Clinical trial NCT03788434
Conditions: Clostridium Difficile Infection Recurrence Clostridium Difficile Infection Clostridium Difficile Clostridioides Difficile Infection Recurrence Clostridioides Difficile Infection Clostridioides Difficile CDI
Keywords: Clostridium Difficile Infection Recurrence Clostridium Difficile Infection Clostridium Difficile VE303 Consortium Vedanta CDI C. Diff CDiff Clostridiodes Difficile Infection Recurrence Clostridiodes Difficile Infection Clostridioides Difficile
Sponsor: Vedanta Biosciences, Inc.
Start date: 2019-02-08; Completion date: 2021-09-15
Enrollment: 79 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluated the safety and efficacy of VE303 for participants with primary C. difficile infection (pCDI) at high risk for recurrence or subjects with recurrent C. difficile infections (rCDI).

Detailed description:
CONSORTIUM was a randomized, placebo-controlled double-blind Phase 2 study to evaluate safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy of VE303 in prevention of subsequent Clostridioides difficile infection (CDI) -associated diarrhea compared with placebo following completion of at least 1 successful course of standard-of-care (SOC) antibiotics. VE303 or placebo capsules were taken orally for 14 days after completion of a course of SOC antibiotics. The proportions of subjects experiencing a confirmed CDI recurrence within 8 weeks after the first dose of study treatment were compared across the study arms, to understand the efficacy of VE303 in preventing rCDI.

The study originally planned to enroll 146 subjects but through a protocol amendment was revised to an enrollment target of 60 to 80 subjects with a prior history of CDI diarrhea or first occurrence of CDI diarrhea with a higher risk for recurrence. Subjects must have had a positive C. difficile stool sample and have responded to SOC antibiotic treatment.

Arms: arm 1: Study subjects assigned the high dose VE303 arm took 10 capsules (dosage: 8.0 × 10\^9 CFU daily) containing VE303 per day for 14 days. arm 2: Study subjects assigned to the low dose VE303 arm took 2 capsules (dosage: 1.6 × 10\^9 CFU daily) containing VE303 per day for 14 days. arm 3: Study subjects assigned to the placebo dose arm took placebo capsules each day for 14 days. The capsules did not contain any VE303.
Interventions: intervention 1: VE303 intervention 2: Placebo
Intervention descriptions: intervention 1: VE303 is a live biotherapeutic product containing 8 clonal human commensal bacterial strains manufactured under Good Manufacturing Practices (GMP) conditions. intervention 2: Placebo capsules contained microcrystalline cellulose and were visually identical to VE303 capsules. Placebo capsules did not contain any VE303 Drug Product.

Protocol documents:
Prot_002.pdf: 
 
 
Vedanta Biosciences, Inc. | 19 Blackstone Street, Cambridge MA 02139 | 857-706-1427 
 
 
Phase 2 Study of VE303 for Prevention of Recurrent Clostridioides Difficile Infection 
 
 
NCT03788434 
 
 
Submitter: Isabella Newbert– Clinical Trial Associate at Vedanta Biosciences 
 
 
Included in this submission:  
Redacted Protocol (Version 7.0 15JUL21)  
 
 
Document Date: 15JUL21 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CLINICAL STUDY VE303-002 
Protocol Version 7.0: 15 July 2021 
Study Title: 
A Double-Blind Placebo-Controlled Phase 2 Study of VE303 
for Prevention of Recurrent Clostridium (Clostridioides) 
Difficile Infection 
Study Number: 
VE303-002 
Study Phase: 
Phase 2 
Product Name: 
VE303 
IND Number: 
017750 
Indication: 
Prevention of Recurrent Clostridium (Clostridioides) Difficile 
Infection 
Sponsor: 
 
Vedanta Biosciences, Inc. 
19 Blackstone Street 
Cambridge, Massachusetts 02139 
United States of America 
Phone: (857) 706-1427 
Responsible Medical Officer: 
 
 
 
 
 
CONFIDENTIAL INFORMATION: This protocol contains trade secrets and other confidential information. 
Accordingly, this protocol shall be treated as confidential and restricted to its intended use, namely, the guidance of 
the clinical Investigator. This material is the sole property of Vedanta Biosciences, Inc and shall not be disclosed or 
used by others except as authorized in writing by Vedanta Biosciences, Inc. This material may be disclosed to and 
used by your staff and associates only to the extent necessary to conduct the clinical study. 
 




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INVESTIGATOR SIGNATURE PAGE 
Declaration of the Principal Investigator 
Study VE303-002: A Double-Blind Placebo-Controlled Phase 2 Study of VE303 for 
Prevention of Recurrent Clostridium (Clostridioides) Difficile Infection 
 
I have read this study protocol, including all appendices. By signing this protocol, I agree to 
conduct the clinical study, following approval by an Independent Ethics Committee/Institutional 
Review Board, in accordance with the study protocol, the current International Council for 
Harmonisation Guideline for Good Clinical Practice, and applicable regulatory requirements. I 
will ensure that all personnel involved in the study under my direction will be informed about the 
contents of this study protocol and will receive all necessary instructions for performing the 
study according to the study protocol. 
 
 
 
 
 
  
Printed Name 
 
Signature 
 Date 
 


VE303 
 
 
Vedanta Biosciences, Inc. 
Clinical Study VE303-002 
 
Protocol Version 7.0 
 
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PROTOCOL SYNOPSIS 
Title 
A Double-Blind Placebo-Controlled Phase 2 Study of VE303 for 
Prevention of Recurrent Clostridium (Clostridioides) Difficile Infection 
Protocol 
Number 
VE303-002 
Phase 
2 
Study Sites 
Up to 80 sites in the United States and Canada 
Objectives and 
Endpoints 
Objectives 
The primary objective is to determine the recommended VE303 Phase 3 
dose regimen(s) based on safety and efficacy, as indicated by the 
Clostridioides difficile (C. difficile) infection (CDI) recurrence rate. 
Secondary objectives are to characterize VE303 colonization and changes 
in the fecal microbiome. 
Endpoints 
Safety endpoints include the overall safety profile and treatment-
emergent adverse events (TEAEs). 
Efficacy endpoints include: 
• Proportion of subjects with CDI recurrence before or at Week 8 
(i.e., 8 weeks after the first dose of study drug). 
• Proportion of subjects without CDI recurrence before or at 
Week 4 (i.e., 4 weeks after the first dose of study drug), Week 12 
(i.e., 12 weeks after the first dose of study drug), and Week 24 
(i.e., 24 weeks after the first dose of study drug). 
Pharmacodynamic and pharmacokinetic endpoints include: 
• Fecal VE303 component bacteria colonization abundance and 
duration. 
• Changes in fecal microbiota diversity and taxonomic composition. 
• Changes in the fecal metabolomic profile, including short chain 
fatty acids and bile acids. 
Study Design 
This Phase 2, randomized, parallel-arm, double-blind, placebo-controlled, 
dose-selection study will evaluate the safety, microbiota changes, and 
efficacy of VE303 in the prevention of subsequent CDI-associated 
diarrhea compared with placebo following completion of at least 1 
successful course of standard-of-care (SOC) antibiotics for subjects with 


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primary C. difficile infection (pCDI) at high risk for recurrence or 
subjects with recurrent C. difficile infection (rCDI). 
Eligible subjects will be randomized into 4 treatment arms in a 2:1:2:1 
ratio to receive VE303 high dose (10 capsules):placebo high dose (10 
capsules):VE303 low dose (2 capsules):placebo low dose (2 capsules), 
respectively. Approximately 60 to 80 subjects are anticipated for 
enrollment. 
A Data Monitoring Committee (DMC), which will include independent 
clinicians with knowledge of the target population, a biostatistician, and 
Sponsor representatives, will be established to oversee subject safety. 
Investigators and subjects will remain blinded for the duration of the 
study period. 
Randomization will be stratified by 1) number of previous CDI episodes 
at Baseline (0 vs ≥ 1 episodes, excluding the qualifying episode; i.e. 
Inclusion criterion 2a vs 2b/2c subjects), 2) SOC antibiotic treatment 
(non-vancomycin [fidaxomicin or metronidazole] or an alternative oral 
vancomycin dosing regimen vs vancomycin QID [four times a day; this 
category will include subjects who receive vancomycin QID on at least 
the last day of treatment]), and 3) results of CDI laboratory diagnostic 
method (free toxin [enzyme immunoassay (EIA) for Toxin A/B or Cell 
Cytotoxicity Neutralization Assay (CCNA)] vs other [polymerase chain 
reaction (PCR)/cytotoxic culture if EIA for Toxin A/B and/or CCNA 
results are negative or not available]). 
On the last planned day of SOC antibiotic administration for a qualifying 
CDI episode, or no later than 1 day after completion of antibiotic dosing, 
subjects will be randomized and begin daily oral administration of 
placebo or VE303 (both at low and high doses) for 14 consecutive days. 
The first dose of the study drug will be administered under the 
supervision of study personnel at the Day 1 visit. After the 14-day dosing 
period is completed, follow-up will be performed every 2 to 4 weeks for 
24 weeks after the first dose of study drug. 
Study-specific Definitions 
An episode of diarrhea consistent with diarrhea due to C. difficile is 
characterized by ≥ 3 loose/unformed bowel movements (Bristol Score 
5-7, see Appendix 1) within 24 hours for at least 2 consecutive days or 
> 8 loose/unformed bowel movements within 24 hours, and considered 
unlikely to have another etiology. 
The following are specific protocol definitions: 
A prior occurrence of CDI is based on a subject’s medical history and 
defined as an episode of diarrhea consistent with diarrhea due to 
C. difficile, with a stool sample that is positive for C. difficile (e.g., PCR, 
or EIA for Toxin A/B, and GDH antigen, or CCNA). The CDI episode 


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must have initially responded to SOC antibiotic treatment, with no other 
identifiable cause for the diarrhea. 
A qualifying CDI episode is defined as an episode of diarrhea consistent 
with diarrhea due to C. difficile, which includes a positive diagnostic stool 
test for free toxin or toxigenic C. difficile. 
• Diagnostic tests for enrollment may be performed at the local 
laboratory or at the central laboratory. Subjects with a positive 
test (either EIA for Toxin A/B or PCR or CCNA or toxigenic 
culture assay, performed at the local laboratory or at the 
central laboratory) may be enrolled in the study. Confirmation 
of a positive local test by central laboratory test is not required 
for subject enrollment, provided documentation of a local 
positive test is available.  
• Subjects’ allocation to a proper stratum is dependent on timely 
reports of laboratory results from both local and central 
laboratories. To ensure subjects are allocated to a proper 
stratum, an effort should be made to obtain and send a stool 
sample to the central laboratory for confirmation of free toxin 
or toxigenic C. difficile prior to randomization. Additional 
requirements are provided in Inclusion Criteria #3 and #4. 
A successful clinical response to antibiotic therapy by the time of 
randomization to the study treatment is required for a subject to be 
eligible. A successful clinical response is defined as the symptomatic 
control of the qualifying/current CDI episode, i.e., < 3 loose/unformed 
bowel movements within 24 hours for at least 2 consecutive days. 
An on-study CDI recurrence is defined as an episode of diarrhea 
consistent with diarrhea due to C. difficile infection, which includes a 
stool sample positive for free toxin (EIA for Toxin A/B or CCNA) per 
test performed at the local laboratory or at the central laboratory. An 
on-study CDI recurrence may occur at any time after administration of 
the first dose of study drug.  
• If recurrent CDI is suspected, a stool sample must be collected for 
laboratory confirmation. Regardless of the test(s) performed at the 
local laboratory, samples must be collected from all subjects 
during each episode of diarrhea for CDI testing at a central 
laboratory.  
• After an initial sample collected for suspected recurrence, it is 
required to collect and submit samples on subsequent day(s) if the 
laboratory test results are not available or negative for free toxin 
(EIA for Toxin A/B or CCNA) before initiating antibiotic therapy. 




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• Have kidney dysfunction, defined as creatinine 
clearance of < 60 mL/min/1.73 m2 at the time of the 
current CDI episode 
• Have a history of regular use of proton pump 
inhibitors (PPIs) within the past 2 months and will 
be continuing use of PPIs throughout the study 
• Have a history of CDI at any time 
c. Subjects ≥ 75 years of age. 
3. The qualifying episode must meet all of the following criteria: 
a. New onset of ≥ 3 loose/unformed bowel movements 
(i.e., Types 5 to 7 on the Bristol stool scale, see 
Appendix 1) within 24 hours for 2 consecutive days or 
> 8 loose/unformed bowel movements within 24 hours 
b. CDI symptoms started within 30 days (inclusive) prior to 
the day of randomization 
c. Stool sample collected before (or no later than 72 hours 
after) initiation of SOC antibiotic therapy and positive for 
CDI laboratory test as defined in the “qualifying CDI 
episode” section (NOTE: every effort must be made to 
collect the diagnostic sample before SOC antibiotic 
therapy or within 24 hours after antibiotic therapy 
initiation, whenever possible) 
d. Diarrhea considered unlikely to have another etiology. 
4. Prior to randomizing a subject to receive the first dose of the study 
medication, a subject should: 
a. Receive and complete an Investigator’s choice SOC 
antibiotic regimen of a minimum of 10 days and up to 
21 days of total duration (NOTE: antibiotic tapering is not 
allowed) 
b. Meet successful clinical response criteria defined as the 
symptomatic control of the qualifying/current CDI 
episode, i.e., < 3 loose/unformed bowel movements within 
24 hours for at least 2 consecutive days 
c. Have a positive C. difficile diagnostic stool test by either 
EIA for Toxin A/B or PCR or CCNA or toxigenic culture 
assay performed at the local laboratory or at the central 
laboratory. 
5. Females of childbearing potential must have a negative pregnancy 
test and must agree to either use a highly effective acceptable 
form of birth control (e.g., established hormonal birth control plus 
a barrier method, double barrier method: intrauterine device plus 


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condom or spermicidal gel plus condom) or remain celibate 
during the study period and up to 3 months after the last dose of 
study drug. 
6. Able to receive the first dose of study drug on the last planned day 
of SOC antibiotic administration for a qualifying CDI episode, or 
no later than 1 day after completion of antibiotic dosing. 
7. Able and willing to follow study procedures (e.g., ingest up to 
10 size 0 (2 cm) capsules per day for 14 days, comply with study 
visits, provide stool samples, and record information/interact with 
study tools). 
8. Recovered from any complications of severe or fulminant CDI 
and be clinically stable by the time of randomization. 
Exclusion Criteria: 
1. History of diarrhea (defined as 3 or more loose stools per day 
lasting for at least 4 weeks) that is not related to C. difficile 
infection within the 3 months prior to randomization. 
2. Known or suspected toxic megacolon or small bowel ileus at the 
time of randomization. 
3. Contraindication to oral/enteral therapy (e.g., severe reflux, severe 
nausea/vomiting, or ileus) at the time of randomization. 
4. Presence of white blood cell (WBC) count > 15 × 109 cells/L, or 
body temperature > 38.5 °C at the time of randomization. 
5. Prior administration of genetically modified investigational live 
bacterial/fungal/bacteriophage/viral isolates for CDI-associated 
diarrhea (Exception: use of yogurt or other food products 
containing live bacterial cultures or over the counter probiotics is 
permitted). 
6. History of administration of fecally-derived investigational live 
biotherapeutic products, or fecally-derived live bacterial isolates 
for CDI-associated diarrhea including fecal microbiota 
transplantation within the last 6 months. 
7. Use of drugs that alter gut motility (e.g., loperamide, 
diphenoxylate) within 3 days prior to the planned first dose of 
study drug. 
8. Planned administration of oral or parenteral antibacterial therapy 
for a non-CDI indication after randomization. 
9. History of acute leukemia or hematopoietic stem cell 
transplantation or myelosuppressive chemotherapy within 
2 months prior to randomization. 
10. Subjects with compromised immune system, including: 




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Criteria for 
Evaluation 
Safety will be evaluated continuously for the duration of a subject’s study 
participation, including assessment of adverse events (AEs) reported by a 
subject or observed by study personnel from the date of informed consent 
until the end of the 6-month follow-up period, evaluation of 
gastrointestinal symptoms, electrocardiograms, physical examination, 
assessment of vital signs, and clinical laboratory measurements. Adverse 
events will be coded using the most current version of Medical Dictionary 
for Regulatory Activities at the time of study initiation, and the severity 
of AEs and laboratory abnormalities will be graded using the National 
Cancer Institute Common Terminology Criteria for Adverse Events 
version 5.0. 
Stool samples must be collected at the time points specified in Table 7-1 
for C. difficile testing (e.g., EIA for Toxin A/B, PCR, CCNA, toxigenic 
culture assay) and for the exploratory analyses (microbiota composition, 
VE303 component bacteria detection, antibiotic concentrations, 
metabolomics, culture, detection of antibiotic resistant bacteria (ARB) 
other than C. difficile (e.g., carbapenem-resistant Enterobacteriaceae 
[CRE], extended spectrum β-lactamase producing Enterobacteriaceae 
[ESBL], or vancomycin-resistant Enterococcus [VRE]), and calprotectin). 
Subjects will be continuously monitored for clinical events of diarrhea 
that may be indicative of a CDI recurrence. 
Guidance on 
Study Drug 
Discontinuation 
for Suspected 
on-Study CDI 
Recurrence 
As per the Primary Efficacy Analysis, the discontinuation of study 
treatment for subjects with suspected on-study CDI recurrence is based 
on the results of free toxin test (EIA for Toxin A/B or CCNA) performed 
at the local or the central laboratory regardless of the results of toxin 
PCR. If initial results of free toxin test are negative or not available and 
the symptoms persist, repeated samples should be collected and tested on 
subsequent day(s). The subjects will be continuously monitored (more 
than once/day by telephone) to determine if the suspected rCDI persists 
and the study drug needs to be discontinued.  
• If a subject has a new episode of diarrhea consistent with diarrhea 
due to C. difficile (Section 4.2) after starting the study drug but the 
free toxin test (EIA for Toxin A/B or CCNA) is negative or 
unavailable at the time and the SOC antibiotic is not administered 
for this episode, the study treatment should be continued. This 
episode will not be considered a CDI recurrence if free toxin test 
(EIA for Toxin A/B or CCNA) is negative or not available.  
• If a subject has a new episode of diarrhea consistent with diarrhea 
due to C. difficile after starting the study drug but the free toxin 
test (EIA for Toxin A/B or CCNA) is negative or unavailable at 
the time and the SOC antibiotic is administered for this episode, 


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the study treatment should be discontinued. This episode will not 
be considered a CDI recurrence if free toxin test is negative or not 
available. The discontinuation of study drug due to SOC antibiotic 
treatment in such a case will be considered a protocol deviation 
and should be reported as such in the eCRF. 
• If the subject has a new episode of diarrhea consistent with 
diarrhea due to C. difficile after starting the study drug and the 
free toxin test (EIA for Toxin A/B or CCNA) is positive, the study 
treatment should be discontinued. This episode will be considered 
a CDI recurrence. Such an event should be reported as confirmed 
recurrence in the eCRF. 
Statistical 
Considerations 
Final Analysis 
 Safety and efficacy endpoints will be based on approximately 60 to 80 
subjects completing the intended duration of the study (through Week 
24/Day 168) with descriptive statistics. 
Sponsor 
Vedanta Biosciences, Inc. 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ..................................................................................................2 
INVESTIGATOR SIGNATURE PAGE......................................................................................3 
PROTOCOL SYNOPSIS ..............................................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................17 
1.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ...................19 
2.0 
INTRODUCTION............................................................................................................20 
2.1 
Background of C. Difficile Infection .....................................................................20 
2.1.1 
Current Management of C. Difficile Infections ....................................21 
2.2 
VE303 Composition and Characterization ............................................................22 
2.2.1 
Nonclinical Studies ...............................................................................23 
2.2.2 
Clinical Studies .....................................................................................27 
2.3 
Rationale and Dose Selection for the Study ..........................................................29 
3.0 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................30 
3.1 
Objectives ..............................................................................................................30 
3.2 
Endpoints ...............................................................................................................30 
4.0 
STUDY DESIGN ..............................................................................................................31 
4.1 
Study Design Overview .........................................................................................31 
4.2 
Study-Specific Definitions .....................................................................................32 
4.3 
Study Dosing Regimens .........................................................................................33 
4.3.1 
Subject Monitoring ...............................................................................33 
4.4 
Guidance on Study Drug Discontinuation for Suspected On-Study CDI 
Recurrence .............................................................................................................34 
4.5 
Data Monitoring Committee ..................................................................................34 
5.0 
SUBJECT POPULATION ..............................................................................................35 
5.1 
Selection of Subjects ..............................................................................................35 
5.1.1 
Inclusion Criteria ...................................................................................35 
5.1.2 
Exclusion Criteria..................................................................................36 
6.0 
INVESTIGATIONAL MEDICINAL PRODUCT AND CONCOMITANT 
MEDICATIONS ..............................................................................................................39 
6.1 
VE303 and Placebo Supply ...................................................................................39 
6.2 
Study Drug Dispensing ..........................................................................................39 
6.3 
Study Drug Administration ....................................................................................39 
6.3.1 
General Administration .........................................................................39 
6.3.2 
Missed or Partial Dosing .......................................................................40 


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6.4 
Accountability and Dosing Compliance ................................................................40 
6.5 
Antibiotic Rescue Therapy Guidance ....................................................................40 
7.0 
STUDY PROCEDURES AND ASSESSMENTS ..........................................................42 
7.1 
Informed Consent...................................................................................................42 
7.1.1 
Optional Pre-Screening Informed Consent ...........................................42 
7.1.2 
Screening ...............................................................................................42 
7.2 
Randomization and Blinding .................................................................................42 
7.2.1 
Breaking the Blind ................................................................................43 
7.3 
Safety Assessments ................................................................................................43 
7.3.1 
Demographics and Medical History .....................................................43 
7.3.2 
Prior and Concomitant Medications .....................................................44 
7.3.3 
Adverse Events .....................................................................................45 
7.3.4 
Gastrointestinal Symptoms Self-Administered Questionnaire .............45 
7.3.5 
Vital Signs .............................................................................................45 
7.3.6 
Physical Examination ............................................................................46 
7.3.7 
Laboratory Tests....................................................................................46 
7.3.8 
12-Lead Electrocardiogram ...................................................................46 
7.4 
Stool Analyses .......................................................................................................46 
7.4.1 
Stool C. Difficile and Other Stool Testing ............................................47 
7.5 
Exploratory Serum Analyses .................................................................................47 
7.6 
Hygiene for C. Difficile-Associated Diarrhea and Study Drug Handling .............47 
8.0 
STUDY DISCONTINUATION ......................................................................................51 
8.1 
Sponsor Discontinuation Criteria ...........................................................................51 
8.2 
Study Discontinuation for Individual Subjects ......................................................51 
9.0 
ADVERSE EVENTS .......................................................................................................52 
9.1 
Adverse Event ........................................................................................................52 
9.1.1 
Assessment of Toxicity Grade ..............................................................52 
9.1.2 
Assessment of Causality .......................................................................52 
9.1.3 
Action Taken with Study Drug .............................................................53 
9.1.4 
Outcome of Adverse Event ...................................................................53 
9.2 
Serious Adverse Event ...........................................................................................54 
9.2.1 
Clarification of Serious Adverse Event Definition ...............................54 
9.2.2 
Serious, Unexpected, Suspected Adverse Reactions ............................55 
9.3 
Adverse Events of Special Interest ........................................................................55 
9.3.1 
Management of Diarrhea or Loose/Watery Stools................................55 


