Clinical trial NCT03595553
Conditions: Clostridioides Difficile Infection
Keywords: Clostridioides difficile Clostridium difficile C. difficile C. diff
Sponsor: Summit Therapeutics
Start date: 2019-01-28; Completion date: 2021-11-17
Enrollment: 759 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Summit is developing ridinilazole as a novel antimicrobial for Clostridioides difficile Infection (CDI), formerly known as Clostridium difficile Infection, with the goal of demonstrating an improved Sustained Clinical Response rate in subjects treated with ridinilazole as compared to subjects treated with vancomycin.

A phase 2 proof of concept study, with vancomycin as comparator, demonstrated these attributes with a comparable safety profile. A high fecal concentration of ridinilazole and little systemic exposure were noted.

The rationale for this phase 3 study is to confirm the improvement in sustained clinical response of CDI over vancomycin and to compare the safety and tolerability of ridinilazole to that of vancomycin.

Ridinilazole plasma concentration will be assessed in a subset of patients.

Detailed description:

Arms: arm 1: ridinilazole 200mg bid arm 2: vancomycin 125 mg qid
Interventions: intervention 1: Ridinilazole intervention 2: Vancomycin
Intervention descriptions: intervention 1: ridinilazole (200 mg bid) intervention 2: vancomycin (125 mg qid)

Protocol documents:
Prot_000.pdf: 
Study Number: SMT19969/C004 
Compound No: SMT19969 
Version 9.0; 09Aug2021  
CO-007-B-03  Ref: SOP-CO-007-03 
CONFIDENTIAL 
 Page 1 of 94 
 
 
Protocol Title: A Phase 3, randomized, double-blind, active controlled study to compare 
the efficacy and safety of ridinilazole (200 mg, bid) for 10 days with vancomycin (125 mg, 
qid) for 10 days in the treatment of Clostridium difficile infection (CDI). 
Protocol Number: SMT19969/C004 
Protocol Amendment Number: 8 
Version: 9 
Compound Number: SMT19969 
Short Title: Comparison of ridinilazole versus vancomycin treatment for Clostridium 
difficile infection 
Sponsor Approval Date: 09 August 2021 
Regulatory Agency Identifying Number(s): IND No: 119626 
EudraCT: 2017-001641-27 
Sponsor Name and Legal Registered Address:  
Summit Therapeutics Inc. 
One Broadway 
14th Floor 
Cambridge, MA 02142 
USA 
 
Summit (Oxford) Limited 
136A Eastern Avenue 
Milton Park 
Abingdon 
OX14 4SB 
United Kingdom 
 
 
 
 
 
 
The information contained in this document is the property of Summit (Oxford) Limited and may not be 
produced, published or disclosed to others without written authorization from Summit (Oxford) Limited. Summit 
(Oxford) Limited is a wholly owned subsidiary of Summit Therapeutics plc. 


Study Number: SMT19969/C004 
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Sponsor Signatory 
 
Priyanka Mandava 
Vice President, Global Clinical Operations 
Head of Clinical Operations 
Date 
Annie Hung, MA 
Executive Director, Biostatistics 
Study Statistician 
Date 
Camilla Graham, MD, MPH 
Head of Clinical Affairs  
Interim Global Head of Clinical Development 
Date 
Medical Monitor Contact Information can be found in the Investigator Trial Site File. 
Priyanka Mandava (Aug 9, 2021 14:29 PDT)
Priyanka Mandava
Annie Hung (Aug 9, 2021 15:41 PDT)
Camilla Graham (Aug 9, 2021 20:07 EDT)


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Investigator Signature Page 
I agree to conduct this Study in accordance with the requirements of this document (the Clinical 
Study Protocol), the Study Reference Manual and in accordance with the following:  
• Declaration of Helsinki (revised version of Edinburgh, Scotland, 2000, Note of 
Clarification on Paragraph 29 added by the World Medical Association General Assembly, 
Washington 2002). 
• INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL 
REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE (ICH): Guideline 
for GCP E6 (R2)  
• Any amendments to these regulations  
• Local laws and regulations. 
 
Investigator Name and Qualifications: _____________________________________ 
 
 
 
 
Investigator Signature 
 
Date 
[Investigator Affiliation] 
 
 
 


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Protocol Amendment Summary of Changes Table 
Note: Please refer to separate rationale of changes document for full explanation of and 
justification for protocol updates.  
DOCUMENT HISTORY 
Document 
Date 
Original Protocol Version 1.0 (not submitted to any Competent Authority or 
EC/IRB) 
28 SEP 2017  
Amendment 1; Protocol Version 2.0  
• 
Removal of a blinded data review 
• 
Exclusion of patients with a colostomy or ileostomy or likely requirement of 
an ostomy during the study 
• 
Various clarifications and minor amendments 
26 OCT 2017 
Amendment 2; Protocol Version 3.0 
• 
Allowance of sites to use a regulatory approved, Sponsor agreed, local free 
toxin test as an alternative to a Sponsor provided specific test  
• 
Requirement for the free toxin test to be conducted as soon as possible and 
no later than 48 h after a suspected recurrence is identified  
• 
Clarification that in the event of a suspected recurrence, the result of a free 
toxin test should be available to determine whether CDI treatment is 
required 
• 
Removal of the requirement for a routine urinalysis at baseline 
• 
Extension of collection of concomitant medications throughout the study 
(rather than just up to D40) 
• 
Addition of IVIG as a potentially confounding medication 
• 
Allowance low dose and topical steroids during the study  
• 
Inclusion of the requirement of >3 UBMs for the mITT population 
• 
Signs and symptoms of CDI: use of the term “loose stools” rather than 
“diarrhea” to distinguish from the protocol definition of diarrhea 
• 
Clarification that the PP populations will have a hierarchical order  
• 
Update of pharmacovigilance vendor name from Quintiles to IQVIA 
• 
Numerous minor administrative clarifications and minor administrative 
amendments to aid clarity and consistency 
29 Mar 2018 
Amendment 3; Protocol Version 4.0 
• 
Revision of the protocol definition of diarrhea (number of UBMs) and 
recurrence (added the requirement for CDI treatment) 
• 
Revision of the exploratory endpoint definition for time to resolution of 
diarrhea 
• 
Clarification of the exclusion criterion of >24h antimicrobial therapy 
• 
Revision and clarification of requirements for contraception, pregnancy 
testing and avoidance of sperm donation 
04 Jul 2018 


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DOCUMENT HISTORY 
Document 
Date 
• 
Probiotics and prebiotics exclusion extended from Day 12 (AOC) to end of 
study 
• 
Addition of permitted and non-permittable changes for eDiary data 
• 
Other clarifications for eDiary management 
• 
Addition of a blinded sample size assessment 
• 
Change of the primary analysis population for the important secondary 
endpoint from PP to mITT population 
• 
Updates to the statistical analysis section to align with protocol changes 
made 
• 
Minor clarifications and administrative amendments to aid clarity and 
consistency 
Amendment 4; Protocol Version 5.0 
• 
Sponsor company logo updated 
• 
Investigator Signature Page statement amended 
• 
Addition of a microbiome secondary objective and endpoint 
• 
Investigator assessment of clinical cure and sustained clinical response 
moved from exploratory to secondary endpoints 
• 
Day 40 visit window amended from ±3 days to +5 days 
• 
Allowance of a negative Free Toxin Test (FTT) to be repeated once at 
baseline and for suspected recurrence 
• 
Addition of an instruction that invalid FTT results should be repeated at 
baseline and for suspected recurrence 
• 
Addition of a CCNA for patients with a negative FTT for suspected 
recurrence  
• 
Clarification of Legally Authorized Representatives (LAR) for patients if 
IRB/EC permit and addition of an impartial witness if required 
• 
Revision of exclusion criteria 6 (immunosuppressed patients) 
• 
Additional section to further clarify exclusion criteria 6 (immunosuppressed 
patients) 
• 
Clarification of exclusion criteria 7 (prior antimicrobial treatment) 
• 
Revision of exclusion criteria 8 (antitoxin antibodies) 
• 
Revision of exclusion criterion 9 in line with changes made to the 
potentially confounding medication section 
• 
Additional instructions for administration of study treatment 
• 
Revisions and reorganization of potential confounding medications for 
clarity and to reflect clinical practice 
• 
Allowance for telephone consent to conduct a Free Toxin Test where the 
test is not standard of care 
• 
Revision of the requirement for an eDiary from up to Day 100 to up to 
Day 40 
19 Dec 2019 


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DOCUMENT HISTORY 
Document 
Date 
• 
Allowance of the Investigator, or a 3rd party vendor where available, to call 
the patient daily as an alternative to the eDiary  
• 
Addition of weekly calls to the patient post Day 40 to check for 
diarrhea/suspected recurrence 
• 
Stool sampling instructions added  
• 
Medical history requirements were updated and clarified 
• 
Disease Related Events (DREs) definition was revised and further guidance 
added  
• 
Allowance for a FTT to be conducted without patient consent on a stool 
sample collected per standard of care for diagnostic purposes 
• 
Addition of end of treatment blood sampling for PK analysis  
• 
Increase from 60 to 100 patients in the PK sub-group  
• 
Additional instruction to collect PK samples after specific doses  
• 
Adverse event assessment of causality revised from 4 possible grades 
(probable, possible, unlikely, not related) to 2 possible grades (related, not 
related) 
• 
Guidance on how to assess adverse event causality has been added 
• 
Male contraception language was clarified. 
• 
A list of current Sponsor agreed FTT has been added as an appendix 
• 
Updates to the statistical analysis section to align with protocol changes 
made 
• 
Addition of the EQ-5D-5L and Cdiff32 as appendices 
• 
Addition of references for the EQ-5D-5L and Cdiff32 
• 
Minor clarifications and administrative amendments to aid clarity and 
consistency 
Amendment 5; Protocol Version 6.0 
• 
Reformatted front page, logo placement, headers, and footers in line with 
sponsor SOP.  
• 
Clarified the position and role of the Global Medical Lead and rearranged 
the ordering of the sponsor signatories 
• 
Indented Declaration of Helsinki language on Investigator signature page 
• 
Updated Summary of Changes section to specify that full rationale for 
changes associated with the amendment is available via separate document.  
• 
Added allowance for screening and Day 100 visits to be completed over the 
phone.  
• 
Added the option to conduct the physical exam at screening or baseline. If 
conducted at screening, the vital sign assessment must still be repeated at 
baseline. 
• 
Added the option to complete the 12-lead ECG assessment at screening or 
baseline 
3 Sept 2020 


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DOCUMENT HISTORY 
Document 
Date 
• 
Added allowance for baseline visit to be completed at home with assistance 
from site staff or a home healthcare vendor approved by sponsor with the 
addition of video conferencing for certain procedures.  
• 
Added allowance for Day 12, Day 40, and any recurrence visit(s) to be 
completed at home synchronously over video conference with site staff and 
with the addition of a home healthcare vendor where required by the 
Investigator.  
• 
Clarified stool collection requirements for free toxin testing in footnote 6 
• 
Clarified stool sample requirements, including timing and use of a courier, 
in footnote 8 
• 
Added allowance for consent to be captured electronically (eConsent) or via 
email, printing, signing, scanning to site as back-up 
• 
Added allowance for ‘physical exam and vital signs’ along with ‘signs and 
symptoms of CDI’ procedures to be completed remotely with assistance 
from site staff or a sponsor provided home healthcare nursing vendor at 
baseline. Physical exam and vitals must be completed first for safety and 
need to be completed over synchronous video conference with Investigator.  
• 
Added instruction that if a recurrence visit is done remotely, addition of a 
focused physical exam completed by patient on them self over video 
conference with the Investigator.  
• 
Added allowance for a focused physical exam to be completed remotely by 
patient over synchronous video conference with Investigator and for patient 
to take their own vitals at Day 12, Day 40, and recurrence.  
• 
Added instruction that the ECG does not need to be completed at baseline if 
patient’s most recent ECG was normal and was completed in the 12 months 
prior.  
• 
Added instruction that the urine and blood samples, including PK, may be 
collected at patient’s home by site staff or home healthcare vendor. Urine 
and blood samples (except PK sampling) may alternately be completed by 
other qualified person at alternate location, where needed. 
• 
Clarified in footnote 16 that either site or 3rd party vendor may contact 
patient daily to collect dosing and bowel movement information until 
Day 40 
• 
Modified risk/benefit assessment section to include COVID-19 pandemic 
and added risk mitigation language 
• 
Added allowance for eDiary and IMP to be shipped or couriered from site to 
patient’s home 
• 
Added allowance for used eDiary and IMP wallet to be returned to site via 
courier or shipping 
• 
Added confirmation of no meal, dietary, caffeine, alcohol, tobacco, or 
activity restrictions. 
• 
Updated section 10.1.1 to state that Investigators have a regulatory and 
ethical obligation to ensure patient safety and medical care is paramount  


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DOCUMENT HISTORY 
Document 
Date 
• 
Clarified in Informed Consent section the telephone consent process for free 
toxin testing (FTT) where FTT is not SOC  
• 
Clarified that consent for retention of samples is captured via separate 
signature line within the Main ICF 
• 
Removed bullet point depicting third-party vendor ICF as a separate ICF 
document 
• 
Removed bolded instruction to “Discuss with the Medical Monitor before 
unblinding a patient (whenever possible)”.  
• 
Clarified terminology used in the Population for Analyses table. 
• 
Added guidance that a withdrawn patient may request destruction of 
samples taken and not tested. 
• 
Clarified language in footnote 1 of Appendix 2, Table 3 
• 
Added the following abbreviations: Council for International Organizations 
of Medical Sciences (CIOMS), Coronavirus Disease 2019 (COVID-19), 
Enzyme Immunoassay (EIA), Food and Drug Administration (FDA), Free 
Toxin Test (FTT), Home healthcare (HHC), Protected Health Information 
(PHI), Video Conference (VC), electronic Case Report Form (eCRF), 
Ethics Committee (EC), European Society of Clinical Microbiology and 
Infectious Diseases (ESCMID), Legally Authorized Representative (LAR), 
Ribosomal ribonucleic acid (rRNA), and Suspected Unexpected Serious 
Adverse Reaction (SUSAR).  
• 
Updated list of tests in Appendix 6: Sponsor agreed Free Toxin Tests 
• 
Minor formatting, clarifications and administrative amendments to aid 
clarity and consistency, including the removal of duplicate footnotes carried 
across some rows 
Amendment 6; Protocol Version 7.0 
• 
Updated sponsor signatories. 
• 
Revised exclusion criterion 4 to improve clarity and readability, to add 
pancreatectomy to the examples of prohibited gastrointestinal tract surgery, 
and to clarify that cholecystectomy is not prohibited. 
• 
Deleted exclusion criterion 6 and corresponding Section 5.2.1 
(immunosuppressed patients). 
• 
Revised exclusion criteria 7, 8, and 9 for clarity and readability 
(prior/concomitant therapy) 
• 
Revised exclusion criterion 12 to provide additional examples of conditions 
that would make a patient unsuitable for inclusion in the study and to 
improve clarity and readability. 
03 Feb 2021 
Amendment 7; Protocol Version 8.0 
• 
Updated sponsor signatories. 
• 
Minor formatting, clarifications and administrative edits to add clarity and 
consistency. 
21 Jun 2021 


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DOCUMENT HISTORY 
Document 
Date 
• 
Modified the definition of Sustained Clinical Response (Sections 1.1 and 3). 
• 
Updated secondary and exploratory endpoints including microbiome, bile 
acid, and antibiotic susceptibility endpoints (Sections 1.1, 3 and 9). 
• 
Clarified the use of Cell Cytotoxicity Neutralization Assay (CCNA) in case 
of negative free toxin test (Sections 1.1, 3 and 8). 
• 
Updated schedule of activities (SoA) and associated footnotes in 
Section  1.3 to reflect changes made within the COVID-19 section to reflect 
regulatory requirements and actual operationalization of remote visits; 
clarified that patients should remain in the study even if they discontinue 
study treatment early; clarified timing of blood draws for PK samples; and 
minor wording changes to reduce ambiguity. 
• 
Added two stratification factors (number of UBMs and 
immunocompromised) to ensure balance of the treatment arms with respect 
to the known prognostic factors for SCR. Note that there is no impact to 
procedures or data collection as the information required for stratification 
was covered in the previous version of the protocol (Sections 4.1, 6.3 and 
9.1). 
• 
Clarified that more than one recurrence may occur and each needs to be 
assessed (Section 4.1). 
• 
Simplified the COVID-19 language in Section 4.1 to reflect regulatory 
requirements and actual operationalization of remote visits. 
• 
Updated instructions for missed dose to reduce risk of underdosing 
ridinilazole while recognizing the lack of safety concern when doubling a 
dose of vancomycin; total daily dose is not altered (Section 6.1). 
• 
Clarified class and route of administration of potentially confounding 
medications (Section 6.5.1). Clarified that patients should remain in the 
study even if they discontinue study treatment early (Section 7.2). 
• 
Clarified reporting requirement by the patient through Day 40 and from 
Day 40 through Day 100 (Sections 8.1.1 and 8.1.4). 
• 
Clarified that suspected recurrence applies after the patient is deemed cured 
(Sections 8.1.1 and 8.1.4). 
• 
Added coverage expectations during holiday and vacation and allowed 
flexibility when adequate supporting documentation is available 
(Section 8.1.1). 
• 
Clarified that a positive free toxin test result is not required to determine the 
need for treatment (Section 8.1.3). 
• 
Clarified the Investigator assessment of cure and sustained clinical response 
to align with CRF reporting requirements (Section 8.1.4). 
• 
Clarified assessments and procedures for stool collection (Section 8.1.5). 
• 
Clarified events not meeting the AE/SAE definition and disease-related 
events not qualifying as AEs/SAEs (Sections 8.3.6 and 8.3.7). 
• 
Clarified management of overdose (Section 8.4). 


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DOCUMENT HISTORY 
Document 
Date 
•
Updated the estimate of SCR rate for vancomycin in sample size
determination to align with the vancomycin rate in the fidaxomicin label.
Removed the testing order for secondary endpoints, which will be specified
in the statistical analysis plan. Updated the analysis population for efficacy
endpoints, aligned efficacy endpoint analyses, and clarified safety analyses.
Amended protocol to allow for an interim analysis to be conducted
(Section 9).
•
Rectified improper use of witness and legally authorized representative
(LAR) for the informed consent process and clarified that telephone means
verbal consent (Section 10.1).
•
Clarified data protection laws governing the trial (Section 10.1).
•
Included additional free toxin tests (Section 10.6).
Amendment 8; Protocol Version 9.0 
•
Updated sponsor signatories.
•
Modified protocol to combine the ongoing Phase 3 studies,
SMT19969/C004 and SMT19969/C005, into one study with a pre-specified
Statistical Analysis Plan when these blinded, identical studies are at least
half enrolled (Sections 1.1, 4.3, and 9.4).
09 Aug 2021 


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TABLE OF CONTENTS 
Sponsor Signatory ............................................................................................................................2 
Investigator Signature Page .............................................................................................................3 
Protocol Amendment Summary of Changes Table .........................................................................4 
Table of Contents .........................................................................................................................11 
List of Tables ................................................................................................................................13 
1. 
Protocol Summary ........................................................................................................14 
1.1. 
Synopsis ..........................................................................................................................14 
1.2. 
Schema ............................................................................................................................18 
1.3. 
Schedule of Activities (SoA) ..........................................................................................19 
2. 
Rationale for Study .......................................................................................................23 
2.1. 
Introduction .....................................................................................................................23 
2.2. 
Background .....................................................................................................................24 
2.3. 
Study Rationale ...............................................................................................................26 
2.4. 
Scientific Rationale for Study Design ............................................................................27 
2.5. 
Justification for Dose ......................................................................................................27 
2.6. 
Benefit/Risk Assessment ................................................................................................28 
3. 
Objectives and Endpoints ............................................................................................30 
4. 
Study Design ..................................................................................................................32 
4.1. 
Patient Enrolment and Overall Design ...........................................................................32 
4.2. 
End of Study Definition ..................................................................................................33 
4.3. 
Combination of Databases of Studies SMT19969/004 and SMT19969/005 .................34 
5. 
Study Population ...........................................................................................................35 
5.1. 
Inclusion Criteria ............................................................................................................35 
5.2. 
Exclusion Criteria ...........................................................................................................36 
5.3. 
Lifestyle Considerations .................................................................................................37 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................37 
5.3.2. 
Caffeine, Alcohol, and Tobacco .....................................................................................37 
5.3.3. 
Activity ...........................................................................................................................37 
5.4. 
Screen Failures ................................................................................................................37 
6. 
Study Treatment ...........................................................................................................38 
6.1. 
Study Treatment(s) Administered ...................................................................................38 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................38 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................39 
6.4. 
Study Treatment Compliance .........................................................................................40 
6.5. 
Concomitant Therapy .....................................................................................................41 
6.5.1. 
Potential Confounding Medications ...............................................................................41 
6.6. 
Dose Modification ..........................................................................................................44 
7. 
Discontinuation of Study Treatment and Withdrawal from Study .........................45 
7.1. 
Discontinuation of Study Treatment ...............................................................................45 
7.2. 
Patient Withdrawal from the Study ................................................................................45 
7.3. 
Lost to Follow Up ...........................................................................................................45 


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8. 
Study Assessments and Procedures.............................................................................47 
8.1. 
Efficacy Assessments .....................................................................................................47 
8.1.1. 
Patient Reporting of Diarrhea/Suspected Recurrence ....................................................47 
8.1.2. 
Signs and Symptoms of CDI ..........................................................................................49 
8.1.3. 
Suspected Recurrence .....................................................................................................49 
8.1.4. 
Investigator Assessments of Cure and Sustained Clinical Response .............................51 
8.1.5. 
Stool (Fecal) Collection for Characterization .................................................................51 
8.2. 
Safety Assessments .........................................................................................................53 
8.2.1. 
Medical History (Including CDI History) ......................................................................53 
8.2.2. 
Physical Examinations ....................................................................................................53 
8.2.3. 
Vital Signs.......................................................................................................................53 
8.2.4. 
Electrocardiograms .........................................................................................................54 
8.2.5. 
Clinical Safety Laboratory Assessments ........................................................................54 
8.3. 
Adverse Events and Serious Adverse Events .................................................................54 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information ...........................55 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................55 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................55 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................55 
8.3.5. 
Pregnancy........................................................................................................................56 
8.3.6. 
Events NOT Meeting the AE/SAE Definition: ...............................................................56 
8.3.7. 
Disease-Related Events Not Qualifying as AEs or SAEs: .............................................56 
8.4. 
Treatment of Overdose ...................................................................................................57 
8.5. 
Pharmacokinetics ............................................................................................................57 
8.6. 
Pharmacodynamics .........................................................................................................57 
8.7. 
Genetics ..........................................................................................................................57 
8.8. 
Biomarkers ......................................................................................................................58 
8.9. 
Medical Resource Utilization and Quality of Life ..........................................................58 
8.9.1. 
Medical Resource Utilization .........................................................................................58 
8.9.2. 
EQ-5D-5L .......................................................................................................................58 
8.9.3. 
Cdiff32 Patient Reported Outcome .................................................................................58 
9. 
Statistical Considerations .............................................................................................59 
9.1. 
Statistical Hypotheses .....................................................................................................59 
9.2. 
Sample Size Determination ............................................................................................59 
9.3. 
Populations for Analyses ................................................................................................59 
9.4. 
Statistical Analyses .........................................................................................................60 
9.4.1 
Efficacy Analyses ...........................................................................................................60 
9.4.2 
Safety Analyses...............................................................................................................61 
9.4.3 
Pharmacokinetic Analyses ..............................................................................................61 
9.5. 
Interim Analyses .............................................................................................................61 
10. 
Supporting Documentation and Operational Considerations ..................................62 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.........................62 
10.1.1. 
Regulatory and Ethical Considerations...........................................................................62 
10.1.2. 
Financial Disclosure .......................................................................................................62 
10.1.3. 
Informed Consent Process ..............................................................................................62 
10.1.4. 
Data Protection ...............................................................................................................63 
10.1.5. 
Dissemination of Clinical Study Data ............................................................................64 


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10.1.6. 
Data Quality Assurance ..................................................................................................64 
10.1.7. 
Source Documents ..........................................................................................................65 
10.1.8. 
Study and Site Closure ....................................................................................................65 
10.1.9. 
Publication Policy ...........................................................................................................65 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................66 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................................67 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ..........73 
10.5. 
Appendix 5: Bristol Stool Chart .....................................................................................76 
10.6. 
Appendix 6: Sponsor Agreed Free Toxin Tests..............................................................77 
10.7. 
EQ-5D-5L .......................................................................................................................78 
10.8. 
Cdiff32 ............................................................................................................................79 
10.9. 
Appendix 7: Abbreviations .............................................................................................90 
10.10. 
References .......................................................................................................................93 
 
LIST OF TABLES 
Table 1: 
Dosing Schedule per 24 Hours ............................................................................. 38 
Table 2A: 
Potentially Confounding Medications Which May Exclude Patients from 
Randomization ...................................................................................................... 42 
Table 2B: 
Potentially Confounding Medications Which May Not Be Permitted During 
Study Treatment (Day 1 to Day 12 and/or during Follow-up (Day 12 to 
Day 100)................................................................................................................ 43 
Table 3: 
Protocol-Required Safety Laboratory Assessments .............................................. 66 
Table 4: 
Highly Effective Contraceptive Methods ............................................................. 74 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 3, randomized, double-blind, active controlled study to compare the 
efficacy and safety of ridinilazole (200 mg, bid) for 10 days with vancomycin (125 mg, qid) 
for 10 days in the treatment of Clostridium difficile infection (CDI). 
Short Title: Comparison of ridinilazole versus vancomycin treatment for CDI 
Rationale: 
Clostridioides difficile (formerly Clostridium difficile) infection (CDI) is an infection of the colon 
that invariably develops following prior antibiotic use. The disease is associated with significant 
morbidity and mortality and primarily affects the hospitalized elderly (>65 years of age) although 
CDI is becoming increasingly associated with the community setting and younger age groups. Of 
concern is recurrent infection with up to 30% of patients experiencing a subsequent episode 
following initial infection with rates increasing to 65% after a third episode [1, 2]. Recurrent 
disease remains a central unmet medical need in CDI. It is difficult to treat, associated with 
increased morbidity and poorer clinical outcomes, and further increased risk of mortality. Summit 
is developing ridinilazole as a novel antimicrobial for CDI with the goal of achieving comparable 
cure rates to standard of care and reducing rates of recurrent disease. A Phase 2 proof of concept 
study, with vancomycin as the standard of care, demonstrated these attributes.  
The rationale for this Phase 3 study is to demonstrate the improvement in sustained clinical 
response of ridinilazole over vancomycin and compare the safety of ridinilazole to that of 
vancomycin. A second Phase 3 study of identical design will be run in parallel. 
Primary Objective 
• To compare the efficacy of 10 days’ dosing with ridinilazole (200 mg bid) with 
vancomycin (125 mg qid) in the treatment of patients with CDI 
Secondary Objectives 
• To compare the safety and tolerability of 10 days’ dosing with ridinilazole (200 mg bid) 
with vancomycin (125 mg qid) in the treatment of patients with CDI 
• To characterize the systemic exposure of ridinilazole in a subset of patients treated with 
ridinilazole (200 mg bid) tablets 
• 
To compare the effect of 10 days’ dosing with ridinilazole (200 mg bid) and vancomycin 
(125 mg qid) on the gut bile acid composition and on the gut microbiome diversity at the 
end of treatment (EOT)  


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Exploratory Objectives 
• To compare the effects of ridinilazole (200 mg bid) and vancomycin (125 mg qid) on 
the gut bile acid composition, microbiome, and antibiotic resistance gene profile at EOT 
and during the follow-up period 
• To assess the antibiotic susceptibility and ribotype of C. difficile isolates in patients 
receiving ridinilazole (200 mg bid) and vancomycin (125 mg qid) 
• To assess the impact of ridinilazole treatment on patient reported quality of life, resource 
utilization and health economics 
Primary Endpoint 
• Sustained Clinical Response (SCR) is defined as Clinical Response and no recurrence of 
CDI through 30 days post EOT. 
 
