Subject was screened for Part A. 
STUDY TREATMENTS 
Investigational treatment 
Oral cadazolid provided as granules in five strengths (250, 200, 
150, 100, and 50 mg) for oral suspension taken b.i.d. with or 
without food. 
Part A: 
For subjects ≥ 12 years to < 18 years: 250 mg b.i.d. for 10 days.  
Subjects from birth to < 12 years: anticipated starting doses are 
based on weight categories (as shown in the table below).  
Doses may be adjusted depending on PK and safety results of 
the previously enrolled subjects. 
Weight 
(kg) 
Cadazolid 
dose per day 
(mg/day) 
Cadazolid dose 
per dosing 
(mg/dose) 
Total volume 
administered per 
dosing (mL) 
3 to ≤ 5 
100 
50 
5 
> 5 to ≤ 10  
200 
100 
10 
> 10 to ≤ 15 
300 
150 
15 
> 15 to ≤ 20 
400 
200 
20 
> 20  
500 
250 
25 
Part B:  
Cadazolid b.i.d. for 10 days; dose to be determined based on PK 
and safety results from Part A. 
Comparator 
Vancomycin for 10 days either as oral capsule of 125 mg four 
times a day (q.i.d.), or as oral solution at a dose of 
40 mg/kg/day divided into 3 or 4 doses (max. 500 mg per day). 
CONCOMITANT 
THERAPY 
Prohibited medications 
1. Antimicrobial treatment active against Clostridium difficile 
or FMT up to EOS (Visit 5) unless provided for Clinical 
Failure or Recurrence. 


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2. Other 
medication 
active 
against 
CDAD 
(e.g., cholestyramine, probiotics) up to EOS (Visit 5). 
3. Initiation of treatment with opiates or change in dose or 
regimen up to 2 days after EOT. 
4. Anti-peristaltic medications, kaolin, pectin and charcoal 
containing anti-diarrheal medication up to EOS (Visit 5). 
Auxiliary medicinal products / auxiliary therapy 
At any time during the study treatment, if there is progressively 
worsening diarrhea, persistent fever > 38.3 °C, evidence of 
fulminant (severe-complicated) or life-threatening CDAD 
including the development of hypotension, septic shock, ileus, 
megacolon, or peritoneal signs, or hypersensitivity to study 
treatment, the investigator must consider the subject as 
Treatment Failure. 
In case of Clinical Failure or Recurrence, an antimicrobial 
treatment active against CDAD (or alternatively, FMT) should 
be initiated as recommended per local guidelines and/or 
physician judgment. Subject considered as a treatment failure 
must discontinue study treatment (but be followed up to EOS 
[Visit 5]). 
ENDPOINTS 
Primary efficacy endpoints 
There is no primary efficacy endpoint in Part A. 
The primary efficacy endpoint for Part B is Clinical Cure  
assessed by the blinded efficacy assessor and recorded in the 
CRF based on the following criteria:  
• Less than 3 UBMs (or no watery diarrhea if subject is 
< 2 years) per day for 2 consecutive days between first dose 
of study treatment up to EOT (inclusive), 
AND 
• Subject remains well up to EOT + 2 days (inclusive) based 
on investigator judgment, 
AND 
• No need for additional antimicrobial treatment active 
against CDAD between first dose of study treatment up to 
EOT + 2 days (inclusive). 
 


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Secondary efficacy endpoints 
Key secondary efficacy endpoints in Part A are Clinical Cure 
[as described in Section 6.1.1.1], Sustained Clinical Cure 
[Section 6.1.2.2], and Recurrence [Section 6.1.2.1] assessed by 
the investigator. 
Key secondary efficacy endpoints in Part B are Sustained 
Clinical Cure [Section 6.1.1.2], Recurrence [Section 6.1.2.1], 
time to Recurrence [Section 6.1.2.3], and time to ROD 
[Section 6.1.2.4] assessed by the blinded efficacy assessor. 
Other efficacy endpoints 
Other efficacy endpoints are described in Section 6.1.3. 
Safety endpoints 
Safety assessments will be evaluated during treatment (up to 
EOT) and the Follow-up period (up to EOS) after last dose of 
study treatment: 
• Deaths up to EOS 
• Serious adverse events (SAEs), adverse events (AEs) up to 
EOS. 
• Treatment-emergent AEs and SAEs up to 7 days after EOT. 
• AEs leading to premature discontinuation of study 
treatment. 
• Change from baseline** up to 7 days after EOT in vital 
signs (systolic blood pressure [SBP], diastolic blood 
pressure [DBP], heart rate [HR]) and body weight. 
• Change from baseline** up to 7 days after EOT in 
hematology and blood chemistry. 
• Marked abnormalities in vital signs (SBP and DBP) up to 
7 days after EOT (treatment-emergent). 
• Marked abnormalities in hematology, and blood chemistry 
up to 7 days after EOT (treatment-emergent).  
**Baseline is defined as the last assessment prior to study treatment start.  
PK endpoints 
The primary endpoint of Part A will be based on plasma 
(pre-dose, and 1 h, 2 h, 4 h, and 12 h post-dose) and fecal 
concentrations of cadazolid. 
• The 
following 
endpoints 
will 
be 
derived 
by 


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non-compartmental 
analysis 
of 
cadazolid 
plasma 
concentration-time profiles obtained at Visit 3. 
o Cmax, time to Cmax (tmax), and area under the 
concentration-time curve during a dose interval 
(AUCτ). 
• Cadazolid fecal concentration will be measured at Visit 3.  
In Part B, the cadazolid plasma concentration 2 h post-dose at 
Visit 3 (and fecal PK concentration if a stratum is administered 
a cadazolid dose that was not tested in subjects of the 
corresponding cohort in Part A) will be evaluated. 
Other endpoints 
Palatability of cadazolid (Part A and Part B) and vancomycin 
(Part B) formulations will be assessed at Day 1 and at Visit 3 
using a 5-point facial hedonic scale. 
Acceptability of cadazolid and vancomycin formulations will be 
assessed through a 3-point categorical scale at Day 1 and at 
Visit 3. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 2 and Table 3. 
STATISTICAL 
METHODOLOGY 
Analysis Sets 
Screened Analysis Set (SCRAS) 
This analysis set, SCRAS, includes all subjects who were 
screened and received a subject number. 
Full Analysis Set (FAS) 
The FAS includes all enrolled subjects assigned to a study 
treatment, whether or not they have received study treatment. 
Two FAS including subjects from Part A and from Part B, 
respectively, will be defined (FAS_A and FAS_B). 
Safety Set (SS) 
The SS includes all subjects who received at least one dose of 
study treatment in Part A or in Part B. 
Modified ITT Analysis Set (mITT) 
The mITT analysis set includes subjects in the FAS who have 
received at least one dose of study treatment and have a 
confirmed diagnosis of CDAD. Two mITT including subjects 
from Part A and from Part B, respectively, will be defined 


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(mITT_A and mITT_B). 
Per-Protocol Analysis Set (PPS) 
The PPS will be prepared only for subjects in Part B and will 
include any subjects from the mITT without any major protocol 
deviations. The PPS will be fully defined in the Statistical 
Analysis Plan (SAP). 
Efficacy analyses will be performed on the mITT and the PPS 
analysis sets. 
PK Sets (PKS) 
Part A 
The plasma PK Set A (PKS_A) comprises all subjects treated 
with cadazolid included in the FAS who were able to provide at 
least evaluable pre-dose, 2 h and 12 h post-dose samples.  
The stool PK Set A1 (PKS_A1) comprises all subjects treated 
with cadazolid included in the FAS_A who were able to provide 
an evaluable stool sample. 
Part B 
The plasma PK Set B (PKS_B) comprises all subjects treated 
with cadazolid included in the FAS who were able to provide an 
evaluable 2 h PK sample (± 1 h). 
The stool PK Set B1 (PKS_B1) comprises all subjects treated 
with cadazolid included in the FAS_B who were required and 
able to provide an evaluable stool sample. 
Description of Statistical Analysis 
The objective of the study is to evaluate PK, safety and 
efficacy. 
Overall testing strategy 
As planned efficacy analyses are exploratory, no formal 
hypothesis testing is planned and consequently there is no 
overall testing strategy.  
General statistical methods 
Descriptive statistics will be used to summarize all endpoints. 
Listings will be prepared on the FAS_A and FAS_B analysis 


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sets. 
For the analyses conducted using data from part A, the results 
will be presented by age cohort, unless otherwise specified.  
For the analyses conducted using data from part B, the results 
will 
be 
presented 
by 
treatment 
group 
(cadazolid or 
vancomycin), unless otherwise specified. 
The full details of the analyses will be provided in the SAP that 
will be finalized before database closure. 
Safety variables 
All safety variables will be summarized with descriptive 
statistics using the SS.  
• AEs up to EOS. 
• SAEs up to EOS. 
• Treatment-emergent AEs up to 7 days after EOT. 
• Treatment-emergent SAEs up to 7 days after EOT. 
• AEs leading to permanent discontinuation of study 
treatment. 
All AEs and SAEs will be coded using the MedDRA dictionary 
version 19 or higher. 
All AEs will be listed by treatment group, age cohort, and 
subject in chronological order (using onset date). 
Deaths 
The primary reason for death as reported in the Death electronic 
case report form will be listed and summarized in a frequency 
table, by treatment group.  
Vital Signs and Laboratory parameters 
Descriptive summary statistics by visit and treatment will be 
provided for absolute values and changes from baseline in SBP, 
DBP, HR, body temperature, and body weight as well as in all 
laboratory parameters. The number of subjects with at least one 
marked abnormality up to EOT + 7 days (treatment-emergent) 
for the vital signs and laboratory parameters, will be 
summarized with counts and percentages. Treatment-emergent 
abnormality is defined as an abnormality post first dose study 


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treatment not present at baseline. The analyses of laboratory 
values will be performed on Standardized International (SI) 
units. If laboratory values are received in a different unit, they 
will be converted to SI before being analyzed.  
Treatment exposure and compliance 
• Total study treatment dose (mg) is defined as the sum of all 
doses received during the treatment period. 
• Duration of exposure to treatment for cadazolid and 
vancomycin (days) is defined as the time elapsing between 
study treatment initiation and discontinuation, inclusive.  
• Compliance will be described in terms of the percent of 
doses taken out of planned doses. 
Treatment exposure and compliance variables will be 
summarized descriptively for Part A and Part B. 
Efficacy variables  
The following efficacy variables will be evaluated: 
Clinical Cure Rate (CCR) and Sustained Cure Rate (SCR)  
Clinical Cure Rate (%) and Sustained Cure Rate (%) will be 
presented with their 95% 2-sided confidence limits (CLs) by 
treatment arm, in Part A on the mITT_A, and in Part B on the 
mITT_B and the PPS_B analysis set.  
Time to Resolution of Diarrhea (ROD) and Time to 
Recurrence 
Time to ROD and Time to Recurrence will be analyzed using 
Kaplan-Meier estimation and presented graphically for Part B 
on the mITT_B. 
Other variables 
Palatability and acceptability 
Palatability and acceptability of cadazolid and vancomycin 
formulations at Day 1 and at Visit 3, rated on a 5-point facial 
hedonic scale and a 3-point categorical scale, respectively, will 
be summarized per treatment using counts and percentages. 
 


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PK parameters 
Part A:  
PK endpoints: the PKS_A will be used. 
Concentration-time data of cadazolid in plasma: 
• Individual concentration-time data will be listed by age 
cohort, dose, subject, and time. 
• Concentration-time data will be summarized by dose 
presenting the number of observations, arithmetic mean, 
median, minimum, maximum, standard deviation (SD), 
standard error (SE), % coefficient of variation (%CV), and 
95% CI of the arithmetic mean. 
Cadazolid fecal concentrations: 
Fecal PK endpoints: the PKS_A1 will be used. 
• Individual fecal concentration will be listed by age 
group, dose and subject. 
• Fecal concentrations will be summarized by dose presenting 
the number of observations, arithmetic mean, geometric 
mean, median, minimum, maximum, SD, SE, %CV, 95% 
CI of the arithmetic and the geometric means, and the fold 
over MIC90 for the geometric mean and for the observed 
minimum. 
Derived plasma PK parameters of cadazolid: 
• Individual PK parameters (Cmax, tmax, and AUCτ) will be 
listed by dose and by subject. 
• Cmax, tmax, and AUCτ will be summarized by dose with 
arithmetic mean, geometric mean, minimum, median, 
maximum, SD, SE, coefficient of variation (CV) in %, and 
95% CI of the arithmetic and geometric means (for tmax the 
geometric mean and its 95% CI will not be calculated) 
Part B: 
PK endpoint: for cadazolid plasma concentration: The PKS_B 
will be used. 
Cadazolid plasma concentrations: 
• Individual concentration at 2 h will be listed by dose and by 
subject. 


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• Concentrations at 2 h will be summarized by dose 
presenting the number of observations, arithmetic mean, 
geometric mean, median, minimum, maximum, SD, SE, 
%CV, and 95% CI of the arithmetic and the geometric 
means. 
Cadazolid fecal concentrations (if a stratum is administered a 
cadazolid dose that was not tested in subjects of the 
corresponding cohort in Part A): 
• Fecal PK endpoints: the PKS_B1 will be used. The fecal 
concentrations will be listed and summarized as for Part A. 
SAMPLE SIZE 
ASSUMPTIONS 
Approximately 156 pediatric subjects treated with cadazolid at 
the proposed duration of treatment, 24 in Part A and 132 in 
Part B. Assuming that systemic absorption in children is as low 
as in adults, a database of approximately 156 pediatric subjects 
is adequate to characterize the safety profile of cadazolid, 
including gastrointestinal tolerability side effects that are the 
most likely with a non-absorbed medication and which occurred 
at a rate of approximately 4–5% in the adult Phase 2 study. 
Assuming that a treatment-emergent AE is not observed, there 
is 95% confidence that the upper bound of the true rate is at 
most 2%. 
STUDY COMMITTEES 
Independent Data Monitoring Committee (IDMC) 
An IDMC has overall responsibility for safeguarding the 
interests of subjects by monitoring PK, safety and efficacy data 
obtained in the study and making appropriate recommendations 
based on the reported data, thus ensuring that the study is being 
conducted with the highest scientific and ethical standards.  
The IDMC will be fully operational prior to enrolment of the 
first subject into the study. The composition and operation of 
the IDMC is described in the IDMC charter. 


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PROTOCOL 
1 
BACKGROUND 
1.1 Clostridium difficile-associated diarrhea  
1.1.1 Introduction 
Clostridium difficile-associated diarrhea (CDAD), also known as C. difficile infection 
(CDI), is an infectious disease of the gastrointestinal tract. CDI 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 CDI includes a wide 
spectrum of clinical presentations ranging from diarrhea to pseudomembranous colitis, to 
a fulminant, relapsing, and/or fatal colitis [Dallal 2002, Voelker 2010]. 
1.1.2 Epidemiology 
The etiology, pathogenesis, evolution of infection, clinical manifestations, and treatment 
of CDI are similar in adults and children, however, the epidemiologic data in the pediatric 
population are very limited.  
Children are born with a minimal intestinal microbiome that is unable to resist C. difficile 
colonisation. Consequently, rates of C. difficile colonisation in children < 1 year of age is 
at least 70% [Khalaf 2012] and with toxigenic strain colonisation is at least 50% 
[Cerquetti 1995, Jangi 2010]. Subsequently, C. difficile colonization decrease to adult 
levels in children aged 3–5 years old due to the development of a more adult microbiome 
able to resist C. difficile colonization and/or the progressive maturation of the immune 
system as demonstrated by the rise in serum antibodies to toxin A and B [Enoch 2011]. 
The incidence of CDI in children is lower than in adults [Lessa 2015]. The estimated 
number of CDI cases in children 1–17 years old in the US in 2011 was 16,900 
(95% confidence interval [CI] 13,200–20,800) with an incidence per 100,000 persons of 
24.2 (95% CI 18.7–29.7) [Lessa 2015]. The incidence per 100,000 persons in children 
1-17 years old for community-associated CDI and healthcare associated CDI were 
17.9 (95% CI 14.1–21.4) and 6.3 (95% CI 4.6–8.3), respectively [Lessa 2015]. Recent 


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data suggest that CDI is an increasingly prevalent infection in children although the 
age-specific epidemiology of CDI in the pediatric population remains poorly studied 
[Khanna 2013, Kim 2008, Zilberberg 2010]. Whether the changing epidemiology is due 
to the emergence of the epidemic hypervirulent strains is unclear. 
Recognized risk factors for children acquiring CDI included antimicrobial therapy, use of 
proton pump inhibitors, repeated enemas, use of diapers, prolonged nasogastric tube 
insertion, 
gastrostomy 
and 
jejunostomy 
tubes, 
underlying 
bowel 
disease 
(e.g., Hirschsprung’s disease), gastrointestinal tract surgery, renal insufficiency, and 
impaired humoral immunity. Published data suggest that a larger proportion of 
pediatric than adult CDI cases are community-associated infections [Lessa 2015, 
Zilberberg 2010], and that many of these cases lack the traditional risk factor of 
exposure to antimicrobial drugs though recent studies suggest higher antibiotic exposure 
(> 70%) and higher healthcare exposure than previously recognized [Morinville 2005, 
Khanna 2013]. 
1.1.3 Current CDAD therapies 
Metronidazole and vancomycin are the mainstays of antibiotic therapy for adult and 
pediatric CDI and the choice of agent depends on the episode type (first episode or 
recurrence) and the severity of illness. As in adults, an estimated 20–30% of children 
experience a recurrence following antibiotic therapy for CDI though rates as high as 67% 
have been described [Khanna 2013, McFarland 2000, Morinville 2005]. 
Oral metronidazole is the drug of choice in children for initial treatment of the first 
episode of CDI and for first recurrence of mild-moderate CDI. It is rapidly absorbed from 
the upper small intestine and, although high levels are achieved in tissue, lower levels are 
found in the lower intestine. Metronidazole is associated with side effects, including 
nausea, metallic taste, emesis, extremity numbness, convulsive seizures, and neuropathy. 
Oral vancomycin is the drug of choice for severe disease and second recurrence and those 
children who have not responded to metronidazole. It is not absorbed to a great extent 
after oral administration and achieve high gut concentrations; therefore infrequent side 
effects are noted. Clinically significant serum concentrations, especially with the use of 
higher than standard doses, have been reported in some patients. Concerns about the 
increasing frequency of vancomycin- resistant enterococci have limited its use. 
Several factors, including the 027/BI/NAP1 epidemic hypervirulent strain and the 
recurrence rate, have contributed to the overall morbidity and mortality of CDI and have 
resulted in the re-emergence of C. difficile as a major global health problem. New drug 
therapy that reduces recurrence rates and spares the gut microbiome, or improves 
outcomes for patients infected with the epidemic hypervirulent strain or those with severe 
disease, remains a significant unmet medical need. 