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9.4 
Reporting of Adverse Events .................................................................................56 
9.5 
Pregnancy ...............................................................................................................57 
9.6 
Clinical Laboratory Abnormalities ........................................................................57 
9.7 
Review of Safety Data ...........................................................................................58 
10.0 
STATISTICAL METHODS ...........................................................................................59 
10.1 
Study Design and Primary Analysis ......................................................................59 
10.2 
Analysis Populations ..............................................................................................59 
10.2.1 
Sensitivity Efficacy Analyses ...............................................................59 
10.3 
Procedures for Handling Missing, Unused, and Spurious Data.............................60 
10.4 
Administrative Interim Analyses ...........................................................................60 
10.5 
General Methods ....................................................................................................60 
10.5.1 
Disposition of Subjects .........................................................................60 
10.5.2 
Baseline Comparisons ...........................................................................61 
10.5.3 
Safety Analysis .....................................................................................61 
10.5.4 
Stool and Other Exploratory Analyses ..................................................61 
10.5.5 
Procedures for Reporting Deviations to the Statistical Analysis Plan ..61 
10.6 
Changes in the Conduct of the Study or Planned Analysis ...................................62 
11.0 
DATA RECORDING, RETENTION AND MONITORING ......................................63 
11.1 
Case Report Forms .................................................................................................63 
11.2 
Data Retention .......................................................................................................63 
11.3 
Protocol Deviations ................................................................................................64 
11.4 
Data Monitoring .....................................................................................................64 
11.5 
Quality Control and Quality Assurance .................................................................65 
12.0 
REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS ...................................66 
12.1 
Good Clinical Practice ...........................................................................................66 
12.2 
Institutional Review Board/Independent Ethics Committee ..................................66 
12.3 
Informed Consent...................................................................................................66 
12.4 
Subject Confidentiality ..........................................................................................67 
12.5 
Disclosure of Information ......................................................................................67 
12.6 
Publication of Study Data ......................................................................................67 
12.7 
Ethical Standards ...................................................................................................68 
13.0 
REFERENCES .................................................................................................................69 
Appendix 1: 
Bristol Stool Scale .................................................................................72 
Appendix 2: 
PROMIS® Scale Questionnaires ...........................................................73 
 


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LIST OF TABLES 
Table 2-1: 
VE303 Strain Identity ......................................................................................23 
Table 4-1: 
Planned Study Arms ........................................................................................33 
Table 7-1: 
Schedule of Events ...........................................................................................48 
 
LIST OF FIGURES 
Figure 2-1: 
Survival Benefit and Recovery from Weight Loss Conferred by VE303 
and a Human FMT Preparation in the Mouse Cefoperazone-induced CDI 
Model ...............................................................................................................26 
 
LIST OF APPENDICES 
APPENDIX 1: ............................................................................................................. BRISTOL STOOL 
SCALE ...............................................................................................................................72 
APPENDIX 2: ............................................................................................................. PROMIS® SCALE 
QUESTIONNAIRES .........................................................................................................73 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
°C 
degree(s) Celsius 
CBC 
complete blood count 
CCNA 
Cell Cytotoxicity Neutralization Assay 
CDI 
Clostridioides difficile infection 
CFU 
colony-forming unit(s) 
CFR 
Code of Federal Regulations 
CLSI 
Clinical and Laboratory Standards Institute 
CPK 
creatine phosphokinase 
CRE 
carbapenem-resistant Enterobacteriaceae 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EIA 
enzyme immunoassay 
ESBL 
extended β-lactamase producing Enterobacteriaceae 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FMT 
fecal microbiota transplantation 
GCP 
Good Clinical Practice 
GDH 
glutamate dehydrogenase 
HIV 
human immunodeficiency virus 
IA 
interim analysis 
ICH 
International Council for Harmonisation  
IRB 
Institutional Review Board 
LAR 
legally authorized representative 
LBP 
live biotherapeutic product 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
PacBio 
Pacific Biosciences 
pCDI 
primary Clostridioides difficile infection 
PCR 
polymerase chain reaction 
PPI 
proton pump inhibitor 
PPS 
per-protocol analysis set 
PROMIS® 
Patient-Reported Outcomes Measurement Information System 
rCDI 
recurrent Clostridioides difficile infection 
QID 
four times a day 
QTc 
QT interval corrected for heart rate 
SAE 
serious adverse event 


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Abbreviation 
Definition 
SAP 
statistical anaylysis plan 
SOC 
standard-of-care 
TEAE 
treatment-emergent adverse event 
US 
United States 
VRE 
vancomycin-resistant Enterococcus 
WBC 
white blood cell 


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1.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
The Principal Investigator is the person responsible for the conduct of the study at the 
investigational site. A sub-Investigator is any member of the clinical study team designated and 
supervised by the Principal Investigator to perform critical study-related procedures and/or to 
make important study-related decisions. 
Prior to study initiation, the Principal Investigator at the study site will provide to Vedanta 
Biosciences, Inc. (also referred to as “Vedanta” or “Sponsor”) or its representative/designee 
(e.g., Contract Research Organization [CRO] personnel) a signed protocol signature page, a fully 
executed and signed United States (US) Food and Drug Administration (FDA) Form 1572, a 
current signed curriculum vitae, a medical license, and a signed financial disclosure form. 
Financial disclosure forms, current curriculum vitaes and medical licenses will also be provided 
for sub-Investigators listed on Form 1572, who will be directly involved in the evaluation of 
subjects. 
Prior to initiation at study sites in Canada, a No Objection Letter will be received by the Sponsor 
and appropriate Clinical Trial Site Information Forms for each site/qualified Investigator in 
Canada will be provided to Health Canada. 
The study will be administered and monitored by employees or representatives of Vedanta in 
accordance with applicable regulations. Clinical research associates will monitor investigative 
sites on a periodic basis and perform verification of source documentation for each subject. 
Vedanta or designee will be responsible for ensuring timely reporting of expedited serious 
adverse event (SAE) reports to regulatory authorities and Investigators. 


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2.0 
INTRODUCTION 
2.1 
Background of C. Difficile Infection 
Clostridium difficile (or more recently Clostridioides difficile according to the US National 
Center for Biotechnology Information; C. difficile) infection (CDI) is the most common 
health care-associated infection, with an estimated incidence of 453,000 cases and approximately 
29,000 deaths in the US in 2011 [1]. The health care costs related to CDI are estimated to be as 
high as US $4.8 billion for acute care facilities, which does not account for the increasing reports 
of CDI treatment occurring outside of acute care facilities, including community settings in 
which CDI may be diagnosed and treated without hospitalization [1]. 
C. difficile is a gram-positive, spore forming anaerobic bacillus. The spores are resistant to heat, 
acid, and antibiotics; C. difficile is transmitted among humans via the fecal-oral route. Following 
oral ingestion, the spores resist the acidity of the stomach and germinate into the vegetative form 
in the small intestine [2]. Carriage of C. difficile occurs in 5% to 15% of healthy adults but may 
be as high as 84.4% in newborns and healthy infants and up to 57% in residents of long-term 
care facilities [3]. The two biggest risk factors to infection are exposure to antibiotics and 
exposure to the organism [4]. Thus, disruption of the commensal flora of the colon, typically 
through exposure to antimicrobials, allows C. difficile to flourish and produce toxins that lead to 
colitis. The majority of infections occur following iatrogenic nosocomial exposure, although 
spores are present in low levels in the environment and food supply, allowing for 
community-acquired infections [5]. More than 400 strains of C. difficile have been identified, but 
only strains producing the exotoxins, Toxin A and Toxin B, are virulent. The toxins are 
endocytosed by colonic epithelial cells, resulting in damage to the actin cytoskeleton, causing 
cell death, loss of intestinal barrier function, and neutrophilic colitis [5, 6]. 
The clinical manifestations of infection with toxin-producing strains of C. difficile range from 
asymptomatic carriage to mild or moderate diarrhea or fulminant colitis. Infection-related 
mortality has been reported in 5% of patients, with all-cause mortality up to 15% to 20% [5]. 
Symptoms of CDI usually begin soon after colonization, with a median time to onset of 2 to 
3 days for the most common symptoms of diarrhea, fever, cramping, abdominal discomfort, and 
peripheral leukocytosis [7]. Patients with severe disease may develop colonic ileus or toxic 
dilation and present with abdominal pain and distension but minimal or no diarrhea. 
Complications of severe C. difficile colitis include dehydration, electrolyte imbalance, 
hypoalbuminemia, toxic megacolon, bowel perforation, hypotension, renal failure, systemic 
inflammatory response syndrome, sepsis, and death. 
A prerequisite for developing disease in infected individuals is disruption of the normal flora. 
Factors associated with CDI vary across infected persons and include host susceptibility, the 
virulence of the infecting C. difficile strain, and the nature and extent of prior antimicrobial 
exposure. The BI/NAP1/027 strain is associated with severe C. difficile disease and is 
characterized by a mortality rate 3 times as high as that associated with less virulent strains [5]. 
Advanced age, antineoplastic chemotherapy, and severe underlying diseases, particularly those 
that lead to altered immune responses, also contribute to susceptibility [5]. The risk of CDI and 
its severity increases as age increases, even in healthy individuals. 


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2.1.1 
Current Management of C. Difficile Infections 
Treatment guidelines for CDI have been published by the Society for Healthcare Epidemiology 
of America in collaboration with the Infectious Disease Society of America and by the American 
Society of Gastroenterology [4, 7]. Cessation of the inciting antibiotic agent, if medically 
appropriate, is often sufficient for complete recovery of mild disease [8]. For more severe 
disease, antimicrobial therapy directed against C. difficile is necessary, with standard therapies 
including vancomycin and fidaxomicin. Metronidazole can be used in cases of non-severe CDI 
when access to vancomycin or fidaxomicin is limited. The antibiotics are considered equivalent 
for the treatment of mild to moderate disease, while vancomycin is more effective for severe 
disease, including patients infected with the BI/NAP1/027 strain [5]. In addition, a Phase 3 
randomized controlled trial and an analysis of a subset of patients with first recurrence have 
confirmed the noninferiority of fidaxomicin 200 mg administered orally twice daily for 10 days 
compared with vancomycin 125 mg administered orally 4 times daily (QID) for 10 days for the 
treatment of first occurrence of mild to moderate CDI and first recurrence, with a primary 
outcome of clinical cure (88% vs 86% and 88% vs 87% for the 2 trials, P = not significant). 
Fidaxomicin had a lower recurrence rate compared with vancomycin, and the sustained clinical 
response (i.e., cure without recurrence) was superior with fidaxomicin versus vancomycin at 
25 days after the end of treatment in both trials (70% vs 57%, P = 0.0011; 72% vs 57%, 
P = 0.0004) [9, 10]. There are no data on fidaxomicin compared with metronidazole for similar 
CDI populations. 
While most patients with initial CDI respond successfully to antibiotic treatment, approximately 
20% to 25% will have at least one recurrence of C. difficile-related diarrhea following 
discontinuation of antibiotic treatment [1, 7, 11]. Recurrent disease can be attributed to relapse or 
re-infection and the mechanisms are similar in clinical practice. Diagnosis and treatment of 
relapse and re-infection are the same. 
The proportion of patients who respond to treatment declines with multiple recurrences. The 
ability to cure subsequent recurrences is difficult because of the persistence of spores in the 
bowel or environment, inability to revert to a more normal eubiotic gastrointestinal microbiota, 
and the inability of the patient to mount an effective immune response to C. difficile toxins. Risk 
factors for recurrent CDI (rCDI) include administration of inciting antibiotics after initial 
successful treatment of CDI; defective humoral anti-toxin immune responses; underlying 
comorbidities; older age; and use of proton-pump inhibitors [7]. Symptoms can recur following 
re-exposure of patients to C. difficile spores transmitted from other patients or from the 
environment. Almost one-half of recurrences have been shown to be caused by reinfection by a 
different bacterial strain rather than by relapse [12, 13]. 
The most common therapy for rCDI is a second course of metronidazole or oral vancomycin; 
however, the 2018 IDSA guidelines favor the use of vancomycin regimens or fidaxomicin over 
metronidazole [7]. The estimated efficacy of antibiotic therapy for a first recurrence is 50% [5]. 
Second recurrences can be treated with fidaxomicin or a tapering and/or pulsed regimen of oral 
vancomycin. The 2018 IDSA guidelines consider the latter recommendation to be of weak 
strength and based on a low Quality of Evidence (7). In addition, for a first recurrence, 
fidaxomicin appears to be non-inferior to vancomycin. However, use of fidaxomicin has been 


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limited by its high-cost relative to oral vancomycin. Management of patients who do not respond 
to treatment or experience a further relapse is challenging. Use of other antibiotics with activity 
against C. difficile, such as rifaximin, nitazoxanide, ramplanin, teicoplanin, and tigecycline, is 
limited by the lack of efficacy data, high cost, unfavorable safety profile, and potential for 
development of resistance. Probiotics have reported preliminary efficacy, but none have shown 
efficacy in controlled studies. Additionally, patients with fulminant colitis may require 
emergency colectomy, which increases their risk for mortality by up to 80% [5]. 
Given that disruption of the indigenous gastrointestinal microbiota is a major risk for CDI, 
particularly for recurrent infection, there has been increasing interest in fecal microbiota 
transplantation (FMT). The procedure involves the transoral or rectal transplantation of feces 
from a healthy, pretested donor, and cessation of antibiotic use in the recipient. Clinical 
experience with FMT indicates that this procedure is effective, although the precise components 
of the gastrointestinal microbiota that provide resistance against C. difficile remain 
undetermined. Disease resolution has been reported to be as high as 89% following a single FMT 
administration to patients, with demonstrated safety of the FMT itself, even in 
immunocompromised hosts, in whom there were no SAEs or infectious complications related to 
the FMT and in whom several procedure-related adverse events (AEs) were reported, with one 
death due to aspiration during the sedation administered for colonoscopy [14,15]. FMT is also 
limited by the need to screen healthy donors for transmissible agents, and, in addition, the 
procedure lacks standardization [7]. Thus, while the FMT approach has provided the clinical 
evidence that changes to the gastrointestinal microbiota can be effective, there is a strong need 
for a defined uniform product that can be produced and administered in a standardized and safe 
manner to a broader spectrum of patients and circumvent the safety issues associated with FMT, 
which include potential transmission of pathogens. 
2.2 
VE303 Composition and Characterization 
The VE303 Drug Product is a live biotherapeutic product (LBP) consisting of 
8 well-characterized clonally derived, nonpathogenic, nontoxigenic, commensal strains of 
Clostridia, including 5 strains from cluster XIVa, 2 strains from IV, and 1 strain from XVII 
(Table 2-1). All strains were originally derived from healthy human individuals. The 
composition of VE303 was rationally selected based upon individual strain and consortia-
specific properties. Strains were evaluated for their association with healthy human intestinal 
microbiomes, absence or decrease in C. difficile-related dysbiosis, and lack of overt pathogenic 
features, and whole genome analysis indicated the absence of virulence and toxin genes in all 
8 strains. Results from in silico studies predicted that use of this LBP would not result in 
antibiotic resistance and in vitro evaluation confirmed that all strains of the VE303 consortia are 
susceptible to a number of clinically relevant antibiotics of different anti-bacterial mechanisms. 
The production of short-chain fatty acids by the bacterial strains of the VE303 LBP, its direct 
suppression of C. difficile growth both in vitro and in an in vivo murine model demonstrating 
superior reproducible protection compared with other unique LBPs, and its equivalent efficacy to 
that provided by a human fecal preparation (as judged by the protective benefit in the 
cefoperazone mouse model of CDI) all provide evidence that this LBP may be of benefit to 
patients with CDI. 


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Illumina and Pacific Biosciences (PacBio) -based whole genome sequence analysis of all 
8 strains of Clostridia in VE303 identified the most closely related species for each strain using 
the One Codex algorithm and whole genome alignment [16]. 
Table 2-1: 
VE303 Strain Identity 
Strain 
Cluster Designation 
Closest Relative as Determined by Whole Genome Sequencinga 
DS-0001 
XIVa 
Clostridium bolteae 90A9 
DS-0002 
IV 
Anaerotruncus colihominis DSM 17241 
DS-0003 
XIVa 
Sellimonas intestinalis 
DS-0004 
XIVa 
Clostridium symbiosum WAL-14163 
DS-0005 
XIVa 
Clostridia bacterium UC5.1-1D4 
DS-0006 
XIVa 
Dorea longicatena CAG:42 
DS-0007 
XVII 
Erysipelotrichaceae bacterium 21_3 
DS-0008 
IV 
Clostridium orbiscindens 1_3_50AFAA 
a Illumina whole genome sequencing One Codex assignment 25 May 2017 
There is evidence of at least 6 mechanisms of action potentially contributing to healthy gut 
maintenance and resistance to C. difficile by bacteria from Clostridium clusters IV, XIVa, and 
XVII: 
1. Conversion of primary bile acids to secondary bile acids which, in turn, may suppress 
C. difficile colonization [17, 18]. 
2. Niche and nutrient competition within the intestinal environment, which limits the 
outgrowth of pathogenic microbes, such as C. difficile [19, 20]. 
3. Prevention of inflammation from C. difficile toxins [21]. 
4. Short-chain fatty acid production, which has been reported to be important for 
maintenance of barrier function [22, 23]. 
5. Induction of T-regulatory cells, which play a critical role in maintaining intestinal 
homeostasis by controlling inflammation [24, 25]. 
6. Direct inhibition of C. difficile growth in vitro (Vedanta internal report). 
2.2.1 
Nonclinical Studies 
2.2.1.1 
In Vitro Characterization of VE303 
Predictions of the presence of antibiotic resistance genes, mobile genetic elements, and virulence 
genes have been performed from the high, quality whole-genome VE303 sequences obtained 
using the Pacific Biosciences platform. 








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Refer to the VE303 Investigator’s Brochure for additional information. 
2.2.2 
Clinical Studies 
A Phase 1a/1b, first-in-human, open-label, single-center, dose-escalation study to evaluate the 
safety and microbiota changes induced by ingestion of VE303 with or without pretreatment with 
oral vancomycin (Study VE303-01 – “A Phase 1a/1b, First-in-human, Open-label Study of 
Escalating Doses of VE303 in Healthy Adult Volunteers after Vancomycin to Evaluate Safety, 
Dosing, and Pharmacodynamics”) has been completed and final results can be found in the 
VE303 Investigator’s Brochure. 
The primary objective is to characterize the highest safe and well tolerated dose regimen of 
VE303 by assessing AEs, including gastrointestinal symptoms, physical examinations, vital 
signs, and changes in clinical laboratory measurements. Secondary objectives include evaluation 
of gut colonization with VE303 component bacteria, changes in the intestinal microbiota because 
of VE303 dosing, and metabolomic changes in stool. As of 21 September 2018, thirty-four (34) 
healthy adult subjects were enrolled and treated with vancomycin (Vancomycin Only cohort 
[N = 5]) and/or VE303 at escalating single doses (Cohorts 1 [N = 4], 2 [N = 3], and 3 [N = 3]) 
and multiple doses (Cohorts 4 [N = 6], 5 [N = 8], and 6 [N = 5]) according to pre-defined 
dose-escalation guidelines at a total daily dose ranging from 1.6 × 109 to 1.7 × 1011 CFU in up to 
9 planned dose cohorts, with exploration of intermediate dose levels permitted if necessary. 
Dose-escalation decisions were determined using pre-specified guidelines by a Safety Review 
Committee. 
Prior to VE303 administration, subjects in Cohorts 1 through 5 received a 5-day course of oral 
vancomycin at a dose of 125 mg administered QID to modulate the intestinal microbiota and to 
determine the potential effect of residual vancomycin in the stool on VE303 colonization. In 
addition, 1 cohort of subjects received only oral vancomycin to serve as a control group (N = 5). 
Subjects in Cohort 6 were not pretreated with vancomycin and received VE303 at the Cohort 5 
dose level for 21 consecutive days. Subjects were admitted to an inpatient unit for baseline 
assessment, vancomycin dosing and washout (if applicable), for the duration of VE303 dosing, 
and for 5 days postdose to closely monitor the safety and tolerability of VE303 administration 
(Cohort 6 did not undergo inpatient postdose monitoring but attended a modified postdose 
follow-up with increased outpatient monitoring visits). The total duration of inpatient monitoring 
ranged from 13 to 26 days depending on cohort assignment. Subsequently, postdose follow-up 
visits are being performed every 2 to 4 weeks for approximately 3 months after initiation of 
dosing, with continued telephone for approximately 6 months following the first ingestion of 
study drug. For all VE303-treated subjects who agree and provide written informed consent, 
additional visits for stool collection are scheduled approximately 6 and 12 months after initiation 
of VE303 dosing. 
Preliminary draft results are available. Demographics for the 34 subjects showed that 20 subjects 
were male and 14 were female, with a median age of 34 (range 25 to 59) years; 22 subjects were 
Black or African American, 11 were White, and 1 was mixed/other race. One subject in Cohort 1 
discontinued early prior to receiving VE303 due to an inability to tolerate the vancomycin 
dosing, and 1 subject from Cohort 5 discontinued VE303 dosing early due to an inability to 


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swallow intact capsules. The remaining 32 subjects (28 of whom received at least 1 dose of 
VE303) completed dosing assignments as scheduled. 
Among the 28 subjects who received at least 1 dose of VE303 at the time of data cutoff, the most 
frequently reported treatment-emergent adverse events (TEAEs) were largely gastrointestinal in 
nature and included soft feces (21%), abdominal distension (18%), diarrhea (14%), and 
abdominal pain, hard feces, headache, and increased lipase (each 11%). Most AEs (regardless of 
causal relationship to study treatment) were Grade 1 or 2 in severity, with 4 of 28 
VE303-treated subjects (14%) experiencing Grade 3 or higher TEAEs on study (all considered 
not related to VE303), including Grade 4 increased lipase in 2 subjects (7%); Grade 3 increased 
lipase in 1 subject (4%); and Grade 4 acute kidney injury and Grade 4 increased blood creatine 
phosphokinase (CPK) in 1 subject (4%). 
Among the 28 subjects who received at least 1 dose of VE303, TEAEs were considered by the 
Investigator to be related to VE303 for 10 subjects (36%), 9 of whom were enrolled in the 
multiple dose cohorts. The TEAEs that were most frequently attributed to VE303 treatment 
included abdominal distension and diarrhea (each 11%) and increased alanine aminotransferase 
(ALT), increased aspartate aminotransferase (AST), and soft feces (each 7%). All VE303-related 
TEAEs were Grade 1 in severity. 
Among the 29 subjects who received at least 1 dose of vancomycin, TEAEs were considered by 
the Investigator to be related to vancomycin for 14 subjects (48%). The TEAEs that were most 
frequently attributed to vancomycin treatment included abdominal distension and soft feces 
(each 17%), nausea (14%), abdominal pain and diarrhea (each 10%), and decreased appetite, 
discolored feces, dysgeusia, increased ALT, increased AST, and increased lipase (each 7%). 
Most vancomycin related TEAEs were Grade 1 or 2 in severity, with Grade 3 
vancomycin-related events including increased lipase (7%) and hypotension (3%). 
No deaths were reported. One subject in Cohort 2 experienced SAEs of Grade 4 acute kidney 
injury and Grade 4 increased blood CPK (> 60,000 U/L) that were judged to be unrelated to 
VE303 and occurred after discharge from the 5-day inpatient follow-up. 
Preliminary draft VE303 detection and colonization data are available for Cohorts 1 to 6. In the 
cohorts that received vancomycin, all 8 of the VE303 component bacteria were detectable in the 
stool within 2 days after dosing and colonized in a dose-dependent manner. The multiple dose 
cohorts (Cohorts 4 and 5) had more subjects colonize with more strains for a longer time period; 
however, durable colonization was observed even in the single-dose cohorts (2, 5, and 10 
capsules × 1 day). In many individuals, VE303 bacteria were detectable for at least 12 weeks 
after the last dose. VE303 bacteria appeared to favorably enhance subjects’ microbiota recovery 
after vancomycin ingestion. VE303 component bacteria colonization was reduced when subjects 
were not administered vancomycin. When compared with the vancomycin-only control cohort, 
subjects who ingested VE303 had earlier recovery of beneficial taxa (e.g., Bacteroides and 
Firmicutes) and reduction in potentially inflammatory taxa (e.g., Proteobacteria). 
In summary, these preliminary results demonstrate that single and multiple doses of VE303 
ranging up to 1.7 × 1011 total CFU administered over 14 days were well tolerated and safe. 
VE303 demonstrated early, robust, and durable colonization with early recovery of a normal 
microbiota in a dose-dependent manner following vancomycin administration. 