Secondary Endpoints 
• Clinical Response  
• Clinical Cure 
• Sustained Clinical Response over 60 days – defined as Clinical Response and no 
recurrence of CDI through 60 days post EOT 
• Sustained Clinical Response over 90 days – defined as Clinical Response and no 
recurrence of CDI through 90 days post EOT 
• Change from baseline to EOT of the relative abundance of the 3 main bile acid groups 
(conjugated primary, primary and secondary bile acids)  
• Change from baseline to EOT of the gut microbiota α-diversity (Shannon) index 
• Change from baseline to EOT of the gut microbiota β-diversity (Bray-Curtis) index in 
stool samples 
 
Definitions for the Primary and Secondary Endpoints 
Clinical Response is defined as  
• less than 3 unformed bowel movements (UBMs) for 2 consecutive days and maintained 
through the EOT without further CDI treatment at EOT+ 2 days or  
• the investigator’s assessment that the subject no longer needs specific CDI antimicrobial 
treatment after completion of the course of study medication.  
Clinical cure is defined as the resolution of diarrhea (<3 UBMs in the 1-day period immediately 
prior to EOT, that is maintained for 2 days after EOT) 
Recurrence is defined as a new episode of diarrhea (≥3 UBMs) in a 1-day period with a positive 
C. difficile free toxin test or Cell Cytotoxicity Neutralization Assay (CCNA) that requires CDI 
treatment. 
A UBM is defined as a Type 5, 6 or 7 bowel movement on the Bristol Stool Chart. 
 


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Safety Endpoints 
• Safety and tolerability as determined by adverse event (AE) and serious adverse event 
(SAE) reporting 
 
PK Endpoints 
• Ridinilazole plasma concentrations in a subset of patients 
 
 
Health Economics and Outcomes Research (HEOR) Endpoints 
• Medical resource utilization and health economics endpoints (e.g., hospital readmission 
rates and length of hospital stay) 
• Change from baseline in EQ-5D-5L dimensions and health state VAS score 
• Change from baseline in Cdiff32 domains (US sites) 
 
Exploratory Endpoints 
• Time to resolution of diarrhea over the first 12 days – defined as the time from starting 
study treatment to the resolution of diarrhea (<3 UBMs in a 1-day period)  
• Change from baseline to Day 40, Day 70, Day 100 and day of recurrence (if applicable) 
of the relative abundance of the bile acid components, conjugated primary, primary, and 
secondary bile acids in stool samples 
• Change from baseline to Day 40, Day 70, Day 100 and day of recurrence (if applicable) 
of the microbiota α-diversity (Shannon) and β-diversity (Bray-Curtis) indices in stool 
samples 
• Change from baseline to EOT, Day 40, Day 70, Day 100 and day of recurrence (if 
applicable) of the relative abundance of bacterial taxa, microbiome gene functions, and 
microbiome antibiotic-resistance genes in stool samples 
• Determination of the ribotype and susceptibility to ridinilazole, vancomycin and other 
antibacterial agents of C. difficile isolates in stool samples collected at baseline, EOT 
and recurrence  
Overall Design: 
A multicenter, randomized, double blind, active controlled, parallel group pivotal Phase 3 study 
designed to investigate the use of ridinilazole 200 mg bis in die (bid), in comparison to vancomycin 
125 mg quarter in die (qid), both administered for 10 days for the treatment of CDI.  
Patients must be aged 18 years or over, have the presence of toxin A and/or B of C. difficile in the 
stool as confirmed by a positive free toxin test and not have had more than one prior episode of 
CDI in the previous 3 months or more than 3 episodes in the past 12 months.  
Sites may use an established local free toxin test laboratory service if it is a suitable test, and it is 
prospectively agreed with the Sponsor. Suitable tests will have appropriate regulatory approvals 
(FDA approval, EU CE Mark or equivalent). Refer to Section 10.6 for a list of known approved 
free toxin tests. Newly approved free toxin tests that become available during the conduct of the 


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study will also be suitable for use with Sponsor approval. Free toxin tests will be provided for the 
site/site laboratory use if a suitable test is not available locally. In case of a negative free toxin test 
result at a suspected recurrence, detection of C. difficile toxin in samples will be performed by the 
more sensitive Cell Cytotoxicity Neutralization Assay at a central laboratory. 
The study will evaluate the efficacy and safety of ridinilazole compared with vancomycin. 
Ridinilazole systemic exposure will be evaluated in a subset of patients at selected sites. The effect 
of the two treatments on the gut microbiome and bile acid composition will be evaluated in patients 
across all sites. The study will also investigate the antibiotic susceptibility and ribotype of 
C. difficile isolates collected at different time points and assess the impact of ridinilazole on quality 
of life and health economic measures.  
Number of Patients: 
The original planned sample size was approximately 680 patients (340 patients per arm) to be 
randomly assigned to study treatment. To minimize the potential, unknown impact of the 
coronavirus disease 2019 (COVID-19) pandemic on the trial and because of a much slower 
enrollment rate than anticipated due to the ongoing pandemic, Summit has decided to combine its 
ongoing, Phase 3 studies, SMT19969/C004 and SMT19969/C005, into one study with a pre-
specified Statistical Analysis Plan when these blinded, identical studies are at least half enrolled. 
As a result, both studies will be closed and will proceed with database lock and statistical analysis. 
The combined analysis will comprise a minimum of 680 randomized subjects. 
To ensure optimal data quality and integrity, it is critical that 
• Inclusion and exclusion criteria are rigorously adhered to. 
• Diagnosis of CDI is always determined by a positive, Sponsor approved, free toxin 
test prior to randomization. 
• A free toxin test must be completed if recurrence of CDI is suspected. Refer to the 
result of the free toxin test to determine whether CDI treatment is required. 
• For all suspected recurrences associated with a negative free toxin test result 
obtained locally by the site, a stool sample aliquot should be prepared for testing 
by CCNA at a central laboratory. 
• Patients take all study treatment as directed and complete the 10 days of treatment. 
• Patients report all study medication doses for the 10 days of treatment. 
• Patients report all bowel movements every day up to Day 12/AOC and all UBMs to 
Day 40.  
Potentially confounding medications (i.e., those affecting disease progression) are avoided 
wherever possible. 
Treatment Groups and Duration: 
Each patient will be enrolled in this study for approximately 100 days. This consists of a 0 to 3-
day screening period, a 10-day treatment period and a 90-day follow-up period (including an 
assessment of cure at Day 12). 
Patients will be randomized (1:1) to receive either a 10-day course of ridinilazole (200 mg, bid) or 
a 10-day course of vancomycin (125 mg, qid). 


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Data Monitoring Committee: No 
1.2. 
Schema 
 
AOC: Assessment of Cure; EOS: End of study; EOT: End of Treatment: SCR: Sustained Clinical 
Response 
 
SCR is defined as Clinical Response and no recurrence of CDI through 30 days post EOT. 
 


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1.3. 
Schedule of Activities (SoA) 
Phase 
Screening 
Treatment Period 
Follow-Up Period 
Recurrence 
Day(D) 
D-3 to D11,2 
D11,3 
D52 
D102 
D124  
D40  
≥30 days from last 
dose or early term 
pre-D405 
D702  
60 days from last 
dose 
D1002  
90 days from last 
dose or early term 
post-D40 
Day 12/AOC  
to D1004 
Assessment 
Screening 
Visit 
Baseline 
Check-in 
End of 
Treatment 
Assessment 
of Cure 
Primary Sustained 
Clinical Response 
Assessment 
Sustained Clinical 
Response 
Assessment 
Sustained Clinical 
Response 
Assessment 
Suspected 
Recurrence 
Visit window 
 
 
±1 day 
±1 day 
+ 3 days 
+ 5 days 
±5 days 
± 5 days 
≤48h of 
identification 
Visit format 
Clinic/ 
Tel1,2 
Clinic/  
HHC with 
VC1,3  
Tel2 
Clinic/Tel2 
Clinic/ VC/ 
HHC4 
Clinic/ VC/ HHC4 
Clinic/Tel2 
Clinic/ Tel2 
Clinic/ VC/ 
HHC4 
Written informed consent6 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Free toxin test7 
X 
 
 
 
 
 
 
 
X 
Medical/CDI history8 
X 
X 
 
 
 
 
 
 
 
Stool sample for microbiology / 
microbiome/metabolome/future 
research9 
X 
X 
 
X 
X 
X 
X 
X 
X 
Physical exam and vital signs10 
X 
X 
 
 
X 
X 
 
 
X 
12-lead ECG11 
X 
X 
 
 
 
 
 
 
 
Blood samples (hematology and 
clinical chemistry)12 
 
X 
 
 
X 
X 
 
 
 
Urine pregnancy test (dipstick) for 
WOCBP13 
 
X 
 
 
X 
 X 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
EDiary training and review 
 
X 
X 
X 
X 
X 
 
 
 


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Phase 
Screening 
Treatment Period 
Follow-Up Period 
Recurrence 
Day(D) 
D-3 to D11,2 
D11,3 
D52 
D102 
D124  
D40  
≥30 days from last 
dose or early term 
pre-D405 
D702  
60 days from last 
dose 
D1002  
90 days from last 
dose or early term 
post-D40 
Day 12/AOC  
to D1004 
Assessment 
Screening 
Visit 
Baseline 
Check-in 
End of 
Treatment 
Assessment 
of Cure 
Primary Sustained 
Clinical Response 
Assessment 
Sustained Clinical 
Response 
Assessment 
Sustained Clinical 
Response 
Assessment 
Suspected 
Recurrence 
Visit window 
 
 
±1 day 
±1 day 
+ 3 days 
+ 5 days 
±5 days 
± 5 days 
≤48h of 
identification 
Visit format 
Clinic/ 
Tel1,2 
Clinic/  
HHC with 
VC1,3  
Tel2 
Clinic/Tel2 
Clinic/ VC/ 
HHC4 
Clinic/ VC/ HHC4 
Clinic/Tel2 
Clinic/ Tel2 
Clinic/ VC/ 
HHC4 
IMP Dosing qid (10 days) 
 
 
 
 
 
 
 
Dosing instruction, compliance + 
accountability 
 
X 
X 
X 
X 
 
 
 
 
Signs and symptoms of CDI10 
 
X 
 
 
X 
 
 
 
X 
EQ-5D-5L  
 
X 
 
 
X 
X 
 
 
X 
Cdiff32 (US sites) 
 
X 
 
 
X 
X 
 
 
X 
Medical resource utilization questions 
 
X 
 
 
X 
X 
X 
X 
X 
Investigator assessment of 
cure/sustained clinical response14 
 
 
 
 
X 
X 
X 
X 
X 
PK Sample (2 & 4 hours post dose in 
subset of patients/sites)15 
 
X 
 
X 
 
 
 
 
 
Concomitant medications 
 
Potential confounding medications16 
 
Patient daily eDiary completion17 
 
 
 
 
 
 
 
 
 
Weekly contact to check for 
diarrhea/suspected recurrence17 
 
 
 
 
AE reporting18 
 
 
 
 
X 
SAE reporting 
 
Notes: Unscheduled telephone calls and/or visits may be conducted if necessary, for the patient’s safety and to ensure dosing and diary completion per protocol.   


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1. Screening and D1/baseline assessments may occur on the same day or within a 1- to 3-day window. Patients can be rescreened once for this study.   
2. D5 visit will be conducted by telephone. Screening, D10, D70, and D100 assessments may be conducted in-clinic or by telephone.  
3. Preferably the Baseline visit should be completed as an in-clinic visit; however, to maximize potential enrollment (e.g., during a pandemic) the visit may be 
conducted remotely. If so, a sponsor-contracted home healthcare vendor or properly trained and delegated site staff must conduct assessments at the patient’s home. 
All assessments should be completed prior to randomization except for the following, which must still be conducted prior to their 1st dose of study medication: 
weight, blood samples (hematology and clinical chemistry), stool collection (if required, to collect a sample for microbiology/microbiome/metabolome that is <24h 
old), eDiary training, EQ-5D-5L, Cdiff32 and medical resource utilization questions.  
4. 
D12, D40 and recurrence visits are preferably in-clinic visits; however, these visits may be conducted remotely.  
5. 
Subjects who have discontinued study drug early should remain in the study and be monitored, e.g., for adverse events. 
6. 
Documented informed consent must be provided by the patient prior to any study procedure being conducted. Informed Consent is allowed in other than face to face 
method as per site local procedure or local regulations. 
7. 
Current/baseline CDI free toxin test: A free toxin test must be the 1st assessment conducted using a sample produced within 72 hours prior to randomization. Patients 
with a negative free toxin test will be excluded from the study. 
Suspected recurrence free toxin test: A free toxin test should be conducted as soon as possible – and at a maximum of 48 hours - after identifying a suspected 
recurrence. Cell Cytotoxicity Neutralization Assay (CCNA) sample is to be collected when free toxin test is negative and sent to a specialized central laboratory.  
Negative or invalid free toxin test results: A negative free toxin test may be repeated once for baseline and suspected recurrence. The same sample may be used if 
collected within 24 hours, otherwise a fresh sample must be used. Invalid test results should be repeated.  
Free toxin test specification: Sites may use an established local free toxin test laboratory service if it is a suitable test, and it is prospectively agreed with the Sponsor. 
Suitable tests will have appropriate regulatory approvals (FDA approval, EU CE Mark or equivalent). Please see Appendix 6 for list of approved tests. Free toxin 
tests will be provided for the site/site laboratory use if a suitable test is not available locally. 
8. 
Record all known historical CDIs along with associated treatment, information on the current/baseline CDI including signs and symptoms, any potential confounding 
medications taken up to 4 weeks prior to randomization, relevant medical history for 12 months prior to randomization and all prior and current medications taken up 
to 4 weeks prior to randomization. 
9. 
Stool samples should be aliquoted and frozen within 24 hours of sample being produced. Only one sample is required at either Screening or D1. Only one sample is 
required at either D10 or D12. Additional stool samples are required at each of the following visits: D40, D70, D100, and each suspected recurrence. If the visit is 
conducted remotely, stool sample drop off or collection from the patient (e.g., courier) must be arranged. 
10. If the visit is conducted remotely physical exam and vital signs if taken by the patient are done through sponsor approved video conferencing between the patient and 
Investigator. 
The following assessments must be included: temperature, blood pressure, pulse, height (baseline only) and weight. The physical exam may be conducted at the 
screening or baseline visit; if conducted at screening, the vital sign assessment must still be repeated at baseline. 
11. The ECG may be conducted at the screening or baseline visit. It does not need to be completed if most recent ECG was normal and was completed in the 12 months 
prior.  
12. An appropriately qualified person will need to collect blood samples (hematology and clinical chemistry per Appendix 2). For visits conducted remotely, this person 
will either need to visit the patient at home or the site will need to arrange an alternative location.  


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13. WOCBP = Women of Child Bearing Potential. Testing in the case of missed menses should also be conducted up to 30 days following the last dose of study 
treatment. An appropriately qualified person will need to perform this procedure. For visits conducted remotely, this person will either need to visit the patient at 
home or the patient may perform a home pregnancy test over video conference with the site. 
14. Based on the Investigator’s assessment of the reduction of UBMs since baseline, clinical signs and symptoms and need for further treatment for CDI. 
15. Approximately 100 patients will undergo PK sampling. Blood draws should occur at on Day 1 or 2 at 2 and 4 hours (±30 minutes) following either Dose 1, 3, 5 or 
7 and at EOT at 2 and 4 hours (±30 minutes) following either Dose 33, 35, 37 or 39. 
PK sampling must be conducted following administration of study medication. A ±30-minute window is allowable for the sampling times relative to dosing. An 
accurate date and time of dose and sampling is required. A home healthcare vendor or appropriately trained and delegated site staff may perform this procedure at the 
patient’s home. 
16. Potential confounding medications should be avoided where possible except for CDI medications required in the case of recurrence. If antimicrobial therapy is 
required for infections other than those due to C. difficile, antimicrobials without activity/efficacy against C. difficile should be prescribed where possible.  
17. Patients will report dosing information daily until EOT and bowel movement information daily until D40 in their eDiary. As an alternative the patient may be 
contacted daily either by site or a 3rd party vendor. After D40 the site will contact the patient weekly to check for new episodes of diarrhea/suspected recurrence. The 
eDiary needs to be collected/returned (e.g., courier) upon study completion. 
18. AEs only need to be reported up to the D40 visit (inclusive). AEs meeting the definition of serious should be reported throughout the study. 


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2. 
RATIONALE FOR STUDY 
2.1. 
Introduction 
Ridinilazole is a novel antimicrobial that is being developed for treating C. difficile infection (CDI) 
and reducing the recurrence of CDI [3]. Ridinilazole is associated with a highly targeted spectrum 
of activity that has been shown to result in minimal collateral impact on the gut microbiota during 
therapy and it is expected that this property will lead to reduced rates of CDI recurrence and 
improved sustained clinical response. This was demonstrated in a Phase 2 proof of concept study 
where treatment with ridinilazole demonstrated superior efficacy compared with vancomycin, 
demonstrated by a marked reduction in rates of CDI recurrence and hence improved sustained cure 
rates [4]. 
Nonclinical and prior clinical studies have shown that ridinilazole is retained in the gastrointestinal 
(GI) tract following oral dosing, therefore maximizing exposure of ridinilazole at the site of 
infection and minimizing systemic exposure. A detailed description of the chemistry, 
pharmacology, efficacy, and safety of ridinilazole is provided in the Investigator’s Brochure. 
C. difficile is an anaerobic Gram-positive spore-forming species of bacteria which is responsible 
for epidemics and individual cases of CDI, with symptoms ranging from mild, self-limiting 
diarrhea to more severe and potentially life-threatening manifestations such as pseudomembranous 
colitis and toxic megacolon [5]. 
C. difficile can often be a harmless resident of the gastrointestinal (GI) tract with levels typically 
kept in check by the complex community of microorganisms that make up the indigenous gut 
microbiota. However, disruption to the healthy ecological balance of the gut microbiota, typically 
by prior antibiotic use, diminishes the ability of the host to resist colonization by C. difficile spores 
that can undergo germination, leading to toxin production and disease symptoms [6, 7].  
Recurrence of CDI occurs in up to 30% of patients following initial therapy, hence the prevention 
of recurrent disease remains a key unmet medical need in the management of CDI [1]. Each 
episode of recurrent disease is associated with an increased risk of further recurrent episodes 
placing a significant burden on patients through increased morbidity and diminished quality of 
life. In a study of 163 patients who had had at least one recurrent episode, the risk of subsequent 
episodes was 45% [8]. Recurrence rates may be > 65% following a 3rd episode of CDI [2, 9]. 
Treatment of recurrent CDI is challenging and there is no uniformly effective therapeutic 
approach.  
While administration of standard CDI antibiotics (vancomycin or metronidazole) may result in a 
reduction in C. difficile and subsequent relief of symptoms, they have been shown to have ongoing 
and deleterious effects to the gut microbiota [10-12]. As such, repeated courses of treatment for 
CDI may exacerbate the situation with the ongoing suppression of the microbiota leaving patients 
prone to further episodes of CDI. Therefore, therapeutic approaches that allow natural restoration 
of a healthy gut microbiome and resistance to C. difficile colonization, especially with narrow 
spectrum C. difficile-targeted antibiotics, are expected to reduce rates of recurrent disease and 
improve sustained clinical response [5, 6]. 