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Fidaxomicin, an antibiotic belonging to the macrocyclic class of anti-bacterials, was 
approved in the EU and in US in 2011 for the treatment of CDAD in patients ≥ 18 years 
of age. It has proven to be comparable to vancomycin with regard to cure rates, and 
importantly, has demonstrated higher Sustained Cure Rate (SCR) [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. The safety and efficacy of 
fidaxomicin in children aged below 18 years has not yet been established, but clinical 
trials are ongoing in the pediatric population. 
In addition to other antimicrobials undergoing evaluation, alternative novel approaches 
including fecal microbiota transplant, monoclonal antibodies, and vaccines are under 
investigation for the treatment and prevention of CDI. 
1.2 Study treatment(s) 
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 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.  
Single oral doses of 30−3000 mg in the single-ascending dose study (AC-061-101) and 
multiple oral doses of 300−3000 mg twice daily (b.i.d.) for 10 days in the 
multiple-ascending dose study (AC-061-102) have been investigated in healthy subjects. 
In addition, an open-label study (AC-061-103) investigated a single oral dose of 3000 mg 
to subjects with severe CDAD. All oral doses of cadazolid were well tolerated. Systemic 
cadazolid exposures were extremely low in all studies with neglible quantities of drug 
detected in the urine. A maximum plasma concentration of 6.88 ng/mL was observed in 
the multiple-ascending dose study at a 3000 mg dose and the highest maximum plasma 
concentration (Cmax) observed in study AC-061-103 was 7.25 ng/mL. Almost the entire 
oral dose was recovered as unchanged drug in the feces. 


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A double-blind, randomized Phase 2 study (AC-061A201) investigated the efficacy and 
safety of three doses of cadazolid (250 mg, 500 mg, and 1000 mg, orally, b.i.d.) and 
vancomycin (125 mg orally, four times a day [q.i.d.]) for 10 days in 84 adult subjects 
with CDAD. All oral doses of cadazolid were well tolerated. All cadazolid doses 
provided Clinical Cure Rates (CCR) similar to or higher than vancomycin at test-of-cure 
24–72 h after the last dose of study treatment. Numerically higher or similar SCRs due to 
lower recurrence rates were observed in all cadazolid doses compared to vancomycin 
[Louie 2013]. Very low systemic exposure was also observed with the maximal 
individual plasma concentration of 18.9 ng/mL in the cadazolid 1000 mg b.i.d. dose 
group. Finally, the gut microbiome was less impacted by cadazolid treatment compared 
to vancomycin. 
1.2.2 Vancomycin 
Among the current mainstays of therapy for the treatment of pediatric CDI, oral 
vancomycin has been chosen as the comparator. It is the comparator for the ongoing 
cadazolid Phase 3 adult clinical trials and has been the comparator of choice in many 
contemporary adult clinical trials. 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 CDI without any qualifier on the severity of disease. 
Emerging clinical evidence suggests that vancomycin is a better therapy than 
metronidazole. The use of oral vancomycin is recommended as the treatment of choice 
for severe CDI in adults by both ESCMID and SHEA/IDSA guidelines and for recurrent 
episodes of CDI 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]. The recent tolevamer trials in which both vancomycin and 
metronidazole were used as control arms also suggested lower clinical success rates in 
metronidazole subjects compared to vancomycin subjects (72.7% versus 81.1%; Odds 
Ratio [95% CI]: 1.681 [1.114, 2.537], p = 0.0134) [Johnson 2012]. 
Vancomycin is a licensed antibiotic for the treatment of adults with CDAD in the US 
[Vancomycin USPI] and in Europe [Vancomycin SPC]. The recommended pediatric dose 
of vancomycin is 40 mg/kg/day in 3–4 divided doses (maximum, 2 g/day) for 7–10 days 
[Vancomycin USPI, Vancomycin SPC]. The safety and effectiveness in patients 
< 18 years of age have not been established [Vancomycin USPI]. This high-dose 
vancomycin (maximum, 2 g/day) may result in higher systemic exposure and require the 
need for serum concentration monitoring, and is currently recommended for children with 
severe complicated or fulminant disease who have not improved on the standard dose of 
vancomycin (maximum, 500 mg/day) that is recommended for children with severe CDI 
[Cohen 2010, Crews 2015, Wood 2014]. 


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Therefore, the comparator in this clinical trial is vancomycin. Vancomycin is provided 
either as oral capsules of 125 mg q.i.d. or as an oral liquid of 40 mg/kg/day in 3-4 divided 
doses (maximum, 500 mg/day) for 10 days. 
See also Section 1.1.3 for information on vancomycin in the treatment of pediatric CDI. 
1.2.3 Summary of benefits and risks 
Summary of benefits 
The AC-061A303 study will be performed in pediatric subjects with CDAD. 
CDAD results from overgrowth of toxin-producing strains in the colon following 
disturbance of the normal protective enteric flora. The etiology, pathogenesis, evolution 
of infection, clinical manifestations, and treatment of C. difficile infections are similar in 
adults and children. 
As in adults, there exists in the pediatric population a need for compounds with: (1) a 
novel mechanism of action, (2) better efficacy (i.e., lower recurrence rates and higher 
sustained cure rates [including in infections due to hypervirulent strains], reduced time to 
resolution of diarrhea, minimal effect on normal gut flora, and low potential for 
resistance development), and (3) potentially better safety in relation to systemic adverse 
reactions. 
Cadazolid is a novel antibiotic with potent and bactericidal activity against C. difficile, 
including hypervirulent strains such as ribotypes 027 and 078. In in vitro studies, 
cadazolid was highly active against all strains of C. difficile tested, with MICs ranging 
from 0.03 to 0.5 μg/mL and MIC90s of 0.125 to 0.5 μg/mL. 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. 
A double-blind, randomized Phase 2 study (AC-061A201) investigated the efficacy and 
safety of three doses of cadazolid (250 mg, 500 mg, and 1000 mg, orally, b.i.d.) and 
vancomycin (125 mg orally, q.i.d.) for 10 days in 84 adult subjects with CDAD. All oral 
doses of cadazolid were well tolerated. The observed effect of all doses of cadazolid on 
clinical cure rate was similar to, or higher than, with vancomycin. The observed sustained 
cure rate was higher for all doses of cadazolid than for vancomycin, suggesting a lower 
recurrence rate. While cadazolid decreased C. difficile viable counts and spore counts, its 
effect on other bacterial groups was minimal and either similar or less pronounced than 
for vancomycin. 


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Summary of risks 
Based on in vitro data, cadazolid demonstrates a low propensity to induce spontaneous 
resistance development. No cross-resistance with fluoroquinolones (moxifloxacin) was 
found in C. difficile, enterococci or Bacteroides spp., and the propensity to induce 
linezolid resistance by cadazolid was also extremely low. 
Intravenous (i.v.) administration of cadazolid over 14 days in dogs was associated with a 
reversible increase of liver enzymes without histological correlation at the highest dose 
tested (10 mg/kg/day). Intravenous administration of cadazolid did not show any 
potential for teratogenicity in rats or rabbits. The no-observed-effect level for maternal 
toxicity and embryo-fetal development was 10 mg/kg/day after daily i.v. administration 
of cadazolid from Days 6 to 17 of gestation (Cmax 6200 g/mL) in rats and 3 mg/kg/day 
after daily i.v. administration of cadazolid from Days 6 to 18 of gestation (mean Cmax 
1450 ng/mL) in rabbits. For pre- and post-natal development including reproductive 
performance of the F1 generation (non-treated offspring) of pregnant dams (rats), the 
no-observed-adverse-effect level was 30 mg/kg/day after daily i.v. administration from 
Day 6 of gestation to Day 20 of lactation (mean Cmax 6520 ng/mL). The increase of liver 
enzymes in dogs and the observations in the pre- and post-natal developmental studies in 
rats are considered to be of negligible safety concern for the intended clinical use, as they 
occurred at systemic exposure several orders of magnitude higher than that observed after 
oral administration in healthy subjects and subjects with CDAD. 
To date, 116 subjects (48 healthy subjects and 68 subjects with mild-to-severe CDAD) 
have been exposed to cadazolid at doses up to 3000 mg b.i.d., administered for 10 days. 
Systemic absorption of cadazolid in subjects treated in these clinical studies was 
extremely low. A Cmax of 6.88 ng/mL was observed in the multiple-ascending dose study 
at a 3000 mg dose, and the highest Cmax observed in study AC-061-103 was 7.25 ng/mL. 
The majority of the oral dose (arithmetic mean: 81–93%) was recovered as unchanged 
drug in feces in healthy subjects (AC-061-101 and AC-061-102). 
In Phase 1 and 2 studies, cadazolid was well tolerated. In the Phase 2 study, the majority 
of adverse events (AEs) were reported for no more than one subject in any individual 
dose group, and the incidence of AEs in the cadazolid groups showed no dose-dependent 
effect. Most of the treatment-emergent AEs were non-serious and of mild-to-moderate 
intensity. In this Phase 2 study, the incidence of AEs considered as treatment-related by 
the investigator was 13.6–25.0% across the cadazolid groups. These events included 
flatulence, headache and pruritus, each occurring in at least two cadazolid-treated 
subjects, and a report of bacterial disease carrier. In the vancomycin group, the incidence 
of AEs considered as treatment-related by the investigator was 31.8%. 


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Based on data from three completed Phase 1 studies, one Phase 2 study, and two ongoing 
blinded Phase 3 studies, no adverse drug reactions with cadazolid were identified. 
In this Phase 2/3 AC-061A303 study in pediatric subjects, all potential subjects with 
CDAD will undergo a medical check-up at study start to confirm eligibility. In both parts 
of the study, subjects will receive study treatment for 10 days and will be followed-up 
until 28–32 days after the last dose of study treatment, including interviews (face-to-face 
or by telephone) daily during treatment and twice weekly thereafter. At any time during 
the course of treatment the investigator may consider stopping the study drug and 
switching to alternative therapy for CDAD. 
An 
Independent Data Monitoring Committee (IDMC) 
will monitor safety, 
pharmacokinetic (PK) and efficacy data obtained in the study and make appropriate 
recommendations (including but not limited to dose recommendations) based on the 
reported data, thus ensuring that the study is conducted with the highest scientific and 
ethical standards. The IDMC will be fully operational prior to enrollment of the first 
subject into the study. 
Conclusion 
Cadazolid is a novel antibiotic which has demonstrated activity against C. difficile in 
nonclinical in vitro and animal studies. High concentrations of cadazolid in the intestine 
and very low systemic absorption make it an attractive candidate for the treatment of 
subjects with CDAD. 
Based on an assessment of the available nonclinical and clinical data there appears to be 
no prohibitive safety issues associated with a 10-day b.i.d. oral administration of 
cadazolid to pediatric subjects with CDAD. 
Provided the protocol is adhered to, careful observation and medical management will 
minimize any associated risk in this study. 
Overall, the benefit/risk assessment for subjects participating in the proposed 
AC-061A303 study in pediatric patients with CDAD is considered positive. 
1.3 Purpose and rationale of the study 
Cadazolid has demonstrated activity against C. difficile in pre-clinical in vitro and animal 
studies. High concentrations of cadazolid in the intestine and very low systemic 
absorption make it an attractive candidate for the treatment of CDAD in man. The results 
of the Phase 2 study in adults have suggested clinical response similar to or numerically 
higher than vancomycin, and higher SCRs than vancomycin. Based on the Phase 2 
results, a cadazolid dose of 250 mg b.i.d. for 10 days was chosen for further evaluation in 
the adult Phase 3 program which is currently ongoing. The program consists of 
2 identical pivotal trials (AC-061A301 and AC-061A302) designed to evaluate the 


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Clostridium difficile-associated diarrhea 
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Doc No D-17.162 
 
efficacy and safety of cadazolid versus vancomycin in adult subjects with mild to severe 
CDAD. The selected dose is expected to optimize the clinical response and to 
limit/reduce the impact on the gut microbiome, leading to improved Sustained Cure 
relative to vancomycin.  
The overall purpose of this study is to provide reassurance on the safety and efficacy of 
cadazolid in children from birth to < 18 years of age. The specific purpose of each part of 
the study is to first provide safety, PK and efficacy data to determine the cadazolid dose 
(Part A) and then to investigate the safety and efficacy of cadazolid versus vancomicin 
(Part B). 
This pediatric clinical trial is not powered to demonstrate efficacy in children from birth 
to < 18 years. It is expected that there will be no difference between the adult and the 
pediatric populations regarding the pharmacodynamic effects of cadazolid. The pediatric 
assessment of PK, safety, and clinical endpoint data in conjunction with efficacy data 
from two adequate and well controlled trials in adults will be used to evaluate the 
efficacy and the benefit/risk of cadazolid in pediatric patients. 
2 
STUDY OBJECTIVES 
2.1 Primary objective(s) 
The primary objective of Part A is to determine the cadazolid dose in children from birth 
to < 18 years of age by investigating the safety, efficacy and the systemic and fecal PK. 
The primary objective of Part B is to assess the safety and efficacy of cadazolid in 
children from birth to < 18 years of age as compared with vancomycin. 
2.2 Secondary objectives 
Secondary objectives of Part A are to assess the efficacy of cadazolid in terms of Clinical 
Cure, Sustained Clinical Cure, and Recurrence. 
Secondary objectives of Part B are to assess the efficacy of cadazolid in terms of 
Sustained Clinical Cure, Recurrence, time to Recurrence, and time to resolution of 
diarrhea as compared to vancomycin. 
2.3 Pharmacokinetic objectives 
For the PK objective in Part A, see Section 2.1. 
The PK objective in Part B is: 
• to evaluate cadazolid plasma concentration 2 h post-dose at Visit 3. 


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Doc No D-17.162 
 
• to evaluate cadazolid fecal PK profile at Visit 3 (only applicable if a stratum is 
administered a cadazolid dose that was not tested in subjects of the corresponding 
cohort in Part A). 
2.4 Other objectives 
Other objectives are: 
• to evaluate the palatability and acceptability of cadazolid and vancomycin 
formulations. 
• to evaluate the susceptibility of C. difficile to cadazolid, vancomycin, linezolid, 
moxifloxacin, metronidazole, and fidaxomicin. 
• to evaluate the Vancomycin-Resistant Enterococci (VRE) count and susceptibility to 
a panel of antibiotics including cadazolid and vancomycin. 
• To evaluate the change in intestinal flora composition including Lactobacilli and 
Bifidobacterium. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
The study is a prospective, multicenter Phase 2/3 study in children from birth to 
< 18 years of age with CDAD. 
The study consists of two parts. In each part, the treatment period will be 10 days of 
treatment followed by a 28 to 32-day Follow-up period. 
Regular visits to assess efficacy and safety are scheduled at Screening, Day 1, Day 5 
(± 1 day), Day 10 (− 2 days), Day 13 (± 1 day), and Day 40 (± 2 days). The visits at 
Day 5 and Day 13 can be performed on site or by telephone. Visits for new episodes of 
diarrhea will be scheduled if required. Protocol-mandated procedures and assessments 
will be performed according to Table 2 and Table 3. 
3.1.1 Part A 
Part A is a multicenter, open-label, dose-finding part, for which safety, PK, and efficacy 
will be assessed in pediatric subjects treated with cadazolid b.i.d. for 10 days. At least 
24 subjects will be enrolled sequentially in five age cohorts: 
Three adolescent subjects aged 12 to < 18 years will be enrolled first.  
After the completion of these 3 adolescent subjects, enrolment will be temporarily put on 
hold and safety, PK and efficacy data will be reviewed by an IDMC before 3 children 
aged 6 to < 12 years will be enrolled. Another 3 adolescent subjects will be enrolled to 
have an adequate sample size for PK assessments in this cohort. 


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• This approach allows the IDMC to review the data and make recommendations as to 
further dosing. Details are described in the IDMC charter. 
After the completion of the 3 children aged 6 to < 12 years, enrolment in that cohort will 
be temporarily put on hold and safety, PK and efficacy data will be reviewed by the 
IDMC before 3 children aged 2 to < 6 years will be enrolled. 
After the completion of the 3 children aged 2 to < 6 years, enrolment in that cohort will 
be temporarily put on hold and safety, PK and efficacy data will be reviewed by the 
IDMC before 3 infants aged 3 months to < 2 years will be enrolled. 
• If the IDMC requires additional data to conclude on a dosing recommendation, an 
additional 3 children aged 6 to < 12 years and/or 2 to < 6 years may be enrolled. 
After the completion of the 3 infants aged 3 months to < 2 years, enrolment in that cohort 
will be temporarily put on hold and safety, PK and efficacy data will be reviewed by the 
IDMC before 3 subjects aged from birth to < 3 months will be enrolled. Another 3 infants 
aged 3 months to < 2 years will be enrolled to collect adequate PK and safety data in this 
cohort. 
The final 3 subjects aged from birth to < 3 months will be enrolled after safety, PK and 
efficacy data of the first 3 subjects of the same age been reviewed by the IDMC. 
The flow of recruitment is displayed in Figure 1. The study design of Part A is depicted 
in Figure 2. 
3.1.2 Part B 
Part 
B 
will 
be 
multicenter, 
randomized, 
assessor-blinded, 
parallel-group, 
active-controlled for which efficacy and safety data will be assessed in pediatric subjects 
treated with cadazolid or vancomycin for 10 days. 
At least 176 subjects will be randomized in a 3:1 ratio to cadazolid or vancomycin. The 
randomization of subjects will be stratified by age groups, with strata corresponding to 
the age cohorts defined for Part A. 
Randomization in Part B for adolescent subjects will start when: 
• Data review from the 6 adolescents in Part A is complete and dosing recommendation 
for adolescents is available 
AND 
• Safety and efficacy results from the 2 adult Phase 3 studies (AC-061A301 and 
AC-061A302) have been analyzed. 


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Cadazolid / ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A303 
Final Version 4 
1 March 2017, page 46/117 
Confidential 
EudraCT 2015-004805-17 
Doc No D-17.162 
 
The EOT visit will take place at Day 10 (Visit 3) or earlier in case of premature 
permanent discontinuation of study treatment. See Footnote 1 in Table 2 (Part A) or 
Footnote 1 in Table 3 (Part B), for special situations. 
3.1.3.3 Follow-up period (28 to 32 days) 
The Follow-up period starts after the last dose of study treatment and ends 28 - 32 days 
after the last dose of study treatment (Visit 5). In case of study withdrawal the EOS visit 
will be Visit 5.  
Visits 4a, 4b, etc., to evaluate for Recurrence, occur when a subject experiences a New 
Episode of Diarrhea (NED) at any time between Day 13 (Visit 4) and Visit 5. 
3.1.4 Study duration 
The overall planned study duration is an estimated 48 months from First Subject First 
Visit (FSFV) in Part A to Last subject-Last visit (LSLV) in Part B. 
Subject participation in the study (either Part A or Part B) will be up to 44 days. 
3.2 Study design rationale 
The study is a prospective, multicenter Phase 2/3 study in children with CDAD from 
birth to < 18 years of age. 
Part A is a multicenter, open-label dose-finding part of at least 24 children from birth to 
< 18 years of age with confirmed CDAD to determine the cadazolid dose to be used in 
the second part of the study (Part B). Twice daily dosing of cadazolid for 10 days is an 
appropriate dosing and duration based on data from the adult clinical development 
program [see Section 1.2.1] and recommended duration of treatment from the CDI 
treatment guidelines [Cohen 2010] and the Committee on Infectious Diseases 
[Schutze 2013]. The design is considered appropriate and the sample size is sufficient to 
provide the necessary information including the systemic cadazolid exposure and fecal 
cadazolid concentrations needed to confirm the cadazolid doses to be used in Part B.  
Part B is a multicenter, randomized, parallel-group, active-controlled part, randomizing at 
least 176 subjects (3:1 randomization ratio) stratified by age (with 5 different strata, 
corresponding to the age groups used for the cohorts of Part A). As specified in 
Section 1.1, the disease is the same in adults and children, and efficacy in the pediatric 
population can be partially extrapolated from adults, therefore a study not powered to 
demonstrate efficacy is acceptable. A placebo-controlled trial would not be ethical given 
the availability of effective treatments. Therefore, vancomycin will be utilized as the 
comparator. See also Section 1.2.2 for the justification for the choice of vancomycin as 
the comparator and for the dose selected. 