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2.3 
Rationale and Dose Selection for the Study 
There is no accepted standard of care (SOC) to prevent rCDI. After a first recurrence, the 
incidence of subsequent CDI recurrence increases, with rates of up to 45% to 65% reported in 
some studies [31]. Thus, an unmet need exists for the patients who present with their second 
episode (first recurrence) of CDI, as they are at a higher risk of additional recurrences. Risk 
factors for multiple recurrent CDI include age, use of antibiotics within 90 days before CDI 
diagnosis, use of proton pump inhibitors (PPIs) within 90 days of CDI diagnosis, chronic kidney 
disease, and diagnosis of CDI in a nursing home, among others [32]. This Phase 2 study will be 
conducted to determine the recommended dose, evaluate the safety, microbiota changes, and 
efficacy of VE303 compared with placebo following completion of a standard course of 
antibiotics for subjects with CDI. A double-blind design will be implemented in conjunction with 
a placebo control in an attempt to mitigate any bias that may be otherwise inherent to evaluating 
the effects of an investigational drug if compared only with historical controls. Because no SOC 
exists for the prevention of CDI recurrence after antibiotic treatment, use of a placebo group is 
not considered to pose any additional risks to subjects compared with the risks they may face in 
the standard treatment setting outside of a clinical trial. Furthermore, study subjects will be 
closely monitored for stool changes and diarrhea-like events, particularly those that may signal a 
recurrence of CDI. 
The doses of VE303 to be evaluated in this Phase 2 trial are based on the preliminary safety and 
VE303 detection and colonization results from the Phase 1 vancomycin-treated normal healthy 
volunteer trial. The Phase 2 doses will include the higher safe and well tolerated doses from 
Study VE303-01 (the Cohort 5 dose of 10 capsules per day for 14 days; total of 1.1 × 1011 CFU) 
and the low dose (2 capsules per day for 14 days 2.2 × 1010 CFU). 
Study drug administration will begin on the last planned day of SOC antibiotic administration for 
a qualifying CDI episode, or no later than 1 day after completion of antibiotic dosing, in order to 
colonize the subject’s intestinal tract as soon as possible. After a 14-day study drug 
administration period, subjects will be followed at 2 weeks after the last dose and then 
approximately every 4 weeks through 24 weeks after the last dose of study drug to monitor 
safety and C. difficile and VE303 colonization and clearance. This follow-up period will also 
provide sufficient time to allow for identification and characterization of any CDI recurrences. 


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3.0 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
The primary objective is to determine the recommended VE303 Phase 3 dose regimen(s) based 
on safety and efficacy, as indicated by the CDI recurrence rate. 
Secondary objectives are to characterize VE303 colonization and changes in the fecal 
microbiome. 
3.2 
Endpoints 
Safety endpoints include the overall safety profile and TEAEs. 
Efficacy endpoints include: 
• Proportion of subjects with CDI recurrence before or at Week 8 (i.e., 8 weeks after the 
first dose of study drug). 
• Proportion of subjects without CDI recurrence before or at Week 4 (i.e., 4 weeks after the 
first dose of study drug), Week 12 (i.e., 12 weeks after the first dose of study drug), and 
Week 24 (i.e., 24 weeks after the first dose of study drug). 
Pharmacodynamic and pharmacokinetic endpoints include: 
• Fecal VE303 component bacteria colonization abundance and duration 
• Changes in fecal microbiota diversity and taxonomic composition 
• Changes in the fecal metabolomic profile, including short chain fatty acids and bile acids 


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4.0 
STUDY DESIGN 
4.1 
Study Design Overview 
This Phase 2, randomized, parallel-arm, double-blind, placebo-controlled, dose-selection study 
will evaluate the safety, microbiota changes, and efficacy of VE303 in the prevention of 
subsequent CDI-associated diarrhea compared with placebo following completion of at least 1 
successful course of SOC antibiotics for subjects with primary C. difficile infection (pCDI) at 
high risk for recurrence or subjects with rCDI. Eligible subjects will be randomized into 4 
treatment arms in a 2:1:2:1 ratio to receive VE303 high dose (10 capsules):placebo high dose (10 
capsules):VE303 low dose (2 capsules):placebo low dose (2 capsules), respectively.   
The Sponsor study clinical operations team that interacts with the sites and the database will 
remain blinded to administrative IA results, as well as the treatment assignments, until the final 
analysis dataset is cleaned, locked and unblinded.  
During the execution of the study, which coincided with the COVID-19 pandemic, changes to 
the study design were introduced, which included deleting the sample size re-estimation, adding 
3 administrative IAs, and modifying the overall sample size to approximately 60 to 80 subjects. 
Three administrative IAs will be performed after at least 24 subjects complete 8 weeks of the 
study, after at least 39 subjects complete 8 weeks of the study, and after at least 54 subjects 
complete 8 weeks of the study.   
Per protocol version #6, randomization will be stratified by 1) number of previous CDI episodes 
at Baseline (0 vs ≥ 1 episodes, excluding the qualifying episode i.e., Inclusion criterion 2a vs 
2b/2c subjects), 2) SOC antibiotic treatment (non-vancomycin [fidaxomicin or metronidazole] or 
an alternative oral vancomycin dosing regimen vs vancomycin QID [four times a day; this 
category will include subjects who receive vancomycin QID on at least the last day of 
treatment]), and 3) results of CDI laboratory diagnostic method (free toxin [enzyme 
immunoassay (EIA) for Toxin A/B or Cell Cytotoxicity Neutralization Assay (CCNA)] vs other 
[polymerase chain reaction (PCR)/cytotoxic culture if EIA for Toxin A/B and/or CCNA results 
are negative or not available]). 
On the last planned day of SOC antibiotic administration for a qualifying CDI episode, or no 
later than 1 day after completion of antibiotic dosing, subjects will be randomized and begin 
daily oral administration of placebo or VE303(both at low and high doses) for 14 consecutive 
days. The high dose of VE303 is 10 capsules per day administered orally for 14 days, for a 
maximum VE303 daily dose of 8.0 × 109 CFU and a maximum total dose over 14 days of 
1.1 × 1011 CFU. The low dose of VE303 is 2 capsules per day administered orally for 14 days, 
for a maximum VE303 daily dose of 1.6 × 109 CFU and a maximum total dose over 14 days of 
2.2 × 1010 CFU. The first dose of the study drug will be administered under the supervision of 
study personnel at the Day 1 visit. After the 14-day dosing period is completed, follow-up will be 
performed every 2 to 4 weeks for 24 weeks after the first dose of study drug. 
Safety will be evaluated continuously for the duration of a subject’s study participation, 
including assessment of AEs reported by a subject or observed by study personnel from the date 
of informed consent until the end of the 6-month follow-up period, evaluation of gastrointestinal 
symptoms, electrocardiograms, physical examination, assessment of vital signs, and clinical 


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laboratory measurements. Stool samples must be collected for C. difficile testing (e.g., GDH, EIA 
for toxin A/B, C. difficile PCR, CCNA) and for the exploratory analyses (microbiota composition, 
VE303 component bacteria detection, antibiotic concentrations, metabolomics, culture, detection 
of antibiotic resistant bacteria other than C. difficile (e.g., carbapenem-resistant 
Enterobacteriaceae [CRE], extended spectrum β-lactamase producing Enterobacteriaceae 
[ESBL], or vancomycin-resistant Enterococcus [VRE]), and calprotectin). Subjects will be 
continuously monitored for clinical events of diarrhea that may be indicative of a CDI 
recurrence. 
For each subject, the duration of study drug administration will be 14 days and the total study 
participation will be approximately 7 months from Screening through the last follow-up visit. 
4.2 
Study-Specific Definitions 
An episode of diarrhea consistent with diarrhea due to C. difficile is characterized by 
≥ 3 loose/unformed bowel movements (Bristol Score 5-7, see Appendix 1) within 24 hours for at 
least 2 consecutive days or > 8 loose/unformed bowel movements within 24 hours, and 
considered unlikely to have another etiology. 
The following are specific protocol definitions: 
A prior occurrence of CDI is based on a subject’s medical history and defined as an episode of 
diarrhea consistent with diarrhea due to C. difficile, with a stool sample that is positive for 
C. difficile (e.g., PCR, EIA for Toxin A/B, and GDH antigen, or CCNA). The CDI episode must 
have initially responded to SOC antibiotic treatment, with no other identifiable cause for the 
diarrhea. 
A qualifying CDI episode is defined as an episode of diarrhea consistent with diarrhea due to C. 
difficile, which includes a positive diagnostic stool test for free toxin or toxigenic C. difficile. 
• Diagnostic tests for enrollment may be performed at the local laboratory or at the central 
laboratory. Subjects with a positive test (either EIA for Toxin A/B or PCR or CCNA or 
toxigenic culture assay, performed at the local laboratory or at the central laboratory) may 
be enrolled in the study. Confirmation of a positive local test by central laboratory test is 
not required for subject enrollment, provided documentation of a local positive test is 
available.  
• Subjects’ allocation to a proper stratum is dependent on timely reports of laboratory 
results from both local and central laboratories. To ensure subjects are allocated to a 
proper stratum, an effort should be made to obtain and send a stool sample to the central 
laboratory for confirmation of free toxin or toxigenic C. difficile prior to randomization.  
• Additional requirements are provided in Inclusion Criteria #3 and #4. 
A successful clinical response to antibiotic therapy by the time of randomization to the study 
treatment is required for a subject to be eligible. A successful clinical response is defined as the 
symptomatic control of the qualifying/current CDI episode, i.e., < 3 loose/unformed bowel 
movements within 24 hours for at least 2 consecutive days. 


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An on-study CDI recurrence is defined as an episode of diarrhea consistent with diarrhea due to 
C. difficile infection, which includes a stool sample positive for free toxin (EIA for Toxin A/B or 
CCNA) per test performed at the local laboratory or at the central laboratory. An on-study CDI 
recurrence may occur at any time after administration of the first dose of study drug.  
• If recurrent CDI is suspected, a stool sample must be collected for laboratory 
confirmation. Regardless of the test(s) performed at the local laboratory, samples must be 
collected from all subjects during each episode of diarrhea for CDI testing at a central 
laboratory.  
• After an initial sample collected for suspected recurrence, it is required to collect and 
submit samples on subsequent day(s) if the laboratory test results are not available or 
negative for free toxin (EIA for Toxin A/B or CCNA) before initiating antibiotic therapy. 
4.3 
Study Dosing Regimens 
On the last planned day of SOC antibiotic administration for a qualifying CDI episode, or no 
later than 1 day after completion of antibiotic dosing, eligible subjects will be randomized into 4 
treatment arms in a 2:1:2:1 ratio to receive 1 of 2 placebo doses or 1 of 2 VE303 doses daily for 
14 consecutive days as outlined in Table 4-1. Each study dose will comprise 2 or 10 capsules per 
day administered orally (see Section 6.3). Subjects will ingest the first dose in the clinic on 
Day 1 and subjects will remain at the study site for at least 30 minutes after the first dose for 
monitoring of potential AEs. 
Table 4-1: 
Planned Study Arms 
Study Arm 
VE303 Daily Dose 
VE303 Total Dose 
Over 14 Days 
Number of Capsules Ingested Per 
Day (Active/Placebo) 
VE303 (low) 
1.6 × 109 CFU 
2.2 × 1010 CFU 
2 (2/0)  
VE303 (high) 
8.0 × 109 CFU 
1.1 × 1011 CFU 
10 (10/0) 
Placebo (“low”) 
Not applicable 
Not applicable 
2 (0/2) 
Placebo (“high”) 
Not applicable 
Not applicable 
10 (0/10) 
Abbreviations: CFU = colony-forming unit(s) 
4.3.1 
Subject Monitoring 
Study personnel will telephone outpatient subjects daily during the 14-day study drug 
administration period to ensure dosing compliance; explore any concerns or issues with study 
drug ingestion, administration, handling or storage; capture potential AEs; review potential 
C. difficile-associated symptoms and assess the need for an unscheduled visit or stool test for 
CDI; remind subjects to collect stool to bring to their next clinic visit (if applicable); and answer 
any questions that the subject may have. If a subject is inpatient or attending a site visit on a 
scheduled telephone follow-up day, this contact will be performed in person, when possible. 
Telephone follow-up may be omitted on weekends or public holidays if this is necessary for 
logistical reasons. 
After completion of the study drug administration period (Days 1 through 14, inclusive), 
postdose monitoring visits will be performed for 24 weeks after the first dose of study drug. In 


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addition, telephone follow-up will be performed at Week 12/Day 84, Week 16/Day 112, and 
Week 20/Day 140 to monitor safety and recurrence of diarrhea. 
Any clinical event of diarrhea or loose/watery stools will be recorded as an AE. Subjects who are 
suspected of having a possible recurrence (e.g., subjects who have ≥ 3 loose/unformed bowel 
movements within 24 hours for at least 2 consecutive days, or > 8 loose/unformed bowel 
movements within 24 hours, or diarrhea of concern to the subject or Investigator) will contact 
study personnel as promptly as possible for assessment and to arrange for collection of a stool 
sample, as further detailed in Section 9.3.1. 
4.4 
Guidance on Study Drug Discontinuation for Suspected On-Study CDI Recurrence 
As per the Primary Efficacy Analysis, the discontinuation of study treatment for subjects with 
suspected on-study CDI recurrence is based on the results of free toxin test (EIA for Toxin A/B, 
or CCNA) performed at the local or the central laboratory regardless of the results of toxin PCR. 
If initial results of free toxin test are negative or not available and the symptoms persist, repeated 
samples should be collected and tested on subsequent day(s). The subjects will be continuously 
monitored (more than once/day by telephone) to determine if the suspected rCDI persists and the 
study drug needs to be discontinued.  
• If a subject has a new episode of diarrhea consistent with diarrhea due to C. difficile 
(Section 4.2) after starting the study drug but the free toxin test (EIA for Toxin A/B or 
CCNA) is negative or unavailable at the time and the SOC antibiotic is not administered 
for this episode, the study treatment should be continued. This episode will not be 
considered a CDI recurrence if free toxin test (EIA for Toxin A/B or CCNA) is negative 
or not available.  
• If a subject has a new episode of diarrhea consistent with diarrhea due to C. difficile after 
starting the study drug but the free toxin test (EIA for Toxin A/B or CCNA) is negative 
or unavailable at the time and the SOC antibiotic is administered for this episode, the 
study treatment should be discontinued. This episode will not be considered a CDI 
recurrence if free toxin test is negative or not available. The discontinuation of study drug 
due to SOC antibiotic treatment in such a case will be considered a protocol deviation 
and should be reported as such in the eCRF. 
• If the subject has a new episode of diarrhea consistent with diarrhea due to C. difficile 
after starting the study drug and the free toxin test (EIA for Toxin A/B or CCNA) is 
positive, the study treatment should be discontinued. This episode will be considered a 
CDI recurrence. Such an event should be reported as confirmed recurrence in the eCRF. 
4.5 
Data Monitoring Committee 
The DMC will comprise independent clinicians with knowledge of the target population, a 
biostatistician, and Sponsor representatives. Meeting frequency, procedures for halting study 
enrollment and study drug administration, and details regarding the data to be reviewed are 
described in the DMC Charter. 
 


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5.0 
SUBJECT POPULATION 
5.1 
Selection of Subjects 
Subjects who are candidates for enrollment will be evaluated for eligibility by the Investigator to 
ensure that the inclusion and exclusion criteria outlined in Sections 5.1.1 and 5.1.2 have been 
satisfied and that the subject is eligible. 
5.1.1 
Inclusion Criteria 
Subjects must meet all of the following to be eligible: 
1. Able and willing to provide written informed consent prior to initiation of any 
study-specific procedure or study drug administration and understands the potential risks 
and benefits of study enrollment and study drug administration. When appropriate, 
informed consent may be provided by a legally authorized representative (LAR). 
2. Subjects with a qualifying CDI episode in at least one of the following categories: 
a. ≥ 18 years of age with a second or greater occurrence of CDI within the last 6 
months 
b. Subjects ≥ 65 years of age with or without prior episodes of CDI who exhibit one 
or more of the following risk factors for recurrence: 
• Have kidney dysfunction, defined as creatinine clearance of < 60 
mL/min/1.73 m2 at the time of the current CDI episode 
• Have a history of regular use of PPIs within the past 2 months and will be 
continuing use of PPIs throughout the study 
• Have a history of CDI at any time 
c. Subjects ≥ 75 years of age 
3. The qualifying episode must meet all of the following criteria: 
a. New onset of ≥ 3 loose/unformed bowel movements (i.e., Types 5 to 7 on the 
Bristol stool scale, see Appendix 1) within 24 hours for 2 consecutive days or 
> 8 loose/unformed bowel movements within 24 hours 
b. CDI symptoms started within 30 days (inclusive) prior to the day of 
randomization 
c. Stool sample collected before (or no later than 72 hours after) initiation of SOC 
antibiotic therapy and positive for CDI laboratory test as defined in the 
“qualifying CDI episode” section (NOTE: every effort must be made to collect 
the diagnostic sample before SOC antibiotic therapy or within 24 hours after SOC 
antibiotic therapy initiation, whenever possible) 


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d. Diarrhea considered unlikely to have another etiology 
4. Prior to randomizing a subject to receive the first dose of the study medication, a subject 
should: 
a. Receive and complete an Investigator’s choice SOC antibiotic regimen of a 
minimum of 10 days and up to 21 days of total duration (NOTE: antibiotic 
tapering is not allowed) 
b. Meet successful clinical response defined as the symptomatic control of the 
qualifying/current CDI episode, i.e., < 3 loose/unformed bowel movements within 
24 hours for at least 2 consecutive days 
c. Have a positive C. difficile diagnostic stool test by either EIA for Toxin A/B or 
PCR or CCNA or toxigenic culture assay performed at the local laboratory or at 
the central laboratory  
5. Females of childbearing potential must have a negative pregnancy test and must agree to 
either use a highly effective acceptable form of birth control (e.g., established hormonal 
birth control plus a barrier method, double barrier method: intrauterine device plus 
condom or spermicidal gel plus condom) or remain celibate during the study period and 
up to 3 months after the last dose of study drug. 
6. Able to receive the first dose of study drug on the last planned day of SOC antibiotic 
administration for a qualifying CDI episode, or no later than 1 day after completion of 
antibiotic dosing. 
7. Able and willing to follow study procedures (e.g., ingest up to 10 size 0 (2 cm) capsules 
per day for 14 days, comply with study visits, provide stool samples, and record 
information/interact with study tools). 
8. Recovered from any complications of severe or fulminant CDI and be clinically stable by 
the time of randomization. 
5.1.2 
Exclusion Criteria 
Subjects meeting any of the following are not eligible: 
1. History of diarrhea (defined as 3 or more loose stools per day lasting for at least 4 weeks) 
that is not related to C. difficile infection within the 3 months prior to randomization. 
2. Known or suspected toxic megacolon /or small bowel ileus at the time of randomization. 
3. Contraindication to oral/enteral therapy (e.g., severe reflux, severe nausea/vomiting, or 
ileus) at the time of randomization. 


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4. Presence of white blood cell (WBC) count > 15 × 109 cells/L, or body temperature 
> 38.5 °C at the time of randomization. 
5. Prior administration of genetically modified investigational live 
bacterial/fungal/bacteriophage/viral isolates for CDI-associated diarrhea (Exception: use 
of yogurt or other food products containing live bacterial cultures or over the counter 
probiotics is permitted). 
6. History of administration of fecally-derived investigational live biotherapeutic products, 
or fecally-derived live bacterial isolates for CDI-associated diarrhea including FMT 
within the last 6 months. 
7. Use of drugs that alter gut motility (e.g., loperamide, diphenoxylate) within 3 days prior 
to the planned first dose of study drug. 
8. Planned administration of oral or parenteral antibacterial therapy for a non-CDI 
indication after randomization. 
9. History of acute leukemia or hematopoietic stem cell transplantation or myelosuppressive 
chemotherapy within 2 months prior to randomization. 
10. Subjects with compromised immune system, including: 
a. Absolute neutrophil count (ANC) of < 0.5 × 109 cells/L on 2 consecutive occasions 
within 7 days prior to randomization or sustained ANC < 1 × 109 cells/L 
b. Corticosteroid use at daily doses higher than 20 mg of prednisone equivalent within 
14 days prior to randomization, with the exception of inhaled or topical 
corticosteroids, which are permitted. 
NOTE: subjects with well-controlled human immunodeficiency virus (HIV) infection and 
CD4 count > 300 cells/mcL may be enrolled, provided that all other protocol eligibility 
requirements are met. 
11. Current or immediate potential for mechanical ventilation or vasopressors for 
hemodynamic support. 
12. Life expectancy of < 3 months. 
13. Major gastrointestinal surgery (e.g., significant bowel resection or diversion) within 
3 months prior to randomization, current ileostomy, or history of total colectomy. 
NOTE: appendectomy, cholecystectomy, or restrictive procedures, such as banding, may 
be permitted upon discussion with the Medical Monitor if at least 1 month since surgery 
has elapsed and upon the subject’s full recovery. 