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2.2. 
Background 
CDI is an infection of the colon that typically develops following prior antibiotic use. The disease 
is associated with significant morbidity and mortality and primarily affects the hospitalized elderly 
(>65 years of age), although CDI is becoming increasingly associated with the community setting.  
Of particular concern is recurrent infection with up to 30% of patients experiencing a subsequent 
episode following initial infection, with rates increasing to 65% after a third episode. Prevention 
of recurrent disease remains a central unmet medical need in CDI as it is difficult to treat, 
associated with increased morbidity and poorer clinical outcomes, and further increased risk of 
mortality. 
A recent EU wide survey of 1,047 healthcare professionals involved in the management of 
CDI, [13] revealed a high level of agreement (97.3% and 90.7%, respectively) with the statements 
that “recurrent CDI is a strong contributor to poor clinical outcomes, increased length of hospital 
stay and increased costs” and that “treatment decisions for both initial infection and recurrent CDI 
should take into account the impact on resource utilization and wider societal costs.”. 
Therefore, the optimal strategy in CDI therapy is to achieve high levels of clinical response at the 
end of therapy and to minimize rates of recurrent disease such that the initial clinical response at 
the end of dosing is sustained for a period of time following the EOT. 
Current treatment options are limited and of sub-optimal efficacy. Oral vancomycin and 
metronidazole are the current mainstay antibiotics and both are associated with high rates of 
recurrent disease [14]. The most recent Infectious Diseases Society of America (IDSA) guidelines 
state metronidazole is only recommended in settings where access to vancomycin or fidaxomicin 
is limited, and then only for initial cases of non-severe CDI. Vancomycin and fidaxomicin are 
recommended for initial CDI. [15-17]. There is evidence that metronidazole is associated with 
inferior clinical response at end of therapy compared to vancomycin across all disease severities 
[18, 19] and may be associated with higher 30 day all –cause mortality rates in subjects with severe 
CDI [20]. Response to metronidazole treatment in the frail and elderly is generally slow, with 
patients prone to recurrence; 30-day-mortality of 21% has been reported after treatment with 
metronidazole [21]. Oral vancomycin remains the currently recognized standard of care and, based 
on recent clinical trial experience, is typically associated with initial cure rates of 80-90% based 
on recent Phase 3 clinical trials [22-24]. Given vancomycin may be used in both severe and non-
severe CDI, is associated with higher clinical response rates and faster symptomatic resolution 
when compared with metronidazole and is generally considered the standard of care in CDI it will 
be the active comparator for this study. A description of oral vancomycin’s efficacy, safety and 
pharmacology can be found in the Prescribing Information (FDA Reference ID: 3058238). 
Fidaxomicin is approved in the US and EU for the treatment of CDI and has seen limited routine 
use in clinical practice. Fidaxomicin has been shown in Phase 3 clinical studies to be non-inferior 
on clinical response to vancomycin at the end of treatment and in a secondary analysis to be 
superior to vancomycin on SCR to 25 days post end of therapy, although fidaxomicin was not 
shown to be superior to vancomycin for SCR for the subgroup of patients infected with BI/NAP 
1/027 strains of C. difficile [22, 23]. ESCMID treatment guidelines give equal recommendation 
(Quality of Evidence = II; Strength of Recommendation = B) on the use of fidaxomicin and 
vancomycin in the treatment of a first episode of CDI and they note that there is no evidence for 
use of fidaxomicin in severe life-threatening disease. In treatment of first recurrence, both 


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vancomycin and fidaxomicin receive an equal recommendation strength (B-I). Only in the 
treatment of multiple recurrences do ESCMID recommend fidaxomicin or taper/pulsed 
vancomycin regimens over a standard regimen of vancomycin (B-II vs. C-II respectively).  
New antibiotic treatments, such as ridinilazole, that can treat the initial infection and minimize the 
subsequent risk of recurrent infection are needed. 
A Phase 2 randomized, double-blind study (SMT19969/C002) conducted in 100 patients with CDI 
comparing the safety and efficacy of ridinilazole 200 mg bis in die (bid) for 10 days versus the 
approved dose of vancomycin 125 mg quarter in die (qid) in the treatment of CDI has been 
completed [4]. The primary endpoint used was sustained clinical response, defined as clinical cure 
at test of cure (TOC) and no recurrence of CDI within 30 days post end of therapy. The important 
secondary endpoint was Investigator-assessed clinical response at test of cure (TOC). The primary 
analysis population was a modified Intent to Treat (ITT) population comprising patients (36 
ridinilazole; 33 vancomycin) whose diagnosis was confirmed by the presence of free toxin in stool. 
In the mITT population, SCR rates were 24/36 (66.7%) and 14/33 (42.4%) for patients on 
ridinilazole and vancomycin, respectively. The difference between treatment proportions was 
21.1% with a 90% CI (3.1%, 39.1%), which showed ridinilazole was non-inferior to vancomycin 
(15% non-inferiority margin; p = 0.0004). Furthermore, as the 90% confidence interval lies 
entirely above zero it was concluded ridinilazole was superior to vancomycin at the pre-specified 
10% level of significance (2-sided test). Clinical response at TOC was 28/36 (77.8%) and 23/33 
(69.7%) for patients on ridinilazole and vancomycin, respectively (mITT population). The 
difference between treatment proportions was 8.3% (90% CI −9·3, 25·8), demonstrating non-
inferiority (pre-specified 15% margin) on initial cure. In addition, the study showed that 
ridinilazole was well tolerated, with an adverse event profile comparable to that of vancomycin. 
In the safety population (all treated patients), 82% (41/50) and 80% (40/50) in the ridinilazole and 
vancomycin groups, respectively, reported adverse events, while 16% (8/50) and 18% (9/50) of 
patients in the respective groups reported serious adverse events. There were no study drug-related 
adverse events that led to discontinuation in the ridinilazole group. Full details of the study results 
are provided in the Investigators Brochure.  
An exploratory Phase 2, multi-centre, open-label, randomised, active-controlled, parallel-group 
study (SMT19969/C003) was conducted to evaluate the safety and tolerability of 10 days of dosing 
with ridinilazole (200 mg BID) compared with fidaxomicin (200 mg BID). Secondary objectives 
included efficacy of ridinilazole compared with fidaxomicin as determined by sustained clinical 
response to 30 days post EOT and the assessment of the qualitative and quantitative effect of 
ridinilazole and fidaxomicin on the gut microbiota of patients. The study was not designed to 
demonstrate efficacy differences and the primary aim was to assess the relative impact of the two 
agents on the gut microbiota. A total of 27 patients (14 ridinilazole: 13 fidaxomicin) were 
randomised to study treatment and all were included in the safety and primary efficacy analysis 
populations. Overall, ridinilazole was considered safe and generally well tolerated. All patients in 
the safety population, except two patients in the fidaxomicin group, experienced TEAEs. The 
majority of TEAEs were mild in severity and resolved without treatment and there were no 
discontinuations due to TEAEs. Sustained clinical response was comparable between the 
ridinilazole group (50.0%) and the fidaxomicin group (46.2%) with an overall treatment difference 
of 2.9% (95% CI: -30.8%, 36.7%). The ridinilazole group had a higher proportion of patients with 
risk factors for CDI recurrence than fidaxomicin including concomitant antibacterial use, severe 
disease, and age ≥65 years. Analysis of the microbiome of the patients showed that ridinilazole 


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was associated with reduced negative impact on the indigenous microbiota as measured through 
reduced α-diversity and changes in major taxa identified via 16S rRNA sequencing. Full details 
of the study results are provided in the Investigators Brochure.  
Ridinilazole is being developed specifically with the dual concept of achieving high cure rates of 
the initial acute episode of CDI and reducing rates of recurrent CDI and improving Sustained 
Clinical Response. As such, the endpoints proposed for the Phase 3 trials are designed to 
demonstrate cure of initial disease and improvement of Sustained Clinical Response. 
2.3. 
Study Rationale 
The rationale for this Phase 3 study is to demonstrate the improvement in sustained clinical 
response of ridinilazole over standard of care and compare the safety of ridinilazole to that of 
standard of care. A second Phase 3 study of identical design will be run in parallel. 
This Phase 3 study is a pivotal study designed to investigate the use of ridinilazole 200 mg bid, as 
a 10-day therapy, in comparison with the approved dose and duration of vancomycin (125 mg 
[qid] given for 10 days) for the treatment of CDI. The study will evaluate the efficacy of 
ridinilazole compared with vancomycin in terms of Sustained Clinical Response (SCR) defined as 
Clinical Response and no recurrence of infection with C. difficile through 30 days post end of 
treatment (EOT). The efficacy of ridinilazole will also be compared with vancomycin with respect 
to Clinical Response, and SCR through 60- and 90-days post EOT. Safety and tolerability of 
ridinilazole will be compared with vancomycin, as well as various health economic measures. The 
study will also investigate the antibiotic susceptibility and ribotype of C. difficile isolates collected 
at different time points and assess the effect of the two treatments on the gut microbiome and bile 
acid composition. Ridinilazole plasma concentration will be assessed in a subset of patients. 
Oral vancomycin has been selected as a comparator as it is the current standard of care for the 
treatment of CDI and is generally recommended for use in the treatment of moderate to severe 
CDI, in treatment of a first recurrent episode and in treatment of those at high risk of recurrent 
disease [16, 21].Vancomycin therapy is associated with increased rates of clinical response, faster 
resolution of diarrhea [21] and other symptoms and reduced rates of recurrent disease when 
compared to metronidazole for all disease severities [19]. Although higher doses are routinely used 
clinically, the recommended clinical dose of oral vancomycin is 125mg four times daily. In 
addition, recent studies have shown high dose regimens of vancomycin are no more effective that 
standard dose regimens [25]. Vancomycin remains the standard active comparator used in clinical 
trials of novel agents. As such, Summit will use 125 mg of vancomycin dosed four times daily as 
the active comparator in the pivotal Phase 3 trials. 
Pharmacokinetic samples will be collected from a subset of the patients to allow characterization 
of the systemic exposure of ridinilazole with the tablet formulation. In vitro dissolution profiles 
and a cross-over study in dogs indicate that the tablet formulation behaves similarly to the Phase 2 
capsule formulation. These data indicate that the physicochemical characteristics of ridinilazole 
govern its behavior leading to very poor absorption from the gut. Therefore, the expectation is that 
systemic exposure will continue to be negligible in CDI patients with the tablet formulation. Prior 
studies have indicated that most plasma samples are near or below the limit of quantification of 
the assay, therefore it is not possible to determine PK parameters nor is there evidence of 
accumulation upon repeat dosing. To further assess systemic exposure of the tablet formulation, 
two post-dose samples, at 2 and 4 hours, will be collected on Day 1 or 2, and at EOT. As the study 


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is blinded, samples will be collected from approximately 100 patients to ensure approximately 40 
patients have received ridinilazole. Some of these patients are expected to meet the IDSA criteria 
for severe CDI (white blood cell count ≥15,000 cells/mm3 or serum creatinine >1.5 mg/dL). In 
order to assess the systemic exposure of ridinilazole in patients with severe CDI, the number of 
patients with severe CDI in the PK subgroup will be monitored, and additional PK patients may 
be enrolled as required.  
2.4. 
Scientific Rationale for Study Design 
Ridinilazole is a novel antibiotic being developed for the treatment of CDI and reducing the 
recurrence of CDI. Ridinilazole has been shown to demonstrate potent growth inhibition with a 
narrow minimum inhibitory concentration (MIC) range against a broad range of C. difficile 
ribotypes collected from both the US and Europe. This range includes hyper virulent ribotypes 
such as 027 and isolates showing reduced susceptibility to vancomycin and metronidazole. 
Importantly, ridinilazole has a narrow spectrum of activity with typically >1,000-fold selectivity 
for C. difficile over Gram-positive and Gram-negative anaerobic and facultative members of the 
gut microbiota. This feature of ridinilazole has been shown to result in minimal collateral damage 
to the gut microbiota [26] compared with vancomycin, throughout the course of treatment of CDI 
during a Phase 2 clinical trial and ultimately led to a marked reduction in rates of recurrent CDI.  
Therefore, this study will use a similar design to the Phase 2 study to provide confirmatory 
evidence of ridinilazole’s effect on CDI recurrence of infection. The primary endpoint of SCR is 
the most appropriate measure of efficacy for comparison to vancomycin since it captures both cure 
of the initial infection and any onset of CDI recurrence. An important aspect of the design is that 
the randomized population will have a diagnosis of CDI confirmed by the presence of free toxin 
in stool to ensure the study population has the most rigorous diagnosis of true infection (and not 
colonization) in accordance with treatment guidelines [16, 27]. 
2.5. 
Justification for Dose 
In the Phase 2 clinical trials of ridinilazole a single dose of 200mg bid for 10 days was assessed. 
The dose was selected based on known effective gut concentrations of drug from animal models 
and from fecal concentrations established during Phase 1 clinical trials.  
As recognized in guidelines the use of PK/pharmacodynamic (PD) analyses do not assist in the 
prediction of an effective dose for oral agents intended to act locally within the gut lumen and this 
has been clearly demonstrated for other GI restricted antibiotics where no correlation between 
baseline MIC values, fecal concentrations and outcome could be demonstrated. Previous CDI 
antibiotic studies which varied the daily drug exposure generally failed to demonstrate any 
significant dose response treatment effect [28-30]. In addition, it has recently been shown that 
there is no significant improvement in rates of clinical improvement at end of therapy with high 
dose vancomycin regimens when compared to standard dose regimens [25]. 
In the Phase 2 study, 50 patients were administered ridinilazole 200 mg bid for 10 days for 
treatment of CDI. The dose was shown to be safe and well-tolerated and demonstrated superiority 
in sustained clinical response over vancomycin at the 10% level of significance (2-sided test). 
Furthermore, at this dose there was negligible systemic exposure of ridinilazole with mean (SD) 
plasma concentrations of 0.06 (0.11), 0.16 (0.26), and 0.18 (0.22) ng/mL at nominal 4 hours post-
dose on Days 1, 5, and 10, respectively. Furthermore, there was no notable effect on systemic 


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exposure due to food, gender, concomitant medication, age, or disease severity. Corresponding 
fecal concentrations of drug (Day 10 mean = 1,373 µg/g) were significantly above the MIC90 value 
of 0.125 µg/mL for C. difficile. 
Based on these results and the acceptable safety and tolerability profile seen in both the Phase 1 
and Phase 2 studies the same dose will be used in this larger Phase 3 study. 
As per IDSA guidelines, vancomycin 125 mg qid over 10 days is recommended therapy option for 
all severities of CDI.  
2.6. 
Benefit/Risk Assessment 
In 28-day oral toxicity studies in rats and dogs up to ridinilazole 1000 mg/kg/day no adverse study 
findings were seen with associated plasma levels below the LLOQ. Assessment of the systemic 
toxicity of ridinilazole for 28 days by the i.v. route in the rat and the dog identified the liver, lungs 
(findings possibly caused by particulate deposition of ridinilazole in capillary beds due to plasma 
saturation), spleen and kidneys (rat only), thymus and gall bladder (dog only) as target organs from 
a dose-level of ridinilazole 0.5 mg/kg/day. The associated ridinilazole plasma levels were several 
hundred-fold higher than the plasma levels observed in humans so far. 
In a Phase 1 study 42 healthy male patients received single oral doses of up to 2000 mg in the 
fasted state, a single oral dose of 1000 mg in the fed state or repeated doses at up to 500 mg bid 
for 9 days in the fed state with ridinilazole being considered safe and well tolerated. The most 
frequent drug-related AEs were classified as GI disorders: diarrhea and abdominal distension/pain. 
In Phase 2 studies a total of 64 patients (SMT19969/C002 50 patients; SMT19969/C003 
14 patients) received ridinilazole 200 mg bid for 10 days with no additional safety signals 
observed. The most frequent AEs were GI related. The safety profile of ridinilazole in the 
SMT19969/C002 study was comparable to the comparator, vancomycin, which will be used in this 
proposed study. 
In the SMT19969/C002 Phase 2 study in patients with CDI ridinilazole was shown to be superior 
at the pre-specified 10% level of significance (2-sided test) over standard of care vancomycin with 
respect to its primary endpoint of SCR and non-inferior with respect to its key secondary endpoint 
at AOC. In the SMT19969/C003 study ridinilazole displayed comparable clinical efficacy to 
fidaxomicin on sustained clinical response (SCR).  
In both Phase 2 clinical studies the plasma concentrations of ridinilazole were either below or close 
to the LLOQ, with a maximum systemic concentration of 1.31 ng/mL across all patients and 
assessment days. Therefore, GI related local tolerability AEs can be expected to be the main safety 
risks for ridinilazole. 
Together with pre-clinical data showing ridinilazole has a narrow spectrum activity against 
C. difficile and microbiome sparing properties, these clinical data provide a positive risk-benefit 
profile for patients in this study. Safety procedures during this clinical trial consist of vital signs, 
physical examinations, and laboratory assessments. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of ridinilazole may be found in the Investigator’s Brochure including the 
Reference Safety Information (RSI). A risk assessment for vancomycin can be found in the 
SPC/package insert. 


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Summit Therapeutics believes it is important to continue developing ridinilazole for patients with 
CDI while ensuring the safety of study patients, study personnel, and the public during 
Coronavirus Disease 2019 (COVID-19) pandemic. We have carefully assessed the Ri-CoDIFy 
studies in the context of the COVID-19 pandemic. Both CDI and COVID-19 are emerging 
infections that occur in at-risk populations (e.g., elderly, those with pre-existing medical 
conditions) and can result in significant morbidity and mortality. Like SARS-COV-2, C. difficile 
is a transmissible pathogen and infection rates may be lower initially with the recent 
implementation of COVID-19 public health actions. However, antibacterial treatments used 
empirically when a patient is being assessed with a respiratory infection or complicated by post-
COVID-19 bacterial pneumonias could lead to an increase in CDI infections and associated 
changes to the gut microbiome. New therapies for CDI that are effective, safe and have lower post-
treatment recurrences are needed.  
To mitigate the risk of exposure to COVID-19 and optimize data integrity, protocol amendment 5 
provides guidance for sites, including the allowance of all study visits to be completed remotely.  
 


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3. 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
• To compare the efficacy of 10 days’ dosing with ridinilazole (200 mg bid) with 
vancomycin (125 mg qid) in the treatment of patients with CDI 
 
Secondary Objectives 
• To compare the safety and tolerability of 10 days’ dosing with ridinilazole (200 mg bid) 
with vancomycin (125 mg qid) in the treatment of patients with CDI 
• 
To characterize the systemic exposure of ridinilazole in patients treated with ridinilazole 
(200 mg bid) tablets 
• 
To compare the effect of 10 days’ dosing with ridinilazole (200 mg bid) with 
vancomycin (125 mg qid) on the gut bile acid composition and on the gut microbiome 
diversity at the end of treatment (EOT) 
• 
 
Exploratory Objectives 
• To compare the effect of ridinilazole (200 mg bid) and vancomycin (125 mg qid) on the 
gut bile acid composition, microbiome, and antibiotic resistance gene profile at EOT and 
during the follow-up period  
• To assess the antibiotic susceptibility and ribotype of C. difficile isolates in patients 
receiving ridinilazole (200 mg bid) and vancomycin (125 mg qid) 
• To assess the impact of ridinilazole treatment on patient reported quality of life, resource 
utilization and health economics 
 
Primary Endpoint 
• Sustained Clinical Response (SCR) is defined as Clinical Response and no recurrence 
of CDI through 30 days post End of Treatment (EOT). 
 
Secondary Endpoints 
• Clinical Response 
• Clinical Cure 
• Sustained Clinical Response over 60 days – defined as Clinical Response and no 
recurrence of CDI through 60 days post EOT 
• Sustained Clinical Response over 90 days – defined as Clinical Response and no 
recurrence of CDI through 90 days post EOT 
• Change from baseline to EOT of the relative abundance of the 3 main bile acid groups 
(conjugated primary, primary and secondary bile acids) in stool samples 
• Change from baseline to EOT of the microbiota α-diversity (Shannon) index in stool 
samples 
• Change from baseline to EOT of the gut microbiota β-diversity (Bray-Curtis) index in 
stool samples 
 


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Definitions for the Primary and Secondary Endpoints 
Clinical Response is defined as  
• less than 3 unformed bowel movements (UBMs) for 2 consecutive days and maintained 
through EOT without further CDI treatment at EOT + 2 days, or  
• the investigator’s assessment that the subject no longer needs specific CDI antimicrobial 
treatment after completion of the course of study medication.  
Clinical cure is defined as the resolution of diarrhea (<3 UBMs in the 1-day period immediately 
prior to EOT, that is maintained for 2 days after EOT). 
Recurrence is defined as a new episode of diarrhea (≥3 UBMs) in a 1-day period with a positive 
C. difficile free toxin test or Cell Cytotoxicity Neutralization Assay (CCNA) that requires CDI 
treatment. 
A UBM is defined as a Type 5, 6 or 7 bowel movement on the Bristol Stool Chart. 
 
Safety Endpoints 
• Safety and tolerability as determined by AE and SAE reporting 
 
PK Endpoints 
• Ridinilazole plasma concentration in a subset of patients 
 
Health Economics and Outcomes Research (HEOR) Endpoints 
• Medical resource utilization and health economics endpoints (e.g., hospital readmission 
rates and length of hospital stay) 
• Change from baseline in EQ-5D-5L dimensions and health state VAS score 
• Change from baseline in Cdiff 32 domains (US sites) 
• 
 
Exploratory Endpoints 
• Time to resolution of diarrhea over the first 12 days – defined as the time from starting 
study treatment to the resolution of diarrhea (<3 UBMs in a 1-day period) 
• Change from baseline to Day 40 and up to Day 100 and at time of recurrence (if 
applicable) of the relative abundance of the bile acid components, conjugated primary, 
primary, and secondary bile acids in stool samples 
• Change from baseline to Day 40 and up to Day 100 and at time of recurrence (if 
applicable) of the microbiota α-diversity (Shannon) and β-diversity (Bray-Curtis) 
indices in stool samples 
• Change from baseline to EOT, Day 40 and up to Day 100 and at time of recurrence (if 
applicable) of the relative abundance of bacterial taxa, microbiome gene functions, and 
microbiome antibiotic-resistance genes in stool samples 
• Determination of the ribotype and susceptibility to ridinilazole, vancomycin and other 
antibacterial agents of C. difficile isolates collected in stool samples at baseline, EOT 
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4. 
STUDY DESIGN 
4.1. 
Patient Enrolment and Overall Design 
SMT19969/C004 is a Phase 3 randomized, double-blind, active controlled, parallel group, multi-
center study to compare the efficacy of 10 days’ dosing with ridinilazole 200 mg bid with 
vancomycin 125 mg qid in the treatment of patients with CDI. Approximately 680 patients 
(340 per arm) with a confirmed diagnosis of CDI will be enrolled in the study. 
It comprises a screening visit, a 10-day treatment period (beginning on the day of screening or the 
following day) and a 90-day follow-up period. 
Due to the acute nature of CDI and typical requirement for immediate treatment it is expected that 
the screening and the baseline/D1 assessments will be conducted on the same day but, the 
screening visit can be conducted within 3 days prior to the baseline/D1 visit if required for practical 
reasons. In addition, protocol v.6.0 introduces the option for all study visits to be conducted 
remotely due to the COVID-19 public health emergency. However, patients should continue to 
attend in-clinic visits whenever possible or as required. All assessments should be completed prior 
to randomization except for the following:  
• May be conducted after randomization but prior to 1st dose: weight, hematology and 
clinical chemistry samples, stool collection, eDiary training, EQ-5D-5L, Cdiff32 and 
medical utilization questions.  
• In a subset of patients, samples for PK analysis must be obtained (refer to Section 8.5). 
Randomization will occur after confirmation of eligibility is established with reference to the 
protocol inclusion and exclusion criteria. Patients will be randomized to receive ridinilazole or 
vancomycin in a 1:1 fashion. Randomization will be stratified by age (<65 years and ≥65 years), 
number of UBMs (<10 or ≥10) in the 24 hours prior to randomization, immunocompromised 
(YES/NO), and history of recurrent CDI (either none or 1 to 3 previous occurrences in the past 
12 months). Dosing with study treatment starts on Day 1 following randomization. Further visits 
will be scheduled at Day 10 (EOT), 12 (AOC), 40 (SCR), 70 (SCR) and 100 (SCR). A telephone 
check will be conducted at Day 5. Day 10 and Day 70 assessments may be conducted by telephone 
per Investigator judgement/convenience although arrangements will be required for patient drop-
off or site collection of a stool sample. The AOC visit will be conducted on Day 13 if the patient's 
10 days’ dosing is completed on Day 11.  
Patients will report dosing information to EOT and bowel movements daily up to Day 40, to 
support the primary endpoint analyses. Weekly contact with the patient will occur after Day 40 
until study completion to check for diarrhea/suspected recurrence. Investigators or designee will 
take measures to ensure patients are compliant with reporting diarrhea/suspected recurrence during 
the study.  
An assessment of suspected recurrence visit will occur for each suspected recurrence (≥ 3UBMs 
in one day, after assessment of cure or resolution of previous recurrence). 
Unscheduled visits may occur at the Investigator’s discretion (e.g. in the case of AEs). 
Additionally, patients should be requested to attend an in-clinic visit in the event of suspected 
recurrence of CDI. If they have a suspected recurrence and are not able to visit the clinic, this visit 


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may be completed at home over video conference with the site and with the additional assistance 
of a home health vendor, where required by the Investigator.  
Note: The term “Investigator” refers to the Principal Investigator of a clinical site or delegate as 
documented on the site Delegation of Authority log. 
Details on the timing of treatment and assessments are given in the Schedule of Activities Table 
(Section 1.3). 
COVID-19 
All assessment visits may be conducted at the clinic or remotely; however, whenever possible, 
screening/baseline visits should be conducted in-person at the clinic. Below are modifications to 
the protocol when remote assessments are necessary to protect patients, site personnel, or 
community safety, or to respond to COVID-19-related public health measures.  
For study visits that must be conducted remotely, and where the patient is not residing at home, 
investigative site staff or home healthcare vendor with proper delegation and training may see 
patients at an alternative location(s) where they have the privileges to do so, as permitted by local 
law and policies. Informed Consent is allowed in other than face to face method as per site local 
procedure or local regulations. This may include electronic signature or e-Consent if already in 
place and used at the site. Consent form(s) must be received and acknowledged by the site prior to 
the commencement of any study procedures. Original, signed consent form(s) must be returned to 
the site either at the next in-clinic visit, posted to the site, or returned via courier or any other 
approved alternate method.  
The stool sample may be couriered to the site. 
A sponsor contracted home healthcare vendor or appropriately trained and delegated site staff may 
conduct remote visit at the patient’s home or alternate agreed on location.  
The patient may take their own vital signs using their vital signs machine if they already have one 
or one that is provided to them (where available). The physical exam and vital signs when taken 
by the patient, ‘signs and symptoms of CDI’ assessments must be done via sponsor approved video 
conferencing between the Investigator and the patient.  
Following Investigator assessment of eligibility and randomization, eDiaries C-diff 32 
questionnaire (where applicable) and IMP should be provided directly to the patient (shipped by 
courier, provided by site staff or picked up by the patient or caregiver). 
Used IMP wallets and any unused medication should be returned to the site, either during the next 
in-clinic visit or shipped or couriered to site.  
4.2. 
End of Study Definition 
A patient is considered to have completed the study if he/she has completed all phases of the study 
including D100 assessments (EOS). 
The end of the study is defined as the date of the last study assessment of the last patient in the 
study. 