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Part B will utilize an assessor-blinded (single-blind) design for the following reasons: 
1. The clinical efficacy endpoints are commonly accepted objective definitions of 
efficacy for CDAD. The introduction of a blinded efficacy assessor will further 
minimize the introduction of bias into the assessment. 
2. Given that cadazolid and vancomycin are in different formulations, a 
double-blinding would require a double-dummy design that reduces the convenience 
for the subjects. In addition, palatability and acceptability of cadazolid need to be 
assessed in this study and a double-dummy design would complicate these 
assessments, especially in young children. 
3.3 Site staff and their roles 
Site personnel should have the appropriate medical and clinical expertise to perform the 
required study assessments. 
It is recommended that the designated personnel remain unchanged throughout the entire 
course of the study and that an adequately trained back-up is designated in case of 
absence of any of the staff listed below. 
3.3.1 Principal investigator 
The principal investigator (PI) is responsible for the overall conduct of the study at the 
clinical site. It is her/his responsibility to assign appropriate personnel to the 
protocol-requested assessments (including safety, efficacy, and PK) and to define their 
roles. The PI oversees the accrual of appropriate subjects, the conduct of the study 
according to the trial protocol, and the collection of the required data. 
3.3.2 Clinical coordinator/study nurse 
Depending on the organization of the investigational site, a clinical coordinator / study 
nurse may be required to assist the PI in all aspects of subject management. She/he will 
be responsible for scheduling visits and assessments as planned in the study protocol, 
recording concomitant medications, maintaining source documentation and transcription 
of data into the electronic case report form (CRF). She/he will instruct the subjects (or 
their parents) on study treatment administration, and collect, process, and send all blood 
and fecal samples to the central laboratory (and to the analytical laboratory for PK 
samples). 
3.3.3 Blinded efficacy assessor 
Each site participating in Part B must have a designated physician who is fully blinded to 
a subject’s treatment allocation (referred to as blinded efficacy assessor).  
The blinded efficacy assessor must not have access to IRT (Interactive Response 
Technology), study treatment accountability logs, unblinding information in the CRF, 


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patient charts which indicate the actual treatment, or any other potentially unblinding 
information. 
The blinded efficacy assessor must not be involved in any aspects of the subject’s clinical 
care and management. She/he will perform all the efficacy assessments in Part B as 
detailed in Section 6.1.1 and Section 6.1.2 according to protocol schedule, in a blinded 
fashion. 
A back-up blinded efficacy assessor may conduct those efficacy assessments as detailed 
above and must not be involved in the clinical care and management of the subject.  
3.4 Study committees 
An independent Data Monitoring Committee (IDMC) has overall responsibility for 
safeguarding the interests of subjects by monitoring safety, PK and efficacy data obtained 
in the study and making appropriate recommendations (including but not limited to dose 
recommendations) based on the reported data, thus ensuring that the study is being 
conducted with the highest scientific and ethical standards. The IDMC will be fully 
operational prior to enrolment of the first subject into the study. The composition and 
operation of the IDMC is described in the IDMC charter. 
4 
SUBJECT POPULATION 
4.1 Subject population description 
Study AC-061A303 will enroll children from birth to < 18 years with CDAD, which is 
defined by the presence of diarrhea and laboratory confirmation with a diagnostic 
Clostridium difficile test. Overall, at least 200 subjects will be enrolled in Part A and 
Part B. 
In Part A, at least 24 subjects will be enrolled in five cohorts: 
• Cohort A: From 12 to < 18 years (at least 6 subjects)  
• Cohort B: From 6 to < 12 years (at least 3 subjects; 3 additional subjects may be 
added to this cohort if recommended by the IDMC) 
• Cohort C: From 2 to < 6 years (at least 3 subjects; 3 additional subjects may be added 
to this cohort if recommended by the IDMC) 
• Cohort D: From 3 months to < 2 years (at least 6 subjects) 
• Cohort E: From birth to < 3 months (at least 6 subjects) 
Subjects who discontinue the treatment before the PK sampling day will be replaced 
within the same cohort. 


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In Part B, at least 176 subjects will be randomized in a 3:1 ratio to cadazolid or 
vancomycin (approximately 132 cadazolid; 44 vancomycin), stratified by age.  
• Stratum F: From 12 to < 18 years (at least 20 subjects)  
• Stratum G: From 6 to < 12 years (at least 30 subjects) 
• Stratum H: From 2 to < 6 years (at least 30 subjects) 
• Stratum I: From 3 months to < 2 years (at least 20 subjects) 
• Stratum J: From birth to < 3 months (no minimum number) 
4.2 Rationale for the selection of the study population 
The etiology, pathogenesis, evolution of infection, clinical manifestations, and treatment 
of CDI are similar in adults and children. Children with 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 toxin assay, as suggested in the addendum to the 
guideline on the evaluation of medicinal products indicated for treatment of bacterial 
infections (EMA/CHMP/351889/2013) [EMA 2013]. Only subjects with first occurrence 
or first recurrence of CDAD will be eligible since treatment for subjects with multiple 
recurrences is not standardized by regimen, dose, and/or duration. 
Risk factors for severe disease have been reported but there is no consensus on a specific 
CDI severity index in adults. 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]. 
In the pediatric population, children can experience severe disease and complications 
from disease. No adult severity index has been validated in children and use of adult 
criteria results in overestimation of disease severity [Pai 2012, Tschudin-Sutter 2014]. 
Complications such as the development of fulminant disease or death are uncommon 
[Crews 2015, Pai 2012, Tschudin-Sutter 2014, Kim 2012]. Fulminant CDAD is often 
unresponsive to medical therapy and a life-saving emergent colectomy is often required. 
The associated mortality rate in adults is up to 40% [Bhangu 2012]. Therefore, no 
severity criteria will be used in the trial; however, children with CDAD meeting the 
definition of fulminant (severe-complicated) CDAD within 72 h of enrolment will be 
excluded. Children who meet the criteria for fulminant (severe-complicated) CDAD on 
therapy will be discontinued from study treatment and treated as recommended per local 
guidelines and/or physician judgment. 
In both Part A and Part B, the study population will be representative of children with 
laboratory confirmed CDAD. Subjects < 5 years of age with a positive Rotavirus test are 
excluded due to the high incidence of rotavirus infection in this age group. In Europe 
rotavirus is responsible for > 50% of hospitalizations in this age group [Ciccarelli 2013]. 
Children with inflammatory bowel diseases will be excluded.  


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The pathogenesis of CDAD is the same as in adults and children have similar risk factors 
for disease as adults. Similar to adults, risk factors for CDAD in the pediatric population 
include 
antibiotic 
therapy, 
healthcare 
exposure, 
immunosuppression, 
and 
acid-suppressive therapy. Other less traditional risk factors include rare intestinal 
conditions, such as Hirschsprung disease and primary immunosuppressive conditions. 
Subjects with immunosuppressive conditions or requiring immunosuppressive therapy 
and subjects with gastrointestinal abnormalities such as Hirschsprung disease will not be 
excluded from the pediatric study. Actelion will have investigators at tertiary care 
medical centres that potentially care for such at risk patient populations. 
4.3 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject: 
Parts A and B: 
1. 
Signed informed consent by parents or legally authorized representatives (LAR) 
and assent by the child according to local requirements prior to initiation of any 
study-mandated procedure. 
2. 
Male or female from birth to < 18 years. 
3. 
A female of childbearing potential [see definition in Section 4.5.1] is eligible only 
if the following applies: 
a. Negative pregnancy test at Screening. 
b. Agreement to undertake another pregnancy test 28 - 32 days after the last 
dose of study treatment. 
c. Agreement to use an adequate method of birth control described in 
Section 4.5 from Screening up to at least 30 days after study treatment 
discontinuation. 
4. 
Subject is diagnosed with CDAD. As a minimum there must be a positive 
detection, within 72 h prior to enrolment/randomization1, of either: 
a. Enzyme Immuno-Assay (EIA) for glutamate dehydrogenase (GDH) plus 
EIA toxin A/B in stool or 
b. EIA for GDH plus Nucleic Acid Amplification Test (NAAT) / Polymerase 
Chain Reaction (PCR) for toxin A/B in stool or 
c. Positive cell cytotoxicity assay or 
                                                 
1 Subjects who have failed at least 72 h of treatment of the current episode with metronidazole, continue to meet the 
definition of diarrhea without significant clinical improvement in the judgment of the investigator, and remain 
toxin positive (with a positive stool test done on a sample collected no more than 48 h prior to enrolment) may be 
enrolled in the study. Metronidazole therapy must be stopped prior to first dose of study treatment. 


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d. Toxigenic culture 
and: 
e. For subjects from birth to < 2 years: Watery diarrhea within the 48 h 
period prior to enrolment/randomization. 
f. For subjects from 2 years to < 18 years: ≥ 3 unformed bowel movements 
(UBMs) in a 24 h period within the 48 h period prior to enrolment/ 
randomization. 
4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to 
waive any of the criteria for any subject: 
Parts A and B: 
1. 
Positive Rotavirus test for subjects < 5 years. 
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 enrolment/randomization and 
related to the fulminant or life-threatening CDAD episode excludes the potential 
subject from the study:  
a. Septic shock based on the investigator judgment 
b. Peritonitis 
c. Ileus 
d. Toxic megacolon 
e. Significant dehydration based on investigator judgment 
f. White blood cells count > 30.0 × 109/L 
g. Core body temperature > 40 °C 
3. 
More than one previous episode of CDAD in the 3-month period prior to 
enrolment/randomization. 
4. 
Antimicrobial treatment active against CDAD administered within 24 h prior to 
Screening except for metronidazole treatment failures (MTF) [see Note 1 in 
Section 4.3]. 
5. 
Subjects with body weight < 3 kg. 
6. 
Life expectancy less than 30 days from any cause. 
7. 
Inflammatory bowel disease, chronic abdominal pain, or chronic diarrhea of any 
etiology. 
8. 
Planned treatment with forbidden concomitant medications. 
9. 
Fecal 
microbiota 
transplant 
(FMT), 
immunoglobulin 
therapy, 
or 
any 
investigational drug to prevent or treat CDAD within 1 month period (or 
5 half-lives in case of investigational drug, whichever is longer) prior to 
enrolment/randomization. 


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10. 
Subject has received an investigational therapy within 1 month prior to 
enrolment/randomization except primary therapy for cancer with non-novel 
mechanisms of action and that do not affect the assessment of diarrhea. 
11. 
Monoclonal antibodies against C. difficile within 6 months prior to enrolment/ 
randomization. 
12. 
Previous vaccination against C. difficile. 
13. 
Known hypersensitivity or contraindication to cadazolid, oxazolidinones, 
quinolones or drugs of the same class, or any of their excipients. 
14. 
Females who are breastfeeding, or pregnant, or planning to become pregnant 
during the study. 
15. 
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. 
16. 
Known mental disorders. 
Part B: 
All listed above exclusion criteria and the following additional exclusion criteria: 
17. 
Known hypersensitivity or contraindication to vancomycin or any of its 
excipients. 
18. 
Subject was screened for Part A. 
4.5 Criteria for female subjects of childbearing potential 
4.5.1 Definition of childbearing potential 
A female subject is considered to be of childbearing potential unless she meets at least 
one of the following criteria: 
1. Previous bilateral salpingectomy, bilateral salpingo-oophorectomy, or hysterectomy. 
2. Premature ovarian failure (confirmed by a specialist), XY genotype, Turner 
syndrome, uterine agenesis, 
3. Pre-pubescence. 
4.5.2 Acceptable methods of contraception 
Females of childbearing potential [for definition, see Section 4.5.1] and who are sexually 
active must use one of the following methods of birth control from Visit 1 up to at least 
30 days after study treatment discontinuation: 
1. Diaphragm, female condom or cervical cap, partner’s use of a condom, any of which 
must be used in combination with a spermicide (if spermicides are commercially 
available in the subject’s country of residence).  
– Double barrier methods are not considered as highly effective (failure rate < 1%) 
contraceptive measures, and the acceptance of double barrier methods varies 
between concerned countries. 


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2. Intra-uterine devices. 
3. Oral or injectable contraceptive agents, implants, or transdermal contraceptive 
hormone patches. If a hormonal contraceptive is used, it must have been taken for at 
least one month prior to enrolment/randomization. 
4. Sterilization method (tubal ligation/occlusion, or partner’s vasectomy). 
5. True abstinence from intercourse with a male partner only when this is in line with 
the preferred lifestyle of the subject. 
Rhythm methods are not considered acceptable methods of contraception for this study. 
The methods of birth control used (including non-pharmacological methods) must be 
recorded in the CRF. 
5 
TREATMENTS 
5.1 Study treatment 
Study treatments include the investigational drug cadazolid and the active comparator 
vancomycin. 
5.1.1 
Investigational treatment: description and rationale 
Oral cadazolid is provided by Actelion as granules in five strengths (250, 200, 150, 100, 
and 50 mg) for oral suspension to be reconstituted prior to administration. Cadazolid is 
supplied in an aluminum sachet. The inactive ingredients of the formulation are listed in 
the IB [Cadazolid IB]. 
5.1.1.1 Dosing in Part A 
Based on similarities of the disease in children and adults and the very low systemic 
absorption of cadazolid, it is considered appropriate to initiate treatment of subjects from 
≥ 12 years to < 18 years (Cohort A) with the dose for cadazolid (250 mg b.i.d.) similar to 
that tested in the ongoing Phase 3 studies in adults.  
The anticipated starting doses of cadazolid in subjects from birth to < 12 years (Cohort B 
to Cohort E) are based on weight categories. Using as a reference the dose received by 
the lowest anticipated body weight of children of 12 years based on available Center for 
Disease Control (CDC) and UK/WHO growth charts (500 mg per day for a body weight 
of approximately 25 kg), it is proposed to initiate therapy at approximately 20 mg/kg/day, 
given as two daily doses of 10 mg/kg.  
This weight category based dosing schedule is supported by simulations performed with a 
pediatric Physiologically Based Pharmacokinetic (PBPK) model (Gastroplus) that 
predicted that the systemic exposure obtained with a b.i.d. dose of 10 mg/kg will remain 
below the systemic concentrations observed in adults for all children aged from birth to 
12 years old. 


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The anticipated starting dosing regimen based on weight categories for subjects 
< 12 years is shown in Table 1.  
Table 1 
Anticipated starting dosing regimen based on weight categories for 
subjects < 12 years 
Weight categories 
(kg) 
Cadazolid dose per 
day  
(mg/day) 
Cadazolid dose per 
dosing (mg/dose) 
Total volume administered 
per dosing (mL) 
3 to ≤ 5 
100 
50 
5 
> 5 to ≤ 10  
200 
100  
10 
> 10 to ≤ 15 
300 
150 
15  
> 15 to ≤ 20 
400 
200 
20 
> 20  
500 
250  
25 
The daily doses are rounded up to adjust for the highest weight value of each weight category in order to ensure 
adequate concentrations. 
The dose in any cohort may be adjusted based on accrued PK and safety information. 
5.1.1.2 Dosing in Part B 
Cadazolid b.i.d. for 10 days; dose to be determined based on PK and safety results from 
Part A. 
5.1.2 Comparator: description and rationale 
Vancomycin will be provided by Actelion as capsules of 125 mg and vancomycin 
powder for injection. 
Vancomycin will be administered as oral capsule of 125 mg given q.i.d. for 10 days or as 
oral liquid at a dose of 40 mg/kg/day (500 mg/day maximum) in 3 or 4 divided doses for 
10 days depending on the age of the child and ability to swallow capsules. 
See also Section 1.2.2 for the rationale for the comparator chosen and the dose given. 
5.1.3 
Study treatment preparation and administration 
Preparation and administration of, at least, the first dose of cadazolid prepared by the 
subject or the subject’s parent(s) or LAR(s) must be done under the guidance of the site 
personnel. 
If the subject is an out-patient or if subject is discharged from the hospital between 
Visit 1 and Visit 3, the subject’s parent(s) or LAR(s) receive the instructions and 
reminder regarding study treatment intake and handling of study treatment. 