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14. Anticipated admission to an intensive care unit during or after the study drug 
administration treatment period. NOTE: nursing homes, rehabilitation units, assisted 
living centers, and acute care hospitals are acceptable. 
15. Female subject who is pregnant or breastfeeding. 
16. Known hypersensitivity/allergy/intolerance to any ingredient in the VE303 study 
formulation
 
 
17. Clinically significant medical or surgical condition not mentioned in the above criteria 
that, in the Investigator’s opinion, could interfere with the administration of study drug, 
interpretation of study safety or efficacy data, or compromise the safety or well-being of 
the subject. 
18. History of confirmed celiac disease, inflammatory bowel disease, short gut, 
gastrointestinal tract fistulas, or ischemia. 




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If the subject has difficulty taking all capsules at the same time, the subject can take with some 
time intervals, but all capsules should be taken prior to 4 PM each day. If a study drug dose is 
missed and discovered before 4 PM, the dose may be taken that day, as long as the subject has 
not eaten for at least 1 hour prior to the delayed dose and will not eat for at least 1 hour after the 
dose following the administration guidelines. 
All capsules should be ingested with a beverage of choice that contains no solid food substances 
(i.e., water is ideal, but any clear or carbonated beverage may be used). Beverages should be at 
room temperature, cool, or warm (not hot) to avoid any effect on study drug contents. 
Anyone who touches or handles the study drug capsules (not necessary if only handling the 
plastic bottles) should wash their hands after handling.  
6.3.2 
Missed or Partial Dosing 
All efforts should be made to ensure that a subject takes all assigned capsules each day for 
14 days. However, if a study drug dose is missed on a given study day, and this is discovered 
before 4 PM, the dose may be taken that day as long as the subject has not eaten for at least 
1 hour prior to the delayed dose and will not eat for at least 1 hour after the dose following the 
administration guidelines in Section 6.3.1. 
If the missed dose is discovered after 4 PM, the dose should be skipped and the assigned once 
daily dosing regimen should resume the next day according to the original schedule (i.e., the 
dose should not be doubled the next day). If study drug is missed or interrupted on any study 
day(s), the end of the study drug administration period will remain fixed at a maximum of 
14 days after starting therapy. 
The same instructions as above are to be followed if a study drug dose has only been partially 
ingested prior to 4 PM on a given study day. Subjects will be instructed to make every effort to 
consume all assigned capsules before 4 PM. If a subject misses or only partially completes a 
dose, the subject will be instructed to contact study site personnel to review the requirements for 
compliance with the dosing guidelines outlined in Section 6.3.1. 
6.4 
Accountability and Dosing Compliance 
Subjects will be instructed to return all study drug supplies (including empty, partially empty, 
and full bottles) at the end of the treatment period for accountability and compliance review by 
study personnel. Study personnel will reinforce dosing instructions and answer subject questions 
at each clinic visit and during telephone follow-up. 
6.5 
Antibiotic Rescue Therapy Guidance 
If systemic antibiotics are deemed necessary during this study for a presumed infection, and 
VE303 component bacteria may be implicated, consideration should be given to the use of one or 
more of the 5 following broad spectrum antibiotics to which all of the bacteria contained in 
VE303 are susceptible (based on in vitro testing – refer to the VE303 Investigator’s Brochure for 
more details), according to institutional standard of care guidelines regarding antibiotic dose, 
route, and frequency: 
• piperacillin/tazobactam 




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7.0 
STUDY PROCEDURES AND ASSESSMENTS 
Before recruitment of subjects, written Institutional Review Board (IRB)/Ethics Committee (EC) 
approval of the protocol, informed consent documents, advertising and subject-facing documents 
will be obtained. 
Study procedures and assessments are summarized in Table 7-1 (Schedule of Events). 
Detailed instructions for the processing, handling, packaging, and shipping of hematology, 
clinical chemistry, and all other specimens will be outlined in the study manuals provided to each 
investigative site. 
7.1 
Informed Consent 
Informed consent must be obtained before any study-specific procedure is performed. This study 
may implement a Pre-Screening process (when approved by IRB/IEC and permitted by related 
institution) to determine preliminary subject eligibility in advance of the formal Screening 
process. For subjects who sign a Screening written informed consent form but are not 
randomized, the reason for screen failure will be recorded. 
7.1.1 
Optional Pre-Screening Informed Consent 
Once identified as potential study candidates, where applicable, subjects or their LAR will sign a 
Pre-screening informed consent form to enable collection of a stool sample, which may be 
collected at home by a qualified home healthcare provider, to confirm the qualifying event of 
CDI recurrence in accordance with eligibility criteria. A history of C. difficile infection and 
medications may also be reviewed. 
7.1.2 
Screening 
Once identified as potential study candidates, subjects or their LAR will sign an informed 
consent form to enable collection of a stool sample to confirm the qualifying event of pCDI high 
risk for recurrence or rCDI in accordance with eligibility criteria. The stool collected on this day 
will also be used for baseline evaluations of stool microbiota composition, VE303 component 
bacteria detection, antibiotic concentrations, metabolomics, culture, detection of antibiotic 
resistant bacteria other than C. difficile (e.g., CRE, ESBL, or VRE), and calprotectin. Physical 
examination findings, vital signs, safety laboratory measurements, medical history, and 
medications will also be reviewed (see Table 7-1). 
Results from Screening evaluations, including laboratory results and CDI confirmation, are 
required to confirm eligibility and must be available before randomization and study drug 
administration. 
7.2 
Randomization and Blinding 
After all Screening procedures have been performed and the SOC antibiotic therapy completed, 
eligibility has been confirmed on Day 1, a centralized interactive web response system will 
assign each subject a randomization number and subjects will receive study drug. 


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Investigators, study subjects and the Sponsor study clinical operations team that interacts with 
the sites and the database will remain blinded to IA results, as well as the treatment assignments, 
for the full duration of the study period until the final analysis dataset is cleaned, locked and 
unblinded. Select members of the Sponsor’s senior management team, who do not interact with 
study sites and are not involved in execution of the study, will be unblinded at the treatment 
group level according to the approved Data Access and Unblinding Plan for development and 
future planning purposes only. This unblinding will have no impact on the ongoing study. In 
addition, as spelled out in the Data Access and Unblinding Plan, relevant members of the 
Systems Biology Department will be unblinded at the subject level to enable effective analysis of 
subject samples. 
7.2.1 
Breaking the Blind 
Unblinding of study drug assignment may be requested (see contact information on page 1) in an 
emergency if unblinding is considered necessary for the medical management of a subject. The 
Investigator will discuss the circumstances for the requested unblinding with the Sponsor’s 
Medical Monitor. Emergency unblinding without the Medical Monitor’s input should occur only 
if knowledge of study drug assignment will affect the immediate workup or treatment of an AE. 
Communications related to unblinding will be documented, including the date, time, and reason 
for the requested unblinding. 
7.3 
Safety Assessments 
Safety will be assessed throughout the study and the safety data will include reported AEs, 
SAEs, gastrointestinal symptoms, clinical laboratory data, electrocardiograms (ECGs), 
concomitant medications, physical examinations, and vital signs. 
7.3.1 
Demographics and Medical History 
Subject demographics and past and present medical history will be recorded at Screening. 
Ongoing medical conditions and signs and symptoms observed prior to the time a subject signs 
the informed consent form will be recorded as medical history. 
In addition to general medical history, specific information relative to the qualifying CDI episode 
at presentation will include: 
• Date of onset of clinical symptoms of the qualifying CDI episode 
• Whether the subject was inpatient (e.g., in an acute care hospital) or outpatient at the time 
of onset of clinical symptoms of the qualifying CDI episode 
• Method(s) of local laboratory diagnosis of C. difficile for the qualifying CDI episode 
• Whether the qualifying CDI episode represented the first, second, or later, and time since 
previous CDI episode 
• Antibiotic/treatment regimen for the qualifying episode 
• Total number of unformed (loose or watery) stools within a 24-hour period for the 
qualifying CDI episode 


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• Highest blood WBC count associated with the qualifying CDI episode 
• Date of a successful clinical response defined as the symptomatic control of the 
qualifying/current CDI episode, i.e., < 3 loose/unformed bowel movements within 
24 hours for at least 2 consecutive days. 
Dates of onset and antibiotic/treatment regimens used for prior CDI episodes within the 6 months 
before the day of randomization also will be recorded. 
7.3.2 
Prior and Concomitant Medications 
All medications and supplements, including those administered for treatment of the qualifying 
CDI episode, administered within 60 days prior to Screening through the end of the study will be 
recorded in the eCRFs using generic drug names when possible. Prior medications are those 
administered prior to study drug administration, and concomitant medications are those 
administered from the time of the first dose of study drug through the end of the study. 
Concomitant medications may be administered at the Investigator’s discretion to conform to 
standard practice, including routine medications a subject will continue during study 
participation as well as newly prescribed medications, except for those excluded medications 
described in Section 7.3.2.2. Overall, VE303 has a low likelihood for eliciting clinically relevant 
drug-drug interactions; however, no formal drug-drug interaction studies have been done and the 
Investigator will need to use caution when prescribing concomitant medications. The 
Investigator is strongly encouraged to contact the Medical Monitor when unsure of a possible 
drug-drug interaction. 
Initially, if clinically appropriate, gastrointestinal symptoms or signs should be observed to 
determine whether they resolve without therapy. For routine treatment of constipation, a glycerin 
suppository per rectum is recommended as the initial treatment (other agents may cause 
interference with the colonization and detection of VE303 component bacteria) but other agents 
may be used at the Investigator’s discretion. 
7.3.2.1 
Concomitant Antacids and Acid Reducers 
Use of medications changing the gastric acidity may potentially reduce the effectiveness of 
VE303. Use of these medications should be restricted to the following: 
• Subjects should not consume food or fast-acting antacids (e.g., calcium-, aluminum-, or 
magnesium-containing products such as TUMS® or Maalox®) for at least 1 hour before 
and at least 1 hour after study drug ingestion. 
• Subjects should not receive a histamine2-receptor antagonist (ranitidine, famotidine, etc.) 
within the 12 hours before or 1 hour after study drug ingestion. 
• Subjects should not receive a proton-pump inhibitor (omeprazole, pantoprazole, etc.) 
within the 12 hours before or 1 hour after study drug ingestion. 
7.3.2.2 
Prohibited Therapies and Substances 
The following therapies are prohibited during the 14-day study drug administration period, 
unless otherwise specified or necessary for management of a medical condition. If any of the 


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following are medically indicated and prescribed, these should be entered in the eCRF as 
concomitant medications: 
• Drugs that alter gut motility (e.g., loperamide, diphenoxylate) 
• Oral or parenteral antibacterial therapy for a non-CDI indication 
• Corticosteroids at daily doses higher than 20 mg of prednisone equivalent, with the 
exception of inhaled or topical corticosteroids, which are permitted. 
• Genetically modified investigational live bacterial/fungal/bacteriophage/viral isolates for 
CDI-associated diarrhea, with the exception of live-bacteria-containing food products 
(such as yogurt) or over the counter probiotics. 
• Fecally-derived investigational live biotherapeutic products, or fecally-derived live 
bacterial isolates for CDI-associated diarrhea including FMT 
• Other investigational products (through Week 8/Day 56) 
7.3.3 
Adverse Events 
Adverse events will be assessed by direct observation and subject assessments/interviews from 
the time a subject signs the informed consent form through Week 24/Day 168. Complete details 
on the definition, reporting, and management of AEs, including AEs of special interest, are 
provided in Section 9.0. 
7.3.4 
Gastrointestinal Symptoms Self-Administered Questionnaire 
Subjects will be evaluated for gastrointestinal symptoms using the self-administered 
Patient-Reported Outcomes Measurement Information System (PROMIS®) scale questionnaire 
in order to assess 8 gastrointestinal symptoms (belly pain, bowel incontinence, constipation, 
diarrhea, disrupted swallowing, gas/bloating, nausea/vomiting, and gastroesophageal reflux; see 
Appendix 2). The questionnaires are intended to be filled out by the subject or LAR after training 
by the site staff. To obtain an adequate baseline, questionnaires must be completed before the 
first dose of study drug on Day 1. Subsequently, questionnaires should be completed on Days 7 
and 14. All attempts must be made to have questionnaires completed at approximately the same 
time of day at each time point outlined in the protocol. 
7.3.5 
Vital Signs 
Vital signs (pulse, blood pressure, and body temperature) will be collected at Screening and on 
Days 1, 7, 14, 28, 56, and 168 (end of study) as well as at unscheduled times as medically 
indicated. Subjects are required to remain in the supine position for at least 3 minutes prior to 
obtaining vital signs. On Day 1, vital signs will be measured prior to administration of study 
drug. 
Abnormal vital sign measurements will be recorded as AEs only if they are considered to be 
clinically significant by the Investigator. 


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7.3.6 
Physical Examination 
Physical examinations will be performed by trained medical personnel. A complete physical 
examination will be performed at Screening. On Days 1, 14, 28, 56, and 168 (end of study), 
physical examinations will include abdominal examinations, with limited symptom-directed 
examinations performed for other organ systems. Abnormal physical examination findings will 
be recorded as AEs only if they are considered to be clinically significant by the Investigator. 
Height will be collected at Screening only. Weight will be collected at Screening and on Days 1, 
14, 28, 56, and 168 (end of study). Weight is to be measured consistently in the same manner 
each time and noted in the source –without heavy items/shoes/bulky clothing, etc. 
7.3.7 
Laboratory Tests 
The following laboratory tests will be performed: 
• Hematology (performed at Screening and on Days 1, 7, 14, 28, 56, and 168 [end of 
study]): Complete blood count (CBC) with differential. 
• Serum chemistry (performed at Screening and on Days 1, 7, 14, 28, 56, and 168 [end of 
study]): sodium, potassium, chloride, albumin, alkaline phosphatase, direct and total 
bilirubin, ALT, AST, gamma-glutamyl transferase, blood urea nitrogen, calcium, 
creatinine, phosphorus, glucose, lactate dehydrogenase, amylase, and lipase. 
• Urinalysis (performed at Screening and on Day 14) in accordance with the Laboratory 
Manual. 
• Pregnancy testing (performed at Screening [serum] and Day 1 [urine]) for females of 
childbearing potential. Day 1 pregnancy test results must be negative prior to initiation of 
study drug dosing. 
The diagnosis corresponding to clinically significant abnormalities (including abnormalities 
requiring treatment/intervention) observed after a subject signs the informed consent will be 
recorded as AEs. 
7.3.8 
12-Lead Electrocardiogram 
Single 12-lead ECGs will be performed at Screening, Day 28, and at unscheduled time points as 
medically indicated. ECG parameters to be evaluated include the respiration rate, QT interval 
corrected for heart rate (QTc), QRS, and PR intervals. Post-baseline abnormal ECG 
measurements will be recorded as AEs if they are considered to be clinically significant by the 
Investigator. 
7.4 
Stool Analyses 
Stool samples must be collected at the time points specified in Table 7-1 for C. difficile testing 
(e.g., GDH, toxin A/B, C. difficile PCR, CCNA) and for exploratory analyses (microbiota 
composition, VE303 component bacteria detection, antibiotic concentrations, metabolomics, 
culture, detection of antibiotic resistant bacteria other than C. difficile (e.g., CRE, ESBL, or 
VRE), and calprotectin. Whenever possible, stool sample collection should occur at the study 
site. However, because it is important to collect a stool sample at scheduled time points or while 


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a subject is symptomatic, subjects will be provided with a kit and instructions for stool sample 
collection at home, if necessary. Applicable instructions will be provided with the Laboratory 
Manual. 
7.4.1 
Stool C. Difficile and Other Stool Testing 
A stool sample must be collected and submitted for C. difficile testing as soon as a potential 
qualifying CDI episode is identified based on the criteria outlined in Section 4.2. Ideally, this 
stool sample will be obtained prior to starting SOC antibiotics for CDI; however, if SOC 
antibiotics have been started, the stool sample will be collected no later than 72 hours after the 
first antibiotic administration. Every effort must be made to collect the diagnostic sample before 
SOC antibiotic therapy or within 24 hours after the start of SOC antibiotic therapy. 
Throughout the study, stool samples collected at every scheduled time point will be sent to a 
central laboratory for exploratory analyses, and aliquots of each sample will be stored at the 
central laboratory. Under the direction of the Sponsor, stored stool samples may be used for 
additional testing, specifically, characterization of other stool bacteria and pathogen analysis.  
On-study CDI recurrences, as defined in Section 4.2, will require laboratory conﬁrmation using 
free toxin test (see Section 9.3.1 for further details). 
7.5 
Exploratory Serum Analyses 
Serum samples must be collected at Screening and on Days 14, 56, and 168 (end of study) and 
will be stored for future exploratory analyses, including cytokines and other soluble factors that 
may influence the efficacy and/or safety of study drug. 
7.6 
Hygiene for C. Difficile-Associated Diarrhea and Study Drug Handling 
To avoid the potential transmission of C. difficile, study subjects will be instructed to thoroughly 
wash their hands with soap and water after handling stool samples or after each fecal elimination. 
Study personnel will wear gloves and wash their hands after handling subject stool samples 
following standard hand-washing requirements for C. difficile contact at their institution, if 
applicable. NOTE: The physical action of washing and rinsing hands is recommended versus 
alcohol-based antiseptic cleaning, as alcohol-based antiseptics have demonstrated poor activity 
against C. difficile spores. 
In addition, these hygiene techniques will be implemented by study subjects and study personnel 
when handling or administering study drug to mitigate the possible transmission of VE303 
component bacteria, which may be present on the outside of the capsules (but not on the drug 
kits or plastic bottles containing the capsules) (see Section 6.3.1 for more details). Subjects will 
also be informed that they may remain colonized with VE303 strains (and possibly transmit the 
bacteria to others) even after discontinuation of study drug dosing. 






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provided documentation of a local positive test is available. To ensure subjects are allocated to a proper stratum, an effort should be made to obtain and send a stool sample to 
the central laboratory for confirmation of toxin or toxigenic C. difficile prior to randomization. . 
n Stool samples must be sent to a central laboratory. The Day 1 stool sample must be collected prior to administration of any study drug. This sample should be collected predose 
on Day 1, if possible; however, if a subject cannot produce a stool sample predose on Day 1, a sample from up to 24 hours prior to Day 1 may serve as the Day 1 sample. 
Thereafter, if a subject cannot produce a stool sample on the planned day of a clinic visit or at the time of diarrhea that may indicate CDI recurrence (see Section 9.3.1), then a stool 
sample may be obtained within ± 24 hours of the visit/diarrhea event. However, if CDI recurrence is suspected after ingestion of the first dose of study drug, all attempts should 
be made to collect a stool sample before administration of antibiotics to treat the recurrence. 
o PROMIS® gastrointestinal symptom questionnaires (see Appendix 2) are to be completed by each subject or LAR before the first dose of study drug on Day 1. Subsequently, 
questionnaires should be completed on Days 7 and 14. All attempts must be made to have questionnaires completed at approximately the same time of day at every time point. 
p AEs will be collected continuously from the time of informed consent through Week 24/Day 168. 
q Study personnel will telephone outpatient subjects daily during the 14-day study drug administration period to ensure dosing compliance; explore any concerns or issues with 
study drug ingestion, administration, handling or storage; capture potential AEs; review potential C. difficile-associated symptoms and assess the need for an unscheduled visit 
or stool test for CDI; remind subjects to collect stool to bring to their next clinic visit (if applicable); and answer any questions that the subject may have. If a subject is 
inpatient or attending a site visit on a scheduled telephone follow-up day, this contact will be performed in person, when possible. Telephone follow-up may be omitted on 
weekends or public holidays if this is necessary for logistical reasons. If a subject is discovered to have had an SAE or a recurrence of diarrhea at any time, an unscheduled visit 
must be arranged as soon as possible. 


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8.0 
STUDY DISCONTINUATION 
8.1 
Sponsor Discontinuation Criteria 
This study may be discontinued at any time due to safety concerns, failure to meet expected 
enrollment goals, administrative reasons, or at the discretion of the Sponsor. Should the study be 
terminated prematurely, the Sponsor will provide written notification to the Investigator and 
regulatory authorities and will specify the reason(s) for early termination. The Investigator must 
inform the IRB/EC promptly and provide the reason(s) for the termination as well as subject 
status of all participants at their site. 
8.2 
Study Discontinuation for Individual Subjects 
Subjects may withdraw their consent at any time for any reason without prejudice to their future 
medical care by the physician or at the institution. If a subject withdraws consent, the date and 
stated reason for consent withdrawal will be documented. Subject data, including samples 
(e.g., blood, serum, stool), collected up to the date of consent withdrawal (i.e., early termination) 
will be included in the analyses. 
Wherever possible, the tests and evaluations listed for the End of Treatment Visit (same as 
Day 14 [+ 1 day]) will be carried out at the time of discontinuation of study drug. Subjects who 
discontinue study drug prematurely for reasons other than withdrawal of consent, lost to 
follow-up, or AE event with an outcome of death will continue to be followed for the intended 
duration of the study (i.e., through Week 24/Day 168). The Sponsor will be notified of all study 
withdrawals. 
Subjects meeting any of the following criteria must discontinue study drug dosing: 
• Subject experiencing related Grade 3 or higher AE and/or any related SAE 
• Any allergic reaction during study drug administration, regardless of grade, should 
prompt study drug discontinuation unless there is a clear alternative etiology for the 
event. The study drug may be restarted if a clear alternative etiology for the event is 
identified 
• Withdrawal of consent/early termination 
• Pregnancy 
• Lost to follow-up 
• Discretion of the Investigator (e.g., protocol violations, noncompliance, continued study 
drug administration not in the subject’s best interest) 
• Study termination by the Sponsor 


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9.0 
ADVERSE EVENTS 
9.1 
Adverse Event 
An AE is any untoward medical occurrence, including the exacerbation of a pre-existing 
condition, in a subject administered a pharmaceutical product or study medication regardless of 
causality. 
Adverse events will be recorded in the eCRF during the time periods specified in Section 9.4, 
including documentation of start and stop dates, outcome, severity, seriousness, relationship to 
study drug, action taken with respect to study drug, and medication required to manage the event. 
Adverse events will be reported in accordance with the guidelines set forth in 21 Code of Federal 
Regulations (CFR) 312.32 and International Council for Harmonisation (ICH) E6R2. 
9.1.1 
Assessment of Toxicity Grade 
The toxicity grade of an AE refers to its severity. The severity of AEs will be categorized using 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0 [33], which is appropriate for grading and assessing the range of potential 
AEs that may be observed in the targeted study population of subjects with rCDI-associated 
diarrhea. This is because most of these subjects will be elderly, have multiple co-morbidities, and 
be taking a variety of prescription medications appropriate for the management of their comorbid 
conditions. For any term that is not specifically listed in the CTCAE scale, severity must be 
assigned a grade of 1 through 5 using the following CTCAE guidelines: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
9.1.2 
Assessment of Causality 
Medical judgment will be used to determine the cause of the AE, considering all relevant facts 
such as (but not limited to) the underlying study indication, comorbidities, concomitant 
medication(s), medical history, pattern of the AE (continuous, intermittent, etc.), temporal 
relationship to the study drug, and de-challenge or re-challenge. 
The Investigator will be responsible for selecting “Yes” or “No” as detailed below for the 
relationship of each AE to the study drug. 