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4.3. 
Combination of Databases of Studies SMT19969/004 and SMT19969/005 
Measures were taken in Protocol Amendments 5 and subsequent amendments to mitigate the 
impact of the COVID-19 pandemic on the trial. To minimize the potential, unknown impact of the 
COVID-19 pandemic on the trial and because of a much slower enrollment rate than anticipated 
due to the ongoing pandemic, Summit has decided to combine its ongoing, Phase 3 studies, 
SMT19969/C004 and SMT19969/C005, into one study with a pre-specified Statistical Analysis 
Plan when these blinded, identical studies are at least half enrolled. As a result, both studies will 
be closed and will proceed with database lock and statistical analysis. The combined analysis will 
comprise a minimum of 680 randomized subjects. The modifications to the statistical handling of 
the study are described briefly in Section 9 and in detail in the Statistical Analysis Plan. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Patient must be at least 18 years of age, at the time of signing the informed consent. 
Type of Patient and Disease Characteristics 
2. Have signs and symptoms of CDI including diarrhea such that in the Investigator’s opinion 
CDI antimicrobial therapy is required. Diarrhea is defined as a change in bowel habits, 
with ≥3 UBMs (5, 6 or 7 on the Bristol Stool Chart) in the 24 h prior to randomization. 
3. Have the presence of either toxin A and/or B of C. difficile in the stool determined by a 
positive free toxin test (using a Sponsor agreed test). The stool sample must be current 
(produced within 72 hours prior to randomization). 
Sex 
4. Male or Female 
Male patients: 
• 
A male patient must agree to use contraception as detailed in Section 10.4 of this protocol 
during the treatment period and for at least 30 days after the last dose of study treatment 
and refrain from donating sperm during this period. 
Female patients:  
• A female patient is eligible to participate if she is not pregnant (see Section 10.4), not 
breastfeeding, and at least one of the following conditions applies: 
i. 
Not a woman of childbearing potential (WOCBP) as defined in Section 10.4 
OR 
ii. 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
during the treatment period and for at least 30 days after the last dose of study 
treatment. 
Informed Consent 
5. Has provided documented signed informed consent and any authorizations required by 
local law (e.g. Protected Health Information [PHI]). If unable to read, understand and sign 
the informed consent form a legally authorized representative (LAR) may provide consent 
on the patient’s behalf if permitted by the Institutional Review Board (IRB)/Ethics 
Committee (EC). 


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5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Have had more than one prior episode of CDI in the previous 3 months or more than 
3 episodes in the past 12 months prior to randomization. 
2. Have a history of chronic diarrheal disease including inflammatory bowel disease (Crohn’s 
disease or ulcerative colitis). 
3. Have had a positive diagnostic test for other GI pathogens, considered to be clinically 
relevant, within 2 weeks of randomization.  
4. Have had major gastrointestinal (GI) tract surgery (e.g. significant bowel resection or 
pancreatectomy) within 3 months of randomization (this does not include appendectomy 
or cholecystectomy); or the presence of a colostomy or ileostomy or likely requirement of 
an ostomy during the study.  
5. Have life threatening or fulminant CDI with evidence of hypotension, septic shock, 
peritoneal signs or absence of bowel sounds, or toxic megacolon. 
6. This number (EC #6) has been intentionally left blank. 
Prior/Concomitant Therapy 
7. Have had more than the equivalent of 24 hours of dosing of antimicrobial treatment against 
the current episode of CDI prior to randomization. (i.e. more than four doses of oral 
vancomycin, two doses of fidaxomicin or teicoplanin, or three doses of metronidazole).  
8. Prior or current use of anti-toxin antibodies including bezlotoxumab within the 6 months 
prior to randomization. 
9. Are unable to discontinue products affecting disease progression at randomization 
(see Section 6.5.1 for a list of potentially confounding medications).  
Prior/Concurrent Clinical Study Experience 
10. Has been involved in a clinical trial and received an investigational medicinal product for 
indications other than CDI within 1 month or five half-lives (whichever is longer) or within 
3 months if the investigational medical product was for CDI. 
11. Have received an investigational vaccine against C. difficile. 


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Other Exclusions 
12. Patients that the Investigator feels are inappropriate for the study:  
a. patients with any condition that, in the Investigator's judgment, would make the 
patient unsuitable for inclusion in the study, such as chronic diarrhea, vomiting that 
cannot be managed with anti-emetics, inability to swallow study medication, or 
medically unstable with critical illness (e.g. requiring vasopressors, intubation, etc.).  
b. patients who, in the opinion of the Investigator, are not likely to complete the study, 
e.g. life expectancy less than 100 days.  
c. patients with known hypersensitivity or intolerance to ridinilazole, vancomycin, 
and/or their excipients  
d. patients or their caregivers who are unable to comply with protocol requirements, e.g. 
attend study visits, report bowel movements and suspected recurrence, provide stool 
samples or undergo blood draws. 
Note: Investigators are encouraged to contact the medical monitor to discuss individual cases as 
required. 
5.3. 
Lifestyle Considerations 
There are not any lifestyle restrictions applicable through the study. 
5.3.1. 
Meals and Dietary Restrictions 
No meal or dietary restrictions.  
5.3.2. 
Caffeine, Alcohol, and Tobacco 
No caffeine, alcohol, or tobacco restrictions.  
5.3.3. 
Activity 
No activity restrictions.  
5.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in any of the clinical study 
assessments but are not subsequently randomized into the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
reasons and any serious adverse event (SAE). 
It is possible for patients to be rescreened once for this study. If a patient is rescreened a new 
patient number will be assigned.  
 


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6. 
STUDY TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study patient per the study protocol. All study 
treatments will be provided on behalf of Summit (Oxford) Limited. 
6.1. 
Study Treatment(s) Administered 
Patients will be randomized into one of two treatment arms 
Table 1: 
Dosing Schedule per 24 Hours 
 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Ridinilazole Arm 
Ridinilazole 200mg 
& Vancomycin 
Dummy Placebo 
Ridinilazole 
Dummy Placebo & 
Vancomycin 
Dummy Placebo 
Ridinilazole 200mg 
& Vancomycin 
Dummy Placebo 
Ridinilazole 
Dummy Placebo & 
Vancomycin 
Dummy Placebo 
Vancomycin Arm 
Ridinilazole Dummy 
Placebo & 
Vancomycin 125mg 
Ridinilazole 
Dummy Placebo & 
Vancomycin 
125mg 
Ridinilazole 
Dummy Placebo & 
Vancomycin 
125mg 
Ridinilazole 
Dummy Placebo & 
Vancomycin 
125mg 
Patients will take one dose (one tablet and one capsule) four times a day for 10 days (40 doses). 
It is important that patients: 
• Are instructed to complete the full 10-day course of IMP in order to fully evaluate efficacy. 
• Take doses strictly in numerical order to ensure correct timing of active vs placebo 
o Must only remove one dose at a time (one tablet and one capsule) from the 
provided wallet. Removing multiple doses from the wallet is not permitted. 
• Do not crush or break the tablets or open the capsules (e.g. to pass through a feeding tube). 
Study treatment will be provided in a blister wallet labeled per country requirements. Each wallet 
will have a unique identifier which will be used to allocate double-blind study treatment to each 
patient via the Interactive Response Technology (IRT) system. Each wallet will contain all doses 
required for the total treatment period (40 doses over 10 days). Doses will be clearly labeled 1 to 
40 on the wallets. It is important the patient takes each dose in order number starting with 1 and 
finishing with 40. If a patient misses a dose, they should be instructed to take the missed dose 
before or with the next dose. No more than 2 doses should be taken at any one time. For example, 
if Dose 3 is missed, take Dose 3 before or with Dose 4.  
6.2. 
Preparation/Handling/Storage/Accountability 
The Investigator or designee must confirm appropriate temperature conditions (below 25°C and 
not refrigerated or frozen) have been maintained during transit for all study treatment received 
and any product complaints or discrepancies are reported and resolved before use of the study 
treatment. 
Only patients enrolled in the study may receive study treatment and only authorized site staff may 
supply or administer study treatment (as documented by the Investigator on the Delegation of 
Authority log). All study treatment must be stored in a secure, environmentally controlled, and 


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monitored (manual or automated) area in accordance with the labeled storage conditions with 
access limited to the Investigator and authorized site staff. 
Any product complaints or storage temperature excursions identified during storage of 
investigational product should be reported to the Sponsor and resolved prior to use. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
The Investigator or Pharmacist should arrange for destruction of any unused IMP following full 
reconciliation of IMP and Sponsor (or delegate) approval. Destruction will be conducted locally 
where possible using a method in line with Sponsor provided requirements. Destruction should be 
conducted per the sites standard operating procedure (SOP) and a destruction certificate, including 
method of destruction, should be issued. IMP may be returned to the Sponsor if local destruction 
is not possible. 
Further guidance and information for the final disposition of unused study treatments are provided 
in the Investigator Trial Site File.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization will occur on Day 1 after eligibility for the study has been confirmed.  
Patients will be randomized to one of two treatment groups in a 1:1 ratio to either the ridinilazole 
arm or the vancomycin arm.  
The Investigator or designee will use the IRT system to randomize a patient.  
A computer-generated central randomization will be used which will be stratified by age 
(<65 years and ≥65 years), number of UBMs (<10 or ≥10) in the 24 hours prior to randomization, 
immunocompromised (YES/NO), and history of recurrent CDI (either none or 1 to 3 previous 
occurrences in the past 12 months). Once a randomization number has been assigned it will not be 
re-assigned. 
Study treatment will be dispensed at the randomization visit (Day 1) as summarized in SoA 
(Section 1.3). Returned study treatment should not be re-dispensed to patients. 
This is a double-blind study. To maintain the blind, a double-dummy approach for study treatment 
will be employed. Vancomycin will be encapsulated within a Size 0 Swedish Orange, hard gelatin, 
and immediate release capsule. There will be a matching vancomycin placebo. Ridinilazole is 
presented as a coated tablet. There will be a matching ridinilazole placebo. Patients randomized to 
ridinilazole will receive active ridinilazole, ridinilazole placebo and vancomycin placebo to 
achieve dosing with ridinilazole bid. Patients randomized to vancomycin will receive active 
vancomycin and ridinilazole placebo to achieve dosing with vancomycin qid. The study drug and 
packaging will be manufactured in such a way that patients and study site staff will not know to 
which arm a patient has been assigned. 


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The adverse event profile of vancomycin and ridinilazole indicates that most adverse events can 
be managed without unblinding. If the Investigator believes unblinding is necessary to manage 
a patient, then emergency unblinding may be conducted via the IRT system but should only be 
performed when knowledge of the treatment is essential for medical decisions and/or further 
emergency management of the patient.  
In case of an emergency, the Investigator (whenever possible) is responsible for determining if 
unblinding is warranted. Patient safety must always be the first consideration.  
If unblinding is determined to be warranted, the Investigator should make every effort to contact 
the Medical Monitor prior to unblinding, unless this could delay emergency treatment of the 
patient.  
If unblinding occurs, the Sponsor must be notified within 24 hours. The Sponsor should remain 
blind to the treatment assignment. The date and reason that the blind was broken must be 
recorded in the source documentation. 
6.4. 
Study Treatment Compliance  
In accordance with ICH-GCP, each study center will account for all supplies of blinded 
medication. Details of receipt, storage, assembly, and return will be recorded. The unit of 
accountability will be one capsule or one tablet. 
Several measures are in place to ensure patients are compliant with their medication schedule. 
These include clear labelling of treatment wallet, the use of a patient eDiary or frequent contact 
with the patient, and reminders from the site staff. Patients should record the time and date they 
take each dose.  
Compliance with the study treatment and documentation of dosing and bowel movements 
is critical to the integrity of the primary endpoint.  
To help ensure compliance the Investigator will discuss compliance with the patient: 
• At Day 5 to ensure the treatment is being administered per protocol and to remind 
the patient to continue to complete all doses regardless of resolution of symptoms.  
• If records indicate that the patient has not been reporting dosing and/or bowel 
movements as required. 
The eDiary will be programmed with reminders for patients to take the medication and to 
complete their eDiary daily until D40. 
The patient will be required to return all empty packaging and unused study medication to the 
Investigator at the Day 12 (AOC) visit so that a final compliance check can be conducted. If the 
patient is unable to attend in-clinic visits it may be shipped or couriered to the site.  
In the event of overdose see Section 8.4. 


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6.5. 
Concomitant Therapy 
Concomitant therapy is any medication, vaccine, procedure or therapy (including over-the-counter 
or prescription medicines, vitamins, and/or herbal supplements) that the patient is receiving at the 
time of enrollment or receives during the study. 
All concomitant therapies should be recorded from 4 weeks prior to randomization and throughout 
the study up to D100 (see Section 6.5.1). The reason for use, dates of administration and dosing 
information should be recorded in the CRF. 
6.5.1. 
Potential Confounding Medications  
Refer to Table 2A and B below for a list of medications that may impact CDI status and hence 
have the potential to confound study results. Control over administration of these medications is 
necessary, considering the primary endpoint of the study, but it is understood that a medication 
should not be withheld for purposes of the study if an alternative and comparable treatment cannot 
be provided and the patient’s health would otherwise be compromised. 
Potentially Confounding Medications:  
Medications that could potentially confound data analysis should be avoided if possible, 
without compromising the care of the patient.  
If antimicrobial therapy is required for infections other than those due to C. difficile, 
antimicrobials without activity/efficacy against C. difficile should be prescribed,  
Confounding medications include, but are not limited to, these listed in the following table.  
 


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Table 2A: 
Potentially Confounding Medications Which May Exclude Patients from 
Randomization 
Contact the Medical Monitor to discuss individual cases as required 
Drug Class 
At Randomization 
CDI Treatments 
Antimicrobial treatments for CDI (including but 
not limited to oral vancomycin, IV or oral 
metronidazole, fidaxomicin, oral teicoplanin) 
Exclude patient if more than 24 hours (or 
equivalent) of treatment for the current/baseline 
CDI. 
Anti-toxin antibodies including bezlotoxumab 
Exclude patient if taken within 6 months of 
randomization 
Antimicrobial treatments that may be effective at 
treating CDI (including but not limited to oral 
rifaximin, tigecycline, nitazoxanide, oral 
bacitracin, fusidic acid) 
Exclude patient if more than 24 hours (or 
equivalent) of treatment immediately prior to 
randomization 
Probiotics or prebiotics  
None permitted 
Intravenous immunoglobulin (IVIG) 
Exclude patient if taken within 3 months prior to 
randomization 
Fecal microbiota replacement 
Exclude patient if taken within 3 months prior to 
randomization 
IMP for CDI 
Exclude patient if taken within 3 months prior to 
randomization  
Investigational vaccine against C. difficile 
Exclude patient if taken any time prior to 
randomization 
Non-CDI Treatments 
 
Other antimicrobials not active against C. 
difficile1 
Permitted 
Opiates 
Stable, decreasing or planned to be stopped by 
Day 7 of randomization 
Anti-diarrheals, anti-peristaltics  
Stable, decreasing or planned to be stopped by 
Day 7 following randomization. 
IMP for other indications 
Exclude patient if used within one month or five 
half-lives (whichever is longer) prior to 
randomization 
Treatment of cancer using chemotherapy, 
radiotherapy, biologic treatments including 
(monoclonal) antibodies, immune-oncological 
treatments 
Only exclude patient if the cancer treatment given 
is generally associated with or is causing diarrhea, 
vomiting and/or severe nausea that cannot be 
managed with antiemetics, severe mucositis and/or 
severe immunosuppression 
 
1 May contribute to recurrence. Important to document in the eCRF throughout the study. 


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Table 2B: 
Potentially Confounding Medications Which May Not Be Permitted During 
Study Treatment (Day 1 to Day 12 and/or during Follow-up (Day 12 to 
Day 100)  
Contact the Medical Monitor to discuss individual cases as required 
Drug Class 
From Randomization to 
Day 12/AOC 
During Follow Up 
CDI Treatments 
 
 
Antimicrobial treatments for 
CDI (including but not limited 
to oral vancomycin, IV or oral 
metronidazole, fidaxomicin, oral 
teicoplanin) 
None permitted 
For recurrence, as per standard 
clinical practice 
Anti-toxin antibodies including 
bezlotoxumab 
None permitted 
For recurrence, as per standard 
clinical practice 
Antimicrobial treatments that 
may be effective at treating CDI 
(including but not limited to oral 
rifaximin, tigecycline, 
nitazoxanide, oral bacitracin, 
fusidic acid) 
None permitted 
Prescribe alternative 
antimicrobial if use is for 
conditions other than CDI where 
possible. 
Probiotics or prebiotics  
None permitted 
For recurrence, as per standard 
clinical practice 
Intravenous immunoglobulin 
(IVIG) 
None permitted 
For recurrence, as per standard 
clinical practice 
Fecal microbiota replacement 
None permitted 
For recurrence, as per standard 
clinical practice 
IMP for CDI 
None permitted 
None permitted 
Investigational vaccine against 
C. difficile 
None permitted 
None permitted 
Non-CDI Treatments 
 
 
Other antimicrobials not active 
against C. difficile2 
Permitted 
Permitted 
Opiates 
Allowed if stable, decreasing or 
planned to be stopped by Day 7 
following randomization3 
Allowed if stable, decreasing or 
stopped3. 
Anti-diarrheals, anti-peristaltics  
Allowed if stable, decreasing or 
planned to be stopped by Day 7 
of randomization3 
For recurrence, as per standard 
clinical practice.  
 
2 May contribute to recurrence. Important to document in the eCRF throughout the study. 
3 Preference is to stop use by Day 7 following randomization 


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Drug Class 
From Randomization to 
Day 12/AOC 
During Follow Up 
IMP for other indications 
None permitted 
None permitted 
Treatment of cancer using 
chemotherapy, radiotherapy, 
biologic treatments including 
(monoclonal) antibodies, 
immune-oncological treatments 
Not permitted if the cancer 
treatment given is generally 
associated with or is causing 
diarrhea, vomiting and/or severe 
nausea that cannot be managed 
with antiemetics, severe 
mucositis and/or severe 
immunosuppression 
Not permitted if the cancer 
treatment given is generally 
associated with or is causing 
diarrhea, vomiting and/or severe 
nausea that cannot be managed 
with antiemetics, severe 
mucositis and/or severe 
immunosuppression 
Any potential confounding medications taken 4 weeks prior to randomization should be recorded 
in the CRF along with any potential confounding medications started, stopped, or changed during 
the study (up to Day 100). 
During the study both the treatment period and follow up period, patients who take any 
confounding medications should not necessarily be discontinued from study treatment and should 
not be withdrawn from the study.  
Investigators should contact the medical monitor for any questions regarding concomitant or prior 
therapy. 
6.6. 
Dose Modification 
Not applicable 
 


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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL FROM STUDY 
7.1. 
Discontinuation of Study Treatment  
A patient will discontinue study treatment for any of the following reasons: 
• Withdrawal of consent to continue taking treatment. The reason for this will be 
documented if provided. 
• The study Investigator or Sponsor, for any reason, decides the patient should be 
discontinued from the treatment.  
• Adverse events, classed as possibly or probably study drug-related by the Investigator, 
which cannot be tolerated by the patient. 
• Pregnancy during the treatment period. See Section 10.4 and Section 8.3.5 Pregnancy. 
If a patient is discontinued from treatment, they should continue with all study visits and 
assessments so that data can be collected. If patients will not agree to this then they should 
complete early termination assessments and return the study treatment wallet.  
See the SoA (Section 1.3) for data to be collected at the time of study treatment discontinuation 
and early termination of follow-up and for any further evaluations that need to be completed.  
Study drug assigned to the discontinued patient must not be assigned to another patient. 
7.2. 
Patient Withdrawal from the Study 
All patients are encouraged to continue through to the end of the study at Day 100 even if they 
discontinue from study treatment early. However, a patient may withdraw from the study at any 
time at his/her own request or may be withdrawn at any time at the discretion of the Investigator 
for safety, behavioural, compliance, or administrative reasons. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site study records. 
See the SoA for data to be collected at the time of study withdrawal and follow-up and for any 
further evaluations that need to be completed. The reason for withdrawal is to be documented on 
the CRF and in the source document. 
7.3. 
Lost to Follow Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether the patient wishes to and/or should continue in the study. 


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• Before a patient is deemed lost to follow up, the Investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 telephone calls and, if necessary, 
a certified letter to the patient’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the study.  
 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions will not be granted by the Sponsor or delegate. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment. 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The Investigator or study team designee will maintain 
a screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
8.1. 
Efficacy Assessments  
8.1.1. 
Patient Reporting of Diarrhea/Suspected Recurrence 
Patients should be instructed to contact the site if their diarrhea returns (≥ 3UBMs per day for at 
least 1 day). 
Additionally, patients will report dosing information daily until EOT and bowel movement 
information daily until D40. After D40 the site will contact the patient weekly to check for new 
episodes of diarrhea/suspected recurrence. 
Patients will be asked to report the following: 
• Date and time of each dose of study medication to EOT. 
• Date, time, and consistency (using the Bristol Stool Chart) of all bowel movements up to 
Day 12/AOC. 
• Date, time, and consistency of all unformed bowel movements (UBMs) through Day 40. 
• During weekly contacts with the patient after Day 40 and through Day 100, any episodes 
of ≥3 UBMs within 1 day since the last site contact. 
Able patients will be provided with an electronic diary (eDiary) to report this information up to 
Day 40. Adequate time should be allocated to ensure that the patient understands how to complete 
the eDiary and is willing and able to do so every day up to and including Day 40 (at least 30 days 
following the last dose of study treatment). The site should contact the patient to collect this 
information if use of an eDiary is not possible. 


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Patient Reported Bowel Movement Data 
• Assessment of response to study treatment and identification of all episodes of CDI 
recurrence rely on bowel movement data collected from the patient.  
• It is critical that the Investigator and patient understands that accurate, complete, 
and contemporaneous data is required to meet the study primary objective. 
• It is specifically important to ensure each patient provides this information every 
day to Day 40 (at least 30 days following the last dose of study treatment). 
• Following Day 40 the site will contact the patient weekly to ask about potential 
diarrhea and assess for suspected recurrence as required. 
Reported information on bowel movements will be used by the Investigator to determine if a 
suspected recurrence of CDI requires assessment. The Investigator or designee will be required to 
monitor the patient’s unformed bowel movement (UBMs) and assess any suspected recurrence of 
CDI.  
Suspected Recurrence: 
After the patient was deemed cured, if ≥3 UBMs are experienced over a 1-day period, the 
Investigator should arrange an assessment for suspected recurrence. If a free toxin test is not 
conducted, the reason should be recorded in the CRF along with a determination of whether 
recurrence of CDI was suspected.  
Changes to eDiary Data: 
For data collected via an eDiary, data changes are not permitted. Changes to eDiary data will be 
limited to administrative corrections such as erroneous patient number, visit date, patient status, 
timestamps and elimination of duplicate data or merging of data sets for the same patient. 
Patient reported eDiary errors will be reported in the CRF describing the error and the correct 
information.  
eDiary Programmed Alerts: 
For data collected via an eDiary, Investigators will be alerted if a daily eDiary completion is 
missed. In these cases, the Investigator will contact the patient, within 72h of the day missed, to 
determine if any UBMs occurred. This information will be documented in the CRF.  
Care Provider Support: 
The preference is that patients enter their own data into the eDiary directly. However, it is expected 
that some patients will have difficulty completing the eDiary. Such patients may be supported by 
a care provider entering the data into the eDiary on behalf of the patient. This is permitted if the 
Investigator is confident that the support provided is adequate to ensure accurate entries into the 
eDiary on the patient’s behalf. The Investigator must document agreement for a care provider to 
enter information into the eDiary on behalf of the patient and the rationale. The care provider must 
only enter information into the eDiary using a unique user ID and PIN following training.  
A care provider will not complete the EQ-5D on behalf of the patient.  


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Alternative to the eDiary: 
The CDI patient population is frequently comorbid, elderly, and reliant on family members. For 
patients that are unable to complete the eDiary, and where the care provider option is not possible, 
an alternative to completion of the eDiary can be utilized. 
The Investigator/site staff or delegate will contact the patient daily to collect dosing and bowel 
movement information. A detailed report of the contact must be documented in the source records 
including date and time of contact, contact participants, details of dosing and bowel movement 
information since the last contact. Details of dosing and bowel movement will be entered into the 
CRF. If an Investigator chose this method of collection the site and patient must be willing to make 
every effort to report this daily. Exceptions may be made (if necessary) over the weekend/national 
holidays. Sites are expected to make all efforts to have adequate holiday and vacation coverage to 
ensure information is collected within 72h of the event. In general information collected >72h after 
the event will be considered missing data for that day unless there is adequate supporting 
documentation to confirm the data (especially for the date and time of each BM). 
Where feasible (available and with applicable local regulatory approvals), a second alternative to 
the eDiary will be made available. Sites may use a 3rd party vendor to contact patients to collect 
dosing and bowel movement information daily. Patients must provide specific consent to use this 
option. Even when utilizing a 3rd party vendor, the Investigator is still responsible for ensuring any 
episodes of ≥3 UBMs in 1- day period are assessed. 
8.1.2. 
Signs and Symptoms of CDI 
The Investigator should record the patient’s current signs and symptoms of CDI at baseline/D1 
and at the Day 12/AOC visit. Current signs and symptoms will also be recorded during an 
assessment of suspected recurrence. The investigator should ask the patient for signs and 
symptoms that have occurred over the 1-day period prior to assessment. 
Suspected recurrence: if there is no recurrence of CDI per the protocol definition (≥3 UBMs in a 
1-day period, a positive C. difficile free toxin test or CCNA and requiring CDI treatment) any 
reported signs and symptoms (or preferably the associated diagnosis) should be reported as 
AEs/SAEs if prior to the Day 40 visit.  
Record all symptoms (loose stools, abdominal cramps or pain, fever, visible blood or pus in stool, 
nausea, vomiting, loss of appetite or other) that apply to the patient at that evaluation on the CRF 
at the visits indicated.  
The Investigator will refer to the patient reported signs and symptoms when assessing cure and/or 
recurrence of CDI. 
8.1.3. 
Suspected Recurrence 
A recurrence of CDI is considered a disease related event (DRE) and not an adverse event (AE or 
SAE). See Section 8.3.7. In the case of a suspected recurrence, a suspected recurrence of CDI CRF 
page should be completed-. Certain specified - DRE complications of CDI should be reported as 
SAEs (refer to Section 8.3.7).  
Recurrence is defined as a new episode of diarrhea (≥3 UBMs in a 1-day period) with a positive 
C. difficile free toxin test or CCNA that requires CDI treatment.  