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5.1.3.1 Oral cadazolid suspension 
Cadazolid granules (single dose sachet) will be administered as an oral suspension in 
water, which must be reconstituted prior to administration, in accordance with the 
following instructions: 
1. Open the sachet and pour its content into a glass (or cup or beaker or goblet). 
2. Add water to the glass: add approximately 12.5 mL (1 tablespoon) for the 250 mg 
sachet, 10 mL (2 teaspoons) for the 200 mg sachet, 7.5 mL (1 and ½ teaspoon) for the 
150 mg sachet, 5 mL (1 teaspoon) for the 100 mg sachet, and 2.5 mL (½ teaspoon) 
for the 50 mg sachet. 
3. Swirl immediately by hand with the base of the glass resting on a flat horizontal 
surface until a uniform suspension is obtained. 
4. a) Drink the suspension. 
or 
b) Tilt the glass and take off the entire volume with a syringe and administer the 
suspension to the subject. 
5. Repeat procedure from Step 2 to Step 4 with the remaining granules in the glass. 
The oral suspension should be drunk within 5 minutes of reconstitution. If the suspension 
is not taken within 5 minutes of reconstitution, then it can be administered within the next 
2 hours after having resumed at Step 3. It is recommended not to store the oral 
suspension in the fridge. 
5.1.3.2 Cadazolid suspension for nasogastric delivery 
If the suspension is to be delivered via nasogastric tube, see the following instructions: 
a. Prepare a cadazolid suspension as described in [Section 5.1.3.1] and continue with 
Step 4b. 
b. Connect the syringe containing the cadazolid suspension to the nasogastric tube. 
c. Press the plunger to empty all syringe contents. 
d. Repeat steps a) and b) after repeating cadazolid suspension preparation steps 2 to 4b. 
e. To clean, flush the nasogastric tube with water. 
5.1.3.3 Oral vancomycin solution 
The vancomycin powder for injection must be reconstituted as per package insert. 
5.1.4 
Treatment assignment 
At the beginning of Visit 1 after the subject has signed the ICF: 
At Screening, the investigator/delegate contacts the Interactive Voice/Web Response 
System (IRT) and obtains a subject number from the IRT which will identify the subject 
throughout the study. Subjects are allowed to be re-screened once if they failed eligibility 


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and were not enrolled in the study. 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 treatment and that the subject fulfills all eligibility criteria, 
the investigator/delegate contacts IRT a second time and subjects will be assigned a:  
• Part A: Treatment kit and a Subject number (it will be the same number obtained at 
Screening). 
• Part B: Treatment kit and a Randomization number. 
The randomization list is generated by an independent contract research organization 
(CRO), 
. The randomization code is generated using SAS 
version 9.3 and is stratified by age. 
5.1.5 
Blinding 
Site staff and subjects will not be blinded to treatment. However, at each site participating 
in Part B, there must be a blinded efficacy assessor who is fully blinded to a subject’s 
treatment allocation [see Section 3.3.3]. 
5.1.6 
Study treatment supply 
Actelion will supply all study treatments to the site according to local regulations. 
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, Good Clinical Practice (GCP), and any local 
or national regulatory requirements. 
All drug supplies are to be used only in accordance with this protocol, and not for any 
other purpose. 
5.1.6.1 Study treatment packaging and labeling 
Cadazolid will be provided as granules in sachet packs within a treatment kit. Each kit 
contains 24 sachets (10 days of treatment plus 2 reserve days) of adequate strength.  
The following kits will be provided:  
• 20 + 4 sachets of cadazolid 250 mg, granules for suspension  
• 20 + 4 sachets of cadazolid 200 mg, granules for suspension  
• 20 + 4 sachets of cadazolid 150 mg, granules for suspension  
• 20 + 4 sachets of cadazolid 100 mg, granules for suspension  
• 20 + 4 sachets of cadazolid 50 mg, granules for suspension 
Vancomycin will be provided as capsules for children or powder for injection for 
children: 


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• 5 Blister packs containing capsules as provided by the supplier. 
• Vials of vancomycin powder for injection (500 mg to be suspended in Water For 
Injection to prepare an oral solution). 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
5.1.6.2 Study treatment distribution and storage 
The investigator is responsible for safe and proper handling and storage of the study 
treatment at the investigational site and for ensuring that the study treatment is 
administered only to subjects enrolled in the study and in accordance with the protocol. 
The study treatment kits must be stored at a temperature between 2 °C and 25 °C / 
35.6 °F and 77 °F; do not refrigerate. It must be kept in a secure location, e.g., a locked 
room or a locked cupboard in a restricted access room, which can be accessed only by the 
pharmacist, the investigator, or another duly designated person as specified on the 
delegation of authority form. A temperature log is to be kept and temperature control 
should occur at least on a weekly basis at each location where study treatment is stored 
prior to subject dispensation. The adequacy of storage conditions should be documented. 
In the event of a temperature excursion, it must be immediately reported to the site 
Clinical Research Associate (CRA), preferably in writing and with supporting 
documentation (e.g., copy of the temperature log showing data for all excursion days). 
The CRA should immediately contact Actelion for further advice. The affected study 
treatment will not be used (e.g., it will be segregated physically at the study center) until 
confirmation from Actelion is obtained that its use is safe. In case the temperature 
deviation is outside of the acceptable limit, the study treatment is kept segregated at the 
study center and returned to Actelion following internal study treatment return processes. 
New study treatment supplies will be provided to the study center.  
Temperature deviation correspondence must be kept in the Investigator Site File (ISF). 
Subjects should store the medication at room temperature, less than 25 °C / 77 °F. The 
subject must be educated on the proper study treatment storage conditions at home. 
Any temperature recording system routinely used at site is acceptable as long as all 
required information is included and certification of calibration is provided. If the 
temperature is captured electronically, a print-out should be made available to the CRA 
during each on-site visit. 
The study treatment label is detached from the kit and placed on a Study treatment Label 
Dispensing Log. The time of study treatment administration and, in the event of the 
suspension, the time of preparation if the subject is an in-patient are recorded in the 


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source documents. The time of study treatment administration at Visit 3 is recorded in the 
CRF. 
5.1.6.3 Study treatment dispensing 
The subjects will receive sufficient study treatment to cover the 10-day treatment period 
and 2 additional days of treatment, if needed. All unused study treatment must be 
returned upon study treatment completion or discontinuation. An accurate record of the 
date and amount of study treatment dispensed to each subject must be available for 
inspection at any time. 
If vancomycin is administered as oral solution, reconstitution and dispensing of the 
solution will be required every day. 
Subjects are asked to return the treatment kit at Visit 3 [see Footnote 6 in Table 2 (Part A) 
or Footnote 7 in Table 3 (Part B), for special situations], including empty sachets, vials 
and blister packs, and all unused study treatment at each site visit. An accurate record of 
the date and amount of study treatment dispensed to each subject must be available for 
inspection at any time. 
During the entire treatment period, a Study treatment Journal recording study treatment 
intake is completed by the study personnel based on the subject’s parent(s) or LAR(s) 
interviews. 
5.1.6.4 Study treatment return and destruction 
On an ongoing basis (if required) or upon study completion or termination of the study at 
site level, the CRA will collect used and unused treatment kits, which will be sent to the 
warehouse, where Actelion personnel or a deputy will check treatment reconciliation. In 
certain circumstances, used and unused study treatment containers may be destroyed at 
the site once study treatment accountability is finalized and has been checked by Actelion 
personnel or the deputy, and written permission for destruction has been obtained from 
Actelion. 
5.1.7 Study treatment accountability and compliance with study treatment 
The inventory of each study treatment dispensed and returned (i.e., study treatment 
accountability) is performed by the study staff on the day of the subject visit. It is 
recorded on the IMP dispensing and accountability log and in the CRF and checked by 
the monitor during site visits and once each individual subject has completed the study. 
The study treatment accountability log in the CRF will include at least the following 
information for each study treatment (sachets/capsules/vials) dispensed to the subject: 
• Kit number 
• Date dispensed / number of sachets or capsules/vials dispensed 


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• Date returned / number of sachets or capsules/vials returned 
All study treatment supplies, including partially used or empty, must be retained at the 
site for review by the monitor. 
Study treatment compliance will be based on study treatment accountability. 
Study treatment compliance will be calculated by site personnel when the IMP is 
returned, using the below formula, and entered in the CRF:  
Compliance = [(number of sachets/capsules/vials dispensed − number of sachets/ 
capsules/vials returned) / Total number of sachets/capsules/vials that should have 
been taken during the period] × 100 
The period is defined as current visit date − previous visit date + 1. The number of 
sachets/capsules/vials that should have been taken is derived from the number of 
treatment days. 
Compliance is expected to be between 80% and 120%. Compliance values outside of this 
range will be considered as a protocol deviation, which will be reported in the CRF by 
the CRA.  
The investigator must discuss the non-compliance with the subject to clarify the reasons 
and to take appropriate actions to avoid reoccurrence. This discussion and its outcome 
must be documented in the source documents. Permanent discontinuation of study 
treatment may be considered after consultation with Actelion.  
5.1.8 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or Actelion. The main reason and whether discontinuation of study 
treatment is the decision of the subject, (e.g., tolerability- or efficacy-related), the 
investigator (e.g., due to pre-specified study treatment discontinuation criteria, an AE or 
lack of efficacy), or Actelion (e.g., study terminated) must be documented in the CRF. 
A subject has the right to prematurely discontinue study treatment at any time by 
withdrawal from study treatment only or by withdrawal from any further participation in 
the study (i.e., premature withdrawal from the study; see Section 8.2). 
At any time during the study, the study treatment must be discontinued if the subject 
experiences progressively worsening diarrhea, persistent fever > 38.3 °C, evidence of 
fulminant (severe-complicated) or life-threatening CDAD including the development of 
hypotension, septic shock, ileus, megacolon, peritoneal signs, or hypersensitivity to study 
treatment. The investigator must consider the subject as Clinical Failure. 


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In any case of Clinical Failure [Section 6.1.1.2] the investigator must discontinue study 
treatment (but follow up the subject until Visit 5 [EOS]) and an antimicrobial treatment 
active against CDAD (or FMT) should be initiated as recommended per local guidelines 
and/or physician judgment [Section 5.2.5].  
In addition, the investigator should discontinue study treatment for a given subject if, on 
balance, he/she believes that continued administration would be contrary to the best 
interests of the subject. Such instances to warrant discontinuation of study treatment may 
include AEs, lack of efficacy (including disease progression), a protocol deviation 
(including eligibility failure, non-compliance with study requirements), a diagnostic or 
therapeutic procedure, a laboratory abnormality, or for administrative reasons. 
In case of premature discontinuation of study treatment, 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 treatment for any reason will not be replaced except in Part A if 
the PK samples were not collected.  
A subject who prematurely discontinues study treatment is NOT considered as 
withdrawn from the study and will be followed up until Visit 5 (EOS), provided that the 
subject’s consent for this limited participation in the study has not been withdrawn.  
If a subject discontinues from study treatment but remains in the study, all subsequent 
visits (telephone or on site) will be performed according to protocol up to Visit 5 (EOS). 
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered as withdrawn from the 
study. Withdrawal from the study and follow-up medical care of subjects withdrawn from 
the study are described in Sections 8.2 and 8.4, respectively. 
5.1.9 Study treatment dose adjustments and interruptions 
Study treatment dose adjustments and/ or interruptions are not permitted. 
5.2 Previous and concomitant therapy 
5.2.1 Definitions 
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 (EOS). 


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5.2.2 Reporting of previous/concomitant therapy / auxiliary products in the CRF 
The use of all study-concomitant therapy (including contraceptives and traditional and 
alternative medicines, e.g., plant-, animal-, or mineral-based medicines) will be recorded 
in the CRF. 
Previous therapy must be recorded in the CRF if discontinued within 7 days or within 
3 months (for antibiotics and acid suppressing medications) prior to signing of the 
informed consent.  
The generic name, start/end dates of administration (as well as whether it was ongoing at 
start of treatment and/or EOS), route, dose, and indication will be recorded in the CRF. 
5.2.3 Allowed concomitant therapy 
Proton pump inhibitors and H2 blockers are allowed during the study. 
5.2.4 Forbidden concomitant therapy 
The following concomitant medications are prohibited during the study: 
• Antimicrobial treatments active against CDAD or FMT up to Visit 5 (EOS) unless 
provided for Clinical Failure or Recurrence [Section 5.2.5]: Oral vancomycin (other 
than assigned comparator for subjects in Part B), metronidazole, bacitracin, fusidic 
acid, nitazoxanide, teicoplanin, tigecycline, fidaxomicin, rifampicin/rifampin or 
rifaximin. 
• Other medication active against CDAD including probiotics, i.v. immunoglobulins, 
and binding agents (e.g., cholestyramine) up to Visit 5 (EOS). 
• Initiation of treatment with opiates2 after enrolment up to and including 2 days after 
the EOT. 
• Anti-peristaltic medications (e.g., loperamide), kaolin or related products, pectin or 
charcoal-containing anti-diarrheals3 up to Visit 5 (EOS). 
• Any investigational drug, antibody or vaccine to prevent or treat CDAD up to Visit 5 
(EOS). 
                                                 
2 In the event of ongoing opiate treatment at enrolment, a stable treatment or a decrease in the dose/regimen or 
discontinuation of treatment with opiates is allowed. For equivalence between opiates see APPENDICES 
Appendix 1.  
3 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 enrolled because 
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). 


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5.2.5 Auxiliary medicinal products / auxiliary therapy 
At any time during the study treatment, if there is progressively worsening diarrhea, 
persistent fever > 38.3 °C, evidence of fulminant (severe-complicated) or life-threatening 
CDAD including the development of hypotension, septic shock, ileus, megacolon, or 
peritoneal signs, or hypersensitivity to study treatment, the investigator must consider the 
subject as Clinical Failure. 
In case of Clinical Failure [Section 6.1.1.2] or Recurrence [Section 6.1.2.1], an 
antimicrobial treatment active against CDAD (or FMT) should be initiated as 
recommended per local guidelines and/or physician judgment. Subject considered as a 
treatment failure must discontinue study treatment (but be followed up to Visit 5 [EOS]). 
6 
STUDY ENDPOINTS 
6.1 Efficacy endpoints 
6.1.1 Primary efficacy endpoints 
There is no primary efficacy endpoint in Part A. 
The primary efficacy endpoint for Part B is Clinical Cure (at EOT + 2 days) assessed by 
the blinded efficacy assessor and recorded in the CRF. 
6.1.1.1 Clinical Cure 
Clinical Cure (at EOT + 2 days) is based on the following criteria:  
• Less than 3 UBM (or no watery diarrhea if subject is < 2 years) per day for 
2 consecutive days between first dose of study treatment up to EOT (inclusive), 
AND 
• Subject remains well up to EOT + 2 days (inclusive) based on investigator judgment, 
AND 
• No need for additional antimicrobial treatment active against CDAD between first 
dose of study treatment up to EOT + 2 days (inclusive).  
6.1.1.2 Clinical Failure 
Subjects who do not fulfill the requirements for Clinical Cure [Section 6.1.1.1], have 
a fatal serious adverse event (SAE), are lost to follow-up, or withdraw from the study 
prior to EOT + 2 days are considered Clinical Failures. 
6.1.2 Key secondary efficacy endpoints 
Key secondary efficacy endpoints in Part A are Clinical Cure [for definition see 
Section 6.1.1.1], Sustained Clinical Cure, and Recurrence assessed by the investigator. 


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Key secondary efficacy endpoints in Part B are Sustained Clinical Cure, Recurrence, time 
to Recurrence, and time to resolution of diarrhea assessed by the blinded efficacy 
assessor. 
6.1.2.1 Recurrence 
Recurrence (at EOT + 28 to 32 days) is based on the following criteria: 
• Clinical Cure up to EOT + 2 days, 
AND  
• NED with ≥ 3 UBMs (or watery diarrhea for subjects < 2 years) on any day between 
EOT + 3 days and EOS,  
AND 
• Stool test showing positive C. difficile (as defined in Inclusion Criterion 4),  
AND 
• Antimicrobial treatment active against CDAD started between EOT + 3 days and 
EOS.  
6.1.2.2 Sustained Clinical Cure 
Sustained Clinical Cure (at EOT + 28 to 32 days) is based on the following criterion:  
• Clinical Cure [Section 6.1.1.1] and no Recurrence [Section 6.1.2.1] until EOS.  
Subjects with Clinical Failure, or with Clinical Cure and Recurrence, are considered to be 
without Sustained Cure. 
6.1.2.3 Time to Recurrence 
Time to Recurrence is defined as the time (in days) elapsed between the last dose of study 
treatment and the onset day of the NED component of the Recurrence endpoint. 
6.1.2.4 Time to resolution of diarrhea 
The date of Resolution of Diarrhea (ROD) is defined as the date of the first day of the 
2 consecutive days on treatment with < 3 UBM (or no watery diarrhea for subjects 
< 2 years of age).  
Time to ROD is the time (in days) elapsed between the first dose of study treatment and 
the ROD. 
6.1.3 Other efficacy endpoints 
For the other efficacy endpoints baseline is defined as the last assessment prior to study 
treatment start. 


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6.1.3.1 C. difficile culture and susceptibility  
Susceptibility of C. difficile isolates to cadazolid, vancomycin, linezolid, moxifloxacin, 
metronidazole, and fidaxomicin will be evaluated at Screening, at EOT in the event of 
Clinical Failure, and at NED Visits in the event of Recurrence.  
Change from baseline in susceptibility of C. difficile in case of Clinical Failure or 
Recurrence will be determined. Post-baseline MIC increases ≥ 4-fold will be considered 
microbiologically relevant. 
6.1.3.2 Vancomycin-Resistant Enterococci culture and susceptibility 
Vancomycin-resistant Enterococcus faecium and vancomycin-resistant Enterococcus 
faecalis will be enumerated at Screening and EOT. Change in count from baseline up to 
EOT will be determined.  
Susceptibility of VRE isolates to a panel of antibiotics including cadazolid and 
vancomycin will be assessed at Screening and EOT. Post-baseline MIC increases  
≥ 4-fold will be considered microbiologically relevant.  
6.1.3.3 Change in Intestinal flora  
Changes in intestinal flora composition including Lactobacilli and Bifidobacterium from 
baseline up to EOS will be determined. Fecal samples for intestinal flora composition 
analysis will be collected at Screening, EOT, NED, and EOS. 
6.2 Safety endpoints 
Safety will be evaluated during treatment and during the follow-up period of 28 to 
32 days occurring after the last dose of study treatment. The following main secondary 
safety endpoints will be specifically evaluated:  
• Deaths up to EOS. 
• SAEs, AEs up to EOS. 
• Treatment-emergent AEs and SAEs up to 7 days after EOT. 
• AEs leading to premature discontinuation of study treatment. 
• Change from baseline up to 7 days after EOT in vital signs (systolic blood pressure 
[SBP], diastolic blood pressure [DBP], and heart rate [HR]) and body weight. 
• Change from baseline up to 7 days after EOT in hematology, and blood chemistry 
parameters. 
• Marked abnormalities in vital signs (SBP and DBP) up to 7 days after EOT 
(treatment-emergent). 
• Marked abnormalities in hematology, and blood chemistry parameters up to 7 days 
after EOT (treatment-emergent).  
Baseline is defined as the last assessment prior to study treatment start. 


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6.3 Pharmacokinetic endpoints 
Systemic and fecal cadazolid concentrations will be analyzed to confirm that they are 
similar to the concentrations of adults in Phase 2. 
Determination of plasma and fecal concentrations of cadazolid is the primary endpoint of 
Part A. 
PK endpoints will be evaluated based on plasma (pre-dose, and 1 h, 2 h, 4 h, and 12 h 
post-dose) and fecal concentrations.  
• The following endpoints will be derived by non-compartmental analysis of cadazolid 
plasma concentration-time profiles obtained at Visit 3. 
– Cmax, time to Cmax (tmax), and area under the concentration-time curve during a 
dose interval (AUCτ). 
• Cadazolid fecal concentration will be measured at Visit 3.  
In Part B, the cadazolid plasma concentration 2 h post-dose at Visit 3 (and fecal PK 
concentration if a stratum is administered a cadazolid dose that was not tested in subjects 
of the corresponding cohort in Part A) will be evaluated. 
6.4 Other endpoints 
6.4.1 Palatability and acceptability 
• Palatability of cadazolid and vancomycin formulations at Day 1 and at Visit 3 using a 
5-point facial hedonic scale.  
• Acceptability of cadazolid and vancomycin formulations through a 3-point 
categorical scale at Day 1 and at Visit 3 whether the child swallowed the medication. 
7 
STUDY ASSESSMENTS 
7.1 Study visits 
The study visits are listed in Table 2 (Part A) and Table 3 (Part B). For all visits, the 
subjects must be seen or called on the designated day within the allowed visit window. A 
follow-up safety visit must be performed 28−32 days after intake of the last dose of study 
treatment. 
In case of premature discontinuation of study treatment, the EOT visit must take place as 
soon as possible and no later than 7 days after the last dose of study treatment.  
Subjects who prematurely discontinue study treatment for any reason will not be replaced 
except in Part A if the PK samples were not collected. 