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Yes (i.e., possibly, probably, or definitely related): there is a reasonable possibility that there is a 
causal relationship to the study drug and one or more of the following criteria apply: 
• The event follows a reasonable temporal sequence from the time of administration of the 
study drug. 
• The event could not be reasonably attributed to the known characteristics of the subject’s 
clinical state, environmental or toxic factors, or other modes of therapy administered to 
the subject. 
• The event follows a known pattern of response to the study drug. 
• The event disappears or decreases on cessation or reduction in dose. (It should be noted 
that in some situations an AE will not disappear or decrease in intensity upon 
discontinuation of study dosing despite other clear indications of relatedness). 
No (i.e., unlikely, probably not related, or definitely not related): there is no reasonable 
possibility that the study drug caused the event; one or more of the following criteria apply: 
• The event does not follow a reasonable temporal sequence from administration of the 
study drug to the time of the AE. 
• The event could be reasonably attributed to the known characteristics of the subject’s 
clinical state, concurrent illness, environmental or toxic factors, or other modes of 
therapy administered to the subject. 
• The event does not follow a known pattern of response to the study drug. 
• The event does not disappear or decrease on cessation, and it does not reappear or worsen 
when dosing is resumed. 
9.1.3 
Action Taken with Study Drug 
For each AE reported, the action taken with the study drug as a result of the AE will be recorded 
as one of the following: 
• Drug withdrawn 
• Dose interrupted 
• Dose not changed 
• Unknown 
• Not applicable (i.e., for AEs occurring prior to first or after the last study drug 
administration) 
9.1.4 
Outcome of Adverse Event 
The outcome of each AE at the time of last observation will be reported as one of the following: 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved/ongoing (e.g., for irreversible congenital anomalies) 


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• Recovered/resolved with sequelae (e.g., for other irreversible medical conditions) 
• Fatal (i.e., death is at least possibly related to the AE) 
• Unknown 
9.2 
Serious Adverse Event 
An SAE is an untoward medical occurrence in the view of the Investigator or Sponsor that meets 
any of the following criteria: 
• Results in death. 
• Is immediately life-threatening (refers to an event in which the subject is 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. 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Based on appropriate medical judgment, represents an important medical event that may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
described above. 
9.2.1 
Clarification of Serious Adverse Event Definition 
• Adverse event seriousness is not necessarily dependent on event severity. AEs that are 
Grade 3 or 4 in severity do not constitute SAEs unless SAE criteria are met, and events 
that are Grade 1 or 2 in severity may meet SAE criteria. 
• Death is an outcome of an SAE and not an SAE in itself. When death is an outcome, the 
event(s) resulting in death should be reported (e.g., “pulmonary embolism” with a fatal 
outcome). The appropriate diagnosis or term should be recorded and assigned severity 
Grade 5. 
• In instances of death due ultimately to an underlying disease, the cause of death should be 
indicated as the specific event or condition resulting in death to the extent possible. If no 
appropriate term with a Grade 5 severity in the CTCAE can be identified, then a term 
should be selected from the CTCAE category “Death”. 
• “Life-threatening” means that the subject was at immediate risk of death from the event 
as it occurred. This does not include an event that might have led to death if it had 
occurred with greater severity. Grade 4 events (e.g., thrombocytopenia) are not always 
serious unless they have life-threatening consequences or result in hospitalization. 
• Pre-planned or elective hospitalizations including social and/or convenience situations 
(e.g., respite care) are excluded from SAE reporting unless they meet another SAE 
criterion. 


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• Overage in dosing of either the study drug or a concomitant medication without overdose 
signs or symptoms unless the event meets SAE criteria (e.g., hospitalization) are 
excluded from SAE reporting; however, such events should still be recorded on the 
appropriate eCRF page. 
9.2.2 
Serious, Unexpected, Suspected Adverse Reactions 
In accordance with regulatory requirements, the Sponsor or designee will immediately notify 
regulatory authorities and the Investigators, who will in turn notify their IRB/EC as necessary, of 
any AE associated with study drug administration or study procedures that is a serious, 
unexpected, suspected adverse reaction or any finding from tests in laboratory animals that 
suggests a significant risk for human subjects, including reports of mutagenicity, teratogenicity, 
or carcinogenicity. An AE or suspected adverse reaction is considered “unexpected” if it is not 
listed in the Investigator’s Brochure or is not listed at the specificity or severity that has been 
previously observed. 
9.3 
Adverse Events of Special Interest 
The following are considered AEs of special interest due to the indication under study (CDI) and 
the nature of the investigational product (live bacteria) and potential for gastrointestinal or 
extraintestinal AEs: 
• Any clinically significant (Grade 2 or higher) gastrointestinal AE considered related to 
study drug. 
• Any clinically significant (Grade 2 or higher) bacterial infection considered related to 
study drug. 
These AEs will be tabulated and analyzed separately from other AEs. 
9.3.1 
Management of Diarrhea or Loose/Watery Stools 
Any clinical event of diarrhea or loose/watery stools (including events reported as C. difficile 
infection/recurrence) will be recorded as an AE. In addition to recording the standard AE 
information, the Investigator will record the following information: 
• Maximum number of unformed (loose or watery) stools within a 24-hour period that are 
associated with the event. 
• Whether a stool sample was collected for this event; if so, the date of collection, method 
of delivery/collection (produced at study site or brought to study site), and type of 
C. difficile test(s) performed (with results) will be recorded along with protocol-mandated 
evaluations. 
• Whether colon endoscopy or surgery was performed for the event and whether 
pseudomembranes were present. 
• Whether there was another likely cause of the diarrhea (instead of or in addition to CDI) 
in the opinion of the Investigator, including, but not limited to, food/diet, non-study 
medication, or other infection. 


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Subjects who have ≥ 3 loose/unformed bowel movements within 24 hours for at least 
2 consecutive days or > 8 loose/unformed bowel movements within 24 hours (or those with any 
diarrhea of concern to the subject or Investigator) will be instructed to contact study personnel as 
promptly as possible for clinical assessment and to arrange for collection of a stool sample. 
Whenever possible, collection of the stool sample should occur at the study site. However, 
because it is important to collect a stool sample while a subject is symptomatic, subjects will be 
provided with a kit and instructions for stool sample collection at home, if necessary. These stool 
samples may be collected within 24 hours of diarrhea onset but must be obtained before 
administration of any antibiotics or no later than on the day after antibiotics were started. Stool 
samples collected in association with an AE of diarrhea or loose/watery stools will be tested for 
C. difficile at the central laboratory and in accordance with the Schedule of Events (Table 7-1) 
and Section 7.4.1. All other aspects of management of subjects with diarrhea or loose/watery 
stools (including local laboratory testing and any treatment for diarrhea/CDI) will occur at the 
discretion of the Investigator based on clinical presentation. Subjects should remain in the study 
(at the discretion of the Investigator) and continue to be followed per protocol. Use of any 
antibacterial treatments administered for CDI will be recorded (see Section 7.3.2). If a subject 
develops diarrhea (as defined above) during the 14-day study treatment period and recurrent CDI 
diagnosis is confirmed by a positive EIA for Toxin A/B or CCNA test, the study treatment 
should be discontinued (See Section 4.4). Such an event should also be reported as confirmed 
recurrence in the eCRF. 
9.4 
Reporting of Adverse Events 
All AEs, serious and nonserious, occurring from the time a subject signs the informed consent 
form through Week 24/Day 168 must be fully recorded on the appropriate eCRF. 
Abnormal clinical laboratory values and vital sign and ECG measurements will be recorded as 
AEs only if they are considered to be clinically significant by the Investigator. If a laboratory 
abnormality is the sole potential AE, the abnormality must be confirmed (if possible) with a 
repeat laboratory test performed as soon as possible. 
All SAEs, regardless of relationship to study drug, must be reported to the CRO within 24 hours 
of the Investigator’s knowledge. This will be done by faxing or emailing the completed SAE 
Report Form to the CRO at the number provided on the SAE Report Form. 


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Contact information for safety reporting is as follows: 
 
 
 
 
 
 
 
 
 
 
 
Investigators must follow subjects with SAEs for a minimum of 30 days or until event resolution 
or stabilization, withdrawal of consent, subject is lost to follow-up, or death, whichever occurs 
first. 
9.5 
Pregnancy 
Female subjects of childbearing potential must provide a negative serum pregnancy test at 
Screening and a negative urine pregnancy test prior to initiation of study drug dosing. 
Pregnancies occurring on study that involve a subject must be brought to the attention of the 
treating physician immediately, and pregnant subjects must discontinue study dosing. Site 
personnel will notify the Sponsor within 24 hours of the Investigator’s knowledge of the 
pregnancy using a Pregnancy Notification Form. Such pregnancies will be followed to outcome, 
as possible. 
9.6 
Clinical Laboratory Abnormalities 
It is the responsibility of the Investigator to assess the clinical significance of all abnormal 
laboratory values as defined by the appropriate reference range(s). All abnormal values assessed 
to be of clinical concern and at least possibly related to the study drug or of uncertain causality 
will be repeated. Persistent abnormal values or changes of possible clinical concern that remain 
within the normal range will be followed up and further evaluated at the discretion of the 
Investigator. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as an 
AE if: 
• a repeat test is performed, when possible, to confirm the abnormality 
• an action on study drug dosing is made as a result of the abnormality 
• an intervention for management of the abnormality is required 
• or the Investigator considers the abnormality to be AE 
Abnormal test results must not be recorded as AEs unless they fulfill the aforementioned criteria. 
All abnormal laboratory values, even if reported as an AE, will be categorized by the 
Investigator as not clinically significant or clinically significant and a severity grade will be 
included in the eCRF. 


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9.7 
Review of Safety Data 
The designated Medical Monitor will be responsible for the ongoing review and evaluation of 
safety data, including AEs, clinical laboratory data, and any other safety evaluations (see 
Section 7.3). 


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10.0 
STATISTICAL METHODS  
10.1 
Study Design and Primary Analysis   
As designed, VE303-002 is a Phase 2, randomized, parallel-arm, double-blind, placebo-
controlled, dose-selection study to evaluate the safety, microbiota changes, and efficacy of 
VE303 in the prevention of subsequent CDI-associated diarrhea compared with placebo 
following completion of a successful course of SOC antibiotics for subjects with pCDI at high 
risk for recurrence or subjects with rCDI.  
The 3 administrative IAs are planned when at least 24 subjects reach study Week 8, when at least 
39 subjects reach study Week 8, and when at least 54 subjects reach study Week 8. 
The primary endpoint is the proportion of subjects with CDI recurrence before or at Week 8 (i.e., 
8 weeks after the first dose of study drug). The difference in the proportion of subjects with CDI 
recurrence before or at Week 8 between each VE303 treatment group and placebo will be 
analyzed using a stratified Cochran-Mantel-Haenszel method. Stratification will involve the 
stratification factors as determined from the clinical database, i.e., number of previous CDI 
episodes at Baseline (0 vs ≥1 episodes, excluding qualifying episodes), SOC antibiotic treatment 
(non-vancomycin [fidaxomicin or metronidazole] or an alternative oral vancomycin dosing 
regimen vs vancomycin QID), and results of CDI laboratory diagnostic method (free toxin or 
other). 
10.2 
Analysis Populations 
The following subject populations (i.e., analysis sets) will be evaluated and used for presentation 
of the data: 
• Full Analysis Set (FAS): All subjects who were randomized and received at least 1 dose 
of study drug. Subjects will be classified according to the planned study drug assignment. 
The FAS will be the default analysis set for all efficacy analyses, unless otherwise 
specified. 
• Per-Protocol Analysis Set (PPS): All subjects in the FAS who had no major protocol 
deviations. The PPS will be used for the primary and secondary efficacy endpoint 
analyses. 
• Safety Analysis Set: All subjects who were randomized and received at least 1 dose of 
study drug. Subjects will be classified according to the actual study drug assignment. The 
Safety Analysis Set will be the primary set for the analysis of safety data. 
10.2.1 
Sensitivity Efficacy Analyses 
Sensitivity analyses will be conducted on the following efficacy variables for the FAS and PPS: 
• Sensitivity Analysis I: In addition to the CDI recurrence definition for the primary 
efficacy endpoint, the CDI recurrence definition for Sensitivity I will also include any 
recurrence that was diagnosed with a positive PCR test (including cytotoxicity assay) and 
treated with an antibiotic that targets C. difficile. 


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• Sensitivity Analysis II: In addition to the CDI recurrence definition for the primary and 
Sensitivity I efficacy endpoints, the Sensitivity II CDI recurrence definition will include 
any recurrence, in the absence of laboratory confirmation, that is treated with an 
antibiotic that targets C. difficile. 
10.3 
Procedures for Handling Missing, Unused, and Spurious Data 
In general, missing values for the primary efficacy endpoint will not be imputed. However, as a 
sensitivity analysis, subjects who discontinued prior to the Week 8 time point will be imputed as 
having a CDI recurrence at Week 8. Details will be provided in a separate statistical analysis 
plan (SAP). 
10.4 
Administrative Interim Analyses  
Three IAs are planned for study administrative purposes only. These 3 administrative IAs will 
provide input to Vedanta senior management regarding development strategy for future 
investigations. These IAs will have no impact on the ongoing study. The administrative IAs will 
be performed after at least 24 subjects complete 8 weeks of the study, after at least 39 subjects 
complete 8 weeks of the study, and after at least 54 subjects complete 8 weeks of the study. 
Further details of these administrative IAs will be described in the SAP, as appropriate. 
10.5 
General Methods 
Continuous variables will be summarized with descriptive statistics (arithmetic mean, standard 
deviation, median, minimum, and maximum) by study arm. Categorical data will be summarized 
with frequency counts and percentages by study arm. 
In addition to the frequency (%), descriptive statistics, and confidence intervals, the hypothesis 
test for CDI recurrence rate (no treatment effect versus at least 1 dose is effective) will be 
conducted using a stratified Cochran-Mantel-Haenszel test (stratified for the stratification factors 
used in randomization). 
The primary efficacy endpoint is the incidence of recurrences that meet the protocol defined 
recurrence definition (Section 4.2); however, a supplemental analysis will be conducted for the 
incidence of recurrences that are both Toxin positive and Toxin negative/unknown. The null 
hypothesis is that the proportion of VE303 subjects with C. difficile recurrence is greater than or 
equal to that of placebo. The alternative hypothesis is that the proportion of VE303 subjects with 
C. difficile recurrence is lower than that of placebo. 
This study may be prematurely terminated with a reduced sample size if, in the opinion of the 
Sponsor, there is sufficiently reasonable cause. In the event of such action, written notification 
documenting the reason for study termination will be provided to each Investigator. 
10.5.1 
Disposition of Subjects 
A tabulation of the disposition of subjects will be presented, including the number of subjects 
who fail Screening after signing informed consent, are randomized, receive study drug, and 
complete or prematurely discontinue, and the reasons for study discontinuation. Entry criteria 
eligibility and protocol deviations will be listed. 


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10.5.2 
Baseline Comparisons 
Demographic and baseline disease characteristic data summaries will be generated to 
descriptively assess the comparability of dose groups. Data to be tabulated will include sex, age, 
race, and ethnicity, as well as disease-specific information such as CDI episode number and prior 
antibiotic or other CDI treatment. 
10.5.3 
Safety Analysis 
Subjects who receive at least 1 dose of study drug will be included in safety analyses. 
Adverse events will be coded using the most current version of Medical Dictionary for 
Regulatory Activities (MedDRA) at the time of study initiation, and the severity of AEs and 
laboratory abnormalities will be graded using the NCI CTCAE, version 5.0 [33]. A by-subject 
AE data listing, including verbatim term, preferred term, system organ class, study drug arm, 
severity, and relationship to study drug, will be provided. The number of participants 
experiencing TEAEs and the number of individual TEAEs will be summarized by study arm, 
system organ class, and preferred term. TEAEs will also be summarized by severity and by 
relationship to study drug. 
Clinical laboratory evaluations and other safety assessments will be summarized by study arm 
and protocol-specified collection time point. A summary of changes from Baseline will also be 
presented for each protocol-specified time point. 
10.5.4 
Stool and Other Exploratory Analyses 
Results from stool microbiota composition and VE303 detection analyses will be presented in 
by-subject listings and summarized by study arm and study day, including absolute values and 
changes from Baseline. 
Tabular and/or graphical summaries for the microbiome and VE303 detection analyses will be 
produced for VE303 strain presence, community composition (relative abundance of the top 
10 species and VE303 strain abundance), community diversity (Shannon Index, Simpson Index, 
and Species Richness calculations), and relative abundance of all species detected in the sample. 
In addition, an analysis will be performed to evaluate the longitudinal microbiome composition 
and VE303 strains within each subject and within each study arm, including changes in diversity 
over time, changes in microbiome species over time, and changes in VE303 strains over time 
(both presence/absence and relative abundance). 
The Sponsor will also collect serum and stool samples (for stool antibiotic concentrations, 
metabolomics, antibiotic resistant bacteria other than C. difficile [e.g., CRE, ESBL, or VRE], and 
culture) from clinical study participants and may analyze them for possible exploratory purposes 
and biomarkers. 
10.5.5 
Procedures for Reporting Deviations to the Statistical Analysis Plan 
All deviations from the statistical analysis plan will be provided in the clinical study report. 


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10.6 
Changes in the Conduct of the Study or Planned Analysis 
Only the Sponsor may modify the protocol. Amendments to the protocol will be made only after 
consultation and agreement between the Sponsor and the Investigator. The only exception is 
when the Investigator considers that a subject’s safety may be compromised without taking 
immediate action. In these circumstances, the Investigator must inform the Sponsor and the full 
IRB/EC within 1 working day after the safety event occurred. All amendments that have an 
impact on subject risk or the study objectives or require revision of the informed consent 
documents must receive approval from the IRB/EC prior to implementation. 


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11.0 
DATA RECORDING, RETENTION AND MONITORING 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator. In accordance with the ICH and Good Clinical Practice (GCP) guidelines, 
the Investigator will maintain complete, accurate, legible, timely, and easily retrievable data, and 
will allow personnel authorized by the Sponsor or recognized regulatory agency to access all 
study data at any time. Such data shall also be secured in order to prevent loss of data and protect 
the privacy of the subject. 
11.1 
Case Report Forms 
Medical records and/or study visit worksheets will be used by the Investigator or designee as 
source documents for recording data specified in the protocol for each subject enrolled. Data 
recorded in the eCRF derived from source documents must be consistent with the data recorded 
on the source documents. All source documents must be completed in a neat, legible manner to 
ensure accurate interpretation of data. Additional data will be collected through clinical 
laboratories. 
Clinical data derived from source documents will be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system at the clinical sites. The data system will include password 
access, consistent backup, and an audit trail. Internal and external quality checks will be applied 
to identify data that appear inconsistent, incomplete, or inaccurate. Data not captured on eCRFs 
will be received and stored as external files by the Sponsor or designee. 
Study plans will describe internal and external quality checks and cross functional data 
monitoring to identify and address data issues via a risk-based approach. Needed queries will be 
issued by the system (some fields may require immediate correction for form submission), CRO, 
or authorized Sponsor staff in an attempt to clarify and/or correct missing, incomplete, or 
illogical data. Changes or corrections to eCRFs will be made by the Investigator or an authorized 
member of the study staff. 
Data entered and compiled for interim analysis and/or DMC review will be monitored as closely 
as possible for accuracy and quality but may not undergo final data cleaning and verification. 
It is the Investigator’s responsibility to ensure eCRFs are complete and accurate, regardless of 
whether this responsibility has been delegated in whole or in part. Following review and 
approval, the Investigator or designee will electronically sign and date the pages, which certifies 
that the Investigator has thoroughly reviewed and confirmed all data on the eCRF. 
A read-only copy of the eCRFs will be provided to study sites after the study has ended and the 
EDC system has been locked. 
11.2 
Data Retention 
Data retention practices will follow ICH guidelines, which note that essential documents must be 
retained for a minimum of 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH region or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 


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investigational product. However, these documents must be retained for a longer period if 
required by the applicable legal requirements. 
11.3 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, ICH GCP, or Manual 
of Procedures requirements. The noncompliance may be either on the part of the subject, the 
Investigator, or the study site staff. Deviations must be reviewed by the site, clinical research 
associate, Sponsor, and designee, as appropriate for potential corrective actions development. 
Corrective actions will be implemented promptly. 
These practices are consistent with ICH GCP: 
• 4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, Section 5.1.1 
• 5.20 Noncompliance, Sections 5.20.1, and 5.20.2 
It is the responsibility of the Investigator to use continuous vigilance to identify and promptly 
report deviations. All deviations must be addressed in study source documents and recorded 
within the Protocol Deviation eCRF. Protocol deviations must be sent to the reviewing IRB/EC 
per their policies. The Investigator is responsible for knowing and adhering to IRB/EC 
requirements. 
11.4 
Data Monitoring 
This study will be closely monitored by representatives of the Sponsor or designee throughout its 
duration. Monitoring will include personal visits with the Investigator and study staff as well as 
appropriate communications by telephone, fax, mail, email, or use of the EDC system, as 
applicable. It is the monitor’s responsibility to inspect all eCRFs at regular intervals throughout 
the study to verify the completeness, accuracy, and consistency of the data and to confirm 
adherence to the study protocol and to GCP guidelines. The Investigator agrees to cooperate with 
the monitor to ensure that any problems detected are resolved promptly. The Investigator and site 
will permit study-related monitoring, audits, IRB/EC review, and regulatory inspection, 
including direct access to source documents. 
It is understood that study monitors and any other personnel authorized by the Sponsor may 
contact and visit the Investigator and will be permitted to inspect all study records (including 
eCRFs and other pertinent data) on request, provided that subject confidentiality is maintained, 
and that the inspection is conducted in accordance with local regulations. 
Every effort will be made to maintain the anonymity and confidentiality of subjects. However, 
because of the experimental nature of the investigational product, the Investigator agrees to allow 
representatives of the Sponsor and authorized representatives of regulatory authorities to inspect 
the facilities used in the conduct of this study and to inspect, for purposes of verification, the 
hospital or clinic records of all enrolled subjects. 