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A UBM is defined as a Type 5, 6 or 7 bowel movement on the Bristol Stool Chart. 
Following cure of the baseline CDI, if diarrhea returns (≥3 UBMs in a 1-day period) the 
Investigator will contact the patient to assess for recurrence. 
It is required that every new episode of diarrhea (≥3 UBMs in a 1-day period) is investigated via 
a free toxin test unless the Investigator is highly confident that the diarrhea is due to a cause other 
than C. difficile.  
• If recurrence of CDI is not suspected: record the reason in the CRF on the “Suspected 
Recurrence of CDI” CRF page. 
• If recurrence is suspected:  
o Conduct a free toxin test as soon as possible and no later than 2 days after 
identifying a suspected recurrence. If the test is invalid it should be repeated. If the 
FTT test is negative it can be repeated once on the same sample or fresh sample. 
o Complete the “Suspected Recurrence of CDI” CRF page 
o In all instances of suspected recurrence of CDI that are associated with a negative 
free toxin result obtained locally by the site, a stool sample should be collected and 
sent for testing by Cell Cytotoxicity Neutralization Assay (CCNA) at a central 
laboratory. This is a requirement irrespective of any locally conducted CCNA.  
In addition, at the scheduled visits indicated in the SoA (Section 1.3), the Investigator should also 
assess whether the patient has met the criteria for recurrence.  
Investigators are requested, subject to local treatment guidelines and Investigator judgement, to 
await the results of the free toxin test prior to initiating antimicrobial treatment for a suspected 
recurrence. The Investigator should discuss with the Medical Monitor if required. 
All the assessments as indicated in the SoA Recurrence Visit (Section 1.3) should be carried out. 
Investigators are urged to follow the patient closely and directly assess and provide medical 
management of each suspected recurrence throughout the study. If a patient is assessed and/or 
treated by a non-study health care professional, the Investigator should obtain as much information 
as possible for CRF entry.  
To ensure the data integrity of the primary and secondary endpoints, it is critical that the 
following requirements are met for all patients where possible: 
• A free toxin test is conducted as soon as possible following suspicion of recurrence. 
• Any potentially confounding medications initiated must be recorded in the CRF 
• For all suspected recurrences associated with a negative free toxin test result 
obtained locally by the site, a stool sample should be collected for testing by CCNA 
at a central laboratory. 


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8.1.4. 
Investigator Assessments of Cure and Sustained Clinical Response 
Assessed by the Investigator at the times outlined in the SoA (Section 1.3).  
Investigator assessment of cure: 
• At the D12/AOC visit the Investigator or medically qualified designee will determine if 
the patient is CURED or has FAILED to respond to study medication.  
• If the Investigator assesses a patient as FAILED at D12/AOC visit, the Investigator will 
continue to follow the patient and record an unscheduled visit as soon as the subject is 
assessed as cured into the CRF. The Investigator’s assessment is based on the reduction of 
UBMs since baseline, clinical signs and symptoms and need for further treatment for CDI. 
A patient will be deemed cured once the Investigator’s assessment is that the baseline CDI 
has resolved such that no further non-study CDI treatment is needed. 
o At D40, D70 and D100 the Investigator or medically qualified designee will 
determine if the patient was CURED since the previous assessment or continues to 
be FAILED. Once CURED has been recorded once (on D40 or D70), the 
subsequent assessments are not required (not applicable). 
• Following cure of the baseline CDI (including patient that initially failed at D12/AOC and 
subsequently cured (meaning their baseline CDI resolved), the Investigator will continue 
to follow-up on any subsequent suspected recurrences and record them in the CRF. 
Investigator assessment of sustained clinical response: 
• At D40, D70 and D100 the Investigator or medically qualified designee will determine if 
the patient has a sustained clinical response or experienced RECURRENCE since the 
previous assessment. When recurrence has been recorded once, the subsequent assessments 
are not required (not applicable).  
• If the Investigator assesses a patient as FAILED for sustained clinical response, then a 
future assessment of sustained clinical response, at subsequent time points, is no longer 
required.  
The Investigator will assess cure/failure and recurrence based on available information which 
includes, but is not limited to, improvement from baseline in the number of UBMs, signs & 
symptoms of CDI, and the requirement for CDI medication. The Investigator should assess 
cure/failure in a way that best reflects the Investigator’s standard clinical practice. 
NOTE: In line with treatment guidelines, laboratory and/or diagnostic testing for CDI should not 
be used to determine AOC [17, 31-33]. 
8.1.5. 
Stool (Fecal) Collection for Characterization 
Patients will be required to provide a stool sample at the time points specified in the SoA 
(Section 1.3). Patients will be provided with a home collection kit. If a sample is requested by the 
Investigator, the patient will provide the sample to the study site within 24 hours of producing the 
sample. Samples will be immediately tested with a free toxin test, in the event of a suspected 
recurrence. Aliquots of the sample will be prepared and immediately frozen and stored for 
shipment to the Central Laboratory. Guidance and instructions for Investigators will be available 
in the lab manual. 


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Stool samples will be subject to the following analyses: 
• Free toxin test for confirmation of eligibility and in the event of suspected recurrence. 
Sites may use an established local free toxin test if it is a suitable test, and it is prospectively 
agreed with the Sponsor. Suitable tests will have appropriate regulatory approvals (FDA 
approval, EU CE Mark or equivalent). Free toxin tests will be provided for the site/site 
laboratory use if a suitable test is not available locally. A negative free toxin test may only 
be repeated once on the same sample or a fresh sample. 
o Since C. difficile free toxin EIA (enzyme immunoassay) kits can have sub-optimal 
sensitivity, a CCNA will be conducted via a central laboratory for those suspected 
recurrence events that had a negative free toxin test result obtained locally by the 
site. 
• Microbiology, microbiome, and bile acid analysis at specialized centralized laboratories. 
The Investigator or designee will follow instructions in the lab manual and aliquot the 
samples as required. 
 
The samples from all patients will undergo the following assessments: 
• 
C. difficile isolates recovered from samples (at baseline, end of treatment, and recurrence) 
will undergo ribotyping and susceptibility testing using a panel of antimicrobials that may 
include, but is not be limited to, ridinilazole, fidaxomicin, vancomycin, metronidazole, 
rifaximin, and tigecycline.  
• 
The presence or absence of vancomycin resistant Enterococci (VRE) may also be 
assessed. 
In addition, the relative impact of ridinilazole and vancomycin on the gut microbiome and bile 
acid composition will also be assessed. Fecal samples will be collected from all patients at the time 
points specified in the SoA (Section 1.3). Selection of samples to be analysed will be based on pre-
specified criteria. Specific assessments may include: 
• 
Shotgun metagenomic sequencing will be used to investigate the gut microbiome 
(microbiota and gene composition) beyond the cultivable species and thus determine 
deeper effects on the bowel microbiome during therapy. 
• A free toxin test is conducted as soon as possible following suspicion of recurrence. 
This is critical to meet the primary objective of the study. 
• Stool samples for free toxin testing should be as fresh as possible (preferably 
produced less than 24 hours prior to the time of the test). 
• Sites should request patients keep samples refrigerated from the point of production and 
sites should maintain refrigeration to the point of testing. 
• A stool sample produced by the patient should be processed and frozen by the site within 
24 hours for microbiology, microbiome, and bile acids. If the sample used for CDI 
testing was produced by the patient >24 hours, a fresh sample should be provided where 
possible. Suspected cases of CDI with a negative free toxin test will be tested at a Central 
Laboratory via a CCNA. 


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• 
Using Liquid Chromatography-mass spectrometry (LC-MS/MS), fecal samples will be 
analyzed for bile acids.  
Stool samples will be stored for up to 5 years for potential future microbiology, microbiome and/or 
metabolome analysis. 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Medical History (Including CDI History)  
The following will be recorded prior to randomization: 
• All relevant and significant medical history for 12 months prior to randomization  
• All medications taken up to 4 weeks prior to randomization 
• All known CDIs along with the treatment administered 
• Use of any potential confounding medication up to 4 weeks prior to randomization  
• Information on the current/baseline CDI including confirmation of positive C. difficile free 
toxin, the number of UBMs in the 24 hours prior to randomization and current signs and 
symptoms of CDI.  
Relevant medical history includes events that may contribute to the outcome of a treatment for 
CDI such as: major gastrointestinal surgery, nonsurgical gastrointestinal procedures, significant 
infections, conditions requiring immunosuppression, gastrointestinal disorders/diseases, or cancer. 
Significant medical history includes pathology (events, diseases, disorders, or conditions) that may 
be useful in assessing a safety event occurring during the study such as: major non-gastrointestinal 
surgery and major pathology of the cardiovascular, respiratory, endocrine, immunological 
(including HIV status) and neurological systems.  
8.2.2. 
Physical Examinations 
The ECG and physical exam may be conducted at the screening or baseline visit; if conducted at 
screening, the vital sign assessment will still need to be repeated at baseline. 
A physical examination will include, at a minimum, assessments of the cardiovascular, respiratory, 
gastrointestinal and neurological systems. Height (baseline only) and weight will also be measured 
and recorded. 
At the discretion of the Investigator, focused physical examinations may be completed on Day 12, 
Day 40, and recurrence visits. The examination should include the measurement of vital signs 
(temperature, blood pressure, pulse) and an abdominal examination.  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.3. 
Vital Signs 
Vital signs will be measured in a semi-supine position after 5 minutes’ rest and will include 
temperature, systolic and diastolic blood pressure and pulse.  
The same arm should be used to measure blood pressure throughout the study for each patient. 


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8.2.4. 
Electrocardiograms 
A single 12-lead ECG will be obtained prior to randomization using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals. Manual 
measurements and calculations may be conducted in the absence of automated reporting of such 
intervals. 
The screening ECG will be reviewed and signed by the Investigator or a medically qualified 
designee. Any abnormalities will be marked as clinically significant or not clinically significant. 
Clinically significant abnormalities will be documented as current medical history and reported as 
an SAE if the definition of serious is met. Importantly, an ECG does not need to be completed if 
patient’s most recent ECG was normal and was completed in the 12 months prior. 
8.2.5. 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA (Section 1.3) 
for the timing and frequency.  
The Investigator must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF.  
The laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the patient's condition. 
All laboratory tests (with the exception of pregnancy tests) with values considered clinically 
significantly abnormal during participation in the study or within 5 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator or medical monitor. 
If such values do not return to normal/baseline within a period judged reasonable by the 
Investigator, the etiology should be identified, and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Section 10.2, must be conducted in 
accordance with the laboratory manual and the SoA (Section 1.3).  
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered clinically 
significant by the Investigator (e.g., SAE or AE), then the results must be recorded in the CRF.  
8.3. 
Adverse Events and Serious Adverse Events 
Refer to Section 10.3 for definitions and for details on how to assess, classify, and report 
AEs/SAEs. 
Adverse Events (AEs) will be reported by the patient (or, when appropriate, by a caregiver, 
surrogate, or the patient's legally authorized representative/guardian).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study treatment or study procedures, or that 
caused the patient to discontinue the study treatment. (See Section 7) 


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8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information  
All Serious Adverse Events (SAEs) will be collected from the signing of the informed consent 
form (ICF) until the D100 End of Study visit. 
All AEs will be collected from the time and date of first dose of study treatment until the D40 
follow up visit. 
Changes in medical conditions that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History page of the CRF and not the AE CRF 
page. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of awareness 
of the event, as indicated in Section 10.3. The Investigator will submit any updated SAE data to 
the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the Investigator must notify the Sponsor within 
24 hours of awareness. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient should be used to inquire about AE occurrences.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of patients and the safety of a study treatment under 
clinical investigation are met.  
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The Sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), 
and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) per local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 


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An Investigator who receives an Investigator safety report describing a SAE or other specific safety 
information (e.g., summary or listing of SAEs) from the Sponsor will review and then file it along 
with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate per local requirements. 
8.3.5. 
Pregnancy 
Details of all pregnancies in female patients and, female partners of male patients will be collected 
after the start of study treatment and until 30 days after the last dose. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Section 10.4. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6. 
Events NOT Meeting the AE/SAE Definition:  
• Disease Related Events (refer to Section 8.3.7) 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).  
8.3.7. 
Disease-Related Events Not Qualifying as AEs or SAEs: 
Disease-related events (DREs) are associated with the disease under study and will not be reported 
according to the standard process for reporting of SAEs even though the event may meet the 
definition of an SAE. 
The following DREs are common in patients with CDI:  
• CDI recurrence 
o CDI recurrences will be recorded for the patient on the “Suspected Recurrence of 
CDI” CRF page.  
Note: If on evaluation, no recurrence is deemed to have occurred, any symptoms (or 
preferably diagnosis) reported by the patient must be reported as AEs (up to Day 40) 
and as SAEs (anytime during the study if the criteria for an SAE are met).  
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with CDI. 
• Treatment failure/lack of efficacy is not an adverse event but will be captured as an efficacy 
endpoint. 
• Signs or symptoms of CDI, including expected progression or worsening of CDI 
However, if any of the following complications related to CDI occurs, then the event must be 
recorded and reported as such as an SAE (instead of a progression or worsening of CDI): 
o Toxic megacolon 


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o Fulminant colitis 
o Colonic perforation  
A medical monitor will monitor suspected recurrence events on a regular basis. 
8.4. 
Treatment of Overdose  
The date and time of each dose will be recorded by patients in the eDiary. There is no specific 
treatment for overdose; general medical support measures are to be in place, if required. Any SAE 
or SAE associated with excessive dosing (overdose) must be followed as any other SAE or AE. 
Overdose is only considered AEs or SAEs if there are associated clinical signs and symptoms (see 
Section 10.3). 
8.5. 
Pharmacokinetics 
• PK samples will be collected on Day 1 or 2, and at EOT. As the study is blinded, samples 
will be collected from approximately 100 patients to ensure approximately 40 patients have 
received ridinilazole. It is understood that patients randomized to the ridinilazole arm will 
receive active ridinilazole in Dose 1, placebo in Dose 2, active ridinilazole in Dose 3, 
placebo in Dose 4, etc. Therefore, to ensure that PK is taken following an active dose of 
ridinilazole, the blood draws for all patients will occur as follows:  
o Day 1 or 2 - at 2 and 4 hours (±30 minutes) post either Dose 1, 3, 5 or 7, and 
o EOT - at 2 and 4 hours (±30 minutes) post either Dose 33, 35, 37 or 39. 
PK sampling must be conducted following in-clinic administration of study medication. 
Accurate times of dosing and sampling should be recorded. 
• It is expected that some of the PK patients will meet the IDSA definition for severe disease 
(white blood cell count ≥15,000 cells/mm3 or serum creatinine >1.5mg/dL). The PK 
samples will be used to assess the impact of severe disease on the plasma exposure of 
ridinilazole.  
• The bioanalytical laboratory will be unblinded for these 100 PK patients and samples from 
ridinilazole assigned patients will be analyzed. Appropriate measures will be taken to 
ensure that the laboratory does not disclose unblinded information to the study sites or 
Sponsor/CRO/Vendor. Sites will not receive any PK results until after database lock.  
• Residual plasma samples may be retained for up to 5 years from the end of the study for 
exploratory analysis of circulating metabolites and/or assessing vancomycin 
concentrations. If performed, this work will be reported separately. 
• Patients selected will be those who consent to take part from sites that are qualified to 
conduct the PK sampling.  
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 


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8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Medical Resource Utilization and Quality of Life 
8.9.1. 
Medical Resource Utilization  
Medical resource utilization and health economics data, associated with medical encounters, will 
be collected in the CRF by the Investigator and study-site personnel for all patients throughout the 
study. Protocol-mandated procedures, tests, and encounters are excluded. Data collected will 
include (but will not be limited to): 
• Length of hospital stay 
• Hospital admission and readmission rates and reasons for admission 
• Patient location at admission and discharge location  
8.9.2. 
EQ-5D-5L 
The EQ-5D-5L [34] is a five-item questionnaire, which has been developed as a standardized 
measure of health status, which can provide a simple, generic measure of health for clinical and 
economic appraisal. It is cognitively undemanding, taking only a few minutes to complete. Patients 
will be asked to complete the EQ-5D-5L at certain intervals throughout the study. Instructions to 
respondents are included in the questionnaire. The EQ-5D-5L essentially consists of 2 pages – the 
EQ-5D descriptive system (page 2) and the EQ visual analogue scale (EQ VAS) (page 3). The 
EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression.  
If, at any visit, the patient is unable to complete the EQ-5D-5L independently then it should not be 
completed for that visit. 
Refer to Section 10.7. 
8.9.3. 
Cdiff32 Patient Reported Outcome  
The Cdiff32 [35] will be administered at US sites. It consists of 32 questions covering 3 major 
domains (physical, mental, and social) with 4 associated subdomains with each question scored on 
a five-point scale.  
If, at any visit, the patient is unable to complete the Cdiff32 independently then it should not be 
completed for that visit.  
Refer to Section 10.8.


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9. 
STATISTICAL CONSIDERATIONS  
9.1. 
Statistical Hypotheses 
The null (H0) and alternative (H1) hypotheses for the primary endpoint, SCR, can be expressed as: 
H0: µRID = µVAN 
H1: µRID ≠ µVAN 
Where µRID and µVAN are the SCR rates for ridinilazole and vancomycin respectively. 
The null (H0) and alternative (H1) hypotheses for the secondary endpoint, Clinical Response, can 
be expressed as: 
H0: µRID - µVAN ≤ -10% 
H1: µRID - µVAN > - 10% 
where µRID and µVAN are the response rates for ridinilazole and vancomycin respectively.  
9.2. 
Sample Size Determination  
Approximately 680 patients (340 patients per treatment arm) will be randomly assigned to study 
treatment. The Modified Intent-to-Treat (mITT) population will be used for primary and secondary 
efficacy endpoints. 
For the primary endpoint of Sustained Clinical Response, there is more than 95% power of 
concluding superiority of ridinilazole over vancomycin using a 2-sided test at the 5% significance 
level. This assumes a 1:1 randomization of 680 patients (340 per group), an improvement of 15% 
with ridinilazole over vancomycin and a SCR rate of 57% with vancomycin [36]. 
For the secondary endpoint of Clinical Response there is about 90% power of concluding non-
inferiority of ridinilazole compared to vancomycin, using a 1-sided test at the 2.5% significance 
level and a NI margin of 10%.  
To preserve the Type 1 error a fixed sequence testing procedure will be adopted for the mITT 
population. The order of testing for secondary endpoints will be detailed in the statistical analysis 
plan. 
A blinded review of the efficacy endpoints will be conducted after approximately 70% of patients 
have completed their AOC assessment. The review will determine if increase sample size is needed 
to maintain adequate power for the primary endpoint. The maximum sample size increase will be 
25% of the initial sample size. Any increase above 25% of the initial sample size will require a 
protocol amendment. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Screened 
All patients who sign the ICF 
Randomized 
All patients randomly assigned to study treatment. 


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Population 
Description 
Modified ITT [mITT] 
(Efficacy) 
All randomized patients who take at least 1 dose of study treatment and have a 
diagnosis of CDI confirmed by the presence of free toxin in stool using a free 
toxin test and have ≥3 UBMs in the 24 hours prior to randomization.  
PK Population 
All ridinilazole randomized patients with at least one ridinilazole concentration 
(including below the lower limit of quantification). 
Safety 
All patients randomly assigned to study treatment and who take at least 1 dose 
of study treatment. Patients will be analyzed according to the treatment they 
received. 
9.4. 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock. This section is 
a summary of the planned statistical analyses of the primary and secondary endpoints. 
Any deviations from the planned analyses post database lock will be described and justified in the 
final clinical study report. 
9.4.1 
Efficacy Analyses 
Efficacy analyses will be conducted on the combined database from the SMT19969/C004 and 
SMT19969/C005 studies for the mITT population. 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary analysis of SCR over 30 days post EOT will be analyzed using the 
Cochran Mantel Haenszel (CMH) test which will be stratified by age (<65 years 
of age and ≥65 years of age), number of UBMs (<10 or ≥10) in the 24 hours 
prior to randomization, immunocompromised (YES/NO), and history of 
recurrent CDI (either none or 1-3 previous occurrences in the past 12 months). 
The treatment difference and 95% confidence interval, based on the stratified 
Miettinen and Nurminen method, will also be presented. 
Secondary 
The secondary endpoints, Clinical Response and Clinical Cure, will be analyzed. 
The difference between treatment proportions will be presented together with 
the 95% confidence interval, based on the stratified Miettinen and Nurminen 
method. Non-inferiority will be established if the lower limit of the 2-sided 95% 
confidence interval for the difference between treatment proportions 
(ridinilazole – vancomycin) is greater than -10%.  
The same methods of analysis as described for the primary endpoint will also be 
used to assess SCR over 60 days post EOT and SCR over 90 days post EOT.  
Additional endpoints and corresponding analysis details will be described in 
the statistical analysis plan. 
Exploratory 
Will be described in the statistical analysis plan.  


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9.4.2 
Safety Analyses 
All safety analyses will be performed on the combined database from the SMT19969/C004 and 
SMT19969/C005 studies for the Safety Population.  
The number and percentage of patients experiencing treatment-emergent all causality AEs/SAEs 
will be summarized by treatment group. Summaries will also be produced for each body system 
as well as each preferred term. Those events regarded as at least possibly treatment related by the 
Investigator will be summarized separately. The number and percentage of patients experiencing 
SAEs will also be summarized by treatment group. 
Changes from baseline in laboratory parameters and vital signs will be summarized for each visit 
and by treatment group. 
9.4.3 
Pharmacokinetic Analyses  
Summary statistics will be reported by sampling timepoints over all patients in the PK population 
and by IDSA severity (non-severe and severe) for ridinilazole plasma concentrations. A count of 
the number of samples below the level of quantification (BLQ) will be provided for each time 
point.  
9.5. 
Interim Analyses  
An interim analysis may be conducted. Details would be provided in the statistical analysis plan 
prior to the analysis. 
 
 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki. 
o Council for International Organizations of Medical Sciences (CIOMS) International 
Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.  
• The Investigator will be responsible for the following: 
o Ensuring patient safety and medical care is paramount 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
• Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities.  
• Investigators are responsible for providing information on financial interests during the 
study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process  
• The Investigator or his/her representative will explain the nature of the study to the patient. 
If a patient is unable to read, an impartial witness will be used to confirm to the patient that 
the consent was accurately read to them. If a patient is unable to understand and sign the 
Informed Consent form, the patient’s legally authorized representative (LAR) may provide 
consent on the patient’s behalf if allowed by the Institutional Review Board or Ethics 


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Committee. Patients must be informed that their participation is voluntary and that they are 
free to refuse to participate and may withdraw their consent at any time and for any reason 
during the storage period. 
• Patients or their legally authorized representative and impartial witness (if applicable) will 
be required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.  
• If the screening visit must be done remotely remote consenting per site’s local procedure 
can be performed, including eSignature or eConsenting if available at the site. Consent 
form(s) must be received and acknowledged by the site prior to the commencement of any 
study procedures. Original, signed consent form(s) must be returned to the site either at the 
next in-clinic visit, posted to the site, or returned via courier or any other approved alternate 
method. The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.  
• A copy of the ICF(s)/must be provided to the patient.  
• Patients who are rescreened are required to sign a new ICF 
• The sponsor considers that consent is not required for either a toxin test conducted per 
standard of care, or to complete a free toxin test on a stool sample collected per standard 
of care for any other diagnostic purpose. This is subject to local regulations; if the above 
approach is not approved, then written or telephone/verbal consent, using the initial free 
toxin test consent form, may be obtained to conduct the free toxin test. If using 
telephone/verbal consent, sites must have, or put in place, a documented procedure to 
conduct telephone/verbal consent including detailed description of the consent and follow-
up with written informed consent prior to baseline assessments if the patient FTT test is 
positive and interested in participating in the study. 
• There will be a separate signature line within the main ICF for retention of samples, to be 
stored for up to 5 years after study completion for exploratory research.  
• There will be a separate ICF that addresses the following optional assessment: 
o Use of blood sample for PK analyses. The Investigator or authorized designee will 
explain to each patient the objectives of the PK research.  
10.1.4. 
Data Protection 
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred.  
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. Data protection laws governing the trial include EU 
GDPR and any local regulation as applicable. The level of disclosure must also be explained to 
the patient.  


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The patient must be informed that his/her medical records may be examined by the Sponsor, 
Clinical Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
The study will be registered in EU Clinical Trials Register, will be posted on ClinicalTrials.gov in 
the United States and posted on other equivalent global registries as required. The results from this 
trial will be uploaded to the various registries when appropriate to do so and in line with the 
requirements of the individual registries.  
Summit will provide the Clinical Study Report to regulatory authorities as required. The 
Investigator will be provided with the full summary of the study results.  
10.1.6. 
Data Quality Assurance 
• All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data, eDiary data).  
• The Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original 
entry, and should be explained if necessary (e.g., via an audit trail). 
• Although no changes will be permitted to patient reported data, the Investigator must 
review the eDiary data with patients to verify completeness, accuracy and 
contemporaneous data entry. Follow-up with patients is required if missing or inaccurate 
data is entered to ensure re-training and prevent repeated non-compliance. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of patients are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Sponsor and the Investigator for 25 years after study completion unless 
local regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor.  