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7.1.1 Screening/re-screening 
Screening starts with the signature of the informed consent. The date on which the first 
screening assessment is performed corresponds to the date of the Screening Visit. 
Screening Visit assessments can be performed up to 48 h prior to subject enrolment 
(Part A), or randomization (Part B). 
Prior to performing any study-specific procedure or assessment, the subject must be 
consented. Pediatric subjects are legally unable to provide informed consent. 
Therefore, fully informed consent should be obtained from parent(s) or LAR(s) in 
accordance with national and/or local regulations. It is the responsibility of the 
investigator to obtain written informed consent from the subject’s parent(s) or 
LAR(s) and assent by the child according to local requirements prior to initiation of 
any study-mandated procedure after adequate face-to-face explanation of the objectives, 
methods, and potential hazards of the study. The subjects who agree to participate in the 
study and the investigator/delegate must sign the ICF prior to any study-related 
assessment or procedure. 
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. 
Subjects who are in screening when the enrolment target has been met may still be 
randomized. 
It is permitted to re-screen subjects once, if the reason for non-eligibility was transient 
(e.g., abnormal laboratory test, insufficient wash-out period of a forbidden medication). 
All screening assessments should be repeated at the time of re-screening. 
For subjects who failed screening, the reason for screen-failure will be recorded in the 
CRF if available: 
7.1.2 Unscheduled visits 
Unscheduled visits (Visits U1, U2, etc.) may be performed at any time during the study. 
Depending on the reason for the unscheduled visit (e.g., AE), appropriate assessments 
will be performed based on the judgment of the investigator and the results will be 
recorded in the CRF. After an unscheduled visit, the regular scheduled study visits must 
continue according to the planned visit and assessment schedule. 
 


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Table 2 
Visit and assessment schedule (PART A) 
PERIODS Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
- 
 
Duration 
Up to 48 h 
10 days 
28 to 32 days 
- 
VISITS  Number 
1 
2 
3 
4 
4a, 4b… 
5 
U1, U2, … 
 
Name 
Screening 
Enrolment 
 
EOT1 
 
NED 
End of Study 
Unscheduled  
 
Time 
Day −2 to 
Day 1 
(within 48 h) 
Day 1 
Day 5 (± 1 day) 
On site or by 
telephone 
Day 10 (- 2 days) 
incl. Premature 
Disc 
Day 13 (± 1 day)2 
On site or by 
telephone 
If applicable, in 
case of 
Recurrence 
Day 40 (± 2 days)2 
or Study 
Withdrawal 
If applicable 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
Dispense kits and guidelines for fecal 
sampling 
X 
 
 
X 
 
X 
 
 
Fecal sampling for microbiology 
X 
 
 
X 
 
X 
X 
 
Fecal sampling for PK 
 
 
 
X 
 
 
 
 
C. difficile test 
X3 
 
 
 
 
X 
 
 
Rotavirus test for children < 5 years  
X 
 
 
 
 
 
 
 
Demographics, medical history 
X 
 
 
 
 
 
 
 
CDAD disease characteristics 
X 
X 
 
 
 
 
 
 
Previous and concomitant medications 
X4 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
X 
 
X 
X5 
X 
Height 
X 
 
 
 
 
 
 
 
Body weight 
X 
 
 
X 
 
X 
X5 
X 
Vital signs, body temperature 
X 
 
 
X 
 
X 
X5 
X 
Palatability of study treatment 
 
X 
 
X 
 
 
 
 
Acceptability of study treatment 
 
X 
 
X 
 
 
 
 
Hematology and blood chemistry 
X 
 
 
X 
 
X 
X5 
X 
Pregnancy test & contraception methods 
(females of childbearing potential only) 
X 
 
  
 
 
 
X 
 
Enrolment 
 
X 
 
 
 
 
 
 
Study treatment dispensation 
 
X 
 
 
 
 
 
 


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PERIODS Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
- 
 
Duration 
Up to 48 h 
10 days 
28 to 32 days 
- 
VISITS  Number 
1 
2 
3 
4 
4a, 4b… 
5 
U1, U2, … 
 
Name 
Screening 
Enrolment 
 
EOT1 
 
NED 
End of Study 
Unscheduled  
 
Time 
Day −2 to 
Day 1 
(within 48 h) 
Day 1 
Day 5 (± 1 day) 
On site or by 
telephone 
Day 10 (- 2 days) 
incl. Premature 
Disc 
Day 13 (± 1 day)2 
On site or by 
telephone 
If applicable, in 
case of 
Recurrence 
Day 40 (± 2 days)2 
or Study 
Withdrawal 
If applicable 
Study treatment intake 
 
Daily 
 
 
 
 
Record time of study treatment intake 
 
 
 
X 
 
 
 
 
Study treatment return 
 
 
 
X6 
 
 
 
 
Interview (face to face or by telephone) 
incl. site stool diary completion 
 
Daily 
X 
Twice weekly 
 
Investigator assessment of Clinical cure 
 
 
 
 
X 
 
 
 
Investigator assessment of Recurrence 
 
 
 
 
 
X 
 
 
Investigator assessment of Sustained cure 
 
 
 
 
 
 
X 
 
PK plasma sample  
 
 
 
X 
 
 
 
 
AEs/SAEs  
X 
X 
X 
X 
X 
X 
X 
X 
CDAD-related procedures (FMT, 
colectomy, hemi-colectomy 
 
 
 
 
 
 
X 
 
1. The treatment period may end on Day 10, or on Day 11 depending on the time of the day when the subject takes the first dose. In case Visit 3 is performed before Day 10, 
treatment must be continued until the subject has completed 10 days of treatment. 
2. If treatment period ends on Day 11, Visit 4 is to be scheduled on Day 14 (± 1 day) and Visit 5 is to be scheduled on Day 41 (± 2 days). 
3. To be performed within 72 h (or 48 h in case of MTF) prior to enrolment/randomization. 
4. Previous and concomitant medications are only collected in the CRF if the subject is enrolled. 
5. Assessments are not required unless indicated as follow-up for an AE/SAE. 
6. Study treatment is to be returned at Visit 4 if Visit 3 is performed before Day 10. 
 
AE = adverse event, BP = blood pressure, C-difficile = Clostridium difficile, EOT = End-of-Treatment, HR = heart rate, MTF = metronidazole treatment failure, NED = new episode 
of diarrhea, PK = pharmacokinetics, SAE = serious adverse event.  


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Table 3 
Visit and assessment schedule (PART B) 
PERIODS 
Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
- 
 
Duration 
Up to 48 h 
10 days 
28 to 32 days 
- 
VISITS 
Number 
1 
2 
3 
4 
4a, 4b… 
5 
U1, U2, … 
 
Name 
Screening 
Randomization 
 
EOT1 
 
NED 
End of Study 
Unscheduled  
 
Time 
Day −2 to 
Day 1 
(within 48 h) 
Day 1 
Day 5 (± 1 
day) 
On site or by 
telephone 
Day 10 (- 2 
days) 
incl. Premature 
Disc 
Day 13 (± 1 day)2 
On site or by 
telephone 
If applicable, in 
case of 
Recurrence 
Day 40 (± 2 days)2 
or Study 
Withdrawal 
If applicable 
Informed consent 
X 
 
 
 
 
 
 
 
Fecal sampling for microbiology 
X 
 
 
X 
 
X 
X 
 
Eligibility 
X 
X 
 
 
 
 
 
 
Fecal sampling for PK3 
 
 
 
X 
 
 
 
 
Dispense kits and guidelines for fecal 
sampling 
X 
 
 
X 
 
X 
 
 
C. difficile test 
X4 
 
 
 
 
X 
 
 
Rotavirus test for children < 5 years  
X 
 
 
 
 
 
 
 
Demographics, medical history 
X 
 
 
 
 
 
 
 
CDAD disease characteristics 
X 
X 
 
 
 
 
 
 
Previous and concomitant medications 
X5 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
X 
 
X 
X6 
X 
Height 
X 
 
 
 
 
 
 
 
Body weight 
X 
 
 
X 
 
X 
X6 
X 
Vital signs, body temperature 
X 
 
 
X 
 
X 
X6 
X 
Palatability of study treatment 
 
X 
 
X 
 
 
 
 
Acceptability of study treatment 
 
X 
 
X 
 
 
 
 
Hematology and blood chemistry 
X 
 
 
X 
 
X 
X6 
X 
Pregnancy test & contraception methods 
(females of childbearing potential only)  
X 
 
 
 
 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
Study drug dispensation 
 
X 
 
 
 
 
 
 


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Clostridium difficile-associated diarrhea 
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PERIODS 
Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
- 
 
Duration 
Up to 48 h 
10 days 
28 to 32 days 
- 
VISITS 
Number 
1 
2 
3 
4 
4a, 4b… 
5 
U1, U2, … 
 
Name 
Screening 
Randomization 
 
EOT1 
 
NED 
End of Study 
Unscheduled  
 
Time 
Day −2 to 
Day 1 
(within 48 h) 
Day 1 
Day 5 (± 1 
day) 
On site or by 
telephone 
Day 10 (- 2 
days) 
incl. Premature 
Disc 
Day 13 (± 1 day)2 
On site or by 
telephone 
If applicable, in 
case of 
Recurrence 
Day 40 (± 2 days)2 
or Study 
Withdrawal 
If applicable 
Study treatment intake 
 
Daily 
 
 
 
 
Record time of study treatment intake 
 
 
 
X 
 
 
 
 
Study treatment return 
 
 
 
X7 
 
 
 
 
Interview (face to face or by telephone) incl. 
site stool diary completion 
 
Daily 
X 
Twice weekly 
 
Blinded assessment of Clinical cure 
 
 
 
 
X 
X 
X 
 
Blinded assessment of Recurrence 
 
 
 
 
 
X 
 
 
Blinded assessment of Sustained cure 
 
 
 
 
 
 
X 
 
Recording of CDAD-related procedures 
 
 
 
 
 
 
X 
 
PK plasma sample8 
 
 
 
X 
 
 
 
 
AEs/SAEs  
X 
X 
X 
X 
X 
X 
X 
X 
CDAD related procedures (FMT, colectomy, 
hemi-colectomy 
 
 
 
 
 
 
X 
 
1. The treatment period may end on Day 10, or on Day 11 depending on the time of the day when the subject takes the first dose. In case Visit 3 is performed before Day 10, 
treatment must be continued until the subject has completed 10 days of treatment. 
2. If treatment period ends on Day 11, Visit 4 is to be scheduled on Day 14 (± 1 day) and Visit 5 is to be scheduled on Day 41 (± 2 days) 
3. Only to be collected if a stratum is administered a cadazolid dose that was not tested in subjects of the corresponding cohort in Part A. 
4. To be performed within 72 h (or 48 h in case of MTF) prior to enrolment/randomization 
5. Previous and concomitant medications are only collected in the CRF if the subject is randomized. 
6. Assessments are not required unless indicated as follow-up for an AE/SAE. 
7. Study treatment is to be returned at Visit 4 if Visit 3 is performed before Day 10. 
8. Blood collection for plasma PK in part B required for patients in cadazolid arm only 
 
 
AE = adverse event, BP = blood pressure, C-difficile = Clostridium difficile,  EOT = End-of-Treatment, HR = heart rate, MTF = metronidazole treatment failure, NED = new episode 
of diarrhea, PK = pharmacokinetic SAE = serious adverse event.  


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7.2 Study assessments 
7.2.1 Demographics / Baseline parameters 
Demographic and baseline characteristic data to be collected on all subjects include: age, 
sex, race and ethnicity. Relevant medical history/current medical conditions (e.g., chronic 
and ongoing acute conditions, serious past conditions) present before signing informed 
consent will be recorded on the medical history page. Where possible, diagnoses and not 
symptoms will be recorded. 
7.2.1.1 Medical history of special interest 
Medical history of special interest will be captured on the specific Medical History CRF 
page and includes: 
• Chronic medical conditions and new acute medical conditions in the past 6 months. 
• Exposure to healthcare settings including outpatient office visits 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 reported as usual by the subject or the parent, 
prior to the episode of CDAD. 
• Serum creatinine, prior to the episode of CDAD, if available. 
7.2.1.2 Baseline CDAD disease characteristics 
Baseline CDAD disease characteristics will be captured on the specific CDAD Disease 
Characteristics CRF page and include: 
• First CDAD occurrence or first Recurrence. 
• MTF. 
• 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). 
• In-patient or out-patient status at enrolment (Part A) or randomization (Part B).  
• Number of bowel movements, including UBM, within 48 h during the screening 
period that qualified the subject for enrolment (Part A) or randomization (Part B). 
• Abdominal physical examination (normal/abnormal and details) at enrolment (Part A) 
or randomization (Part B). 


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• C. difficile strain based on molecular testing at enrolment (Part A) or randomization 
(Part B). 
7.2.1.3 C. difficile test to confirm subject eligibility and in case of Recurrence 
At Visit 1, the result of a positive detection of C. difficile (EIA for GDH plus EIA toxin 
A/B in stool or EIA for GDH plus NAAT/PCR for toxin A/B genes in stool or positive 
cell cytotoxicity assay or toxigenic culture) performed locally is needed to document 
CDAD diagnosis and confirm subject eligibility.  
If a test satisfying the inclusion criteria has been performed within 72 h of enrolment/ 
randomization prior to Screening and returned a positive result, the test should not be 
repeated as this result will document eligibility. 
If CDAD has been diagnosed prior to Screening using a test not satisfying the inclusion 
criteria, the test must be repeated after the subject has signed the ICF. The new test must 
satisfy the inclusion criteria and must show a positive result to confirm eligibility. 
The assay for eligibility must be performed on a sample of stool (only on UBM or 
watery diarrhea) collected within the 72 h (48 h in case of MTF) prior to 
enrolment/randomization. 
In case of suspected Recurrence during a NED, the same test used for eligibility is 
performed locally (only on UBM or watery diarrhea) to confirm Recurrence. If this is not 
possible or impractical then the test must be one that would satisfy the inclusion criteria. 
The result of the test will be recorded in the CRF. 
7.2.2 Efficacy assessments 
7.2.2.1 Subject’s parent(s) or LAR(s) interviews 
After Visit 1, the investigator or site personnel (for Part A) or the blinded efficacy 
assessor (for Part B) perform an interview (face-to-face or by telephone) with the 
subject’s parent(s) or LAR(s) every day up to Visit 4 and then twice weekly no more 
than 4 days apart until Visit 5. Interviews are performed to document the CDAD status 
of the subject and to collect stool information to be recorded in the site stool diary.  
An interview log will be provided to investigators/study personnel to document site 
communication with the subject’s parent(s) or LAR(s). 
During the interviews the following information is discussed: 
• Date and consistency of each bowel movement since last interview. 
• Change in symptoms of CDAD since last interview. 
• New concomitant medications or treatments since last interview. 


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• Compliance with study treatment.  
• New AEs since last interview. 
7.2.2.2 Site Stool Diary 
During the subject’s parent(s) or LAR(s) interviews (face-to-face or by telephone), the 
investigator or site personnel (for Part A) or the blinded efficacy assessor (for Part B) 
will collect and document stool information to be recorded in the site stool diary. 
The investigator or site personnel (for Part A) or the blinded efficacy assessor (for Part B) 
records each bowel movement (or the presence or absence of < 3 UBMs if exact number 
is unknown), evaluates whether the bowel movement meets the definition of a UBM (i.e., 
taking the shape of the container in which it is produced), and determines the total 
number of stools in a site stool diary. For subjects from birth to 2 years of age, the site 
personnel will record the presence or the absence of watery diarrhea. 
The full information from the site stool diary is entered in the Stool Log section of the 
CRF. The investigator is responsible for the accuracy of stool data entered into the 
CRF. The monitors performing source data verification ensure that the CRF entries 
match the site stool diary and the documentation of the daily subject’s parent(s) or 
LAR(s) interviews. 
The subject’s parent(s) or LAR(s) and the study staff can determine when a NED 
happens and trigger a NED (Visit 4a, 4b, etc.) visit for assessment of Recurrence. A visit 
should be scheduled within 48 h. 
7.2.2.3 Investigator or blinded efficacy assessor assessments 
Investigator (for Part A) or blinded efficacy assessor (for Part B) assessments must be 
recorded in the CRF. 
Based on the information gathered during daily subject’s parent(s) or LAR(s) interviews 
[as defined in Section 7.2.2.1], and on clinical judgment, the investigator (for Part A) or 
blinded efficacy assessor (for Part B) will evaluate if the subject meets the definition of 
Clinical Cure [as defined in Section 6.1.1.1] at Visit 4. The information collected during 
the interviews will also allow the investigator or blinded efficacy assessor to assess ROD 
which is needed for the determination of Time to ROD [as defined in Section 6.1.2.4].  
Based on the information gathered during subject’s parent(s) or LAR(s) interviews, the 
investigator or blinded efficacy assessor will evaluate if the subject meets the definition 
of Recurrence [as defined in Section 6.1.2.1] at Visit 4a, 4b, etc., and Sustained Cure at 
Visit 5. The information collected during the interviews will also allow the investigator or 
blinded efficacy assessor to assess the Recurrence with its onset day. 


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7.2.3 Stool microbiology assessments 
7.2.3.1 Stool sampling for microbiology 
Fecal samples for microbiological analysis at the central laboratory will be taken at 
Screening, EOT, in case of NED (Visit 4a, 4b, etc.) and at EOS. If no stool is available 
on the day of the EOT visit, the NED visit, or the EOS visit, then a stool sample may 
be collected within 24 h after the visit and brought to the study site as described below. 
The subject’s parent(s) or LAR(s) 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. They 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 provided by the site. 
At the study site, study staff will allocate stool that has been thoroughly mixed into two 
sample aliquots of 3–5 g or 3–5 mL for samples collected at Screening, EOT, and NED. 
For samples collected at EOS, the study staff will allocate stool that has been thoroughly 
mixed into one sample aliquot of 3–5 g or 3–5 mL. The investigator / site personnel will 
store the tubes containing stools from each sample at −70 °C/−94 °F or below. In 
exceptional cases and after written confirmation by the sponsor, fecal samples for 
microbiology testing may be stored below −20 °C / −4 °F in a frost-free freezer. 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 or watery diarrhea samples must be collected. If the stool 
sample is collected at the subject’s place of residence, the subject’s parent(s) or LAR(s) 
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 subject’s parent(s) or LAR(s) 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 microbiology laboratory. The tubes containing stools will be stored frozen at the 
central microbiology laboratory. Investigators will not receive results from the central 
microbiology laboratories but may be requested from the sponsor after the end of the 
trial.  
7.2.3.2 C. difficile strain identification and susceptibility  
This analysis will be performed on samples collected at Screening, EOT in the event of 
Clinical Failure, and NED in the event of Recurrence. 


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The central laboratory analyzes the feces received in the frozen tubes to isolate 
C. difficile. 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 typing of C. difficile 
strains including identification of epidemic hypervirulent strains currently defined as 
PCR ribotype 027, 078, or 244 [Freeman 2010, Lim 2014, De Almeida 2013]. New 
epidemic 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. 
Investigators will not receive results from the central microbiology laboratory but results 
may be requested from the sponsor after the end of the trial. 
7.2.3.3 VRE quantitative culture and susceptibility  
This analysis will be performed on samples collected at Screening and EOT. 
If adequate fecal sample is available, the central laboratory analyzes the feces received in 
the frozen tubes to culture and enumerate VRE isolates (Enterococcus faecium and 
Enterococcus faecalis). The VRE isolates are then tested for susceptibility against a 
panel of antibiotics including cadazolid and vancomycin, in accordance with the CLSI 
testing standards. 
Investigators will not receive results from the central microbiology laboratories but 
results may be requested from the sponsor after the end of the trial.  
7.2.3.4 Intestinal flora analysis  
This analysis will be performed on samples collected at Screening, EOT, NED, and EOS. 
If adequate fecal sample is available, the feces received in frozen tubes will be analyzed 
to assess changes in intestinal flora composition as compared to baseline, including 
changes in Lactobacilli and Bifidobacterium. 
Investigators will not receive results from the central microbiology laboratories but 
results may be requested from the sponsor after the end of the trial. 
7.2.4 Safety assessments 
The definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 9. 