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11.5 
Quality Control and Quality Assurance 
Quality control procedures will be conducted according to the Sponsor and CRO’s internal 
procedures. The study site may be audited by a quality assurance representative of the Sponsor. 
All necessary data and documents will be made available for inspection along with any required 
study staff. 


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12.0 
REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS 
The study will be performed in accordance with the requirements of the US FDA, any other 
governing regulatory bodies, and will also meet all of the requirements of ICH GCP guidance. 
Amendments to the protocol will be submitted to FDA/other governing regulatory body prior to 
implementation in accordance with applicable regulations. 
12.1 
Good Clinical Practice 
The study will be performed in accordance with the protocol, guidelines for GCP established by 
the ICH, and applicable local regulatory requirements and laws. 
12.2 
Institutional Review Board/Independent Ethics Committee 
The Investigator must inform and obtain approval from the IRB/EC for study conduct at named 
sites, the protocol, informed consent documents, and any other written information that will be 
provided to the subjects and any advertisements that will be used. Written approval must be 
obtained prior to recruitment of subjects and shipment of study drugs. 
Proposed amendments to the protocol (see Section 10.6) and aforementioned documents must be 
submitted to the Sponsor for review and approval, then to the IRB/EC. Amendments may be 
implemented only after a copy of the approval letter from the IRB/EC has been transmitted to the 
Sponsor. 
Per GCP guidelines, the Investigator will be responsible for ensuring that an annual update is 
provided to the IRB/EC until the study is completed (i.e., finalization of the clinical study report) 
to facilitate continuing review of study conduct and that the IRB/EC is informed about the end of 
the study. Copies of the update, subsequent approvals, and final letter must be sent to the 
Sponsor. 
In addition to IRB/EC and regulatory authority approval, all other required approvals (e.g., 
approval from the local research and development board or scientific advisory committee) will 
be obtained prior to recruitment of subjects and shipment of study drugs. 
12.3 
Informed Consent 
Informed consent is a process that is initiated prior to the subject’s agreeing to participate and 
continues throughout the subject’s study participation. It is the Investigator’s (or designee’s) 
responsibility to obtain written informed consent from each subject or their LAR after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards before any study 
procedures are initiated. Each subject or LAR must be given a copy of the signed informed 
consent documents and associated materials. The original copy of the signed and dated informed 
consent documents must be retained at the site and is subject to inspection by representatives of 
the Sponsor or regulatory authorities. If any amendments affect the informed consent form (e.g., 
when new study procedures or assessments have been added), all active subjects and LARs must 
be reconsented using the same process for the initial consent. 


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12.4 
Subject Confidentiality 
The Investigator must ensure that the subject’s privacy is maintained. On eCRFs and other 
documents submitted to the Sponsor, subjects will be identified by their assigned subject number 
only and any other information that may reveal the subject’s identity must be redacted (e.g., first, 
and last name). Documents that are not submitted to the Sponsor (e.g., signed informed consent 
documents) must be kept in a confidential file by the Investigator. 
The Investigator shall permit authorized representatives of the Sponsor, regulatory authorities, 
and IRBs/ECs to review the portion of the subject’s medical record that is directly related to the 
study. As part of the required content of informed consent documents, subjects must be informed 
that their medical records will be reviewed in this manner. 
12.5 
Disclosure of Information 
Information concerning the study, patent applications, processes, scientific data, or other 
pertinent information is confidential and remains the property of the Sponsor. The Investigator 
may only use this information for the purposes of the study. 
It is understood by the Investigator that the Sponsor will use information obtained in this study in 
connection with the clinical development program, and therefore may disclose it as required to 
other clinical Investigators and to regulatory authorities. In order to allow the use of the 
information derived from this study, the Investigator understands the obligation to provide 
complete test results and all data obtained to the Sponsor. 
Verbal or written discussion of results prior to study completion and full reporting must be 
undertaken only with written consent from the Sponsor. 
12.6 
Publication of Study Data 
The Sponsor encourages the scientific publication of data from clinical research studies. 
However, an Investigator(s) many not present or publish partial or complete study results without 
participation and written agreement of the Sponsor. The Investigator and the Sponsor may 
propose appropriate scientific manuscripts or abstracts from the study data. All proposed 
publications must be reviewed and commented on by the Sponsor before submission for 
publication. The detailed procedures for the review of publications are set out in the clinical trial 
agreement entered into with the Sponsor in connection with this study. These procedures are in 
place to ensure coordination of study data publication and adequate review of data for 
publication against the validated study database for accuracy. 
Qualification of authorship will follow the requirements of the International Committee of 
Medical Editors (www.icmje.org). The names of Investigators and Sponsor representatives 
responsible for designing the study and analyzing the results will be included in the 
publication(s). This custom can be adjusted upon mutual agreement of the authors and Vedanta. 
In addition, other than clinical pharmacology studies in healthy volunteers or Phase 1 trials, all 
clinical trials must be registered with ClinicalTrials.gov. 


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12.7 
Ethical Standards 
The Sponsor is committed to designing, implementing, conducting, analyzing, and reporting this 
trial in compliance with the highest ethical and scientific standards. Protection of subject safety 
is the overriding concern in the design of clinical trials. In all cases, Vedanta clinical trials will 
be conducted in compliance with local and/or national regulations and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki. 


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13.0 
REFERENCES 
1. 
Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the 
United States. N Engl J Med 2015; 372(9):825-34. 
2. 
Gould CV, McDonald LC. Bench-to-bedside review: Clostridium difficile colitis. Crit 
Care 2008; 12(1):203. 
3. 
Surawicz CM, Brandt LG, Binion DG, et al. Guidelines for diagnosis, treatment, and 
prevention of Clostridium difficile infections. Am J Gastroenterol 2013; 108(4):478-98; 
quiz 499. 
4. 
Bakken JS, Borody T, Brandt LG, et al. Treating Clostridium difficile infection with fecal 
microbiota transplantation. Clin Gastroenterol Hepatol 2011; 9(12):1044-9. 
5. 
Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med 2015; 
372(16):1539-48. 
6. 
Tonna I, Welsby PD. Pathogenesis and treatment of Clostridium difficile infection. 
Postgrad Med J 2005; 81(956):367-9. 
7. 
McDonald LC, Gerding DN, Johnson S, et al. IDSA Guideline. Clinical practice 
guidelines for Clostridium difficile infection in adults: 2017 update by the Society for 
Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of 
America (IDSA). Clin Infect Dis 2018: 66; e1-e48. 
8. 
Poutanen SM, Simor AE. Clostridium difficile-associated diarrhea in adults. CMAJ 2004; 
171(1):51-8. 
9. 
Louie TJ, Cannon K, Byrne B, et al. Fidaxomicin preserves the intestinal microbiome 
during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin 
reexpression and recurrence of CDI. Clin Infect Dis 2012; 55 Suppl 2:S132-42. 
10. 
Cornely OA, Crook DW, Esposito R, 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):281-9. 
11. 
Kyne L, Kelly CP. Recurrent Clostridium difficile diarrhoea. Gut 2001; 49(1):152-3. 
12. 
Figueroa I, Johnson S, Sambol SP, et al. Relapse versus reinfection: recurrent 
Clostridium difficile infection following treatment with fidaxomicin or vancomycin. 
Clin Infect Dis 2012; 55 Suppl 2:S104-9. 


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13. 
Barbut F, Richard A, Hamadi K, et al. Epidemiology of recurrences or reinfections of 
Clostridium difficile-associated diarrhea. J Clin Microbiol 2000; 38(6):2386-8. 
14. 
Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota 
transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. 
Clin Infect Dis 2011; 53(10):994-1002. 
15. 
Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of 
Clostridium Difficile infection in immunocompromised patients. Am J Gastroenterol 
2014;109(7):1065-71. 
16. 
Minot SS, Krumm N, Greenfield B. One Codex: A sensitive and accurate data platform 
for genomic microbial identification. BioRxiv 2015. 
17. 
Buffie CG, Bucci V, Stein RR, et al. Precision microbiome reconstitution restores bile 
acid mediated resistance to Clostridium difficile. Nature 2015; 517(7533):205-8. 
18. 
Buffie CG, Pamer EG. Microbiota-mediated colonization resistance against intestinal 
pathogens. Nat Rev Immunol 2013; 13(11):790-801. 
19. 
Itoh K, Lee WK, Kawamura H et al. Intestinal bacteria antagonistic to Clostridium 
difficile in mice. Lab Anim 1987; 21(1):20-25. 
20. 
Wilson KH, Perini F. Role of competition for nutrients in suppression of Clostridium 
difficile by the colonic microflora. Infect Immun 1988; 56(10):2610-4. 
21. 
Martz SL, Guzman-Rodriguez M, He SM, et al. A human gut ecosystem protects against 
C. difficile disease by targeting TcdA. J Gastroenterol 2017; 52(4):452-65. 
22. 
Sommer MO, Dantas G, Church GM. Functional characterization of the antibiotic 
resistance reservoir in the human microflora. Science 2009; 325(5944):1128-31. 
23. 
Ghosh TS, et al. In silico analysis of antibiotic resistance genes in the gut microflora of 
individual from diverse geographies and age-groups. PLos One 2013; 8(12):e83823. 
24. 
Atarashi K, Tanoue T, Oshima K, et al. Treg induction by a rationally selected mixture of 
Clostridia strains from the human microbiota. Nature 2013; 500(7461):232-6. 
25. 
Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the 
differentiation of colonic regulatory T cells. Nature 2013; 504(7480):446-50. 
26. 
Jia B, Raphenya AR, Alcock, et al. CARD 2017: expansion and model-centric curation of 
the comprehensive antibiotic resistance database. Nucleic Acids Res 2017; 45(D1):D566-
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27. 
Best EL, Freeman J, Wilcox MH. Models for the study of Clostridium difficile infection. 
Gut Microbes 2012; 3(2):145-67. 
28. 
Smits WK, Lyras D, Lacy DB, Wilcox MH, Kuijper EJ. Clostridium difficile infection. 
Nat Rev Dis Primers 2016; 2:16020. 
29. 
Hutton ML, Mackin KE, Chakravorty A, Lyras D. Small animal models for the study of 
Clostridium difficile disease pathogenesis. FEMS Microbiol Lett 2014; 352(2):140-9. 
30. 
Theriot CM, Koumpouras CC, Carlson PE, et al. Cefoperazone-treated mice as an 
experimental platform to assess differential virulence of Clostridium difficile strains. Gut 
Microbes 2011; 2(6):326-34. 
31. 
McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 
163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002; 
97(7):1769-75. 
32. 
Ma GK, Brensinger CM,Wu Q, Lewis, JD. Increasing incidence of multiply recurrent 
Clostridium difficile infection in the United States - A cohort study. Ann Intern Med. 
2017;167:152-158. doi:10.7326/M16-2733. 
33. 
US Department of Health and Human Services. Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0. Published 27 November 2017. Available at: 
<https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_5x7.pdf> Accessed 17 April 2018. 




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APPENDIX 2: 
PROMIS® SCALE QUESTIONNAIRES 
Patient-Reported Outcomes Measurement Information System (PROMIS®) questionnaires (v1.0, 
dated 01 September 2016/v1.1 dated 01 October 2018) will be administered to subjects at the 
time points specified in the protocol. 
The following best practices for administration of the PROMIS® questionnaires must be 
followed: 
• PROMIS® self-reported measures are intended to be completed by the respondent 
without help from anyone else. 
• If respondents are unable to answer on their own, have someone else (“proxy”) report on 
their behalf. Respondents requiring a proxy may include: young children, people in the 
early stages of dementia who may not recognize the extent of their impairment, people 
with cognitive or communication deficits, and people with severe disease burden. 
• Keep respondents’ privacy in mind, but have staff readily available to help with any 
issues that may arise. 
• It is acceptable for staff to define a term (e.g., “nausea”), but not to define a concept 
where the respondent’s subjective interpretation is the goal of the question (e.g., “quality 
of life”). 
• Utilize the same method (e.g., computer, telephone, or paper) and mode (e.g., self vs. 
interviewer) of administration at every time point for every subject, when possible. 
• Provide respondents with the optimal time needed to capture the most relevant 
perspective and complete data (e.g., before/after clinician visit or in between visits). 
 




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SAP_003.pdf: 
 
 
Vedanta Biosciences, Inc. | 19 Blackstone Street, Cambridge MA 02139 | 857-706-1427 
 
 
Phase 2 Study of VE303 for Prevention of Recurrent Clostridioides Difficile Infection 
 
 
NCT03788434 
 
 
Submitter: Isabella Newbert– Clinical Trial Associate at Vedanta Biosciences 
 
 
Included in this submission:  
Redacted Statistical Analysis Plan (Version 2.0 15JUL21) 
 
 
Document Date: 15JUL21 
 
 
 
 
 
 
 
 
 
 
 
 
 






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Page 3 of 44 
TABLE OF CONTENTS 
APPROVALS .................................................................................................................. 2 
TABLE OF CONTENTS .................................................................................................. 3 
1. 
GLOSSARY OF ABBREVIATIONS ........................................................................ 6 
2. 
PURPOSE ............................................................................................................... 8 
2.1. 
Responsibilities ................................................................................................................................. 8 
2.2. 
Timings of Analyses .......................................................................................................................... 8 
3. 
STUDY OBJECTIVES ............................................................................................. 9 
3.1. 
Primary Objective............................................................................................................................. 9 
3.2. 
Secondary Objectives ........................................................................................................................ 9 
3.3. 
Brief Description ............................................................................................................................... 9 
3.3.1. 
Study Design ................................................................................................................................. 9 
3.3.2. 
Changes in Analyses from Original Protocol ................................................................................... 11 
3.4. 
Subject Selection ............................................................................................................................. 12 
3.5. 
Determination of Sample Size ......................................................................................................... 12 
3.6. 
Treatment Assignment & Blinding .................................................................................................. 12 
3.7. 
Schedule of Assessments and Procedures ........................................................................................ 14 
4. 
ENDPOINTS .......................................................................................................... 17 
4.1. 
Primary and Secondary Efficacy Endpoints .................................................................................... 17 
4.2. 
Safety Endpoints ............................................................................................................................. 17 
4.3. 
Pharmacodynamic and pharmacokinetic Endpoints ........................................................................ 17 
5. 
ANALYSIS POPULATION .................................................................................... 18 
5.1. 
Full Analysis Set (FAS) ................................................................................................................... 18 
5.2. 
Per-Protocol Analysis Set (PPS) ...................................................................................................... 18 
5.3. 
Safety Analysis Set (SAS) ................................................................................................................ 18 


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5.4. 
Protocol Deviations ......................................................................................................................... 18 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ........................................ 20 
6.1. 
General Methods............................................................................................................................. 20 
6.2. 
Key Definitions ............................................................................................................................... 21 
6.2.1. 
Study Day .................................................................................................................................... 21 
6.2.2. 
Baseline Values ............................................................................................................................ 21 
6.2.3. 
Completion of Study ..................................................................................................................... 21 
6.3. 
Missing Data ................................................................................................................................... 21 
6.4. 
Analysis Visit Windows ................................................................................................................... 21 
6.5. 
Study drug exposure ....................................................................................................................... 22 
6.6. 
Pooling of Sites ................................................................................................................................ 22 
6.7. 
Pooling of Placebo ........................................................................................................................... 22 
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..................................... 23 
7.1. 
Subject Disposition and Withdrawals .............................................................................................. 23 
7.2. 
Demographic and Other Baseline Disease Characteristics ............................................................... 23 
7.3. 
Medical History .............................................................................................................................. 23 
7.4. 
Prior and Concomitant Medication ................................................................................................. 24 
7.4.1. 
Antibiotic Medication ................................................................................................................... 24 
8. 
EFFICACY ............................................................................................................. 25 
8.1. 
Primary Efficacy Endpoint and Analysis ......................................................................................... 25 
8.1.1. 
Sensitivity Efficacy Analyses ........................................................................................................ 26 
8.2. 
Secondary Efficacy Analyses ........................................................................................................... 27 
8.2.1. 
Recurrence of CDI up to 4, 12, and 24 Weeks Post-Treatment ......................................................... 27 
8.2.2. 
Time to Recurrence of CDI ........................................................................................................... 27 
8.3. 
Exploratory Analyses ...................................................................................................................... 27 
8.3.1. 
Microbiological Outcomes ............................................................................................................ 27 
8.4. 
Interim Analysis.............................................................................................................................. 28 
8.5. 
Handling of Missing Data ................................................................................................................ 28 
9. 
SAFETY ................................................................................................................. 29 


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9.1. 
Extent of Exposure and Treatment Compliance .............................................................................. 29 
9.2. 
Adverse Events ............................................................................................................................... 29 
9.3. 
Laboratory Evaluations .................................................................................................................. 31 
9.3.1. 
Stool Assessment ......................................................................................................................... 32 
9.4. 
Vital Signs ....................................................................................................................................... 33 
9.5. 
ECG ................................................................................................................................................ 33 
9.6. 
Physical Examination ...................................................................................................................... 33 
9.7. 
Gastrointestinal Symptoms Self-Administered Questionnaire - PROMIS® ...................................... 33 
10. 
CHANGES FROM ANALYSIS PLANNED IN PROTOCOL ............................... 35 
11. 
PROGRAMMING CONSIDERATIONS .............................................................. 36 
11.1. 
General Considerations ................................................................................................................... 36 
11.2. 
Table, Listing, and Figure Format .................................................................................................. 36 
11.2.1. 
General ................................................................................................................................... 36 
11.2.2. 
Headers ................................................................................................................................... 37 
11.2.3. 
Display Titles .......................................................................................................................... 37 
11.2.4. 
Column Headers ...................................................................................................................... 37 
11.2.5. 
Body of the Data Display .......................................................................................................... 38 
11.2.6. 
Footnotes ................................................................................................................................ 40 
12. 
QUALITY CONTROL ......................................................................................... 41 
13. 
ADMINISTRATIVE INTERIM ANALYSES ......................................................... 42 
13.1. 
Efficacy Analysis ............................................................................................................................. 42 
13.1.1. 
Primary Variable: Recurrence Rate before or at Week 8 .............................................................. 42 
13.1.2. 
Sensitivity Efficacy Analysis on Primary Variable ...................................................................... 43 
13.1.3. 
Secondary Variable: Time to CDI Recurrence Before or at Week 8 .............................................. 43 
13.2. 
Safety Analysis ................................................................................................................................ 44 
13.3. 
Unblinding and blinding ................................................................................................................. 44 
13.4. 
Stopping Rule ................................................................................................................................. 44 
 






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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary 
tables, and figures which will be produced, and the statistical methodologies that will be used, 
are complete and appropriate to allow valid conclusions regarding the study objectives. 
This SAP is based on protocol VE303-002, Version 7.0, dated 15 July 2021 and its associated 
electronic case report forms (eCRF) Version 6.0, dated 08 July 2020. 
This SAP may contain modifications to the analysis plans described in the protocol, and thus 
serve as the overriding document describing the statistical analysis to be performed. Any changes 
from the SAP will be presented in the Clinical Study Report (CSR). 
2.1. 
RESPONSIBILITIES 
 will perform the statistical analyses and is responsible for the production and 
quality control of all tables, figures, and listings (TLFs). 
2.2. 
TIMINGS OF ANALYSES 
Besides the final analysis for the CSR, there are 3 interim analyses (IAs) planned for study 
administrative purposes only, to provide input to Vedanta senior management regarding business 
and development strategy. The results of the administrative IAs will not have any impact on the 
design or conduct of the protocol. These 3 administrative IAs will be performed after at least 24 
subjects complete 8 weeks of the study, after at least 39 subjects complete 8 weeks of the study, 
and after at least 54 subjects complete 8 weeks of the study. 


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3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
The primary objective is to determine a recommended VE303 dose regimen(s) for evaluation in a 
Phase 3 study based on safety and efficacy, as indicated by the Clostridioides difficile 
(C. difficile) infection (CDI) recurrence rate. 
3.2. 
SECONDARY OBJECTIVES 
Secondary objectives are to characterize VE303 colonization and changes in the fecal 
microbiome. 
3.3. 
BRIEF DESCRIPTION 
3.3.1. 
Study Design 
As designed, VE303-002 is a Phase 2, randomized, parallel-arm, double-blind, placebo-
controlled, dose-selection study to evaluate the safety, microbiota changes, and efficacy of 
VE303 in the prevention of subsequent CDI-associated diarrhea compared with placebo 
following completion of a successful course of standard-of-care (SOC) antibiotics for subjects 
with primary C. difficile infection (pCDI) at high risk for recurrence or subjects with recurrent 
C. difficile infection (rCDI). 
Eligible subjects are randomized into 4 treatment groups in a 2:1:2:1 ratio to receive VE303 high 
dose (10 capsules): placebo high dose (10 capsules): VE303 low dose (2 capsules): placebo low 
dose (2 capsules), respectively.  
The following is the design of the study, per Study Protocol v6.0, dated 18 September 2019. 
Approximately 146 to 300 subjects were anticipated for enrollment, depending on results of an 
IA and sample size re-estimation (SSR), which was planned to be performed when safety and 
efficacy data up to and including the Week 8/Day 56 follow-up visit were available for at least 
62 evaluable subjects. 
A data monitoring committee (DMC), which includes independent clinicians with knowledge of 
the target population, a biostatistician, and Sponsor representatives, was established to review 
accruing results and safety and to make recommendations based on results of the IA and SSR. 
Investigators and study subjects will remain blinded for the duration of the study period. 
Similarly, the Sponsor study clinical operations team that interacts with the sites and the database 
remain blinded until the final analysis dataset is cleaned and unblinded. 
The DMC was to be unblinded for the IA to allow for analysis of results (safety and efficacy) 
and to provide a recommendation to potentially discontinue one of the VE303 dosing arms based 
on safety and/or an observed lack of efficacy, and/or to potentially increase the sample size.  