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10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the CRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• eDiary data, and/or patient contact reports of dosing and bowel movement information, are 
considered source data.  
• Definition of what constitutes source data can be found in the Investigator Trial Site File. 
10.1.8. 
Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, and sufficient notice is given in 
advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are not 
limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further study treatment development 
10.1.9. 
Publication Policy 
Summit fulfils its commitment to publicly disclose complete clinical trial results, regardless of 
outcome, through posting the results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the 
European Clinical Trials Database (EudraCT), and/or www.summitplc.com and other public 
registries in accordance with applicable local laws/regulations. Additionally, the results from this 
study may be presented in a peer-reviewed journal or at scientific meetings after finalization of the 
clinical study report. As this is a multi-centre trial, the primary manuscript will contain the 
complete results across all sites; authorship will be determined by mutual agreement. All 
publications relating to this study will comply with recognized ethical standards concerning 
publications and authorship, including Section II - “Ethical Considerations in the Conduct and 
Reporting of Research” of the Uniform Requirements for Manuscripts Submitted to Biomedical 
Journals, 
http://www.icmje.org/index.html#authorship, 
established 
by 
the 
International 
Committee of Medical Journal Editors. 


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After publication of the primary manuscript, principal Investigators may publish results based on 
the information collected and data generated at their site, regardless of study outcome. This 
secondary manuscript must reference the primary manuscript. The principal Investigator will 
submit their draft publication to Summit for review at least 30 days prior to submission to a journal 
for review of potentially confidential material and/or intellectual property. 
Summit is committed to sharing key data, relevant to their ongoing care, with patients who 
participate in their clinical trials. After publication of the primary manuscript, patients may request 
their individual data from their Investigator. 
10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 3 will be performed by a Central Laboratory except for the 
pregnancy test. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 3: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
White blood cell (WBC) 
count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell (RBC) Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
Blood urea nitrogen 
(BUN) 
Potassium 
Aspartate Aminotransferase 
(AST)/ Serum Glutamic-
Oxaloacetic Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine Aminotransferase 
(ALT)/ Serum Glutamic-Pyruvic 
Transaminase (SGPT) 
Total Protein 
 
Glucose [non-
fasting] 
Calcium 
Alkaline phosphatase 
Albumin 
Other Tests 
• 
Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential)2 
• 
The PK, microbiology, microbiome & bile acid analyses and CCNA testing will be 
performed by specialized centralized laboratories.  
NOTES: 
1 All events of ALT ≥3 × upper limit of normal (ULN) and bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT ≥3 
× ULN and international normalized ratio (INR) >1.5, if INR measured, which may indicate severe liver injury 
(possible Hy’s Law). These liver chemistries or the diagnosis explaining them must be reported as an SAE.  
2 Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. If serum testing is required, it may be conducted via the local or central laboratory whichever is most 
convenient. 


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Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study patient, temporally 
associated with the use of study treatment, whether or not considered related to the study 
treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study treatment. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
 
A SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred, or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 


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Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical treatment to prevent one of the other outcomes 
listed in the above definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology or clinical chemistry) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (i.e., not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of an overdose or suspected overdose of either 
study treatment or a concomitant medication. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
 


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Events NOT Meeting the AE/SAE Definition  
• 
Refer to Section 8.3.6 and 8.3.7 for events not meeting the AE/SAE definition.  
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records 
to the SAE coordinator in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the SAE coordinator or Medical Monitor. In this case, all patient identifiers, except for the 
patient number, will be redacted on the copies of the medical records before submission to 
the SAE coordinator. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
 
 
Assessment of Intensity 
The Investigator will assess intensity for each AE and SAE reported during the study and assign 
it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the patient, causing minimal discomfort, and not 
interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with a SAE. Severe is a category utilized for rating the intensity of 
an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 


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Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study treatment 
(ridinilazole/vancomycin) and each occurrence of each AE/SAE as “related” or “not 
related” by answering the question: 
‘‘Do you consider that there is a reasonable possibility that the adverse event  
has been caused by the study treatment? ‘’ 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
• 
The Investigator will consult both the Investigator’s Brochure (IB) for ridinilazole and the 
Product Information for vancomycin, in his/her assessment. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to Pharmacovigilance (the SAE coordinator). 
However, it is very important that the Investigator always assess causality for every 
event before the initial transmission of the SAE data to the SAE coordinator. If there 
are limited or insufficient information about the event to make an informed judgment, and 
in the absence of any indication or evidence to establish a causal relationship, a causality 
assessment of “not related” is to be considered. In such instances, the Investigator is 
expected to obtain additional information regarding the event as soon as possible and to re-
evaluate the causality upon receipt of additional information. 
• 
The causality assessment is important to be provided because it is one of the criteria used 
when determining regulatory/authority reporting requirements  
• 
The investigator is requested to provide an explanation for the causality assessment for each 
SAE and must document this in the medical notes, on the SAE form and in the CRF. 
• 
Following a review of the relevant data, the causal relationship between the study 
treatment (vancomycin/ridinilazole) and each (S)AE will be assessed by  
answering ‘yes’ or ‘no’ to the question:  
 
‘‘Do you consider that there is a reasonable possibility that the adverse event has been 
   caused by the study treatment? ‘’ 
• 
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a ‘reasonable possibility’ 
that an (S)AE may have been caused by the study treatment (rather than a relationship 
cannot be ruled out) or if there is evidence to reasonably deny a causal relationship: 
• 
Plausible temporal relationship between exposure to the study treatment and 
(S)AE onset and/or resolution. Has the subject actually received the study 
treatment? Did the (S)AE occur in a reasonable temporal relationship to the 
administration of the study treatment? 
• 
Plausibility; i.e., could the event have been caused by the study treatment? among 
others biologic and/or pharmacologic mechanism, half-life, and preclinical and 


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clinical study data (information can be found in, the IB) or can the event be 
explained by the underlying disease(s) or concomitant drugs? 
• 
De-challenge/Dose reduction/Re-challenge:  
Did the (S)AE resolve or improve after stopping the dose of the study 
treatment? Also consider the impact of treatment for the event when evaluating 
a de-challenge experience. 
Did the (S)AE re-occur when the suspected study treatment was reintroduced 
after having been stopped? 
• 
Laboratory or other test results; a specific laboratory investigation supports the 
assessment of the relationship between the (S)AE and the study treatment (e.g., 
based on values pre- during and post-treatment). 
• 
Available alternative explanations independent of study treatment exposure 
(such as other concomitant drugs, past medical history, concurrent or 
underlying disease, risk factors including medical and family history, season, 
location, etc.) and strength of the alternative explanation. 
• 
The Investigator may change his/her opinion of causality considering follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the SAE 
coordinator to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a patient dies during participation in the study or during a recognized follow-up period, 
the Investigator will provide the SAE coordinator with a copy of any post-mortem findings 
including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to the SAE coordinator within 24 hours 
of receipt of the information. 
 


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SAE Reporting to Pharmacovigilance via email 
• 
SAEs will be transmitted to IQVIA using the Serious Adverse Event Form, which must be 
completed and signed by a member of the study team and transmitted to IQVIA 
pharmacovigilance with 24 hours of awareness of the event.  
All initial and follow up SAE reports should be sent to IQVIA Drug safety Centre  
Email: QLS_SMT19969@quintilesims.com 
 
• 
Country specific toll-free fax numbers for SAE reporting will also be provided in the 
Investigator site file. 
• 
Initial notification by email does not replace the need for the Investigator to complete and 
sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in the Investigator Trial Site File. 
 
 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of the patient’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance: 
Male patients 
Male patients must use a barrier contraceptive method during sexual intercourse with a woman of 
childbearing age or abstain from sexual intercourse during the study if it is their preferred and 
usual lifestyle. 
In addition, male patients must refrain from donating sperm for 30 days after the last dose of study 
treatment. 
Male patients with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration for 30 
days after the last dose of study treatment. 
Female patients 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 4. 


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Table 4: 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• Oral  
• Intravaginal  
• Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral  
• Injectable  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method if the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the treatment period and continuing for 30 days after the end 
of study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the patient.  
NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
patients participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study treatment, which 
may reduce the efficacy of the contraceptive method. In this case, two highly effective 
methods of contraception should be utilized during the treatment period and for at least 
30 days after the last dose of study treatment  
Pregnancy Testing: 
• 
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine or serum pregnancy test (a urine test will be provided by the Central 
Laboratory). 
• 
Pregnancy testing will be performed at Day 12, Day 40 and whenever a menstrual cycle is 
missed or when pregnancy is otherwise suspected up to 30 days after the last dose of study 
treatment. 


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Collection of Pregnancy Information: 
Male patients with partners who become pregnant  
• 
The Investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study up to 30 days following 
the last dose of study treatment.  
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of foetal status (presence or absence of anomalies) or 
indication for the procedure.  
Female Patients who become pregnant  
• 
The Investigator will collect pregnancy information on any female patient who becomes 
pregnant up to 30 days after the last dose of study treatment. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a patient's 
pregnancy. The patient will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the patient and the neonate, and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy 
will be reported, regardless of foetal status (presence or absence of anomalies) or indication 
for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion 
is always considered to be an SAE and will be reported as such. Any post-study pregnancy 
related SAE considered reasonably related to the study treatment by the Investigator will be 
reported to the Sponsor as described in Section 8.3.1. While the Investigator is not obligated 
to actively seek this information in former study patients, he or she may learn of an SAE 
through spontaneous reporting.  


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10.5. 
Appendix 5: Bristol Stool Chart 
 


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10.6. 
Appendix 6: Sponsor Agreed Free Toxin Tests 
The following are Sponsor agreed Free Toxin Tests that can be utilized during the study for 
assessment of eligibility and suspected recurrence. Further tests may be agreed during the course 
of the study without a protocol amendment. Any such test will have FDA, EU or other 
appropriate regulatory approval. 
FDA and EU Approved: 
 
• 
bioMerieux Test System (Vidas and miniVidas) C. difficile Toxin A & B (CDAB) Assay 
• 
Meridian Bioscience ImmunoCard Toxin A&B 
• 
Meridian Bioscience Premier Toxins A & B (visual or spectrophotometric) 
• 
Remel ProSpecT Clostridium difficile Toxin A/B Microplate Assay (visual or 
spectrophotometric) 
• 
Remel Xpect Clostridium difficile Toxin A/B Test  
• 
TechLab C. DIFF QUIK CHEK COMPLETE  
• 
Techlab C. difficile Tox A/B II (visual or spectrophotometric) 
• 
Techlab TOX A/B QUIK CHEK  
 
EU Approved only: 
 
• 
Acro Biotech Inc. Clostridium difficile Toxin A + Toxin B Combo Rapid Test Cassette 
• 
AllTest JusChek Clostridium difficile GDH+ Toxin A + Toxin B Combo 
• 
Beta Diagnostici Clostridium difficile toxin A+B+GDH 
• 
Acro Biotech Inc. Clostridium difficile Toxin A + Toxin B Combo Rapid Test Cassette 
• 
CerTest BIOTEC Clostridium difficile Toxin A + B 
• 
CerTest BIOTEC Clostridium difficile GDH + Toxin A + B 
• 
DiaSorin LIAISON C. difficile Toxins A&B 
• 
Mascia Brunelli S.p.a., CLOSTRIDIUM DIFFICILE TOXIN A+B CARD PLUS 
• 
MonlabTest C. difficile toxins A+B 
• 
Operon Simple GDH-Toxins 
• 
RIDA QUICK Clostridium difficile Toxin A/B 
• 
RIDASCREEN Clostridium difficile Toxin A/B 
• 
Savyon Diagnostics CoproStrip C. difficile GDH + Toxin A + Toxin B 
• 
Stamar Clostridium difficile Toxin A and B 
• 
Trinity Biotech Uni-Gold C. difficile Toxin A/B 
• 
Veda Lab Toxin A+B (Clostridium difficile) DUO 
• 
VITASSAY Clostridium difficile GDH+Toxin A+B 
• 
Vitrotrack Clostridium difficile GDH+Toxin A+Toxin B cassette combo 
GDH, Nucleic Acid Amplification Test (NAAT) or PCR may be done per site’s standard of care prior to 
study start as part of pre-screening reviews but are not acceptable to meet eligibility requirements for the 
study.  
 


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10.7. 
EQ-5D-5L 
Effective_USA (English) EQ-5D-5L Digital Self complete PDA v1.1 (ID 36597) 
 
 
 


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10.8. 
Cdiff32 


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10.9. 
Appendix 7: Abbreviations 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AOC 
Assessment of cure 
AST 
Aspartate Amino Transferase 
bid 
Bis in die (twice daily) 
BLQ 
Below the level of quantification 
BUN 
Blood Urea Nitrogen 
CCNA 
Cell Cytotoxicity Neutralization Assay 
CDI 
Clostridioides (formerly Clostridium) difficile infection 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum observed plasma concentration 
CMH 
Cochran Mantel Haenszel 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
DRE 
Disease related event 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eDiary 
Electronic diary 
EIA 
Enzyme Immunoassay 
EOS 
End of study 
EOT 
End of treatment 
ESCMID 
European Society of Clinical Microbiology and Infectious Diseases 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration  
FSH 
Follicle-Stimulating Hormone 
FTT 
Free Toxin Test 
GC-MS 
Gas Chromatography Mass Spectrometry 
GCP 
Good clinical practice 
GDH 
Glutamate dehydrogenase 
GI 
Gastrointestinal 
hCG 
Human Chorionic gonadotropin 
HEOR 
Health Economic Outcomes Research 
HHC 
Home Healthcare 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
Hormone replacement therapy 


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i.v. 
Intravenous 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDSA 
Infectious Diseases Society of America 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ration (for blood clotting time) 
IMP 
Investigational Medicinal Product 
IRB 
Institutional review board 
IRT 
Interactive Response Technology 
ITT 
Intention-to-treat 
IRT 
Interactive Response Technology 
IUD 
Intrauterine contraceptive device 
IUS 
Intrauterine system 
IVIG 
Intravenous immunoglobulin 
LAR 
Legally Authorized Representative 
LLOQ 
Lower limit of quantification 
MIC 
Minimum inhibitory concentration 
MITT 
Modified intention-to-treat 
NOAEL 
No observable adverse effect level 
NAAT 
Nucleic Acid Amplification Test 
PCR 
Polymerase chain reaction  
PD 
Pharmacodynamics 
PHI 
Protected Health Information  
PK 
Pharmacokinetics 
PP 
Per protocol 
PRO 
Patient Reported Outcome 
qid 
Quarter in die (four times daily) 
QTc(F) 
QT interval corrected according to Fridericia’s formula 
RBC 
Red Blood cell 
RNA 
Ribonucleic acid 
rRNA 
Ribosomal ribonucleic acid 
SAE 
Serious adverse event 
SCR 
Sustained clinical response 
SD 
Standard deviation 
SGOT 
Serum glutamic oxaloacetic transaminase 
SOA 
Schedule of Activities 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TMF 
Trial master file 


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TOC 
Test of Cure 
UBM 
Unformed bowel movements 
ULN 
Upper limit of normal 
VAS 
Visual Analogue Scale 
VC 
Video Conference 
VRE 
vancomycin resistant Enterococci 
WBC 
White Blood Cell 
WOCBP 
Woman of childbearing potential 
 


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10.10. 
References 
1. 
Cornely, O.A., et al., Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus 
vancomycin. Clin Infect Dis, 2012. 55 Suppl 2: p. S154-61. 
2. 
Kelly, C.P., Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol 
Infect, 2012. 18 Suppl 6: p. 21-7. 
3. 
Vickers, R.J., et al., Ridinilazole: a novel therapy for Clostridium difficile infection. Int J Antimicrob Agents, 
2016. 
4. 
Vickers, R.J., et al., Efficacy and safety of ridinilazole compared with vancomycin for the treatment of 
Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. 
The Lancet Infectious Diseases, 2017. 17(7): p. 735-744. 
5. 
Smits, W.K., et al., Clostridium difficile infection. Nature Reviews Disease Primers, 2016. 2: p. 16020. 
6. 
Rupnik, M., M.H. Wilcox, and D.N. Gerding, Clostridium difficile infection: new developments in 
epidemiology and pathogenesis. Nat Rev Microbiol, 2009. 7(7): p. 526-36. 
7. 
Kelly, C.P. and J.T. Lamont, Clostridium difficile — More Difficult Than Ever. N Engl J Med, 2008. 359(18): 
p. 1932-1940. 
8. 
McFarland, Breaking the Cycle: Treatment Strategies for 163 Cases of Recurrent Clostridium difficile 
Disease. American Journal of Gastroenterology, 2002. 97(7). 
9. 
Aslam, S., R.J. Hamill, and D.M. Musher, Treatment of Clostridium difficile-associated disease: old 
therapies and new strategies. The Lancet Infectious Diseases, 2005. 5(9): p. 549-557. 
10. 
Lewis, B.B., et al., Loss of Microbiota-Mediated Colonization Resistance to Clostridium difficile Infection 
With Oral Vancomycin Compared With Metronidazole. J Infect Dis, 2015. 
11. 
Al-Nassir, W.N., et al., Both oral metronidazole and oral vancomycin promote persistent overgrowth of 
vancomycin-resistant enterococci during treatment of Clostridium difficile-associated disease. Antimicrob 
Agents Chemother, 2008. 52(7): p. 2403-6. 
12. 
Louie, T.J., et al., OPT-80 eliminates Clostridium difficile and is sparing of bacteroides species during 
treatment of C. difficile infection. Antimicrob Agents Chemother, 2009. 53(1): p. 261-3. 
13. 
Aguado, J.M., et al., Highlighting clinical needs in Clostridium difficile infection: the views of European 
healthcare professionals at the front line. J Hosp Infect, 2015. 90(2): p. 117-25. 
14. 
Bartlett, J.G., New Drugs for Clostridium difficile Infection. Clin Infect Dis, 2006: p. 428-431. 
15. 
Cohen, S.H., 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). Infect Control Hosp Epidemiol, 2010. 31(5): p. 431-55. 
16. 
Debast, S.B., et al., European Society of Clinical Microbiology and Infectious Diseases: update of the 
treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect, 2014. 20 Suppl 
2(Suppl 2:1): p. 1-26. 
17. 
Surawicz, C.M., et al., Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. 
American Journal of Gastroenterology, 2013. 108(4): p. 478-98; quiz 499. 
18. 
Zar, F.A., et al., A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile-
Associated Diarrhea, Stratified by Disease Severity. Clin Infect Dis, 2007. 45(3): p. 302-7. 
19. 
Johnson, S., et al., Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from 
two multinational, randomized, controlled trials. Clin Infect Dis, 2014. 59(3): p. 345-54. 
20. 
Stevens, V.W., et al., Comparative Effectiveness of Vancomycin and Metronidazole for the Prevention of 
Recurrence and Death in Patients With Clostridium difficile Infection. JAMA Intern Med, 2017. 


Study Number: SMT19969/C004 
Compound No: SMT19969 
Version 9.0; 09Aug2021  
CO-007-B-03  Ref: SOP-CO-007-03 
CONFIDENTIAL 
 Page 94 of 94 
21. 
PHE, Updated guidance on the management and treatment of Clostridium difficile infection. 2013. 
22. 
Cornely, O.A., 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(4): p. 281-9. 
23. 
Louie, T.J., et al., Fidaxomicin versus Vancomycin for Clostridium difficile Infection. N Engl J Med, 2011. 
364(5): p. 422-31. 
24. 
Boix, V., et al., Primary Outcomes From a Phase 3, Randomized, Double-Blind, Active-Controlled Trial of 
Surotomycin in Subjects With Clostridium difficile Infection. Open Forum Infectious Diseases, 2017. 4(1). 
25. 
Chung, P., Comparison of High and Low Dose Oral Vancomycin for Treatment of Clostridium difficile 
Infection in Hospitalized Patients, in ICAAC. 2013. 
26. 
Chang, J., et al., Ridinilazole Preserves Major Components of the Intestinal Microbiota During Treatment of 
Clostridium difficile Infection, in ASM Microbe. 2016: Boston, MA. 
27. 
Crobach, M.J., et al., European Society of Clinical Microbiology and Infectious Diseases (ESCMID): data 
review and recommendations for diagnosing Clostridium difficile-infection (CDI). Clin Microbiol Infect, 
2009. 15(12): p. 1053-66. 
28. 
Lee, C.H., et al., Surotomycin versus vancomycin for Clostridium difficile infection: Phase 2, randomized, 
controlled, double-blind, non-inferiority, multicentre trial. J Antimicrob Chemother, 2016. 
29. 
Louie, T., et al., Clinical outcomes, safety, and pharmacokinetics of OPT-80 in a phase 2 trial with patients 
with Clostridium difficile infection. Antimicrob Agents Chemother, 2009. 53(1): p. 223-8. 
30. 
Fekety, Treatment of Antibiotic-Associated Clostridirrm difficile Colitis with Oral Vancomycin: Comparison 
of Two Dosage Regimens. American Journalof Medicine, 1989. 
31. 
Lawrence, S.J., et al., Clostridium difficile–Associated Disease Treatment Response Depends on Definition 
of Cure. Clin Infect Dis, 2007. 45(12): p. 1648. 
32. 
Luo, R.F. and N. Banaei, Is repeat PCR needed for diagnosis of Clostridium difficile infection? J Clin 
Microbiol, 2010. 48(10): p. 3738-41. 
33. 
Oldfield IV, E.C., E.C. Oldfield III, and D.A. Johnson, Clinical update for the diagnosis and treatment of 
Clostridium difficile infection. World J Gastrointest Pharmacol Ther, 2014. 5(1): p. 1-26. 
34. 
Janssen, M.F., et al., Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight 
patient groups: a multi-country study. Qual Life Res, 2013. 22(7): p. 1717-27. 
35. 
Garey, K.W., et al., Development and Validation of a Clostridium difficile Health-related Quality-of-Life 
Questionnaire. J Clin Gastroenterol, 2016. 50(8): p. 631-7. 
36. 
Dificid (fidaxomicin) [package insert]. Whitehouse Station, NJ: Merck & Company, Inc.; 2021. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
SMT19969-C004-C005 
Version 2.0 19 Nov 2021 
Page 1 of 28 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol Title: A Phase 3, randomized, double-blind, active controlled study to compare the 
efficacy and safety of ridinilazole (200 mg, bid) for 10 days with vancomycin (125 mg, qid) 
for 10 days in the treatment of Clostridium difficile infection (CDI) 
 
 
Protocol Number: SMT19969-C004-C005 
Sponsor Name: Summit Therapeutics 
SAP Version: 2.0 
SAP Version Date: November 19, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
This document is confidential. It contains proprietary information of Summit Therapeutics. Any viewing or disclosure 
of such information that is not authorized in writing by Summit Therapeutics is strictly prohibited. Such information 
may be used solely for the purpose of reviewing or performing these studies. 