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7.2.4.1 Vital signs 
Blood pressure (BP) and HR are to be measured at Screening, Visit 3, in case of a NED, 
at unscheduled visits (if applicable) and EOS (Visit 5) 
SBP and DBP will be measured in a supine or sitting position using the same type of 
device throughout the study. It is recommended to allow the subject to rest for at least 
5 minutes, and to use the same position (supine or sitting) throughout the study for an 
individual subject. 
HR and BP are recorded in the CRF. Clinically relevant vital signs abnormalities which 
meet the definition of an AE [Section 9.1.1] 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 
Screening, Visit 3, in case of a NED, and at unscheduled visits (if applicable) and EOS 
(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 and site of measurement is recorded in the CRF. Conversion to core body 
temperature will be performed programmatically. 
Calibration certificates for the sphygmomanometer and temperature measurement device 
must be available prior to the screening of the first subject. 
7.2.4.2 Weight and height 
Body weight will be measured in indoor clothing for subjects ≥ 2 years of age or in 
underclothes for subjects < 2 years of age but without shoes for all subjects at Screening, 
Visit 3, in case of a NED, at unscheduled Visits (if applicable) and EOS (Visit 5) and 
recorded in the CRF.  
Height is to be measured at Screening and recorded in the CRF. 
Body mass index (BMI) will be derived from height and weight. 
Calibration certificates for the body weight scale must be available prior to the screening 
of the first subject. 
7.2.4.3 Physical examination 
A physical examination will be performed at Screening, Visit 3, in case of a NED, at 
unscheduled Visits (if applicable), and at EOS (Visit 5). 
The observation should be reported according to body system in the CRF as either normal 
or abnormal. If an abnormality is found then it should be specified in the CRF page, 


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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 Visit 1 which meet the definition of 
an AE [Section 9.1.1], must be recorded by the investigator on the AE page of the CRF. 
7.2.5 Laboratory assessments 
7.2.5.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) will be used for all 
protocol-mandated laboratory tests, including re-tests due to laboratory abnormalities and 
laboratory tests performed at unscheduled visits. Central laboratory data will be 
automatically transferred from the central laboratory database to Actelion’s clinical 
database. 
At the time of Visit 1, local laboratory results are used for checking subject eligibility 
since central laboratory results would not be available within the 48 h screening period. If 
laboratory results have been performed as part of routine assessment and the results are 
available prior to the signing of the ICF, they can be used to assess eligibility and does 
not have to be repeated. 
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.  
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 exceptional cases (e.g., subject is hospitalized in a different hospital from the study 
center due to a medical emergency, or missing central laboratory values) local laboratory 
results (with the corresponding normal ranges) must be entered into the clinical database 
via dedicated CRF pages.  
In case a central laboratory sample is lost or cannot be analyzed for whatever reason, the 
investigator will collect an additional sample as soon as possible for repeat analysis, 
unless a local laboratory sample was collected within the same time-window and these 
test results are available. 
Central laboratory reports, with the exception of microbiology results, will be sent to the 
investigator. In case of specific (pre-defined) laboratory abnormalities, the central 
laboratory will alert Actelion and the concerned site. All laboratory reports must be 


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signed and dated by the investigator or delegate within 10 working days of receipt and 
filed with the source documentation. The investigator or delegate must indicate on the 
laboratory report whether abnormal values are considered clinically relevant or not. 
Clinically relevant laboratory findings that are known at the time of signature of informed 
consent must be recorded on the medical history page of the CRF. Any clinically relevant 
laboratory abnormalities detected after signature of informed consent must be reported as 
an AE or SAE as appropriate [see Section 9], and must be followed until the value returns 
to within the normal range or is stable, or until the change is no longer clinically relevant. 
Further laboratory analyses should be performed as indicated and according to the 
judgment of the investigator. 
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. 
7.2.5.2 Laboratory tests 
Hematology 
• Hemoglobin (g/L) 
• Hematocrit (L/L) 
• Erythrocyte count (1012/L) 
• Leukocyte count with differential counts (109/L) 
• Platelet count (109/L) 
Clinical chemistry 
• Alanine aminotransferase (ALT; U/L) 
• Aspartate aminotransferase (AST; U/L) 
• Alkaline phosphatase (U/L) 
• Total and direct bilirubin (μmol/L) 
• Creatinine (μmol/L) 
• Blood urea nitrogen (mmol/L) 
• Sodium, potassium, chloride, calcium (mmol/L) 
• Protein (g/L) 
• Albumin (g/L) 
Pregnancy test 
A urine or serum pregnancy test will be performed locally at Screening for females of 
childbearing potential to document eligibility at Screening prior to enrolment or 
randomization and at Visit 5 (EOS). Approximately 2.5 ml of blood will be collected to 
perform the serum pregnancy test. 
If pregnancy is suspected during the study, a urine pregnancy test must be performed 
immediately. 


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7.2.5.3 Blood samples 
Approximately 5 mL of blood§ for the hematology and chemistry tests will be collected 
and sent to the central laboratory 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 central laboratory manual.  
7.3 Pharmacokinetic assessments 
7.3.1 Blood samples for PK assessments 
7.3.1.1 Timing 
The blood samples for PK assessment will be drawn at Visit 3 at the following time 
points:  
• Part A: Morning pre-dose blood sample should be drawn immediately prior to 
morning study treatment administration, and then 1 h, 2 h, 4 h, and 12 h (prior to the 
evening administration) after cadazolid administration. 
• Part B (only for subjects on cadazolid): 2 h post-dose blood sample (± 1 h). 
The date and exact actual clock time of collection of each blood sample must be entered 
in the CRF. 
The total blood volume to be taken for the PK assessments is 5 × 1 mL = 5 mL in Part A 
and 1 mL in Part B. 
7.3.1.2 Collection  
Approximately 1 mL of blood** will be collected in tubes containing EDTA via an i.v. 
catheter placed in an antecubital vein in the arm or via direct venipuncture. Anesthetic 
cream (e.g., EMLA) may be applied prior to placement of the catheter. 
The indwelling catheter will be kept patent by insertion of a mandrin, which will be 
changed after each blood sampling or by flushing with saline. 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 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 absolute minimum volume of blood required for complete hematology and chemistry tests is 3 mL (see central 
laboratory manual for details). 
** The absolute minimum volume of blood required for PK assessments is 0.5 mL. 


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The plasma will then be transferred into one labelled polypropylene tube, avoiding 
carry-over of erythrocytes. All samples will be stored in an upright position at −20 °C or 
lower. The exact actual clock time of collection of the blood sample must be entered in 
the CRF. 
7.3.1.3 Labeling 
The tubes for both collecting blood for cadazolid determination and storage of plasma 
samples will be provided pre-labeled 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-061A303 Plasma 
Centre number / Subject number 
Study day / scheduled time 
7.3.1.4 Shipping procedures 
The plasma samples for cadazolid determination must be shipped to the bioanalytical 
laboratory (either directly or via central lab) 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 bioanalytical laboratory before the site sends 
the samples to the bioanalytical laboratory. 
7.3.1.5 Bioanalysis 
All samples from subjects on cadazolid will be analyzed by the bioanalytical laboratory. 
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. 
7.3.1.6 Determination of pharmacokinetic parameters 
The PK parameters will be determined on the basis of actual blood sampling time points 
using a non-compartmental analysis.  
Model-independent PK analysis will be performed under the responsibility of Actelion 
Pharmaceuticals Ltd using WinNonlin 6.3.or higher (Pharsight Corporation, Mountain 
View, CA, USA). The following PK parameters will be estimated from the individual 
plasma concentration versus time curves: 


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Cmax 
is the maximum plasma concentration obtained directly from the measured 
plasma concentrations. 
tmax 
 
is the time to reach Cmax. 
AUCτ 
Area Under the concentration-time curve during one dosing interval τ. 
AUCτ will be calculated according to the trapezoidal rule using the 
measured concentration-time values above the LOQ. 
7.3.2 Fecal samples for PK testing 
7.3.2.1 Timing 
Part A: A fecal sample for PK testing will be collected at Visit 3 from each subject. 
Part B: In case subjects in a stratum are administered a cadazolid dose that was not tested 
in subjects of the corresponding age in Part A, a fecal sample will be collected for 
confirmation of the expected PK profile of that stratum at Visit 3, and cadazolid stool 
concentration will be measured. 
7.3.2.2 Collection 
The subject’s parent(s) or LAR(s) will be instructed to collect the stool sample for PK 
testing ideally within 24 h of Visit 3 or agreed upon drop-off time, and to store the 
sample in a refrigerator until departing for the study site. They 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 provided by the site. 
At the study site, study staff will allocate stool that has been thoroughly mixed into a 
sample of 3–5 g or 3–5 mL. The investigator/ site personnel will store the tube containing 
the sample at −70 °C / −94 °F or below. Date and time at which the stool sample was 
produced are recorded on the tube labels and in the CRF. 
The subject’s parent(s) or LAR(s) will receive guidelines for fecal sampling and delivery 
to the study site. 
7.3.2.3 Labeling 
The tubes for fecal samples storage will be provided pre-labeled to each of the 
participating sites by the central laboratory before starting the study.  
Actelion Pharmaceuticals Ltd 
AC-061A303 stool 
Centre number / Subject number 
Study day  


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7.3.2.4 Shipping procedures 
The fecal sample for PK testing of 3–5 g or 3-5 mL will be shipped on dry ice to the 
bioanalytical laboratory (either directly or via central lab)††. 
7.3.2.5 Bioanalysis 
All samples from subjects on cadazolid will be analyzed by the bioanalytical laboratory. 
Cadazolid fecal concentrations will be determined using a validated LC-MS/MS assay. 
The foreseen LOQ is 5 ng/g. 
7.4 Palatability and acceptability of study treatment 
Palatability of cadazolid and vancomycin formulations will be assessed directly by 
children who are able to comply with the instruction of the test using a 5-point facial 
hedonic scale [see Figure 4].  
Figure 4 
5-point facial hedonic scale 
 
[Davies 2008] 
For children not able to comply with the instruction of the test, the palatability will be 
indirectly assessed by the subject’s parent(s) or LAR(s) or study site personnel by 
answering the following question: 
“On the basis of reaction / facial expression of the child, in your opinion, how much 
did the child like the taste of the medication?”: 
1 
dislike very much,  
2 
dislike a little, 
3 
not sure, 
                                                 
†† If in total only one fecal sample of 3–5 g or 3 5 mL could be collected at Visit 3 in Part A, i.e., there is not enough 
stool to prepare aliquots for both microbiology assessments and PK testing, the fecal sample must be used for PK 
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4 
like a little, 
5 
like very much. 
The site study personnel will record the palatability score corresponding to the smiley 
face pointed by the subject or the response provided by subject’s parent(s) or LAR(s) or 
study site personnel in the CRF. 
Acceptability of cadazolid and vancomycin formulations will be assessed through a 
3-point categorical scale. For all subjects, parent(s) or LAR(s) or study site personnel will 
be asked following first dose at Visit 1 and at Visit 3 whether the child swallowed the 
medication:  
a. 
fully, 
b. partially, 
c. 
not at all. 
The site study personnel will record the acceptability score corresponding to the response 
provided by subject’s parent(s) or LAR(s) or study site personnel in the CRF. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion as per protocol 
For an individual subject, study completion is reached when EOS (Visit 5) has been 
completed as per protocol schedule. 
All enrolled or randomized subjects who received study treatment must be followed up to 
EOS (Visit 5), whether or not they are prematurely discontinued from study treatment. 
Enrolled or randomized subjects who do not receive any dose of study treatment will 
complete EOS (Visit 5) as soon as possible. 
EOS on a study level occurs at the time all subjects have completed their EOS visits. 
8.2 Premature withdrawal from study 
Subject’s parent(s) or LAR(s) may voluntarily withdraw the subject from the study 
without justification for any reason at any time. Subjects may voluntarily withdraw their 
assent for any reason at any time.  
Subjects are considered withdrawn if, their parent(s) or LAR(s) state an intention to 
withdraw from further participation in all components of the study (i.e., withdrawal of 
consent), the subject withdraws their assent, the subject dies, or the subject is lost to 
follow-up. If a subject’s parent(s) or LAR(s) withdraws consent or the subject withdraws 
assent, no further data will be collected in the CRF from the date of withdrawal onward. 
The investigator may withdraw a subject from the study (without regard to parent[s] or 


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LAR[s] consent or the subject’s assent) if, on balance, he/she believes that continued 
participation in the study would be contrary to the best interests of the subject. 
Withdrawal from the study may also result from a decision by Actelion for any reason, 
including premature termination or suspension of the study. 
Subjects are considered lost to follow-up if all reasonable attempts by the investigator to 
communicate with parent(s) or LAR(s) of the subject fail. The site must take preventive 
measures to avoid a subject being lost to follow-up (e.g., document different ways of 
contact such as telephone number of parent[s] or LAR[s], home address, email address, 
person to be contacted in case subject’s parent[s] or LAR[s] cannot be reached). If the 
subject’s parent(s) or LAR(s) cannot be reached, the site must make a reasonable effort to 
contact them, document all attempts, and enter the loss of follow-up information into the 
CRF. The following methods must be used: at least three telephone calls must be placed 
to the last available telephone number and one registered letter must be sent by post to the 
last available home address. Additional methods may be acceptable if they are compliant 
with local rules/regulations (e.g., site staff visit to the subject’s home), respecting the 
subject’s right to privacy. If the subject’s parent(s) or LAR(s) is still unreachable after all 
contact attempts listed above, he/she will be considered to be lost to follow-up. 
If premature withdrawal occurs for any reason, the reason (if known) for premature 
withdrawal from the study, along with who made the decision (subject’s parent(s) or 
LAR(s), investigator, or Actelion) must be recorded in the CRF. 
If for whatever reason (except death or loss to follow-up) a subject was withdrawn from 
the study, the investigator should make efforts to schedule a last appointment / telephone 
call to assess the safety and well-being of the subject, collect unused study treatment and 
discuss follow-up medical care. Data obtained during this last appointment / telephone 
call will be recorded in the subjects’ medical records but it will not be collected in the 
CRF. The investigator must provide follow-up medical care for all subjects who are 
prematurely withdrawn from the study, or must refer them for appropriate ongoing care, 
as described in Section 8.4. 
8.3 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. 
If a study is prematurely suspended or terminated, 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 suspended or prematurely terminated for any reason, the investigator in 
agreement with Actelion must promptly inform the parent(s) or LAR(s) of all enrolled 


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subjects, and ensure their appropriate treatment and follow-up, as described in 
Section 8.2. Actelion may inform the investigator of additional procedures to be followed 
in order to ensure that adequate consideration is given to the protection of the subjects’ 
interests. 
In addition, if the investigator suspends or terminates a study without prior agreement 
from Actelion, the investigator must promptly inform Actelion and the IRB/IEC, and 
provide both with a detailed written explanation of the termination or suspension. 
If the IRB/IEC suspends or terminates its approval / favorable opinion of a study, the 
investigator must promptly notify Actelion and provide a detailed written explanation of 
the termination or suspension. 
Any suspension or premature termination of the study must be discussed with the IDMC. 
8.4 Medical care of subjects after study completion/withdrawal from study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to the subjects and subject’s parent(s) or 
LAR(s) what treatment(s)/medical care is necessary and available according to local 
regulations.  
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Adverse events 
9.1.1 Definitions of adverse events 
An AE is any adverse change, i.e., any unfavorable and unintended sign, including an 
abnormal laboratory finding, symptom, or disease that occurs in a subject during the 
course of the study, whether or not considered by the investigator as related to study 
treatment. 
A treatment-emergent AE is any AE temporally associated with the use of study 
treatment (from study treatment initiation until 7 days after study treatment 
discontinuation) whether or not considered by the investigator as related to study 
treatment. 
AEs include: 
• Exacerbation of a pre-existing disease. Failure to achieve Clinical Cure or evidence of 
Recurrence are not to be reported as AEs unless in the investigator opinion the signs 
and symptoms or the disease are exacerbated or are of unusual type or intensity.  
• 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 during the course of the study 
even though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at study start that worsen 
following the start of the study (i.e., signing of informed consent). 
• Abnormal assessments, e.g., change on physical examination, if they represent a 
clinically significant finding that was not present at study start 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 study start or worsened during the 
course of the study or led to dose reduction, interruption or permanent discontinuation 
of study treatment. 
Overdose, misuse, and abuse of the study treatment will be reported as an AE and, in 
addition, study treatment errors must be documented in the study treatment log of the 
CRF. 
9.1.2 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 treatment 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. 
If the intensity of an AE with an onset date between informed consent signature and start 
of study treatment and which is ongoing at the start of treatment worsens after the start of 
study treatment, a new AE page must be completed. The onset date of this new AE 
corresponds to the date of worsening in intensity. 
The three 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. 


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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 9.3.1]. These 
terms are used to describe the intensity of a specific event. Medical judgment should be 
used on a case-by-case basis. 
Seriousness, rather than severity assessment, determines the regulatory reporting 
obligations. 
9.1.3 Relationship to study treatment 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment, and reported as either related or 
unrelated. The determination of the likelihood that the study treatment caused the AE will 
be provided by an investigator who is a qualified physician. 
9.1.4 Reporting of adverse events 
All AEs occurring after study start (i.e., signing of informed consent) and up to Visit 5 
(EOS) (30 ± 2 days after study treatment discontinuation) must be recorded on specific 
AE pages of the CRF except events described in Section 9.1.1 that are an exacerbation of 
the pre-existing disease. 
9.1.5 Follow-up of adverse events 
AEs still ongoing at Visit 5 (EOS) must be followed up until they are no longer 
considered clinically relevant. 
9.2 Serious adverse events 
9.2.1 Definition of 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. 


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• 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 hospitalization are exempted from being reported: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• Hospitalization for pre-planned (i.e., planned prior to signing informed consent) 
surgery or 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. 
However, complications that occur during hospitalization are AEs or SAEs (for example 
if a complication prolongs hospitalization). 
9.2.2 Reporting of serious adverse events 
All SAEs occurring after signing of informed consent up to Visit 5 (EOS) must be 
reported on AE pages in the CRF and on an SAE form, regardless of the 
investigator-attributed causal relationship with study treatment or study-mandated 
procedures. 
An SAE is defined as related to protocol-mandated procedures if it appears to have a 
reasonable possibility of a causal relationship to either the study design or to 
protocol-mandated procedures (e.g., discontinuation of a subject’s previous treatment 
during a washout period, leading to exacerbation of underlying disease). 
9.2.3 Follow-up of serious adverse events 
SAEs still ongoing at Visit 5 (EOS) must be followed up until resolution or stabilization, 
or until the event outcome is provided. The follow-up information obtained after the 
subject’s EOS visit / telephone call must be reported to Actelion Global Drug Safety, but 
it is not recorded in the CRF. 
9.2.4 After the 28 to 32-day Follow-up period 
New SAEs occurring after Visit 5 (EOS) must be reported to the Actelion drug safety 
department within 24 h of the investigator’s knowledge of the event, only if considered 
by the investigator to be causally related to previous exposure to the study treatment. 
9.2.5 Reporting procedures 
All SAEs must be reported by the investigator to Actelion Global Drug Safety within 
24 h of the investigator’s first knowledge of the event. 