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As described in the protocol, some members of the Sponsor team were to be unblinded after an 
IA to enable dose selection decisions and/or possible changes in the overall development plan for 
VE303, as outlined in the protocol’s statistical methods and DMC Charter.  
If the decision were made to drop an inferior VE303 dose treatment arm based on the IA, 
enrollment into that arm was to stop but subjects already randomized to that arm were to 
continue on study with no change to their treatment. 
Randomization per Version 6 of the protocol was to assign subjects into stratification groups by:  
• number of previous CDI episodes at Baseline (0 vs ≥ 1 episodes, excluding the 
qualifying episode; i.e., Inclusion criterion 2a vs 2b/2c subjects) 
• SOC antibiotic treatment received (non-vancomycin [fidaxomicin or metronidazole] 
or an alternative oral vancomycin dosing regimen vs the standard four-times-per-day 
(QID) vancomycin dosing [this category will include subjects who receive 
vancomycin QID on at least the last day of treatment]), and 
• results of CDI laboratory diagnostic method (free toxin [enzyme immunoassay (EIA) 
for Toxin A/B or cell cytotoxicity neutralization assay (CCNA)] vs other [polymerase 
chain reaction (PCR)/cytotoxic culture if enzyme immunoassay (EIA) for Toxin A/B 
and/or CCNA results are negative or not available]). 
Note that prior to Version 6 of the protocol, the randomization stratification was defined as: 
• Per Version 2 of the protocol, stratification by two age groups (≤ 65 years and 
> 65 years) and by number of previous CDI episodes at Baseline (2 to 3 and > 3 
occurrences, inclusive of the qualifying episode).  
• Per Version 3 of the protocol, stratification by age group (≤ 65 years and > 65 years), 
by number of previous CDI episodes at Baseline (2 to 3 and > 3 occurrences, 
inclusive of the qualifying episode), and by SOC antibiotic treatment received (non-
vancomycin [fidaxomicin or metronidazole] or tapered vancomycin vs vancomycin 
QID). 
• Per Version 4 of the protocol, Stratification by age group (≤ 65 years and > 65 years), 
by number of previous CDI episodes at Baseline (2 to 3 and > 3, inclusive of the 
qualifying episode), and SOC antibiotic treatment (non-vancomycin [fidaxomicin or 
metronidazole] or an alternative vancomycin dosing regimen vs vancomycin QID 
[subjects receiving vancomycin QID on at least the last day of treatment]). 
• Per Version 5 of the protocol, stratification by 1) number of previous CDI episodes at 
Baseline (0 vs ≥ 1 episodes, excluding the qualifying episode; i.e., Inclusion criterion 
2a vs 2b/2c subjects), and 2) by SOC antibiotic treatment received (non-vancomycin 
[fidaxomicin or metronidazole] or an alternative vancomycin dosing regimen vs 
vancomycin QID) 
 




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Note: a data cut-off for each Administrative IA pertains to Week 8 of last randomized subject in 
the group. 
 
Original 
Plan 
Revised 
Plan 
Comments 
Total Sample Size 
140-300 
Approximately 
60 to 80 
 
Admin IA#1 
N/A 
Minimum 24  
 
IA#1 SSR 
62 
N/A 
SSR not to be performed under revised 
plan 
Admin IA#2 
N/A 
Minimum 39  
 
Admin IA#3 
N/A 
Minimum 54  
 
 
This updated version of the SAP provides more detail on the approach for the administrative IAs, 
in addition to the final analyses, which are intended to understand the safety and clinical activity 
of VE303. The goal of the administrative analyses and final analysis is to define future 
development steps for VE303 in patients with rCDI, beyond this ongoing Phase 2 trial. The 
administrative analyses do not change the design, objectives, endpoints, or conduct of this 
Phase 2 study. The intent is to guide future business strategy and inform potential design of 
subsequent pivotal trials.  
No unblinded data will be reviewed by those with day-to-day interactions for the trial (e.g., the 
DMC, investigators, Study Steering Committee, medical monitors, contract research 
organization [CRO] or the Vedanta project team) as a result of this strategy change.  
3.4. 
SUBJECT SELECTION 
Inclusion and exclusion criteria for study entry must be met prior to screening and 
randomization. See Section 5.0 of the protocol for the most recent list of eligibility criteria. 
3.5. 
DETERMINATION OF SAMPLE SIZE 
The original protocol was based on a planned 2-stage adaptive design with potential for sample 
size increase, where the total sample size was expected to range from 124 to 255 evaluable 
subjects (approximately 146 to 300 randomized subjects, accounting for a 15% non-evaluable 
rate) depending on whether the sample size was to be increased after interim analysis.  
As per Section 3.3.2, a total revised sample size of approximately 60 to 80 subjects was deemed 
appropriate for the study in view of poor enrollment and external events from the pandemic. 
3.6. 
TREATMENT ASSIGNMENT & BLINDING 
On the last planned day of SOC antibiotic administration for a qualifying CDI episode, or no 
later than 1 day after completion of antibiotic dosing, eligible subjects will be randomized into 
4 treatment groups in a 2:1:2:1 ratio to receive 1 of 2 placebo doses or 1 of 2 VE303 doses daily 


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for 14 consecutive days as outlined in Table 3-1. Each study dose will comprise 2 or 10 capsules 
per day administered orally (see protocol Section 6.3). Subjects will ingest the first dose in the 
clinic on Day 1 and subjects will remain at the study site for at least 30 minutes after the first 
dose for monitoring of potential adverse events (AEs).  
Table 3-1: Planned Study Arms 
Study Arm 
VE303 Daily 
Dose 
VE303 Total Dose 
Over 14 Days 
Number of Capsules 
Ingested Per Day 
(Active/Placebo) 
VE303 (low) 
1.6 × 109 CFU 
2.2 × 1010 CFU 
2 (2/0)  
VE303 (high) 
8.0 × 109 CFU 
1.1 × 1011 CFU 
10 (10/0) 
Placebo (“low”) 
Not applicable 
Not applicable 
2 (0/2) 
Placebo (“high”) 
Not applicable 
Not applicable 
10 (0/10) 
Abbreviations: CFU = colony-forming unit(s) 
Randomization will be used to avoid bias in the assignment of subjects to double-blind treatment 
(VE303 or placebo) and to increase the likelihood that known and unknown subject 
characteristics will be evenly distributed between the treatment groups. 
After all Screening procedures and assessments have been performed and eligibility has been 
confirmed on Day 1, a centralized Interactive Web Response System will assign each subject a 
randomization number and subjects will receive study drug.  
Investigators and subjects will remain blinded for the duration of the study period. 
Unblinding of study drug assignment may be requested in an emergency if unblinding is 
considered necessary for the medical management of a subject. The Investigator will discuss the 
circumstances for the requested unblinding with the Sponsor’s Medical Monitor. Emergency 
unblinding without the Medical Monitor’s input should occur only if knowledge of study drug 
assignment will affect the immediate workup or treatment of an AE. Communications related to 
unblinding will be documented, including the date, time, and reason for the requested 
unblinding. 
 


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3.7. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
The Schedule of Events per Table 7-1 in protocol v6 is as follows: 
 
 
Screening: 
Start of SOC 
Antibioticsa, b 
Study Drug Administration Period 
Postdose Follow-Up Period 
Study Day 
 
Assessmentc 
-22 
 
1d 2–6q 
 
7 
 
8–13q 
 
14 
(+ 1 day)/ 
EOT 
28 
(± 3 days) 
(Week 4) 
56 
 (± 3 days) 
(Week 8) 
84 
(± 7 days) 
(Week 12) 
112 
(± 7 days) 
(Week 16) 
140  
(± 7 days) 
(Week 20) 
 
168 
(± 7 days) 
(Week 
24/EOS/ET) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility criteria 
X 
Xk 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Medications e 
X 
Physical examination f 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight g 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
Vital signs h 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
12-lead ECG i 
X 
 
 
 
 
 
X 
 
 
 
 
 
Hematology/Chemistry 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
Exploratory serum 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
X 
 
 
 
 
 
 
Pregnancy test j 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization k 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug dosing c, l 
 
X 
 
 
 
 
 
 
C. difficile testing m, n 
Xm 
 
 
 
 
 
 
 
 
 
 
 
Stool microbiota composition n 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
VE303 detection n 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
Antibiotic resistance gene detection n 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
Stool antibiotic concentrations n 
 
X 
 
X 
 
 
 
 
 
 
 
 
Stool metabolomics evaluation n 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
Glycerol-preserved stool culture n 
 
 X 
X 
 
 
 
X 
 
X 
 
 
 
X 


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Screening: 
Start of SOC 
Antibioticsa, b 
Study Drug Administration Period 
Postdose Follow-Up Period 
Study Day 
 
Assessmentc 
-22 
 
1d 2–6q 
 
7 
 
8–13q 
 
14 
(+ 1 day)/ 
EOT 
28 
(± 3 days) 
(Week 4) 
56 
 (± 3 days) 
(Week 8) 
84 
(± 7 days) 
(Week 12) 
112 
(± 7 days) 
(Week 16) 
140  
(± 7 days) 
(Week 20) 
 
168 
(± 7 days) 
(Week 
24/EOS/ET) 
Stool culture for whole genome 
sequencing n 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
Stool/fecal calprotectin extraction n 
 
X 
 
 
 
X 
X 
X 
 
 
 
X 
PROMIS® questionnaire o 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Adverse events p 
X 
Telephone follow-up  
 
X q 
 
 
X 
X 
X 
 
Abbreviations: AE = adverse event; CDI = C. difficile infection; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; LAR = legally authorized representative; 
PCR = polymerase chain reaction; SOC = standard of care; ET = Early Termination 
a Once identified as potential study candidates, subjects or their LAR will sign an informed consent form to enable collection of a stool sample to confirm the qualifying event of 
CDI recurrence in accordance with eligibility criteria. 
b Upon confirmation of CDI recurrence, subjects will be evaluated for eligibility criteria. 
c All tests/assessments scheduled on in-clinic dosing days will be performed prior to study drug administration. 
d Day 1 (i.e., the day of the first dose of study drug) is the beginning of the study drug administration period, which will begin on the last planned day of SOC antibiotic 
administration for a qualifying CDI episode, or no later than 1 day after completion of antibiotic dosing. Day 1 tests/assessments will be considered baseline. The Screening 
results must be available for confirmation of eligibility. Vital signs and physical examinations should be performed on Day 1; tests/assessments must be performed prior to 
study drug administration. 
e Medications administered within 14 days prior to Screening and/or on study will be recorded continuously for the duration of each subject’s study participation. 
f 
A complete physical examination will be performed during Screening; subsequent physical examinations must include abdominal examinations performed by the study 
physician, with limited symptom-directed examinations performed for other organ systems. 
g To be collected in the same manner each time – without heavy items/shoes/bulky clothing. 
h Includes pulse, blood pressure, and body temperature. Subjects are required to remain in the supine position for at least 3 minutes prior to obtaining vital signs. On Day 1, vital 
signs will be measured prior to administration of study drug. 
i 
Additional ECGs may be performed if clinically indicated. 
j 
For females of childbearing potential, serum pregnancy testing will be performed during Screening; a rapid urine pregnancy test will be performed at the study site on Day 1 
prior to administration of study drug. 
k After all Screening assessments and procedures have been performed and eligibility has been confirmed on Day 1, subjects will be randomized and receive the first dose of 
blinded study drug. 
l 
The study drug administration period is from Day 1 to Day 14, inclusive. On Day 1, study drug will be administered under the supervision of study personnel, and subjects will 
remain at the study site for at least 30 minutes after the first study drug dose for monitoring of potential AEs. On Day 1, the subject diary will be given to each subject and the 
subject will be instructed to complete the diary for study drug accountability and compliance. 


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m A stool sample or documentation of recent C. difficile testing must be collected and/or submitted as soon as a potential qualifying CDI episode is identified. Ideally, this sample 
will be obtained prior to starting SOC antibiotics for CDI; however, if SOC antibiotics have been started, the stool sample must be collected no later than 72 hours after the first 
antibiotic administration. Every effort must be made to collect the diagnostic sample before SOC antibiotic therapy or within 24 hours after SOC antibiotic therapy initiation, 
whenever possible. Samples collected as part of SOC within this window may be submitted for the purpose of C. difficile diagnosis. Diagnostic tests may be performed at the 
local laboratory or at the central laboratory. Subjects with a positive test (either EIA for Toxin A/B or PCR or CCNA or toxigenic culture assay performed at the local 
laboratory or at the central laboratory) may be enrolled in the study. Confirmation of a positive local test by the central laboratory test is not required for subject enrollment, 
provided documentation of a local positive test is available. To ensure subjects are allocated to a proper stratum, an effort should be made to obtain and send a stool sample to 
the central laboratory for confirmation of toxin or toxigenic C. difficile prior to randomization. 
n Stool samples must be sent to a central laboratory. The Day 1 stool sample must be collected prior to administration of any study drug. This sample should be collected predose 
on Day 1, if possible; however, if a subject cannot produce a stool sample predose on Day 1, a sample from up to 24 hours prior to Day 1 may serve as the Day 1 sample. 
Thereafter, if a subject cannot produce a stool sample on the planned day of a clinic visit or at the time of diarrhea that may indicate CDI recurrence (see Section 9.3.1 of the protocol), 
then a stool sample may be obtained within ± 24 hours of the visit/diarrhea event. However, if CDI recurrence is suspected after ingestion of the first dose of study drug, all 
attempts should be made to collect a stool sample before administration of antibiotics to treat the recurrence. 
o PROMIS® gastrointestinal symptom questionnaires (see Appendix 3 of the protocol) are to be completed by each subject or LAR before the first dose of study drug on Day 1. 
Subsequently, questionnaires should be completed on Days 7 and 14. All attempts must be made to have questionnaires completed at approximately the same time of day at 
every time point. 
p AEs will be collected continuously from the time of informed consent through Week 24/Day 168. 
q Study personnel will telephone outpatient subjects daily during the 14-day study drug administration period to ensure dosing compliance; explore any concerns or issues with 
study drug ingestion, administration, handling or storage; capture potential AEs; review potential C. difficile-associated symptoms and assess the need for an unscheduled visit 
or stool test for CDI; remind subjects to collect stool to bring to their next clinic visit (if applicable); and answer any questions that the subject may have. If a subject is 
inpatient or attending a site visit on a scheduled telephone follow-up day, this contact will be performed in person, when possible. Telephone follow-up may be omitted on 
weekends or public holidays if this is necessary for logistical reasons. If a subject is discovered to have had an SAE or a recurrence of diarrhea at any time, an unscheduled visit 
must be arranged as soon as possible. 
 
 
 
 


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4. 
ENDPOINTS 
4.1. 
PRIMARY AND SECONDARY EFFICACY ENDPOINTS 
The primary efficacy endpoint is the proportion of subjects with CDI recurrence before or at 
Week 8 (i.e., 8 weeks after the first dose of study drug). See Section 8.1, Primary Efficacy 
Endpoint and Analysis, for more details regarding the definition of an on-study CDI recurrence. 
Secondary endpoints include the proportion of subjects without:  
• CDI recurrence before or at Week 4 (4 weeks after the first dose of study drug) 
• CDI recurrence before or at Week 12 (12 weeks after the first dose of study drug) 
• CDI recurrence before or at Week 24 (24 weeks after the first dose of study drug) 
 
4.2. 
SAFETY ENDPOINTS 
• Incidence of AEs 
• Laboratory results 
• Vital signs 
• Electrocardiogram (ECG) 
• Physical examination findings 
 
4.3. 
PHARMACODYNAMIC AND PHARMACOKINETIC ENDPOINTS  
Pharmacodynamic and pharmacokinetic endpoints include: 
• Fecal VE303 component bacteria colonization abundance and duration 
• Changes in fecal microbiota diversity and taxonomic composition 
• Changes in the fecal metabolomic profile, including short chain fatty acids and bile 
acids 
 
 
 
 
 
 


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5. 
ANALYSIS POPULATION  
5.1. 
FULL ANALYSIS SET (FAS) 
All subjects who were randomized and received at least 1 dose of study drug. Subjects will be 
classified according to the planned study drug assignment. The FAS will be the default analysis 
set for all efficacy analyses, unless otherwise specified. 
5.2. 
PER-PROTOCOL ANALYSIS SET (PPS) 
All subjects in the FAS who had no major protocol deviations. The PPS will be used for the 
primary and secondary efficacy endpoint analyses. Major protocol violations are defined as those 
that may have a substantial impact on efficacy assessments. The criteria to be used for excluding 
subjects from the PPS population will be determined before database lock and will be 
documented. The PPS analysis may be performed only for the primary and secondary efficacy 
endpoints, to provide supportive evidence for efficacy. 
5.3. 
SAFETY ANALYSIS SET (SAS) 
All subjects who were randomized and received at least 1 dose of study drug. Subjects will be 
classified according to the actual study drug assignment. The SAS will be the primary set for the 
analysis of safety data. 
5.4. 
PROTOCOL DEVIATIONS 
Protocol deviations will be identified during monitoring visits, discussions with sites, 
correspondence, manual review of data, and programmatically within the iMedidata RAVE 
Electronic Data Capture system. Protocol deviations for all subjects who signed an informed 
consent will be entered into 
Clinical Trial Management System. The deviation 
categories based on protocol v7.0 are: 
• Violation of inclusion and/or exclusion criteria 
• Violation of the informed consent process 
• Non-compliance with dosing, such as wrong treatment (kit assignment), incorrect 
dose, or not taking all capsules by 4:00pm each day 
• Missing data for the primary endpoints 
• Administration of prohibited concomitant medications  
• Not tracking diarrhea events 
• Not collecting protocol-required samples associated with rCDI 
• Treating subject with SOC antibiotic for an on-study CDI recurrence without a 
positive Toxin A/B or CCNA result (subsequently added as permissible and included 


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in a sensitivity analysis, as described in Section 17.1.2 of SAP v1.0 and Section 
14.1.2 of this document) 
• Subjects who develop withdrawal criteria but were not withdrawn 
• Any deviation related to COVID-19 
A protocol deviation is any noncompliance with the clinical study protocol, International 
Conference for Harmonisation (ICH) Good Clinical Practices, or Manual of Procedures 
requirements. The noncompliance may be either on the part of the subject, the Investigator, or 
the study site staff. Deviations must be reviewed by the site, clinical research associate, Sponsor, 
and designee, as appropriate for potential corrective actions development. 
All deviations will be reviewed by Vedanta and 
medical and clinical (including 
statisticians) personnel and classified as either minor or major deviations prior to database lock 
and unblinding. Protocol deviations will be summarized by presenting all incidences of protocol 
deviations counted separately in each deviation category as a major or minor deviation by 
treatment group. The total count of protocol deviations within each treatment group will be used 
as the denominator for percentages in this table. 
A listing of all protocol deviations by subject and deviation category will be provided, indicating 
which are major deviations as determined before unblinding. 


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
• All analyses and summaries will be produced using SAS® version 9.4 (or higher). 
• Descriptive statistics, including the numbers and percentages for dichotomous or 
categorical variables, and the numbers, means, standard deviations, medians, 
minimums, and maximums for continuous variables will be provided. 
• Unless otherwise specified, summaries will be presented for each treatment group 
(VE303 high dose, VE303 low dose, and Placebo), where placebo subjects will be 
from Placebo low dose and Placebo high dose combined. 
• Inferential statistical analyses of the primary and secondary clinical efficacy 
endpoints will be conducted as outlined below. All comparisons will be between each 
VE303 dose versus placebo. 
• Continuous variables will be summarized using the number of subjects with evaluable 
data, mean, standard deviation (SD), median, minimum, and maximum values. The 
same number of decimal places as in the raw data will be presented when reporting 
minimum and maximum, 1 more decimal place than in the raw data will be presented 
when reporting the mean and median, and 2 more decimal places than in the raw data 
will be presented when reporting the SD. 
• Categorical variables will be summarized using the number of observations (n), 
frequency and percentage of subjects. All percentages will be presented as one-
decimal point, unless otherwise specified. Percentages equal to 100 will be presented 
as 100% and percentages will not be presented for zero frequencies. 
• Unless stated otherwise, the percentages will be based on the number of non-missing 
observations, and the header will contain the number of subjects in the treatment 
group.  There will be a row for the number of non-missing observations in the table 
(at each time point, if required) for each variable being summarized.  
• Unless otherwise stated, all formal tests of hypotheses for the primary and secondary 
endpoints will be assessed one-sided at alpha=0.05 to be consistent with the one-sided 
overall power calculations. 
• Any calculated p-values will be presented to 3 decimal places; p-values less than 
0.001 will be presented as ‘p<0.001’ and p-values greater than 0.999 will be 
presented as ‘p>0.999’. 
• All relevant subject data will be included in listings and sorted by treatment, subject 
number, and visit, as applicable, for all randomized subjects. 
• Unscheduled or repeat assessments will not be included in summary tables, unless 
otherwise specified, but they will be included in the subject listings. 


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• All TLFs will include footers that identify the name of the program that created the 
item, together with the date and time on which it was created. Headers will include 
the total number of pages that the presentation contains and, for each page, the 
number of the page within the presentation. 
6.2. 
KEY DEFINITIONS 
6.2.1. 
Study Day 
Study Day 1 is defined as the randomization day. Subsequent days are numbered consecutively 
(Day 2, Day 3, etc.). Before the day of study drug administration, study days are numbered 
sequentially with negative values (Day -2, Day -1, etc.). There is no Day 0. 
6.2.2. 
Baseline Values 
Baseline values will be taken as the last assessments before the first dose of study drug on Day 1. 
In general, these will be taken from the pre-dose assessment on Day 1. 
6.2.3. 
Completion of Study 
A subject will be flagged as having completed the study if the question “Did subject complete 
the study per protocol?” on the End of Study eCRF page is answered as Yes. 
6.3. 
MISSING DATA 
Every effort will be made to collect all data at specified time points according to the schedule of 
study events. Reasons for withdrawal from the study will be recorded on the eCRF. 
See Section 7.4 for imputation of partial dates for prior and concomitant medications. 
See Section 9.2 for imputation of partial dates for adverse events. 
In general, missing values will not be imputed for the primary analysis of the primary efficacy 
endpoint analysis. However, see 8.1 for further imputation rules for treating dropouts as a 
treatment failure (as having a recurrence at Week 8). 
 
6.4. 
ANALYSIS VISIT WINDOWS 
For the primary efficacy endpoint of CDI recurrence before or at Week 8, and secondary 
endpoints of CDI recurrence up to 4 weeks, 12 weeks, and 24 weeks after treatment, CDI 
recurrences will be included in the analyses for the specified endpoints as follows: 
Endpoint 
Recurrences Included in Analysis 
CDI recurrence up to 4 weeks after treatment 
Up to Day 35 


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CDI recurrence up to 8 weeks after treatment 
Up to Day 63 
CDI recurrence up to 12 weeks after treatment 
Up to Day 91 
CDI recurrence up to 24 weeks after treatment 
Up to Day 175 
 
6.5. 
STUDY DRUG EXPOSURE 
Study drug exposure will be summarized as the total number of capsules taken with counts and 
percentages of subjects by treatment group. The summary will be presented for the FAS and SAS 
populations. 
The high dose of VE303 is 10 capsules per day administered orally for 14 days, for a maximum 
VE303 daily dose of 8.0 × 109 colony-forming units (CFU) and a maximum total dose over 
14 days of 1.1 × 1011 CFU. The low dose of VE303 is 2 capsules per day administered orally for 
14 days, for a maximum VE303 daily dose of 1.6 × 109 CFU and a maximum total dose over 
14 days of 2.2 × 1010 CFU. High dose of Placebo is 10 capsules per day administered orally for 
14 days, and low dose Placebo is 2 capsules per day administered orally for 14 days. The first 
dose of the study drug will be administered under study personnel supervision at the Day 1 visit. 
6.6. 
POOLING OF SITES 
All sites will be pooled together for analysis purposes. 
6.7. 
POOLING OF PLACEBO  
For the purposes of both interim and final analyses, the 2 placebo arms will be pooled to 
represent a single treatment group. 