Statistical Analysis Plan 
SMT19969-C004-C005 
Version 2.0 19 Nov 2021 
Page 2 of 28 
 
 
Sponsor Signatory 
 
 
 
Jianling Li (Nov 19, 2021 10:32 PST) 
Nov 19, 2021 
Jianling Li, MS 
Senior Director 
Biostatistics 
Date 
 
 
Nov 19, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nov 19, 2021 
Fong Clow (Nov 19, 2021 10:35 PST) 
Fong Clow, PhD 
Head of Biometrics 
Biometrics 
Date 
Danelle James (Nov 20, 2021 12:35 PST) 
Nov 20, 2021 
Danelle James, MD 
Head of Clinical Development 
Medical Science 
Date 
Erik Poulsen (Nov 19, 2021 10:33 PST) 
Erik Poulsen, MS 
Head of Regulatory Affairs 
Regulatory Affairs 
Date 


Statistical Analysis Plan 
SMT19969-C004-C005 
Version 2.0 19 Nov 2021 
Page 3 of 28 
 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................ 1 
VERSION HISTORY ...................................................................................................................... 5 
1. 
INTRODUCTION ........................................................................................................ 6 
1.1. 
Study Design ................................................................................................................. 6 
1.2. 
Study Objectives ........................................................................................................... 7 
1.3. 
Endpoints ...................................................................................................................... 7 
1.4. 
Statistical Hypotheses ................................................................................................... 8 
1.5. 
Sample Size Determination .......................................................................................... 9 
1.6. 
Testing Procedures and Level of Significance ............................................................. 9 
1.7. 
Blinding and Randomization Methods ......................................................................... 9 
1.7.1. 
Blinding Method ........................................................................................................... 9 
1.7.2. 
Randomization Method ................................................................................................ 9 
1.8. 
Interim Analysis .......................................................................................................... 10 
2. 
GENERAL ANALYSIS CONSIDERATION ........................................................... 10 
2.1. 
Analysis Populations .................................................................................................. 10 
2.2. 
Definition Of Subgroups ............................................................................................. 11 
2.3. 
Visit Windows ............................................................................................................ 12 
2.4. 
Handling Of Missing Data .......................................................................................... 13 
3. 
SUBJECT INFORMATION ...................................................................................... 14 
3.1. 
Subject Disposition ..................................................................................................... 14 
3.2. 
Protocol Deviation ...................................................................................................... 14 
3.3. 
Demographic And Baseline Characteristics ............................................................... 15 
3.4. 
Prior Treatments for Current CDI Episode ................................................................. 15 
3.5. 
Prior And Concomitant Medications .......................................................................... 15 
3.6. 
Treatment Exposure .................................................................................................... 16 
4. 
STATISTICAL ANALYSES ..................................................................................... 16 
4.1. 
Efficacy Analyses ....................................................................................................... 16 
4.2. 
Safety Analyses........................................................................................................... 19 
4.3. 
Microbiology Analysis ............................................................................................... 20 
4.4. 
Pharmacokinetic Analysis .......................................................................................... 21 
4.5. 
Microbiome Analysis .................................................................................................. 21 


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4.6. 
Listings ....................................................................................................................... 21 
4.7. 
Covid-19 Impact ......................................................................................................... 21 
5. 
SUPPORTING DOCUMENTATION ........................................................................ 22 
5.1. 
Appendix 1: List of Abbreviations ............................................................................. 22 
5.2. 
Appendix 2: Changes to Protocol-planned Analyses ................................................. 23 
5.3. 
Appendix 3: Schedule of Activities ............................................................................ 24 
5.4. 
Appendix 4: Sensitivity Analysis for SCR Using Multiple Imputation ..................... 28 


Statistical Analysis Plan 
SMT19969-C004-C005 
Version 2.0 19 Nov 2021 
Page 5 of 28 
 
 
VERSION HISTORY 
 
 
Version 
Approval Date 
Description 
1.0 
12Feb2019 
Original version 
2.0 
19Nov2021 
Summary: 
The previous version of SAP was based on Protocol Amendment 3. This 
version is based on the most recent Protocol Amendment 8. To align with 
the protocol, major changes include the following: 
• 
Combine SMT19969/C004 and SMT19969/C005 into one study 
for analyses 
• 
Modify the definition of Sustained Clinical Response (SCR) 
• 
Update secondary and exploratory endpoints including 
microbiome, bile acid, and antibiotic susceptibility endpoints 
Other major changes include: 
• 
Add recurrence as one of the secondary endpoints 
• 
Clinical Cure is removed from the list of secondary endpoints and 
will be considered as sensitivity analysis for Clinical Response. 
SCR over 60 days post EOT is removed from the list of secondary 
endpoints and considered as an exploratory endpoint. 
• 
Update the ordering of secondary endpoints for testing 
• 
Add analyses for bile acids, ribotype and antibiotic susceptibility, 
medical resource utilization, patient reported outcomes, and CDI 
signs and symptoms 
• 
Update the analysis visit window for efficacy assessments 
• 
Update the analysis populations and variables for subgroup 
analyses 
This version also applies the latest template with updated structure and 
sections (e.g. removal of the sections for exploratory objectives and 
responsibilities). 


Statistical Analysis Plan 
SMT19969-C004-C005 
Version 2.0 19 Nov 2021 
Page 6 of 28 
 
 
1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of combined efficacy and safety data as described in both SMT19969/C004 and 
SMT19969/C005 Protocol Amendment 8 dated August 9, 2021. Per Protocol Amendment 8, to 
minimize the potential, unknown impact of the coronavirus disease 2019 (COVID-19) pandemic 
on the trial and because of a much slower enrollment rate than anticipated due to the ongoing 
pandemic, Summit has decided to combine its ongoing, Phase 3 studies, SMT19969/C004 and 
SMT19969/C005, into one study with a pre-specified SAP when these blinded, identical studies 
are at least half enrolled. As a result, both studies will be closed and will proceed with database 
lock and statistical analysis. The combined analysis will comprise a minimum of 680 randomized 
subjects. The SAP will be finalized and approved prior to the unblinding for the final analysis. 
All analyses/outputs will be prepared by combining these two studies for reporting. Analysis 
methods specified in this document supersede those described in the study protocol should there 
be any difference. 
 
1.1. 
Study Design 
Each study is a Phase 3, randomized, double-blind, active controlled, parallel group, multi-center 
study to compare the efficacy of 10 days’ dosing of ridinilazole 200 mg bid with vancomycin 125 
mg qid in the treatment of subjects with Clostridioides difficile (C. difficile) infection (CDI). 
Approximately 680 subjects (340 per arm) with a confirmed diagnosis of CDI will be enrolled in 
the study. 
It comprises a screening visit, a 10-day treatment period (beginning on the day of screening or the 
following day) and a 90-day follow-up period. The Schedule of Activities can be found in 
Section 5.1. 
Figure 1: Study Schema 
 
AOC: Assessment of Cure; EOS: End of study; EOT: End of Treatment; SCR: Sustained Clinical Response 


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Version 2.0 19 Nov 2021 
Page 7 of 28 
 
 
1.2. 
Study Objectives 
Primary Objective 
• To compare the efficacy of 10 days’ dosing of ridinilazole (200 mg bid) with vancomycin 
(125 mg qid) in the treatment of patients with CDI 
Secondary Objectives 
• To compare the safety and tolerability of 10 days’ dosing of ridinilazole (200 mg bid) with 
vancomycin (125 mg qid) in the treatment of patients with CDI 
• To characterize the systemic exposure of ridinilazole in a subset of patients treated with 
ridinilazole (200 mg bid) tablets 
• To compare the effect of 10 days’ dosing of ridinilazole (200 mg bid) with vancomycin 
(125 mg qid) on the gut bile acid composition and on the gut microbiome diversity at the 
end of treatment (EOT) 
 
1.3. 
Endpoints 
Primary Endpoint 
The primary endpoint is Sustained Clinical Response (SCR) defined as Clinical Response and no 
recurrence of CDI through 30 days post EOT. 
A sensitivity analysis for SCR will be conducted using the definition (i.e. Clinical Cure and no 
recurrence of CDI through 30 days post EOT) as stated in the Protocol Amendment 6 and earlier 
versions. 
Secondary Endpoints 
• Clinical Response is defined as 
o less than 3 unformed bowel movements (UBMs) for 2 consecutive days and maintained 
through the EOT without further CDI antimicrobial treatment at EOT+ 2 days or 
o the investigator’s assessment that the subject is cured and no longer needs specific CDI 
antimicrobial treatment after completion of the course of study medication. 
The Investigator’s assessment is based on the reduction of UBMs since baseline, clinical 
signs and symptoms and need for further treatment for CDI. A patient will be deemed cured 
once the Investigator’s assessment is that the baseline CDI has resolved such that no further 
non-study CDI treatment is needed. 
Clinical Cure will be analyzed as a sensitivity analysis for Clinical Response. Clinical Cure 
is defined as the resolution of diarrhea (<3 UBMs in the 1-day period immediately prior to 
EOT that is maintained for 2 days after EOT). 
• Recurrence is defined as a new episode of diarrhea (≥3 UBMs) in a 1-day period with a 
positive C. difficile free toxin test or Cell Cytotoxicity Neutralization Assay (CCNA) that 
requires CDI antimicrobial treatment in subjects who achieved Clinical Response. 
• Change from baseline to EOT of the relative abundance of microbiome-derived secondary 
bile acids. 


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• SCR over 90 days post EOT is defined as Clinical Response and no recurrence of CDI 
through 90 days post EOT. 
Exploratory Endpoints 
• Time to resolution of diarrhea over the first 12 days – defined as the time from starting 
study treatment to the resolution of diarrhea (<3 UBMs in a 1-day period) 
• CDI signs and symptoms 
• Change from baseline of the relative abundance of the bile acid components – conjugated 
primary bile acids and microbiome-derived primary and secondary bile acids in stool 
samples 
• SCR over 60 days post EOT is defined as Clinical Response and no recurrence of CDI 
through 60 days post EOT. 
• Microbiome analysis 
Safety Endpoints 
• Adverse Events, clinical laboratory values, vital signs 
Microbiology Endpoints 
• Ribotype and susceptibility to ridinilazole, vancomycin and other antibacterial agents of 
C. difficile isolates collected in stool samples at baseline, EOT and recurrence 
Pharmacokinetics (PK) Endpoints 
• Ridinilazole concentrations in plasma 
Health Economics and Outcomes Research (HEOR) Endpoints 
• Medical resource utilization and health economics endpoints (e.g., hospital readmission 
rates and length of hospital stay) 
• Change from baseline in EQ-5D-5L dimensions and health state visual analog scale (VAS) 
score 
 
1.4. 
Statistical Hypotheses 
The null (H0) and alternative (H1) hypotheses for the primary endpoint, SCR, can be expressed as: 
H0: μRID = μVAN 
H1: μRID  ≠ μVAN 
Where μRID and μVAN are the SCR rates for ridinilazole and vancomycin, respectively. 
The null (H0) and alternative (H1) hypotheses for the secondary endpoint Clinical Response can 
be expressed as: 
H0: μRID - μVAN ≤ -10% 
H1: μRID - μVAN > - 10% 
Where μRID and μVAN are the Clinical Response rates for ridinilazole and vancomycin, respectively. 


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1.5. 
Sample Size Determination 
Approximately 680 subjects (340 subjects per treatment group) will be randomly assigned to study 
treatment. The Modified Intent-to-Treat (mITT) population will be used for primary and secondary 
efficacy endpoints. 
For the primary endpoint of Sustained Clinical Response, there is approximately 95% power of 
concluding superiority of ridinilazole over vancomycin using a 2-sided test at the 5% significance 
level under the assumption of an improvement of 15% with ridinilazole over vancomycin. 
For the secondary endpoint of Clinical Response, there is about 90% power of concluding non- 
inferiority (NI) of ridinilazole compared to vancomycin using a 1-sided test at the 2.5% 
significance level and an NI margin of 10%. 
 
1.6. 
Testing Procedures and Level of Significance 
Superiority tests will be 2-sided at the 5% significance level. Non-inferiority will be established if 
the lower limit of the 2-sided 95% confidence interval (CI) for the difference between treatment 
proportions (ridinilazole - vancomycin) is not more than 10% worse (i.e. > -10%). To preserve 
the Type 1 error, a fixed sequence testing procedure will be used. The hierarchical testing order 
will be as follows. Specifically, if superiority is established for the primary endpoint SCR, then a 
test of non-inferiority in Clinical Response between ridinilazole and vancomycin will be triggered, 
using the estimated difference and its 95% CIs. Noninferiority will be declared if the lower limit 
of the 2-sided 95% CI for the estimated difference is > -10%. If the lower limit of the 2-sided 95% 
CI excludes 0%, superiority of ridinilazole in Clinical Response will be declared. If non-inferiority 
is established for Clinical Response, then test for the next secondary endpoint will be conducted 
at the 5% significant level (2-sided). 
1. SCR 
2. Clinical Response 
3. Change from baseline to EOT of the relative abundance of microbiome-derived secondary 
bile acids 
4. Recurrence 
5. SCR over 90 days post EOT 
 
1.7. 
Blinding and Randomization Methods 
1.7.1. 
Blinding Method 
The is a double-blind study. The blinding method is described in protocol Section 6.3. 
 
1.7.2. 
Randomization Method 
Central randomization is implemented in this study. Subjects are randomly assigned to one of the 
two treatment groups in a 1:1 ratio based on a computer-generated randomization schedule. The 
randomization is to be stratified by age (<65 years and ≥65 years), number of UBMs (<10 or ≥10) 
in the 24 hours prior to randomization, immunocompromised (Yes/No), and history of CDI (either 
none or 1 to 3 previous occurrences in the past 12 months). Of note, in Protocol Amendment 7, 


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number of UBMs and immunocompromised were added as randomization stratification factors but 
have not been implemented. Therefore, at the time of data cutoff all the subjects are randomized 
based on the two stratification factors: age and history of CDI. 
 
1.8. 
Interim Analysis 
No interim analysis will be performed. 
 
2. 
GENERAL ANALYSIS CONSIDERATION 
Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized using 
frequencies and percentages. 
In general, baseline value is defined as the last non-missing value collected prior to the 
administration of the first dose of study treatment. 
Study Day is derived as (assessment date - the first dose date +1) if assessment date is on or after 
the first dose date. Study Day is derived as (assessment date - the first dose date) if assessment 
date is prior to the first dose date. The first dose date will be identified as Study Day 1. 
All statistical analyses will be performed using SAS® (Version 9.4 or higher) except that R 
packages may be used for data visualization and for specific exploratory analyses on microbiome 
data as needed. 
 
2.1. 
Analysis Populations 
Intent-to-Treat (ITT) Population 
The ITT population includes all randomized subjects, regardless of the actual treatment received. 
Safety Population 
The safety population includes all subjects who received at least one dose of study treatment 
(ridinilazole or vancomycin). Subjects in this population will be analyzed based on the actual 
treatment received. This population will be used for all safety analyses. 
Modified Intent-to-Treat (mITT) Population 
The mITT population includes all randomized and treated subjects who have: 
• ≥3 UBMs in the 24 hours prior to randomization 
• A diagnosis of CDI confirmed by positive result obtained by regulatory approved free 
toxin tests or CCNA test 
This population will be the primary population for the summary/analyses of efficacy endpoints, 
disposition, demographic and baseline characteristics, patient reported outcomes, bile acids and 
microbiome measures. 
Subjects will be analyzed based on the randomized treatment assignment via IXRS. 
Per-Protocol (PP) Population 


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Analysis for the primary and key secondary efficacy endpoints may be conducted based on the PP 
population if needed. 
Pharmacokinetics (PK) Population 
The PK population includes all ridinilazole-treated subjects with at least one ridinilazole 
concentration, including those below the level of quantification (BLQ). 
 
2.2. 
Definition Of Subgroups 
Subgroup analyses will be performed for the selected variables to assess the internal consistency 
of the treatment benefit and/or safety. The subgroup variables and the cutoff points are subject to 
change, if warranted, to better represent the data. 
Table 1: Subgroup Definition 
 
Subgroup 
Definition of Subgroup 
Age 
<65, ≥65 years; <75, ≥75 years 
Sex 
Female, Male 
Race 
White, Not White 
Ethnicity 
Hispanic, Non-Hispanic 
Geographic region 
US/Canada, Europe, Latin America, Other 
Number of UBMs at baseline 
<10, ≥10 
History of CDI in the past 12 months (eCRF) 
None, 1-3 previous occurrences 
Time since last episode of CDI (eCRF) 
None, >0-3 months, >3 months 
Baseline IDSA severitya 
Severe, Non-Severe 
Baseline Disease severity (UBM and WBC criteria)b 
Severe, Moderate, Mild 
Hospitalization status at baseline 
Inpatient, Outpatient 
Non-CDI antimicrobials usage at baselinec 
Yes, No 
Antimicrobial treatment for current CDI at randomizationc 
Yes, No 
Proton pump inhibitors usage at baseline 
Yes, No 
Presence of ribotype 027 strain 
Yes, No 
Presence of hypervirulent strain 
Yes, No 
Immunocompromisedc,d 
Yes, No 
US: United States; UBM: unformed bowel movement; CDI: Clostridioides difficile infection; eCRF: Electronic 
Case Record Form; IDSA: Infectious Diseases Society of America; WBC: white blood cell 
a Non-severe: WBC ≤15×109/L and serum creatinine <1.5 mg/dL, Severe: WBC >15×109/L or serum creatinine 
>1.5 mg/dL. 
b Mild: <6 UBM/day or WBC ≤ 12 ×109/L, Moderate: 6-9 UBM/day or WBC >12 – 15 × 109/L, 
Severe: ≥ 10 UBM/day or WBC > 15 × 109/L. 
c Grouping will be based on medical review. 
d Subgroup analysis will be done if at least 5% of subjects are immunocompromised. 


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2.3. 
Visit Windows 
The study protocol gives the overall study schedule and the permissible intervals for the visits (see 
Section 5.1). The analysis windows presented in Table 2 below will be used for key efficacy 
assessments. 
Table 2: Analysis Window for Efficacy Assessments 
 
Assessment 
Visit/Period 
Target 
Day/Period Per 
Protocol 
Analysis Window 
Clinical 
Response 
EOT to 
EOT+2 or 
AOC visit 
EOT: Study Day 
10 (±1) 
AOC: Study Day 
12 (+3) 
Study Days 8– 16 
(UBM data will be used for derivation if 8 ≤ study day 
of last dose ≤14. Investigator assessments will be used 
for derivation if investigator assessment at AOC visit 
is on or prior to Study Day 16.) 
Clinical Cure 
EOT to 
EOT+2 
EOT: Study Day 
10 (±1) 
Study Days 8 – 16 
(UBM data will be used for derivation if 8 ≤ study day 
of last dose ≤14) 
SCR 
Through 30 
days post EOT 
Study Day 40 
(+5) 
Study Days 40 – 45 
(Subjects who exit study before Study Day 40 will be 
considered as failures. Subjects who had other CDI 
antimicrobial treatment between Study Days 2 and 45 
or recurrence on or before Study Day 45 will be 
considered as failures.) 
SCR over 60 
days post EOT 
Through 60 
days post EOT 
Study Day 70 (±5) 
Study Days 65 – 75 
(Subjects who exit study before Study Day 65 will be 
considered as failures. Subjects who had other CDI 
antimicrobial treatment between Study Days 2 and 75 
or recurrence on or before Study Day 75 will be 
considered as failures.) 
SCR over 90 
days post EOT 
Through 90 
days post EOT 
Study Day 100 
(±5) 
Study Days 95 – 105 
(Subjects who exit study before Study Day 95 will be 
considered as failures. Subjects who had other CDI 
antimicrobial treatment between Study Days 2 and 
105 or recurrence on or before Study Day 105 will be 
considered as failures.) 
Recurrence 
Through 90 
days post EOT 
Up to Study Day 
100 (±5) 
Study day of recurrence ≤ 105 
Bile acids 
EOT (or AOC 
visit) 
EOT: Study Day 
10 (±1) 
AOC: Study Day 
12 (+3) 
8 ≤ study day of stool sample collection ≤ 16 
Study Day 40 
Study Day 40 
(+5) 
35 ≤ study day of stool sample collection ≤45 
Study Day 70 
Study Day 70 (±5) 
65 ≤ study day of stool sample collection ≤75 


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Assessment 
Visit/Period 
Target 
Day/Period Per 
Protocol 
Analysis Window 
Study Day 100 
Study Day 100 
(±5) 
95 ≤ study day of stool sample collection ≤105 
Recurrence 
Date of recurrence 
Stool sample collection within 5 days of recurrence 
date (i.e. ±5 days) 
EQ-5D-5L 
AOC visit 
Study Day 12 
(+3) 
8 ≤ study day of assessment ≤ 16 
Day 40 
Study Day 40 
(+5) 
35 ≤ study day of assessment ≤ 45 
Recurrence 
Date of recurrence 
Assessment within 5 days of recurrence date (i.e. ±5 
days) 
 
EOT: End of Treatment; AOC: Assessment of Cure; SCR: Sustained Clinical Response; CDI: Clostridioides difficile 
infection 
 
 
For by-visit analysis of EQ-5D-5L assessments and bile acids, visit windows in Table 2 will be 
used to associate assessment with a scheduled visit based on assessment date in reference to the 
date of first dose of study treatment. If there are multiple assessments in the same window for a 
subject, the one closest to the target day will be used. If two assessments are equally close to the 
target day, then the later assessment will be used. Similar approach will be applied to microbiology 
analysis. 
For by-visit analysis of safety data, data collected at scheduled visits will be analyzed according 
to the visit recorded in the eCRF. Assessments will not be reallocated to different visits according 
to visit window calculations. 
 
2.4. 
Handling Of Missing Data 
Efficacy Data 
Subjects who discontinued from study due to any cause prior to Study Day 40 will be considered 
as failures in the primary analysis for the primary endpoint SCR. A sensitivity analysis for SCR 
may be conducted by implementing multiple imputation methods for missing outcomes. 
Subjects who discontinued from study due to any cause prior to Study Day 65 (protocol specified 
visit window: Day 70 ± 5) will be considered as failures for the SCR over 60 days post EOT, and 
subjects who discontinued from study due to any cause prior to Study Day 95 (protocol specified 
visit window: Day 100 ± 5) will be considered as failures for the SCR over 90 days post EOT. Of 
note, subjects who failed SCR are also failures for SCR over 60 days post EOT and SCR over 90 
days post EOT, and subjects who failed SCR over 60 days post EOT are also failures for SCR over 
90 days post EOT. 
Subjects with missing investigator’s assessment at the Assessment of Cure (AOC) visit will be 
considered as clinical failures for the investigator assessment at AOC. If a subject’s UBM is 


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missing for two days from last dose date through 2 days after last dose of study treatment, then it 
is considered as failure for the criterion based on UBMs in deriving Clinical Response. 
If a subject’s UBM is missing at any day from last dose date through 2 days after last dose of study 
treatment, then it is considered as clinical failure for Clinical Cure. 
For time to resolution of diarrhea over the first 12 days, subjects who discontinued study prior to 
Study Day 12 or received other CDI antimicrobial treatment on or prior to Study Day 12 will be 
censored. 
EQ-5D-5L 
If any question is not answered on the five dimensions of the EQ-5D-5L, the health utility score 
will be missing. 
Missing or Partial Dates for Adverse Events (AEs), Medications and Hospitalization 
AEs with missing or partial dates will be handled such that in the absence of contradictory 
information an AE is considered as treatment emergent. For example, if the start date of an AE is 
missing but the end date is either overlapping into the treatment period or missing, the AE will be 
considered as treatment emergent. For medications with missing or partial dates, the most 
conservative case will be considered when assigning medications to categories. For example, if 
the start date of a medication is missing but the end date is either overlapping into the treatment 
period or missing, the medication will be considered as both prior and concomitant medications. 
Similarly, the most conservative case will be considered for hospitalization with missing or partial 
dates. Imputation of partially missing start or end date for AEs, medications, and hospitalization 
will be made. The imputation rules will follow Summit’s convention and details will be included 
in the analysis data specifications. 
 
3. 
SUBJECT INFORMATION 
3.1. 
Subject Disposition 
For all the randomized subjects, number of subjects in each of the analysis populations will be 
presented by treatment group and overall. Reason for exclusion from the mITT population will be 
presented. The following will be summarized by treatment and overall for the ITT and mITT 
populations: 
• Study treatment disposition and reason for discontinuation 
• Study status and reason for study discontinuation 
• Subject enrollment by region, country and site 
3.2. 
Protocol Deviation 
Subjects with important protocol deviations will be summarized by treatment group. 


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3.3. 
Demographic And Baseline Characteristics 
Demographic information at baseline and baseline characteristics will be summarized for the ITT 
and mITT populations by treatment group and overall. 
Demographic variables include age, age group (<65 years, ≥65 years, <75 years, ≥75 years), sex, 
race, ethnicity, body mass index (BMI), and region (US/Canada, Europe, Latin America, Other). 
BMI (kg/m2) = weight in kilogram / (height in meter × height in meter) 
Baseline disease characteristics include but not limited to the following: 
• History of CDI in the last 12 months per eCRF 
• History of CDI in the last 12 months per IXRS 
• Time since last episode of CDI: no  previous  episode,  >0-3  months,  >3-12  months, 
and >12 months 
• Number of UBMs at baseline: numeric and categorical (3, 4-5, 6-9, ≥10) 
• Free toxin test method 
• IDSA severity: severe, non-severe 
• Disease severity (UBM and WBC criteria): mild, moderate, severe 
• WBC: numeric and categorical (≤12 × 109/L, >12-15 × 109/L, >15 × 109/L) 
• Creatinine: numeric and categorical (<1.5 mg/dL, ≥1.5 mg/dL) 
• Hospitalization status: inpatient, outpatient 
• Immunocompromised: yes, no 
• Non-CDI antimicrobials usage: yes, no 
• Proton pump inhibitors usage: yes, no 
• Presence of ribotype 027 strain: yes, no 
• Presence of hypervirulent strains: yes, no 
• CDI signs and symptoms (will be presented separately) 
3.4. 
Prior Treatments for Current CDI Episode 
Antimicrobial treatments taken by subjects for the current CDI episode at randomization will be 
summarized by treatment group for the mITT population. List of treatments collected on the 
Treatment of Current Episode of CDI eCRF will be provided for medical review and requires 
finalization at the time of the analyses. 
 
3.5. 
Prior And Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization (WHO) drug 
dictionary version March 2021 or later. Prior medications are defined as those medications started 
prior to the administration of study treatment on Study Day 1. Concomitant medications are 
defined as medications taken after the administration of study treatment on Study Day 1 through 
30 days after last dose of study treatment. Hence medications started before the first dose of study 
treatment but continuing after are considered as both prior and concomitant medications. 
Concomitant medications will be summarized by therapeutic subgroup and preferred term for each 
treatment group. 


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Potential confounding medications (e.g. proton pump inhibitors) will be identified based on 
clinical review and summarized by treatment group. 
 
3.6. 
Treatment Exposure 
Exposure to study treatment will be summarized by treatment group for the mITT and safety 
populations. Descriptive statistics will be provided for treatment duration, total number of active 
doses taken, and relative dose intensity. Treatment duration will be calculated as (last dose date of 
study treatment - first dose date of study treatment + 1). The relative dose intensity will be 
calculated as the total number of active doses taken divided by the total number of active doses 
expected during the treatment period, multiplied by 100. 
 