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All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be 
related to study treatment. 
The SAE forms must be sent to Actelion Global Drug Safety (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 treatment. 
Any relevant information from source documents regarding the SAE, e.g., hospital notes 
or discharge summaries, etc., must be summarized on the SAE form. 
Follow-up information about a previously reported SAE must also be reported within 
24 h of receiving it. Actelion Global Drug Safety personnel may contact the investigator 
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. 
The expectedness of an adverse reaction is determined by Actelion in the reference safety 
information (RSI) section provided in the most recent version of the IB for cadazolid and 
for the comparator product, vancomycin, the RSI is its US Prescribing Information. Any 
SAE that is assessed as related and unexpected against the RSI is known as a SUSAR and 
must be reported by Actelion to concerned health authorities (including the 
EudraVigilance database if the study is conducted in Europe), IECs/IRBs and 
investigators. 
9.3 Pregnancy 
If a female subject becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the subject and subject’s parents or LAR(s) 
and discuss the risks of continuing with the pregnancy and the possible effects on the 
fetus. 
9.3.1 Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring after study 
start (i.e., signing of informed consent) up to 30 days following study treatment 
discontinuation must be reported within 24 h of the investigator’s knowledge of the 
event. 
Pregnancies must be reported on the Actelion Pregnancy form, which is faxed to Actelion 
Global Drug Safety (see contact details provided on the Actelion Pregnancy form), and 
on an AE page of the CRF. 


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9.3.2 Follow-up of pregnancy 
Any pregnancies must be followed to their conclusion and the outcome must be reported 
to Actelion Global Drug Safety. 
Any AE associated with the pregnancy occurring during the Follow-up period after study 
treatment discontinuation must be reported on separate AE pages in the CRF. Any SAE 
occurring during the pregnancy must be reported on an SAE form as described in 
Section 9.2.2. 
9.4 Study safety monitoring 
Clinical study safety information (AEs, SAEs, laboratory values, vital signs, and 
project-specific laboratories/examinations as required) is monitored and reviewed on a 
continuous basis by the sponsor (in charge of ensuring subjects’ safety as well as data 
quality). 
In addition, an IDMC is monitoring safety, PK and efficacy data on a regular basis [see 
Section 3.4]. 
10 STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by designated CRO 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. 
10.1 Analysis sets 
10.1.1 Screened Analysis Set 
The screened analysis set (SCRAS), includes all subjects who were screened and 
received a subject number. 
10.1.2 Full Analysis Set  
The Full Analysis Set (FAS) includes all enrolled subjects assigned to a study treatment, 
whether or not they have received study treatment. In order to adhere to the 
intention-to-treat principle as much as possible: 
Subjects are evaluated according to the study treatment they have been assigned to, which 
may be different from the study treatment they have received. 
All available data are included. 
Summaries will be prepared separately for subjects in Part A (FAS_A), and for subjects 
in Part B (FAS_B). 


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10.1.3 Modified ITT Analysis Set  
The mITT analysis set includes subjects in the FAS who have received at least one dose 
of study treatment and have a confirmed diagnosis of CDAD.  
Two sets including subjects from Part A or Part B will be identified respectively by 
mITT_A and mITT_B. 
Like for the FAS, subjects are evaluated according to the study treatment they have been 
assigned to, which may be different from the study treatment they have received. 
10.1.4 Per-protocol Analysis Set 
The Per-Protocol Analysis Set (PPS), pertaining to subjects in Part B alone, will be 
defined in the (SAP). 
Major protocol deviations or conditions which result in the exclusion of subjects from the 
PPS will be fully defined and documented. Full details of the reasons for exclusion from 
the PPS will be documented in the SAP. 
Subjects are evaluated according to the study treatment they have been assigned to. 
10.1.5 Safety Set 
The Safety Analysis Set (SS) includes all subjects enrolled in Part A and Part B who 
received at least one dose of study treatment. 
10.1.6 PK Sets 
Part A 
The plasma PK Set A (PKS_A) comprises all subjects treated with cadazolid included in 
the FAS_A who were able to provide, at least, evaluable pre-dose, 2 h, and 12 h 
post-dose samples.  
The stool PK Set A1 (PKS_A1) comprises all subjects treated with cadazolid included in 
the FAS_A who were able to provide an evaluable stool sample. 
Part B 
The plasma PK Set B (PKS_B) comprises all subjects treated with cadazolid included in 
the FAS_B who were able to provide an evaluable 2 h PK sample (± 1 h).  
The stool PK Set B1 (PKS_B1) comprises all subjects treated with cadazolid included in 
the FAS_B who were required and able to provide an evaluable stool sample. 
10.1.7 Usage of the analysis sets 
Subject disposition and study completion/discontinuation, including reason for screening 
failure, will be summarized using the SCRAS.  


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Protocol 
deviations, 
baseline 
demographic 
and 
disease 
characteristics, 
and 
previous/concomitant medications, will be summarized in the FAS_A and FAS_B. 
The statistical analysis of the efficacy variables CCR, SCR, and recurrence will be 
performed on the mITT_A, miTT_B and the PPS_B. 
All remaining efficacy variables will be analyzed on the mITT_B analysis set only.  
All analyses of PK data will be performed on the PKS_A or PKS_A1 in Part A and on 
PKS_B and PKS_B1 (if applicable) in Part B. 
Summaries of safety parameters will be performed on the SS. 
Listings will be prepared on the FAS_A and FAS_B, unless otherwise specified.  
10.2 Variables 
For efficacy and safety variables, unless otherwise specified, the baseline value is the last 
valid assessment obtained prior to start of study treatment intake. 
10.2.1 Efficacy variable(s) 
The following efficacy variables will be analyzed in Part A and in Part B: 
10.2.1.1 Clinical Cure  
Clinical Cure Rate (CCR; %) is the variable to be analyzed for the primary endpoint 
Clinical Cure, as defined in Section 6.1.1. CCR (%) is the percentage of subjects assessed 
as meeting the criteria for Clinical Cure as assessed by the investigator / blinded efficacy 
assessor up to EOT + 2 days. 
CCR (%) is derived as: 
൤𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑢𝑢𝑢𝑢 𝑡𝑡𝑡𝑡 𝐸𝐸𝐸𝐸𝐸𝐸+ 2 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑠𝑠𝑠𝑠𝑠𝑠
൨ × 100 
Subjects without investigator assessment of Clinical Cure are considered to have Clinical 
Failure as defined in Section 6.1.1.2. 
10.2.1.2 Recurrence 
RR (%) is the variable to be analyzed for the endpoint Recurrence as defined in 
Section 6.1.2.1. RR(%) is the percentage of subjects experiencing a recurrence, as 
assessed by the investigator / blinded efficacy assessor up to EOS. The denominator for 
this variable is the number of of subjects meeting the criteria for Clinical Cure up to EOT 
+ 2 days.  
RR(%) is calculated as: 


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൤
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑎𝑎 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑢𝑢𝑢𝑢 𝑡𝑡𝑡𝑡 𝐸𝐸𝐸𝐸𝐸𝐸
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑙𝑙𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑢𝑢𝑢𝑢 𝑡𝑡𝑡𝑡 𝐸𝐸𝐸𝐸𝐸𝐸+ 2 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑൨ × 100 
 
10.2.1.3 Sustained Clinical Cure 
Sustained Clinical Cure Rate (SCR; %) is the variable to be analyzed for the endpoint 
Sustained Clinical Cure as defined in Section 6.1.2.2. SCR(%) is the percentage of 
subjects assessed as meeting the criteria for Sustained Clinical Cure as assessed by the 
investigator / blinded efficacy assessor up to EOS.  
SCR% is calculated as: 
൤𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑢𝑢𝑢𝑢 𝑡𝑡𝑡𝑡 𝐸𝐸𝐸𝐸𝐸𝐸
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑠𝑠𝑠𝑠𝑠𝑠
൨ × 100 
Subjects with Clinical Failure, or with Clinical Cure and Recurrence, are considered to be 
without Sustained Cure. 
10.2.1.4 Time to Recurrence  
Time to recurrence is the variable to be analysed for the endpoint time to recurrence and 
is defined for subjects meeting the criteria of recurrence as defined in Section 6.1.2.3. 
Time to first recurrence in days, is calculated as: 
[𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟−𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡+ 1] 
or, for censored subjects, as: 
[𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 −𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡+ 1]. 
Subjects considered as sustained clinical cure without establishment of recurrence or 
death, are censored at their date of EOS. Subjects who died after EOT + 3 days are 
censored at the date of death. Subjects who are lost to follow-up without an EOS visit are 
censored at the date of last contact.  
Subjects not clinically cured and therefore not at risk for a recurrence are not considered 
for this endpoint. 
10.2.1.5 Time to Resolution of Diarrhea 
Time to ROD is the variable to be analysed for the endpoint time to ROD and is defined 
for subjects meeting the criteria of ROD as defined in Section 6.1.2.4. 
Time to ROD in days, is calculated as: 
[𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑅𝑅𝑅𝑅𝑅𝑅−𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡+ 1] 


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or, for censored subjects, as: 
[𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 −𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡+ 1]. 
Subjects without ROD are censored at EOT + 2 days. Subjects who died prior to EOT 
+ 2 days are censored at the date of death. Subjects who are lost to follow-up prior to 
EOT + 2 days are censored at the date of last contact. 
10.2.1.6 Other efficacy variables 
10.2.1.6.1 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 
EOT. 
• In case of Recurrence as the maximum MIC of C. difficile in fecal samples collected 
at any NED visit. 
10.2.1.6.2 Change from baseline in susceptibility of C. difficile 
Fold change from baseline in susceptibility of C. difficile is the variable to be analyzed 
for the endpoint change from baseline in susceptibility of C. difficile isolates as defined in 
Section 6.1.3.1. This variable is derived only in subjects with Clinical Failure or 
Recurrence.  
The fold change from baseline is derived as: 
൤MIC at 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏
MIC 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏
൨ 
and is categorized as: 
• ≥ 4 fold decrease,  
• 2-fold decrease,  
• no change,  
• 2-fold increase, or  
• ≥ 4-fold increase. 


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10.2.1.6.3 Change from baseline in VRE count  
Fold change from baseline in VRE count is the variable to be analyzed for the endpoint 
change from baseline in VRE count as defined in section 6.1.3.2. This variable is derived 
for all subjects up to EOT. 
The fold change from baseline is derived as: 
൤VRE count at EOT
VRE at 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏൨ 
 
10.2.1.7 Susceptibility of VRE 
Fold change from baseline in susceptibility of VRE is the variable to be analyzed for the 
endpoint change from baseline in susceptibility of VRE as defined in section 6.1.3.3. This 
variable is derived for all subjects up to EOT. 
The fold change from baseline is derived as: 
൤
MIC 𝑎𝑎𝑎𝑎 𝐸𝐸𝐸𝐸𝐸𝐸
MIC 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏൨ 
 
The proportion of subjects experiencing a ≥ 4-fold increase will be calculated. 
10.2.1.8 Change in intestinal flora composition from baseline up to EOS 
Change from baseline to EOS in intestinal flora composition will be derived for intestinal 
flora components including Lactobacilli and Bifidobacterium and is the variable for the 
analysis of the endpoint, change from baseline to EOS in intestinal flora. 
10.2.2 Safety variables 
The following safety variables will be analyzed during all study periods: AEs, SAEs 
deaths, vital signs, body temperature, laboratory variables, and concomitant medications. 
A treatment-emergent AE is any AE temporally associated with the use of study 
treatment from study treatment initiation up to 7 days after study treatment 
discontinuation. 
• Deaths, AEs and SAEs up to EOS. 
• Treatment-emergent AEs and SAEs up to 7 days after EOT. 
• AEs leading to premature discontinuation of study treatment. 
• Change from baseline up to 7 days after EOT in vital signs (SBP, DBP, and HR), 
body temperature and body weight. 


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• Change from baseline up to 7 days after EOT in hematology, and blood chemistry 
laboratory parameters measured in Standardized International (SI) units. 
• Marked abnormalities in vital signs (SBP and DBP) up to 7 days after EOT 
(treatment-emergent). 
• Marked abnormalities in hematology, and blood chemistry up to 7 days after EOT as 
measured in SI units (treatment-emergent).  
If laboratory values are received in a different unit, they will be converted to SI units. 
10.2.3 PK variables 
Part A 
The following endpoints will be derived by non-compartmental analysis of plasma 
concentration-time profiles obtained at Visit 3: Cmax, tmax, and AUCτ. 
Fecal drug concentration at Visit 3. 
Part B 
Cadazolid plasma concentration (ng/mL) 2 h post-dose and fecal concentration (if 
applicable) at Visit 3. 
10.2.4 Other variables 
10.2.4.1 Treatment exposure and compliance 
• Treatment exposure for cadazolid and vancomycin will be described in terms of 
duration in days. The duration of exposure is defined as the time elapsing between 
study treatment initiation and discontinuation, inclusive. 
• The mean daily dose per subject is defined as the ratio between the total study 
treatment dose taken and the total exposure time. 
• Compliance, in percent, is defined as number of doses taken divided by expected 
number of doses during the treatment period. 
10.2.4.2 Demographic variables 
• Country 
• Sex 
• Age categories 
• BMI 
• Race and Ethnicity 
10.2.4.3 Baseline disease characteristics 
• In-patient or out-patient. 
• First occurrence or first recurrence. 


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• MTF (yes/no). 
• Number of bowel movements, including UBM within 24 h during the screening 
period that qualified the subject for enrolment. 
• C. difficile strain based on molecular testing. 
10.2.4.4 Palatability and acceptability  
Palatability of cadazolid and vancomycin formulations at Day 1 and at Visit 3 assessed 
on a 5-point facial hedonic scale. 
Acceptability of cadazolid and vancomycin formulations at Day 1 and at Visit 3 assessed 
on a 3-point categorical scale. 
10.3 Description of statistical analyses 
10.3.1 Overall testing strategy 
This is a study to evaluate PK, safety, and efficacy. As no formal statistical testing is 
applied, there is no overall testing strategy. Descriptive statistics will be used to 
summarize the PK, safety, and efficacy study endpoint variables.  
Analysis of safety variables will be performed on a pooling of subjects from Part A and 
Part B. 
For the analyses conducted using data from Part A, the results will be presented by age 
cohort, unless otherwise specified.  
Any statistical tests done on efficacy variables will be conducted for exploratory 
purposes. Differences between treatment arms in Part B will be estimated and presented 
with corresponding 95% CLs. 
• SAS version 9.3 or higher will be used for all the statistical analyses.  
• 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, number of subjects at risk, 
and Kaplan-Meier estimates of the survival function 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 


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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. 
Absolute changes from baseline are defined as: post-baseline value minus baseline value, 
such that a positive sign indicates an increase as compared to baseline. 
All listings will be prepared on the FAS. 
10.3.2 Analysis of efficacy variables 
10.3.2.1 Hypotheses and statistical model 
Not applicable.  
10.3.2.2 Handling of 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 imputation 
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,without imputation 
of missing values; exceptions to this rule for the most important variables are described in 
Section 10.3.2.2.1 and Section 10.3.2.2.2. 
10.3.2.2.1 Clinical Cure 
In the event of death, study withdrawal, loss to follow-up, or missing investigator / 
blinded efficacy assessor assessment of Clinical Cure up to EOT + 2 days, the subject is 
considered to have experienced a Clinical Failure.  
10.3.2.2.2 Sustained Clinical Cure 
In the event of death, study withdrawal, loss to follow-up, or missing investigator / 
blinded efficacy assessor assessment of SCR during the period from EOT + 3 days up to 
EOS the subject is not considered to have experienced a SCR. 
10.3.2.3 Main analysis  
The statistical analysis of efficacy variables will be performed on the analysis datasets as 
described in section 10.1.7. 
The CCR, Recurrence rate, and SCR variables will be summarized by treatment group, 
presenting the percentage of subjects experiencing the event along with the 


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corresponding 95% 2-sided confidence limits (CLs), estimated using the Wilson’s Score 
method [Newcombe 1998]. 
10.3.2.3.1 Part B analyses: 
The treatment difference between cadazolid and vancomycin for CCR, Recurrence, and 
SCR will be summarized, presenting the difference in proportions of subjects 
experiencing the event along with corresponding 2-sided 95% CLs, estimated using the 
Wilson’s Score method [Newcombe 1998]. 
Time to Recurrence and Time to ROD will be estimated by treatment group on the 
mITT_B analysis set using the Kaplan-Meier method. Time to Recurrence and Time to 
ROD will be will be analyzed using Kaplan-Meier estimates along with 95% 2-sided CLs 
at relevant timepoints for each treatment group in both graphical and tabular form. In 
addition, the number of subjects with event, the number of subjects at risk, and the 
number of subjects censored will be computed at each timepoint for each group. The 
difference in treatments will be tested by means of the log-rank test comparing cadazolid 
versus vancomycin for each time to event endpoint.  
Graphical displays of time-to-event variables using Kaplan-Meier survival curves will be 
produced. 
10.3.2.4 Subgroup analyses 
Consistency of results on CCR and in SCR will be explored over different subgroups 
defined by anthropometric and baseline characteristics: first occurrence and first 
recurrence, sex, race, age category, in-patient status, and initial strain of CDAD 
(hypervirulent or not). 
10.3.2.5 Analysis of the other efficacy variables 
Susceptibility of C. difficile isolates test results in (MIC in µg/mL) at baseline and 
post-baseline visits will be summarized by treatment group using descriptive statistics on 
MIC range, MIC50, MIC90, and the frequency of isolates at each MIC test concentration 
for each test agent. 
Changes from baseline in susceptibility will be summarized by treatment group in 
subjects with Clinical Failure or Recurrence. Frequency and percent of subjects with 
≥ 4-fold decrease, 2-fold decrease, no change, 2-fold increase or ≥ 4-fold increase will be 
presented. 
VRE counts at baseline and up to EOT, as well as changes from baseline up to EOT in 
difference of VRE counts, will be summarized using descriptive statistics. 