4. 
STATISTICAL ANALYSES 
4.1. 
Efficacy Analyses 
Analysis of efficacy endpoints will be conducted on the mITT population. Table 3 summarizes the 
efficacy endpoints and analysis methods to be performed. Additional supportive or exploratory 
analyses may be performed as needed. The following two randomization stratification factors will 
be used for all the stratified analysis/test: age (<65 years and ≥65 years) and history of CDI (either 
none or 1 to 3 previous occurrences in the past 12 months). Of note, all subjects are randomized 
based on these two stratification factors. All the stratified analyses/tests will be based on the 
randomization stratification factors as recorded in the IXRS. 
Table 3: Summary of Efficacy Analyses to be Performed 
 
Endpoint 
Definition 
Analysis Method 
Primary Endpoint 
SCR 
SCR is defined as Clinical Response and no 
recurrence of CDI through 30 days post 
EOT. Specifically, subjects who had 
Clinical Response (see definition below) 
and no recurrence (see definition below) of 
CDI on or before Study Day 45 are 
considered as responders. Subjects who 
exited study prior to Study Day 40 or 
received 
other 
CDI 
antimicrobial 
treatmenta between Study Days 2 and 45 
are considered as failures. 
Primary Analysis: 
SCR rate will be compared between the two 
treatment groups (ridinilazole vs. vancomycin) 
using Cochran Mantel Haenszel (CMH) chi- 
squared test, adjusted for the two randomization 
stratification factors. The treatment difference and 
95% confidence interval (CI) will be calculated 
based on the stratified Miettinen and Nurminen 
method. The reasons for subjects who failed SCR 
will be summarized. 
Sensitivity Analysis: 
• 
Based on subjects who achieved Clinical 
Cure and had no recurrence of CDI 
through 30 days post EOT: analyzed using 
the same methods stated above. 
• 
Multiple imputation methods (see Section 
5.4 for details) may be used for dealing 
with missing outcomes.  The estimate   of 
the   treatment   effect   as   well   as   the 


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Endpoint 
Definition 
Analysis Method 
confidence interval will be derived from 
the imputed datasets. 
Subgroup Analysis: 
The results of treatment differences (ridinilazole vs. 
vancomycin) and 95% CI for each subgroup of 
selected variables will be presented in a forest plot. 
Secondary Endpoints 
Clinical Response 
Clinical Response is defined as 
• less than 3 UBMs for 2 consecutive days 
and maintained through the EOT without 
further CDI antimicrobial treatment at 
EOT+ 2 days OR 
• the investigator’s assessment that the 
subject is cured and no longer needs 
specific CDI antimicrobial treatment after 
completion of the course of study 
medication. 
Specifically, if the UBM criterion above is 
met or the investigator’s assessment at the 
Assessment of Cure visit is “Cured”, then 
the subject is considered as having clinical 
response as long as he/she did not receive 
other 
CDI 
antimicrobial 
treatmenta 
between Study Day 2 and 2 days post 
treatment. 
The 
treatment 
difference 
(ridinilazole 
vs. 
vancomycin) and 95% CI for clinical response rate 
will be calculated based on the stratified Miettinen 
and Nurminen method. Non-inferiority will be 
established if the lower limit of the 2-sided 95% CI 
for the treatment difference is greater than -10%. If 
non-inferiority is established and the lower limit of 
the 2-sided 95% CI is greater than 0%, superiority 
of ridinilazole in Clinical Response will be 
declared. 
Sensitivity Analysis: 
Clinical Cure will be analyzed using the same 
methods stated above for Clinical Response. 
Clinical cure is defined as the resolution of diarrhea 
(<3 UBMs in the 1-day period immediately prior to 
EOT, that is maintained for 2 days after EOT). 
Specifically, if a subject’s UBMs meet the criterion 
above, then the subject is considered as “Cured” as 
long as he/she did not receive other CDI 
antimicrobial treatmenta between Study Day 2 and 
2 days post treatment. 
Change from 
baseline to EOT of 
the relative 
abundance of 
microbiome- 
derived secondary 
bile acids 
Relative abundance of microbiome-derived 
secondary bile acids is defined as 
proportion 
of 
microbiome-derived 
secondary bile acids concentration against 
total bile acids concentration reported for 
each subject. 
Wilcoxon rank-sum test will be used to compare 
treatment groups. Descriptive summary statistics 
will be provided by treatment group. 
Recurrence 
Recurrence is defined as a new episode of 
diarrhea (≥3 UBMs) in a 1-day period with 
a positive C. difficile free toxin test or 
CCNA that requires CDI antimicrobial 
treatment in subjects who achieved clinical 
response. 
Recurrence rate will be compared between the two 
treatment groups using a chi-squared test. The 
treatment difference (ridinilazole vs. vancomycin) 
and 95% CI will be calculated based on the 
Miettinen 
and 
Nurminen 
method 
without 
stratification factors. 
SCR over 90 days 
post EOTb 
Defined as Clinical Response and no 
recurrence of CDI through 90 days post 
EOT. Specifically, subjects who had 
Clinical Response and no recurrence of 
CDI on or before Study Day 105 are 
considered as responders. Subjects who 
exited  study  prior  to  Study  Day  95  or 
received      other      CDI      antimicrobial 
Same as those for the primary analysis for SCR. 


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Endpoint 
Definition 
Analysis Method 
treatmenta between Study Days 2 and 105 
are considered as failures. 
Exploratory Endpoints 
Time to resolution 
of diarrhea over the 
first 12 days 
Defined as the time from starting study 
treatment to the resolution of diarrhea (<3 
UBMs in a 1-day period). Specifically, it is 
calculated as days from first dose to the first 
day of two consecutive days with <3 UBMs 
that are sustained through Study Day 12. 
Subjects who reached Study Day 12 
without resolution of diarrhea will be 
censored at Study Day 12. Subjects who 
exited study prior to Study Day 12 will be 
censored at the date of last bowel 
movement. Subjects who received other 
CDI antimicrobial treatmenta on or prior to 
Study Day 12 will be censored on the CDI 
treatment start date. 
Time to resolution of diarrhea over the first 12 days 
will be compared between the two treatment groups 
using a stratified log rank test adjusting for the two 
randomization stratification factors. The hazard 
ratio and its 95% CI based on a Cox regression 
model stratified by the two randomization 
stratification factors will be calculated. 
Kaplan-Meier (KM) curves will be plotted for the 
treatment groups. The KM estimated median and 
95% CI for each treatment group will be presented. 
The number and percentage of subjects who have 
resolution of diarrhea or are censored will be 
summarized. 
CDI signs and 
symptoms 
Individual CDI signs and symptoms, total 
number of CDI signs and symptoms for 
each subject and visit 
Descriptive summary statistics by treatment group 
at each visit. Shift table from baseline will be 
generated. 
Relative abundance 
of microbiome- 
derived secondary 
and primary bile 
acids, conjugated 
primary bile acids 
Value and change from baseline. Relative 
abundance is defined as proportion of the 
specific bile acid group (e.g. microbiome- 
derived secondary bile acids) against total 
bile acids concentration reported for each 
subject. 
Wilcoxon rank-sum test will be used to compare 
treatment groups. Descriptive summary statistics 
will be provided by treatment group at each visit. 
Descriptive summary statistics will also be 
provided for the bile acids concentrations. 
For microbiome-derived secondary bile acids 
concentration 
and 
relative 
abundance 
of 
microbiome-derived secondary bile acids at EOT, 
descriptive summary statistics may be presented by 
clinical outcome (e.g. SCR, recurrence). 
SCR over 60 days 
post EOTb 
Defined as Clinical Response and no 
recurrence of CDI through 60 days post 
EOT. Specifically, subjects who had 
Clinical Response and no recurrence of 
CDI on or before Study Day 75 are 
considered as responders. Subjects who 
exited study prior to Study Day 65 or 
received 
other 
CDI 
antimicrobial 
treatmenta between Study Days 2 and 75 
are considered as failures. 
Same as those for the primary analysis for SCR. 
Health Economics and Outcomes Research (HEOR) Endpoints 
Medical resource 
utilization: hospital 
admission, inpatient 
days, readmission 
A subject will be counted as a hospital 
admission if he/she was admitted to 
hospital for any reason. If subject moves 
from one area of a hospital to another (e.g. 
ICU to general hospital ward), it is only 
counted as one hospital admission. Total 
inpatient days is defined as total number of 
Hospital admission rate after first dose of treatment 
and reasons for admission will be summarized by 
treatment group. Planned admissions for a 
scheduled procedure will be excluded from the 
calculation of admission rate. 
Hospital readmission rate and reasons for 
readmission will be summarized by treatment 


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Endpoint 
Definition 
Analysis Method 
days in hospital from Study Day 1 to study 
exit. 
For inpatients at baseline: a subject will be 
counted as a hospital readmission if he/she 
was readmitted to hospital for any reason 
after discharge. 
group in inpatients at randomization. Planned 
readmissions for a scheduled procedure will be 
excluded from the calculation of readmission rate. 
Descriptive summary statistics for number of 
admissions or readmissions, and total inpatient 
days. 
Summaries will also be provided for CDI-related 
and Non-CDI related admissions/readmissions, and 
for admissions/readmissions to ICU. 
EQ-5D-5L 
dimensions and 
VAS score 
Clinically meaningful improvement is 
defined as an increase of ≥7 points for VAS 
score or ≥0.08 points for utility score. 
The proportion of subjects achieving clinically 
meaningful improvement will be compared 
between the two treatments using the CMH test 
stratified by the two randomization stratification 
factors. 95% CI for the difference will be 
calculated. 
Value and change from baseline 
For VAS score and utility score, change from 
baseline will be analyzed using the Mixed-Effects 
Model Repeated Measure (MMRM). The model 
includes the baseline score, age group, history of 
CDI, and disease severity at baseline as covariates; 
treatment, time point and treatment-by-time point 
interaction as fixed effects; and subjects as random 
effect. An unstructured (co)variance structure will 
be used to model the within-subject error. 
Kenward-Roger's approximation will be used to 
estimate denominator degrees of freedom. 95% CIs 
will be calculated for the difference of least square 
means. 
Descriptive summary statistics for the observed 
value and change from baseline will be provided by 
treatment at each visit including recurrence visit. 
a A subject is considered as “received other CDI antimicrobial treatment” if he/she took CDI antimicrobial 
medication(s) other than study treatment for >2 days. 
b Subjects will report bowel movement information daily up to Day 40 to support the primary endpoint analyses. 
Weekly contact with the subject will occur after Day 40 until study completion to check for diarrhea/suspected 
recurrence. 
EOT: End of Treatment; SCR: Sustained Clinical Response; CDI: Clostridioides difficile infection; CMH: Cochran 
Mantel Haenszel; CI: confidence interval; UBM: unformed bowel movement; KM: Kaplan-Meier; VAS: visual analog 
scale; MMRM: Mixed-Effects Model Repeated Measure 
4.2. 
Safety Analyses 
Safety data will be summarized by treatment group. Table 4 summarizes the safety analyses to be 
performed. All safety evaluation will be performed on the safety population. 
Adverse Events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 24 or later. A Treatment-Emergent Adverse Event (TEAE) is defined as an 
AE that occurs or worsens after the first dose of study treatment through 7 days after the last dose 
date or that is related to study treatment. Summary tables will be provided for TEAEs as well for 


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AEs that occur or worsen after the first dose date through 30 days after the last dose date. Serious 
AEs reported up to the end of study visit may be summarized as needed. 
Adverse event of special interest (AESI) is defined as an adverse event (serious or nonserious) of 
scientific and medical concern specific to the product, for which ongoing monitoring and further 
investigation is necessary to characterize and understand it. It is expected that additional aggressive 
follow up efforts are directed at these AESIs. 
All laboratory values will be converted to and reported as international standard (SI) units. 
Table 4: Summary of Safety Analyses to be Performed 
 
Assessment 
Analysis Method 
Adverse Events (TEAEs and AEs through 30 days after the last dose) 
AEs, serious adverse events (SAEs), related AEs, related 
SAEs, AEs leading to treatment discontinuation, AEs 
resulting in death, AESIs (if applicable), infectious AEs 
Frequency and percent of subjects by treatment group 
and severity; listings for all serious AEs, TEAEs 
leading to treatment discontinuation, and all deaths. 
An exploratory analysis of clinical events including 
infections and glucose which could reflect the balance 
of the gut microbiome will also be performed. 
Clinical Laboratory 
Hematological 
parameters: 
hematocrit, 
hemoglobin, 
leukocytes, neutrophils, platelets 
Clinical chemistry parameters: alanine aminotransferase, 
albumin, alkaline phosphatase, aspartate aminotransferase, 
bilirubin, creatinine, glucose, potassium, sodium, urea 
nitrogen 
Descriptive summary for observed value, change, and 
percent change from baseline by treatment group at 
each scheduled visit; shift table from baseline by 
treatment group based on CTCAE criteria; summary 
tables for subjects meeting the Hy’s law 
Vital Signs 
Blood pressure, pulse, temperature, weight 
Descriptive summary for the observed value and 
change from baseline by treatment group at each 
scheduled visit 
 
4.3. 
Microbiology Analysis 
Number of subjects with positive, negative, or undetermined culture result will be summarized by 
treatment group at each visit. Ribotype classification of baseline isolates will be summarized by 
region, country and site for each treatment group and overall. For subject who had CDI recurrence, 
relapse (i.e. same ribotype at recurrence and baseline) rate and reinfection (i.e. difference ribotypes 
at recurrence and baseline) rate will be summarized by ribotype for each treatment group. 
Clinical outcomes (e.g. SCR) will be summarized by baseline ribotype for each treatment group. 
Descriptive summary statistics (including geometric mean, range, MIC50, MIC90) for minimum 
inhibitory concentrations (MICs) and percent of resistant by CLSI/EUCAST interpretative criteria 
will be calculated by treatment group, and will be presented by ribotype, and by region and 
country. 
Descriptive summary statistics for MICs by clinical outcome (e.g. SCR) will be calculated for each 
treatment group, and will be presented by ribotype, and by region and country. Clinical outcomes 
(e.g. SCR) will also be summarized by MIC and ribotype at baseline for each treatment group, and 


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summaries will be presented by region and country. Change from baseline MIC to highest post- 
baseline MIC result recorded in the study will be summarized by treatment group and baseline 
ribotype. This will include only those subjects who had the same ribotype at baseline and the post- 
baseline visit. 
 
4.4. 
Pharmacokinetic Analysis 
Summary statistics will be reported by sampling timepoints over all patients in the PK population 
for ridinilazole plasma concentrations. A count of the number of samples below the level of 
quantification (BLQ) will be provided for each time point. 
 
4.5. 
Microbiome Analysis 
All the analyses for microbiome data including microbiota α-diversity (Shannon) and β-diversity 
(Bray-Curtis) measures will be included in a separate document to support the microbiome report. 
 
4.6. 
Listings 
Patient profiles and key primary or secondary efficacy parameters listings along with individual 
components in the definitions might be generated to facilitate data review. Additional listings may 
be generated as needed. 
 
4.7. 
Covid-19 Impact 
The impact of COVID-19 will be reported following FDA’s guidance documents, ‘Conduct of 
Clinical Trials of Medical Products During the COVID-19 Public Health Emergency, Guidance 
for Industry, Investigators, and Institutional Review Boards’ and ‘Statistical Considerations for 
Clinical Trials During the COVID-19 Public Health Emergency, Guidance for Industry’. Summary 
and/or listing will be considered for the following: COVID-19 AEs including death, subjects with 
diagnosed COVID-19 prior to randomization, protocol deviations related to COVID-19, study 
treatment discontinuation or study discontinuation due to COVID-19. 
Subgroup analysis for the primary endpoint SCR in subjects with diagnosed COVID-19 prior to 
randomization will be performed. 


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5. 
SUPPORTING DOCUMENTATION 
5.1. 
Appendix 1: List of Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
AOC 
Assessment of Cure 
BID 
Twice a day 
BMI 
Body Mass Index 
CCNA 
Cell Cytotoxicity Neutralization Assay 
CDI 
Clostridioides difficile Infection 
CI 
Confidence Interval 
CMH 
Cochran Mantel Haenszel 
eCRF 
Electronic Case Record Form 
EOS 
End of Study 
EOT 
End of Treatment 
HEOR 
Health Economics and Outcomes Research 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IDSA 
Infectious Disease Society of America 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
NI 
Non-Inferiority 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
QID 
Four times a day 
SAP 
Statistical Analysis Plan 
SCR 
Sustained Clinical Response 
SD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
UBM 
Unformed Bowel Movement 
VAS 
Visual Analog Scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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5.2. 
Appendix 2: Changes to Protocol-planned Analyses 
Below are the major changes made from the protocol: 
• Recurrence is added as one of the secondary endpoints. 
 
• Clinical Cure is removed from the list of secondary endpoints and will be considered as 
sensitivity analysis for Clinical Response. SCR over 60 days post EOT is removed from 
the list of secondary endpoints and considered as an exploratory endpoint. 
• Change from baseline to EOT of the relative abundance of the bile acid components – 
conjugated primary and microbiome-derived primary bile acids, and the microbiota α-
diversity (Shannon) and β-diversity (Bray-Curtis) indices in stool samples are removed 
from the list of secondary endpoints and considered as exploratory endpoints in the SAP. 
 
• The following two randomization stratification factors will be used for all the stratified 
analysis/test: age (<65 years and ≥65 years) and history of CDI (either none or 1 to 3 
previous occurrences in the past 12 months). In Protocol Amendment 7 (dated 21 June 
2021), number of UBMs and immunocompromised were added as randomization 
stratification factors but have not been implemented. Therefore, at the time of data cutoff 
all the subjects are randomized based on the two stratification factors: age and history of 
CDI. 
In addition, CDI signs and symptoms are added as exploratory endpoints. Change from baseline 
in Cdiff32 domains (US sites) is excluded. 
All the analyses for microbiome data including microbiota α-diversity (Shannon) and β-diversity 
(Bray-Curtis) measures will be included in a separate document to support the microbiome report. 


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5.3. 
Appendix 3: Schedule of Activities 
 


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Notes: Unscheduled telephone calls and/or visits may be conducted if necessary, for the patient’s safety and to ensure dosing and diary completion per 
protocol. 
1. Screening and D1/baseline assessments may occur on the same day or within a 1- to 3-day window. Patients can be rescreened once for this study. 
2. D5 visit will be conducted by telephone. Screening, D10, D70, and D100 assessments may be conducted in-clinic or by telephone. 
3. Preferably the Baseline visit should be completed as an in-clinic visit; however, to maximize potential enrollment (e.g., during a pandemic) the 
visit may be conducted remotely. If so, a sponsor-contracted home healthcare vendor or properly trained and delegated site staff must conduct 
assessments at the patient’s home. All assessments should be completed prior to randomization except for the following, which must still be 
conducted prior to their 1st dose of study medication: weight, blood samples (hematology and clinical chemistry), stool collection (if required, to 
collect a sample for microbiology/microbiome/metabolome that is <24h old), eDiary training, EQ-5D-5L, Cdiff32 and medical resource utilization 
questions. 
4. 
D12, D40 and recurrence visits are preferably in-clinic visits; however, these visits may be conducted remotely. 
5. 
Subjects who have discontinued study drug early should remain in the study and be monitored, e.g., for adverse events. 
6. 
Documented informed consent must be provided by the patient prior to any study procedure being conducted. Informed Consent is allowed in other 
than face to face method as per site local procedure or local regulations. 
7. 
Current/baseline CDI free toxin test: A free toxin test must be the 1st assessment conducted using a sample produced within 72 hours prior to 
randomization. Patients with a negative free toxin test will be excluded from the study. 
Suspected recurrence free toxin test: A free toxin test should be conducted as soon as possible – and at a maximum of 48 hours - after identifying a 
suspected recurrence. Cell Cytotoxicity Neutralization Assay (CCNA) sample is to be collected when free toxin test is negative and sent to a 
specialized central laboratory. 
Negative or invalid free toxin test results: A negative free toxin test may be repeated once for baseline and suspected recurrence. The same sample 
may be used if collected within 24 hours, otherwise a fresh sample must be used. Invalid test results should be repeated. 
Free toxin test specification: Sites may use an established local free toxin test laboratory service if it is a suitable test, and it is prospectively agreed 
with the Sponsor. Suitable tests will have appropriate regulatory approvals (FDA approval, EU CE Mark or equivalent). Please see protocol 
Appendix 6 for list of approved tests. Free toxin tests will be provided for the site/site laboratory use if a suitable test is not available locally. 
8. 
Record all known historical CDIs along with associated treatment, information on the current/baseline CDI including signs and symptoms, any 
potential confounding medications taken up to 4 weeks prior to randomization, relevant medical history for 12 months prior to randomization and 
all prior and current medications taken up to 4 weeks prior to randomization. 
9. 
Stool samples should be aliquoted and frozen within 24 hours of sample being produced. Only one sample is required at either Screening or D1. 
Only one sample is required at either D10 or D12. Additional stool samples are required at each of the following visits: D40, D70, D100, and each 
suspected recurrence. If the visit is conducted remotely, stool sample drop off or collection from the patient (e.g., courier) must be arranged. 
10. If the visit is conducted remotely physical exam and vital signs if taken by the patient are done through sponsor approved video conferencing 
between the patient and Investigator. 
The following assessments must be included: temperature, blood pressure, pulse, height (baseline only) and weight. The physical exam may be 
conducted at the screening or baseline visit; if conducted at screening, the vital sign assessment must still be repeated at baseline. 


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11. The ECG may be conducted at the screening or baseline visit. It does not need to be completed if most recent ECG was normal and was completed 
in the 12 months prior. 
12. An appropriately qualified person will need to collect blood samples (hematology and clinical chemistry per protocol Appendix 2). For visits 
conducted remotely, this person will either need to visit the patient at home or the site will need to arrange an alternative location. 
13. WOCBP = Women of Child Bearing Potential. Testing in the case of missed menses should also be conducted up to 30 days following the last dose 
of study treatment. An appropriately qualified person will need to perform this procedure. For visits conducted remotely, this person will either 
need to visit the patient at home or the patient may perform a home pregnancy test over video conference with the site. 
14. Based on the Investigator’s assessment of the reduction of UBMs since baseline, clinical signs and symptoms and need for further treatment for 
CDI. 
15. Approximately 100 patients will undergo PK sampling. Blood draws should occur at on Day 1 or 2 at 2 and 4 hours (±30 minutes) following 
either Dose 1, 3, 5 or 7 and at EOT at 2 and 4 hours (±30 minutes) following either Dose 33, 35, 37 or 39. 
PK sampling must be conducted following administration of study medication. A ±30-minute window is allowable for the sampling times relative 
to dosing. An accurate date and time of dose and sampling is required. A home healthcare vendor or appropriately trained and delegated site staff 
may perform this procedure at the patient’s home. 
16. Potential confounding medications should be avoided where possible except for CDI medications required in the case of recurrence. If 
antimicrobial therapy is required for infections other than those due to C. difficile, antimicrobials without activity/efficacy against C. difficile 
should be prescribed where possible. 
17. Patients will report dosing information daily until EOT and bowel movement information daily until D40 in their eDiary. As an alternative the 
patient may be contacted daily either by site or a 3rd party vendor. After D40 the site will contact the patient weekly to check for new episodes of 
diarrhea/suspected recurrence. The eDiary needs to be collected/returned (e.g., courier) upon study completion. 
18. AEs only need to be reported up to the D40 visit (inclusive). AEs meeting the definition of serious should be reported throughout the study. 


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5.4. 
Appendix 4: Sensitivity Analysis for SCR Using Multiple Imputation 
The missing outcomes in sensitivity analysis will be imputed using multiple imputations (MI) method. The MI procedure replaces each missing binary SCR value 
with a set of plausible values that represent the uncertainty about the right value to impute. These multiple imputed data sets are then analyzed by using the same 
method for the primary analysis for complete data. The results from each set of imputed data sets will then be combined using Rubin’s rule. The estimate of the 
treatment effect as well as the confidence interval will be derived from the imputed datasets. 
In the imputation step, missing outcomes will be imputed using a logistic model predicting the probability of SCR with covariates of baseline characteristics. 
Specifically, the following variables will be considered in the logistic model: treatment group, region, sex, age, prior CDI episodes, UBMs at baseline or baseline 
disease severity, immunocompromised, antimicrobial treatment for current CDI at randomization. 
 
Subsets 
SCR: Primary Analysis SCR: Sensitivity Analysis 
No Clinical Response 
No 
No 
Subjects with Clinical Response 
Recurrence prior to or on Study Day 45 
No 
No 
Other CDI antimicrobial treatment prior to or on Study Day 45 with 
diarrhea (i.e. UBM ≥3): negative or missing free toxin test/CCNA 
No 
No 
Other CDI antimicrobial treatment prior to or on Study Day 45 
without diarrhea 
No 
Missing 
Exit study prior to Study Day 40 
No 
Missing if the above criteria are not met 
Meet all criteria for SCR and Clinical Response is based on UBM 
criterion only (i.e. investigator assessment at Assessment of Cure 
visit is “Failed” or missing; no evidence of recurrence) 
Yes 
Missing 
Meet all criteria for SCR and investigator assessment at Assessment 
of Cure visit is “Cured” 
Yes 
Yes 
SCR: sustained clinical response; UBM: unformed bowel movement; CDI: Clostridioides difficile infection. 


 
Created: 
2021-11-19 
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Status: 
Transaction ID: 
Jianling Li (Jianling.Li@summitplc.com) 
Signed 
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Final Audit Report 
2021-11-20 
 
 
 
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