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Susceptibility test results of VRE to a panel of antibiotics including cadazolid and 
vancomycin will be summarized by treatment group for each test agent with descriptive 
statistics including MIC range, MIC50, MIC90. 
10.3.3 Analysis of the safety variable(s) 
10.3.3.1 Adverse events 
The SS will be used to summarize the safety variables on the pooled subject data from 
Part A and Part B. 
All AEs and SAEs will be coded using the MedDRA dictionary version 18 or higher. 
All AEs will be listed by treatment group, age cohort, and subject in chronological order 
(using onset date). Similarly, all SAEs, as well as all AEs leading to discontinuation of 
study treatment and those leading to death, will be listed separately. The listings will also 
include the date of starting study, the number of days from the start of study treatment to 
the onset date (also known as “relative onset day”; relative days in general are associated 
with an assessment or event date, expressed using “days” as a unit). 
Treatment-emergent AEs and treatment-emergent SAEs up to 7 days after EOT will be 
tabulated by system organ class (SOC), and individual preferred terms within each SOC. 
The incidence of subjects who experienced AEs coded with the same preferred term will 
be tabulated by treatment group. AEs will also be tabulated by maximum intensity and by 
relationship to study treatment.  
AEs leading to permanent discontinuation of study treatment will be summarized by SOC 
and individual preferred terms within each SOC. 
AEs and SAEs from first dose up to Visit 5 (EOS) will be summarized in a similar 
manner to that used for treatment-emergent AEs. 
10.3.3.2 Deaths  
The primary reason for death as reported in the Death CRF will be listed and summarized 
in a frequency table, per treatment group.  
10.3.3.3 Vital signs, body weight, and body temperature 
Descriptive summary statistics by visit and treatment group will be provided for observed 
values and absolute changes from baseline at Visit 3 in SBP, DBP, HR, body 
temperature, and body weight. The number of subjects with at least one marked 
abnormality up to EOT + 7 days will be summarized. 
10.3.3.4 Laboratory values 
Statistical analysis of laboratory values will be performed on SI units. Observed values 
and absolute changes from baseline up to EOT + 7 days will be summarized by visit and 


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treatment group using descriptive statistics. 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 will be summarized for each laboratory variable by 
treatment group. Treatment-emergent laboratory test abnormalities will be assessed 
according to the normal ranges. 
10.3.3.5 Treatment exposure and compliance 
All tabulations and listings of exposure to, and compliance with study medication will be 
generated by treatment group and type of study treatment (capsules or sachets). The 
duration of exposure will be summarized using descriptive statistics.  
Compliance will be summarized by treatment group using descriptive statistics. Percent 
compliance and overall mean daily dose will be summarized both continuously and 
categorically by reporting the number and percent of subjects with < 80%, 80–120%, 
> 120%, and indeterminate compliance. Subjects whose compliance cannot be 
determined will be flagged in the listings. 
10.3.4 Analysis of PK parameters 
10.3.4.1 Part A  
PK endpoints: the PKS_A and PKS_A1 will be used for plasma and fecal samples 
analysis, respectively. 
Concentration-time data of cadazolid in plasma: 
• Individual concentration-time data will be listed by age group, dose, subject, and 
time. 
• Concentration-time data will be summarized by dose presenting the number of 
observations, arithmetic mean, median, minimum, maximum, SD, standard error 
(SE), % coefficient of variation (%CV), and 95% CI of the arithmetic mean. 
Cadazolid fecal concentrations (when applicable): 
• Individual fecal concentration will be listed by age group, dose and subject. 
• Fecal concentrations will be summarized by dose presenting the number of 
observations, arithmetic mean, geometric mean, median, minimum, maximum, SD, 
SE, %CV, 95% CI of the arithmetic and the geometric means, and the fold over 
MIC90 for the geometric mean and for the observed minimum. 
Derived plasma PK parameters of cadazolid. 
• Individual PK parameters (Cmax, tmax, and AUCτ) will be listed by dose and by 
subject. 


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• Cmax, tmax*, and AUCτ will be summarized by dose with arithmetic mean, geometric 
mean, minimum, median, maximum, SD, SE, %CV, and 95% CI of the arithmetic 
and geometric means. 
(*For tmax the geometric mean and its 95% CI will not be calculated).  
10.3.4.2 Part B 
PK endpoint: for cadazolid plasma concentration: The PKS_B will be used. 
Cadazolid plasma concentrations: 
• Individual concentration at 2 h will be listed by dose and by subject. 
• Concentrations at 2 h will be summarized by dose presenting the number of 
observations, arithmetic mean, geometric mean, median, minimum, maximum, SD, 
SE, %CV, and 95% CI of the arithmetic and the geometric means. 
Fecal concentrations will be listed and summarized as for Part A if applicable. The 
PKS_B1 will be used. 
10.3.5 Analysis of other variable(s) 
10.3.5.1 Subject disposition 
A detailed description of subject disposition will be provided for all subjects. It will 
include a summary (number and percentage) of subjects screened and undergoing 
enrolment or randomization, with the latter, for Part B, divided into the cadazolid and 
vancomycin treatment groups to which they were randomized. The number of subjects by 
treatment group continuing and discontinuing treatment and study, along with reasons for 
discontinuations will be displayed along with the number of subjects completing the 
study in each treatment group. 
The number and percent of patients included in and excluded from each analysis set, 
based on the set definitions in Section 10.1, will be summarized in tables and listings, and 
will be supported by a summary table of protocol deviations leading to exclusion from 
each analysis set based on the number of subjects in the FAS_B. 
10.3.5.2 Demographic characteristics 
Demographic and baseline characteristic variables: age, sex, race, ethnicity, height, 
weight, and region will be summarized per treatment group and overall.  
10.3.5.3 Baseline disease characteristics  
The baseline CDAD characteristics In-patient / out-patient, first recurrence/occurrence, 
initial strain hypervirulent or not, MTF (yes/no), number of bowel movements, and 
C. difficile strain based on molecular testing will be summarized by treatment group and 
overall. 


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10.3.5.4 Previous and concomitant medications  
Previous and concomitant medications will be coded according to the WHO drug code 
and the Anatomical Therapeutic Chemical class code and will be summarized by 
treatment group, class code, and preferred term for previous and study-concomitant 
medications with the number and percentages of subjects having received each treatment. 
Listings of Concomitant medications will be presented including drug name, start of 
administration, end of administration, dosages administered, and route of administration.  
10.3.5.5 Medical history 
Medical history will be coded using MedDRA and summarized in a similar manner to 
AEs. 
10.3.5.6 Protocol deviations 
Protocol deviations will be listed and summarized per treatment in Part A and Part B. 
10.3.5.7 Palatability and acceptability 
Palatability of cadazolid and vancomycin formulations at Day 1 and at EOT assessed on a 
5-point hedonic facial scale will be summarized by treatment with counts and 
percentages. 
Acceptability of cadazolid and vancomycin formulations at Day 1 and at EOT assessed 
on a 3-point categorical scale will be summarized by treatment arms with counts and 
percentages. 
10.4 Interim analyses 
Not applicable. 
10.5 Sample size 
10.5.1 Sample size justification 
Approximately 156 pediatric subjects will be treated with cadazolid at the proposed 
duration of treatment, 24 in Part A and 132 in Part B. Assuming that systemic absorption 
in children is as low as in adults, a database of approximately 156 pediatric subjects is 
adequate to characterize the safety profile of cadazolid, including gastrointestinal 
tolerability side effects that are the most likely with a non-absorbed medication and 
which occurred at a rate of approximately 4–5% in the adult Phase 2 study. Assuming 
that a treatment-emergent AE is not observed, there is 95% confidence that the upper 
bound of the true rate is at most 2%.  
Part A will include at least 24 subjects treated with cadazolid, which is a number 
considered sufficient to evaluate PK and safety in a dose level cohort. 


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Part B will include approximately 132 subjects treated with cadazolid and 44 treated with 
vancomycin (randomization ratio 3:1).  
11 DATA HANDLING 
11.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy and completeness, of 
the data reported and ensures that it is entered in a timely manner. All source documents 
should be completed in a neat, legible manner to ensure accurate interpretation of the 
data. Data reported in the CRF derived from source documents must be consistent with 
the source documents. 
Electronic CRF data will be captured via electronic data capture. 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). 
For each subject screened, regardless of study treatment initiation, a CRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects 
who fail to complete the study.  
11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On CRFs or 
other documents (e.g., documents attached to SAE reports) submitted to Actelion and any 
external service providers, subjects must be identified only by number, and never by 
name or initials, hospital numbers, or any other identifier. The investigator/delegate must 
keep a subject identification code list, at the site, showing the subject 
screening/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. 
11.3 Database management and quality control 
The investigator will have access to the site CRF data until the database is locked. 
Thereafter, they will have read-only access. The CRF must be kept current to reflect 
subject status at any time point during the course of the study. 
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by Actelion 
on an ongoing basis including but not limited to looking for unexpected patterns in data 


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and study monitoring. If discrepant data are detected, a query specifying the problem and 
requesting clarification will be issued and visible to the investigator/delegate via the 
CRF. All electronic queries visible in the system either require a data correction (when 
applicable) or a response from the investigator/delegate to clarify the queried data. 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 event 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. 
Fecal and blood samples will be processed through a central laboratory and the results 
will be sent electronically to Actelion. 
After the database has been declared complete and accurate, the database will be locked. 
Any changes to the database after that time may only be made as described in the 
appropriate SOP. After database lock, the investigator will receive the CRFs of the 
subjects of her/his site on electronic media or as a paper copy. 
12 PROCEDURES AND GOOD CLINICAL PRACTICE 
12.1 Ethics and Good Clinical Practice 
Actelion and the investigators will ensure that the study is conducted in full compliance 
with ICH Good Clinical Practice (GCP) Guidelines, the principles of the “Declaration of 
Helsinki”, and with the laws and regulations of the country in which the research is 
conducted. 
12.2 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 
Institutional Review Board (IRB) or independent Ethics Committee (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 or subject information leaflet 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 12.6]. 
A list of members participating in the IRB/IEC meetings 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 


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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. 
12.3 Informed consent 
It is the responsibility of the investigator to obtain informed consent and assent by the 
child according to local requirements according to GCP and local regulations from each 
individual participating in this study, after adequate explanation of the aims, methods, 
objectives and potential hazards of the study. 
The investigator must also explain to the parent(s)/LAR(s) and the subjects that they are 
completely free to refuse to enter the study, or to withdraw from it at any time for any 
reason. Appropriate forms for documenting informed consent and assent will be provided 
to the sites prior to the study. 
The ICF and Subject Information Leaflet will be provided in the local language. 
Site staff authorized to participate to the consent process and/or to obtain consent from 
the subject’s parent(s) or LAR(s) will be listed on Actelion Delegation of Authority form. 
A study physician must always be involved in the consent process. 
The subject’s parent(s) or LAR(s) must sign, personally date, and time (if appropriate) 
the ICF before any study-related procedures (i.e., any procedures required by the 
protocol) begin. The ICF must also be signed, personally dated, and timed (if the first 
study-mandated procedure was performed on the same day informed consent was 
obtained) by the authorized site staff listed on Actelion Delegation of Authority form. 
A copy of the signed and dated assent and ICF is given to the subject and subject’s 
parent(s) or LAR(s); the original is filed in the site documentation. The informed consent 
process must be fully documented in the subject’s medical records. This must include the 
study reference, the subject number, the date and, if applicable, time when the subject 
was first introduced to the Actelion clinical study, the date and, if applicable, time 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), a 
copy of the signed assent and ICF given to the subject or parent(s)/LAR(s). 
12.4 Compensation to subjects and investigators 
Actelion 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’s parent(s) or LAR(s) in the event of study-related 
injuries will comply with applicable regulations. 


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12.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the approved version of the 
protocol and must not implement any deviation/change from the protocol, except when 
deviation is necessary to eliminate an immediate hazard to the subject. 
If a protocol deviation occurs, the investigator/delegate will inform Actelion or its 
representative, in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. Deviations considered to be a violation of 
GCP must be reported to the IRB/IEC and regulatory authorities according to Actelion or 
(overruling) local requirements. 
12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. A 
protocol amendment must be submitted to IRB/IEC and regulatory authorities, according 
to their requirements. 
12.7 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 
site file (ISF) 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 (i.e., 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 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. 
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 and restricted 
access to study subjects only, to verify consistency between electronic source data and 
the CRF during monitoring visits. 


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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 printouts will be considered as the 
official clinical study records and must be filed either with the subject medical records or 
with the subject’s CRF. 
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 Actelion’s instructions. If it were not possible 
for the monitor to observe this process, it would not be possible to rely on the site’s 
certified copies and therefore the site cannot be selected for the clinical study. 
12.8 Monitoring 
Prior to study start, a site initiation visit (SIV) will be performed after the required 
essential study documents are approved by Actelion. The study treatment will be shipped 
to the site upon approval of the required essential documents. 
The PI must ensure that all site personnel involved in the study are present during the SIV 
and will dedicate enough time to it. Site Information Technology support should also be 
available during the initiation visit. 
The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter 
will be provided to the PI and filed in the ISF. 
During the study, the monitor will contact and visit the site regularly and must be 
permitted, on request, to have access to study facilities and all source documents needed 
to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered in the CRFs and other protocol-related documents. Actelion 
monitoring standards require full verification that informed consent has been provided, 
verification of adherence to the inclusion/exclusion criteria, documentation of SAEs, and 
the recording of the main efficacy, safety, and tolerability endpoints. Additional checks 
of the consistency of the source data with the CRFs will be performed according to the 
study-specific monitoring plan. The frequency of the monitoring visits will be based on 
subject recruitment rate and critical data collection times. 


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The PI must ensure that the CRF is completed after a subject’s visit (site visit or 
telephone call), and that all requested subject files (e.g., ICFs, medical notes/charts, and 
other documentation verifying the activities conducted for the study) are available for 
review by the monitor. The required site personnel must be available during monitoring 
visits and allow adequate time to meet with the monitor to discuss study related issues. 
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, in accordance with local regulations. 
A close-out visit will be performed for any initiated site when there are no more active 
subjects and all follow-up issues have been resolved. In case a site does not enroll any 
subjects, the close-out visit may be performed prior to study database closure at the 
discretion of Actelion. 
12.9 Investigator site file 
Each site will be provided with an ISF prior to the initiation visit. It will contain all the 
essential documents that are required to always be up-to-date and filed at site as per ICH 
E6 GCP section 8. 
The ISF will include a table of content listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the monitor regarding the filing of the 
study documents outside the ISF. It should be clearly documented where each document 
is filed. This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP, as well as instructions from Actelion. If the site needs to transfer 
the ISF to another location and/or if site facility can no longer store the ISF, the PI must 
inform Actelion immediately. 
If the PI will change, or if the site will relocate, the monitor must be notified as soon as 
possible. 
12.10 Audit 
Actelion’s Global Quality Management representatives 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, and applicable regulations; 
adherence to Actelion’s requirements (e.g., SOPs) will also be verified. Prior to initiating 
this audit, the investigator will be contacted by Actelion to arrange a time for the audit. 


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The investigator and staff must cooperate with the auditor(s) and allow access to all study 
documentation (e.g., subject records) and facilities. 
12.11 Inspections 
Health authorities and/or IRB/IEC may also conduct an inspection of Actelion’s clinical 
study (during the study or after its completion). 
Should an inspection be announced 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. 
12.12 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 (or PI for single-center studies). 
The coordinating investigator and the Steering Committee, if any, will have the 
opportunity to review the analysis of the data and to discuss the interpretation of the 
study results with Actelion prior to publication. 
Actelion will post results from the clinical study on Actelion’s Clinical Trial Register and 
on external/national registries, as required by local 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. 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 (ICMJE) criteria, and be based on: 
• substantial contributions to the conception or design of the study, or the acquisition, 
analysis, or interpretation of data; and 
• drafting of the publication or critical review for important intellectual content; and 
• providing final approval of the version to be published; and 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
The list of authors of any publication of study results may include representatives of 
Actelion and will be determined by mutual agreement. 


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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 policies on Scientific Publications and Disclosure of Clinical Research 
information can be found at:  
 


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13 REFERENCES 
[Bauer 2009] Bauer MP, Kuijper EJ, van Dissel JT. European Society of Clinical 
Microbiology and Infectious Diseases (ESCMID): treatment guidance document for 
Clostridium difficile infection (CDI). Clin Microbiol Infect. 2009;15(12): 
1067-79. 
[Bhangu 2012] Bhangu A, Nepogodiev D, Gupta A, Torrance A, Singh P. Systematic 
review and meta-analysis of outcomes following emergency surgery for 
Clostridium difﬁcile colitis. British Journal of Surgery 2012;99:1501-13. 
[Bryant 2009] Bryant K, McDonald L. Clostridium difficile infections in children. Pediatr 
Infect Dis J. 2009;28:145-46. 
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Investigator’s 
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cadazolid, 
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[Cerquetti 1995] Cerquetti M, Luzzi I, Caprioli A, Sebastianelli A, Mastrantonio P. Role 
of Clostridium difficile in childhood diarrhoea. Pediatr Infect Dis J. 1995;14: 
598-603. 
[Ciccarelli 2013] Ciccarelli S, Stolfi I, Caramia G. Management strategies in the 
treatment of neonatal and pediatric gastroenteritis. Infection and Drug Resistance 
2013;6:133-161. 
[Cohen 2010] Cohen SH, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for 
Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare 
Epidemiology of America (SHEA) and the Infectious Diseases Society of America 
(IDSA): SHEA-IDSA Guideline: Infection Control and Hospital Epidemiology 
2010;31(5). 
[Cornely 2012] Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, et 
al. Fidaxomicin versus vancomycin for infection with Clostridium diﬃcile in 
Europe, Canada, and the USA: a double-blind, non-inferiority, randomised 
controlled trial. Lancet Infect Dis. 2012;12:281-89. 
[Crews 2015] Crews J. Clostridium difficile infection in children: Treatment and 
outcome. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA (Accessed on Jul 
2, 2015). 
[Dallal 2002] Dallal RM, Harbrecht BG, Boujoukas AJ, Sirio CA, Farkas LM, Lee KL, 
et al. Fulminant Clostridium difﬁcile: An Underappreciated and Increasing Cause of 
Death and Complications. Annals Of Surgery 2002;235(3):363-372.  


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Cadazolid / ACT-179811 
Clostridium difficile-associated diarrhea 
Protocol AC-061A303 
Final Version 4 
1 March 2017, page 117/117 
Confidential 
EudraCT 2015-004805-17 
Doc No D-17.162 
 
14 APPENDICES 
Appendix 1 
Equivalence between opiates 
Drug 
Equianalgesic dose 
Interval (h) 
 
Oral (mg) 
IV (mg) 
 
Morphine 
30 
10 
3–4 (PO, SL) 2–4 (IV, 
SQ) 
Hydromorphone 
6–8 
1.5–2 
3–4 (PO, SL) 2–4 (IV, 
SQ) 
Oxycodone 
15–20 
N/A 
3–4 (PO) 
Fentanyl 
N/A 
0.1 (100 mcg) 
0.5 (IV, SQ) 
 
Methadone 
See methadone conversion table 
4 (first 2–3 doses) then  
8–12 (PO, SQ, IV, SL) 
 
IV = intravenously; N/A = not applicable; PO  = orally; SL = sublingual; SQ = subcutaneous. 
Equianalgesic Conversion to Methadone 
Oral morphine equivalent 
               Mg of                                                 Mg of oral    
        oral methadone                 =                       morphine 
 
     ratio 
< 100 mg/day 
1 
3–4 
100–200 mg/day 
1 
5–8 
301–600 mg/day 
1 
10 
601–800 mg/day 
1 
12 
801–1000 mg/day 
1 
15 
> 1000 g/day 
1 
20 
IV methadone is twice as potent as oral methadone 
IV = intravenously. 
[Dana Farber Cancer Institute 2011] 
[Macintyre 2001]