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7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Summary tables for demographics and baseline disease characteristics, medical history, and prior 
and concomitant medication will be summarized by treatment group for the FAS.   
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Summary statistics will tabulate the number and percentage of subjects who are screened, screen 
failures, randomized, received study drug, completed the study, who prematurely discontinued 
the study prior to Weeks 2, 4, 8, 12, 16, 20, and 24, and who prematurely discontinued the study 
overall, together with reasons for discontinuation by treatment group at each of these timepoints. 
The number and percentage of subjects included in each of the analysis populations will be 
presented. No statistical testing will be performed on these data. The number of randomized 
subjects in the FAS of each treatment group will be used as the denominator for percentages. 
A listing of subject disposition will be presented. 
7.2. 
DEMOGRAPHIC AND OTHER BASELINE DISEASE CHARACTERISTICS 
Demographics (age, age group, sex, race, ethnicity, childbearing potential, height, weight, body 
mass index [BMI]) and baseline disease characteristics (number of CDI recurrences prior to and 
including the current episode at baseline, number of previous CDI episodes at Baseline (0 vs ≥1 
episodes, excluding qualifying episodes), SOC antibiotic treatment (non-vancomycin 
[fidaxomicin or metronidazole] or an alternative oral vancomycin dosing regimen vs vancomycin 
QID, and results of CDI laboratory diagnostic method (free toxin or other) will be summarized 
descriptively by treatment group for the FAS and SAS.  
Age group will be categorized as 18 to ≤64 years, 65 to ≤74 years, and ≥75 years old. 
BMI will be calculated using the standard measures of weight in kilograms (kg) and height in 
meters (m) as: 
BMI (kg/m2) = [Weight (kg)]/[Height(m)]2 
Demographic and other baseline disease characteristics will be listed. 
7.3. 
MEDICAL HISTORY 
The number and percentage of subjects with medical history by system organ class (SoC) and 
preferred term (PT) will be produced for subjects in the FAS by treatment group. Medical history 
will be sorted in alphabetical order of SoC and PT using the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary, V21.1. For the summary tables, a subject may appear 
more than once if the subject has more than one medical history finding coded under different 
SoC terms or more than one medical history finding with a different PT under the same SoC 
term. However, the subject will be counted only once in the overall category. 


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A table for CDI medical history will also be presented and include Yes/No counts for “Did 
subject have at least one episode of CDI, prior to the current episode, within the last 6 months” 
and descriptive statistics for the number of CDI recurrences prior to baseline (including current 
episode). 
A by-subject listing with coded SoC and PT along with verbatim eCRF term will also be 
provided. 
7.4. 
PRIOR AND CONCOMITANT MEDICATION 
Prior medications are defined as medications that started before the date of first dose. Any 
medication that started on the first date of dosing will not be considered prior. Concomitant 
medications are defined as all medications (excluding study treatment) taken on or after the first 
date of dosing. This also includes medications ongoing on the first dosing date. Medications that 
started before the date of first dose and are ongoing after the date of first dose will be considered 
as both prior and concomitant. 
Partial start dates in prior and concomitant medications will be imputed with a conservative 
algorithm, to the first day of the month (if missing day) or to the first month of the year (if 
missing month). Partial end dates in prior and concomitant medications will be imputed to the 
last day of the month (if missing day) or the last month of the year (if missing month).   
Prior and concomitant medications will be included in the same listing including a column 
indicating if medication is prior, concomitant, or both. Medications will be coded by using the 
Anatomical Therapeutic Chemical (ATC) classification codes and preferred drug name 
according to the World Health Organization Drug Version SEP2018 GLOBAL B3 dictionary. 
Separate summary tables will be provided for prior and concomitant medications for the FAS, 
presenting the number and percentage of subjects by treatment group, and will be sorted in 
alphabetical order of ATC Level 2 and then by PT in the overall column. For each subject, the 
medication will be counted only once within a given ATC level 2 and only once within a given 
preferred drug name level. A subject may appear more than once if he/she has more than one 
concomitant medication coded under different ATC categories, however, the subject will be 
counted only once in the overall category. 
All medications will be listed. 
7.4.1. 
Antibiotic Medication 
A separate by-treatment summary table and a separate by-subject listing will be provided for 
antibiotic medication taken within 60 days prior to baseline and for concomitant antibiotic 
medication taken in the FAS. 


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8. 
EFFICACY 
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
The primary efficacy endpoint is the proportion of subjects with CDI recurrence before or at 
Week 8 (i.e., 8 weeks after the first dose of study drug). An on-study CDI recurrence is defined 
as an episode of diarrhea consistent with diarrhea due to C. difficile infection, which includes a 
stool sample positive for free toxin (EIA for Toxin A/B or CCNA) per test performed at the local 
laboratory or at the central laboratory. An on-study CDI recurrence may occur at any time after 
administration of the first dose of study drug. 
• If recurrent CDI is suspected, a stool sample must be collected for laboratory 
confirmation. Regardless of the test(s) performed at the local laboratory, samples 
must be collected from all subjects during each episode of diarrhea for CDI testing at 
a central laboratory. 
• After an initial sample is collected for suspected recurrence, it is required to collect 
and submit samples on subsequent day(s) if the laboratory test results are not 
available or negative for free toxin (EIA for Toxin A/B or CCNA) before initiating 
antibiotic therapy. 
The difference in the proportion of subjects with CDI recurrence before or at Week 8 between 
each VE303 treatment group and placebo will be analyzed using a stratified Cochran-Mantel-
Haenszel (CMH) method. Stratification will involve the stratification factors as determined from 
the clinical database, i.e., number of previous CDI episodes at Baseline (0 vs ≥1 episodes, 
excluding qualifying episodes), SOC antibiotic treatment (non-vancomycin [fidaxomicin or 
metronidazole] or an alternative oral vancomycin dosing regimen vs vancomycin QID), and 
results of CDI laboratory diagnostic method (free toxin or other). 
Stratification factors are determined at the time of randomization to randomize subjects to the 
treatment groups. However, in order to assess any possible post-randomization changes to the 
stratification factor values (e.g., the number of previous CDI episodes for a subject determined at 
the time of randomization could have been updated after randomization), a table of 
randomization stratification factors as determined at the time of randomization and as determined 
from the clinical database will be presented by treatment group. Any discrepancies between 
stratification factor values as randomized versus as determined by the clinical database will be 
presented descriptively with counts and percentages by treatment group. 
The number and percentage of subjects with confirmed CDI recurrence, along with 90% C,I will 
also be presented by treatment group descriptively, as well as each VE303 treatment difference 
from placebo, along with 90% CI, for descriptive purposes. This primary efficacy endpoint 
analysis will be presented for the FAS and PPS. 
A similar CDI recurrence rate table as described above will be presented for subjects who were 
exposed to other concomitant antibiotic treatment to treatment infections other than CDI (i.e., not 
used to treat CDI) prior to their CDI recurrence for the FAS. This table will exclude any subject 


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who took an antibiotic other than fidaxomicin, metronidazole, or vancomycin prior to their 
recurrence.   
Subgroup analysis of the primary efficacy endpoint will be presented by age group (18 to ≤64 
years, 65 to ≤74 years, and ≥75 years), and by each of the randomization stratification factors 
using the FAS. 
In addition, the number of subjects with CDI recurrences up to Week 8 presented by 
randomization stratification factor, a tabular summary of testing results (positive, negative, or 
unavailable) for all suspected CDI recurrences, a tabular summary of all diarrhea episodes 
treated with antibiotics, and a table summarizing the number of responders by randomization 
stratum will be presented by treatment group.  
The start date of a CDI recurrence will be defined as follows: 
• If the subject presents on Day X with 8 stools (Bristol type 7) and the central lab Day 
X stool sample is reported after Day X as positive, then the CDI recurrence date is the 
date of Day X 
• If the Day X stool sample is reported as negative but a subsequent stool sample is 
reported as positive sometime after Day X, then the CDI recurrence date should be 
reported as the earliest date for the positive stool test. 
In general, missing values will not be imputed for the primary analysis of the primary efficacy 
endpoint analysis.  However, additional supportive analyses will be performed in which the 
following imputation rules will be applied, with dropouts treated as a failure (as having a 
recurrence at Week 8): 
Put imputation rules here for dropouts treated as failures.  
• Discontinuing early for any reason, including withdrawal of consent: For subjects 
who have not experienced a recurrence prior to Week 8 and who discontinued for any 
reason prior to the Week 8 visit, impute for these subjects a recurrence at Week 8. Per 
the current recurrence counting algorithm applied within the efficacy tables, this 
imputed recurrence at Week 8 will be carried forward to all subsequent weeks in the 
table. 
 
8.1.1. 
Sensitivity Efficacy Analyses 
Sensitivity analyses will be conducted on the following efficacy variables for the FAS and PPS: 
• Sensitivity Analysis I: In addition to the CDI recurrence definition for the primary 
efficacy endpoint, the CDI recurrence definition for Sensitivity I will also include any 
recurrence that was diagnosed with a positive PCR test (including cytotoxicity assay) 
and treated with an antibiotic that targets C. difficile 


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• Sensitivity Analysis II: In addition to the CDI recurrence definition for the primary 
and Sensitivity I efficacy endpoints, the Sensitivity II CDI recurrence definition will 
include any recurrence, in the absence of laboratory confirmation, that is treated with 
an antibiotic that targets C. difficile. 
In addition, Sensitivity I and II analyses will each be presented by age group and for the number 
of subjects with CDI recurrences up to Week 8 by randomization stratification factor for the 
FAS. 
8.2. 
SECONDARY EFFICACY ANALYSES 
8.2.1. 
Recurrence of CDI up to 4, 12, and 24 Weeks Post-Treatment 
The number and percentage of subjects without recurrence of CDI before or at Week 4, 12, and 
24 weeks after start of study drug will each be presented by treatment group for the FAS using 
the same method described for the primary analysis in Section 8.1. 
8.2.2. 
Time to Recurrence of CDI 
For the primary efficacy analysis, as well as for the Sensitivity I and Sensitivity II analyses, the 
time to CDI recurrence will be summarized by treatment group for the FAS only using the 
median and 25th and 75th percentiles from Kaplan-Meier (KM) analysis. The 90% confidence 
intervals (CIs) for the median will also be presented. Subjects who complete the study and do not 
experience a CDI recurrence by the end of the Follow-up Period will be censored on the date of 
last contact. Subjects who are lost to follow-up or who terminated the study prematurely before 
experiencing a CDI recurrence will be censored on the date of last contact. Subjects who die 
before having a CDI recurrence will be censored on the date of death.  
The distributions of time to CDI recurrence for each treatment group will be plotted and the 
differences in these distributions between Placebo and each VE303 treatment group will be 
tested for significance using the stratified log-rank test. The number of subjects at risk and the 
number of subjects with a recurrence event will be presented graphically. The KM method will 
be applied to estimate the curves for each treatment group. Median time to recurrence and 
corresponding 90% CI’s will be calculated and presented in a table. 
8.3. 
EXPLORATORY ANALYSES 
8.3.1. 
Microbiological Outcomes 
Final analysis results from stool microbiota composition and VE303 detection analyses will be 
presented in by-subject listings and graphs and summarized by treatment group and study day. 
The atypical nature and complexity of these analyses requires the use of software tools 
developed by the Sponsor. Any exploratory microbiological analyses not included in the data 
outputs will be reported separately and will not be included in the main CSR. 


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Tabular and/or graphical summaries for the microbiome and VE303 detection analyses will be 
produced for VE303 strain presence, VE303 strain abundance, community diversity (Shannon 
Index, and Species Richness calculations), and relative abundance of all species detected in the 
sample. In addition, an analysis will be performed to evaluate the longitudinal microbiome 
changes within each subject and within each study arm, including changes in diversity over time, 
changes in microbiome species over time grouped by phylum, and changes in VE303 strains 
over time (both presence/absence and relative abundance). 
The Sponsor will also collect serum and stool samples (for stool antibiotic concentrations, 
metabolomics, antibiotic-resistant bacteria other than C. difficile [e.g., carbapenem-resistant 
Enterobacteriaceae (CRE), extended-spectrum beta-lactamase (ESBL), or vancomycin-resistant 
enterococci (VRE)], and culture) from clinical study participants and may analyze them for 
possible exploratory purposes and biomarkers. 
8.4. 
INTERIM ANALYSIS 
Three IAs are planned for administrative purposes only. These 3 administrative IAs will provide 
input to Vedanta management regarding business and development strategy outside of the 
context of this study. The administrative IAs will be performed after at least 24 subjects 
complete 8 weeks of the study, after at least 39  subjects complete 8 weeks of the study, and after 
at least 54  subjects complete 8 weeks of the study. Further details of these administrative IAs are 
described in Section 3.3.2. 
No unblinded review of the efficacy and safety data will be conducted by the independent DMC 
members.   
8.5. 
HANDLING OF MISSING DATA 
In general, missing values for the primary efficacy endpoint will not be imputed. See additional 
details in Section 8.1 for imputation rules for treating dropouts as having a CDI recurrence at 
Week 8. 


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9. 
SAFETY 
All safety analyses will be conducted for the SAS, unless otherwise specified. Subjects will be 
analyzed according to the treatment they actually received, rather than to that which they were 
randomized. Data for placebo subjects will be presented by combining the Placebo High and 
Placebo Low treatment groups. 
9.1. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Exposure will be assessed by treatment group for the total number of capsules taken and for the 
number of days study drug was taken (Last Dose Date – First Dose Date + 1). 
Compliance will be presented descriptively by treatment group for the percentage of subjects 
who were ≥90% in compliance, the percentage of subjects who were 100% in compliance, and 
for the number of missed doses. Compliance will be calculated as: 
Compliance (%) = (Number of capsules taken / Number of expected capsules taken) x 100.  
9.2. 
ADVERSE EVENTS 
Adverse events will be coded using MedDRA V21.1. All treatment-emergent AEs (TEAEs) from 
the start of study drug dosing will be collected. A TEAE is any AE that newly appeared, 
increased in frequency, or worsened in severity following initiation of study drug up to Week 24. 
Serious TEAEs and adverse events of special interest (AESIs) that started on or after start of 
study drug dosing will be considered TEAEs and will be included in separate summary tables 
and listings. 
The following AE summaries will be presented by treatment group: 
• An overall summary table, including the number and percentage of  
o TEAEs 
o TEAEs associated with COVID-19 
o Subjects with at least one TEAE 
o Subjects with no TEAEs 
o Study drug-related TEAEs 
o Subjects with study drug-related TEAEs 
o Serious TEAEs 
o Subjects with serious TEAEs 
o Serious TEAEs related to study drug 
o Subjects with serious TEAEs related to study drug 
o Treatment-emergent AESIs 
o Subjects with treatment-emergent AESIs 
o Treatment-emergent AESIs related to study drug 


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o Subjects with treatment-emergent AESIs related to study drug 
o Severe TEAEs 
o Subjects with severe TEAEs 
o TEAEs leading to study drug discontinuation 
o Subjects with TEAE leading to study drug discontinuation 
o TEAEs leading to death 
o Subjects with TEAEs leading to death 
• TEAEs by SoC and PT 
• Serious TEAEs by SoC and PT 
• Treatment-emergent AESIs by SoC and PT 
• TEAEs leading to study drug discontinuation by SoC and PT 
• TEAEs by SoC, PT, and maximum reported Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 
• Related TEAEs by SoC and PT 
The following subject listings will be provided as a table: 
• Deaths 
• Serious TEAEs  
• AESIs 
• TEAEs leading to study drug discontinuation 
• TEAEs associated with COVID-19 
For all TEAE tables summarized by SoC and PT, a subject contributes only once to the count for 
a given TEAE on the SoC level and on the PT level within SoC. TEAEs will be sorted 
alphabetically, first by SoC and then by PT within the SoC. 
A related AE is defined as a relationship of Definitely Related, Probably Related, Possibly 
Related or missing, and a non-related AE is defined as a relationship of Unlikely, Probably Not 
Related, or Definitely Not Related. 
The following are considered AESIs due to the CDI indication under study and the nature of the 
investigational product (live bacteria) and potential for gastrointestinal or extraintestinal AEs: 
• Any clinically significant (Grade 2 or higher) gastrointestinal AE considered related 
to study drug. 
• Any clinically significant (Grade 2 or higher) bacterial infection considered related to 
study drug. 


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In the summary by maximum severity, subjects reporting AEs at different severities will be 
counted only once at the highest severity reported within an AE level (SoC or PT).  Severity 
categories will include mild, moderate, severe, or medically significant but not immediately 
life-threatening, life-threatening consequences, and death related to AE.  Any missing severity 
will be imputed as severe, which as a result, a subject would be counted as severe due to a 
missing severity, even if the subject reported similar events at a lesser degree of severity. The 
same logic will be applied to the related AEs. 
Partial start dates in AEs will be imputed with a conservative algorithm, to the first day of the 
month (if missing day) or the first month of the year (if missing month). Partial end dates in 
adverse events will be imputed to the last day of the month (if missing day) or the last month of 
the year (if missing month).  All AEs will be assigned on a worse case basis to TEAEs. For 
example, if the start date of an AE is missing or incomplete, it will be assumed to be a TEAE, 
except if the partial start date, say with known year, confirms otherwise. 
No statistical tests will be performed. 
A listing of all TEAEs will be provided. 
 
9.3. 
LABORATORY EVALUATIONS 
Laboratory parameters include: 
Hematology: 
Absolute Basophils, Absolute Eosinophils, Absolute Lymphocytes, Absolute Monocytes, 
Absolute Neutrophils, Absolute Neutrophil Count, Basophils, Eosinophils, Hematocrit, 
Hemoglobin, Lymphocytes, Monocytes, Neutrophils, Parasites Blood, Platelets, Red Blood 
Cells (RBCs), White Blood Cells (WBCs) 
 
Clinical Chemistry: 
Albumin, Alkaline Phosphatase, Alanine Aminotransferase, Amylase, Aspartate 
Aminotransferase, Blood Urea Nitrogen, Calcium, Chloride, Creatinine, Direct Bilirubin, 
Gamma-Glutamyl Transferase, Glucose Serum, Potassium, Lactate Dehydrogenase, Lipase, 
Sodium, Phosphorus, Total Bilirubin, Human Chorionic Gonadotropin Quantitative 
 
Urinalysis: 
Amorphous Phosphate Crystals, Amorphous Urate Crystals, Bacteria, Bilirubin Crystals, 
Bilirubin, Blood, Calcium Carbonate Crystals, Calcium Oxalae Crystals, Coarsely Granular 
Cast, Clarity, Clue Cells, Color, Cystine Crystals, Finely Granular Cast, Glucose, Hyaline 
Cast, Ketones, Leukocytes, Mucous, Nitrite, pH, Protein, RBC Cast, RBCs, Renal Epithelial 
Cells, Specific Gravity, Spermatozoa, Squamous Epithelial Cells, Sulfonamide Crystals, 
Transitional Epithelial Cells, Trichomonads, Triple Phosphate Crystals, Uric Acid Crystals, 
Urobilinogen, Waxy Cast, WBC Cast, WBC Clumps, WBCs, Yeast 
 


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All hematology, chemistry, blood screening, and pregnancy laboratory tests will be performed by 
a central laboratory or by local labs as applicable. Descriptive statistics of the laboratory 
parameters will be presented by treatment group for all study visits at which they were collected. 
The change from baseline of hematology and chemistry laboratory parameters to each 
post-baseline visit, including the early termination visit, and to the minimum and maximum 
post-baseline values will also be summarized by treatment group. Pregnancy laboratory tests will 
be listed only. 
A shift table (low, normal, high) from baseline to each post-baseline visit where laboratory tests 
where assessed will be presented by treatment group for hematology. A shift table for clinical 
hematology tests will be presented only for Leukocytes, Absolute Neutrophil Count, Lipase, and 
Amylase as low/normal/high, and for Fecal Calprotectin as a separate shift table in categories of 
No Inflammation, Mild Inflammation, or Active Organic Disease where No Inflammation is 
defined as <50 µg/g, Mild Inflammation is defined as 50-200 µg/g, and Active Organic Disease 
is defined as >200 µg/g. 
All laboratory evaluations will be included in a subject data listing. 
9.3.1. 
Stool Assessment 
Stool pathogens assessment status (i.e., positive/negative/indeterminate) will be summarized at 
the screening visit. C. difficile toxin assessment status will be presented by visit and treatment 
group. 
Stool vancomycin levels over time will be summarized by treatment group using descriptive 
statistics.  
In addition, stool microbiota composition over time, stool VE303 detection over time, stool 
metabolomics evaluation over time, as well as stool calprotectin levels over time will also be 
summarized by treatment group using descriptive statistics. 
The number and percentage of subjects with either a presence (yes/no) of stool culture will be 
presented by visit and by treatment group.  
Stacked bar charts of the VE303 detection panel will be presented by treatment group and by 
timepoint. 
Stool Analysis 
C. difficile testing (EIA for Toxin A/B, PCR, CCNA, toxigenic culture assay) and for 
exploratory analyses (microbiota composition, VE303 component bacteria detection, 
antibiotic concentrations, metabolomics, culture, detection of antibiotic-resistant bacteria 
other than C. difficile (e.g., CRE, ESBL, or VRE) 
 


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Box and whisker plots of VE303 strain estimated abundance over time will be presented by 
treatment group. In addition, box-and-whisker plots of the microbiome – alpha diversity over 
time will also be illustrated by treatment group. 
Scatter plots showing the correlated by-subject between abundance of each of the 8 component 
bacteria of VE303 versus vancomycin levels, as well as VE303 strain abundance versus diversity 
will also be presented by sample, by treatment group, and by timepoint. 
Stool parameters will be included in a subject data listing. 
9.4. 
VITAL SIGNS 
As per the protocol, vital signs data include measurements of systolic blood pressure (mm Hg), 
diastolic blood pressure (mm Hg), pulse (beats/minute), and body temperature (Celsius). 
Descriptive statistics of the vital signs will be presented by treatment group for all study visits, 
including the early termination visit, at which they were collected. The change from baseline to 
each post-baseline visit, including the early termination visit, and to the minimum and maximum 
post-baseline value will also be summarized by treatment group. 
All vital signs data will be included in a subject data listing. 
9.5. 
ECG  
The overall interpretation of ECGs will be recorded as “Normal”, “Abnormal, not clinically 
significant”, “Abnormal, clinically significant”, or “ECG not readable”. Shifts from baseline to 
Day 28 and to Early Termination in these ECG interpretation categories will be presented by 
treatment group. All ECGs will be listed. 
9.6. 
PHYSICAL EXAMINATION 
A by-subject listing with physical examination findings will be provided. 
9.7. 
GASTROINTESTINAL SYMPTOMS SELF-ADMINISTERED 
QUESTIONNAIRE - PROMIS® 
Subjects will be evaluated for gastrointestinal symptoms using the self-administered Patient-
Reported Outcomes Measurement Information System (PROMIS®) scale questionnaire (v1.0, 
dated 01 September 2016) in order to assess 8 gastrointestinal symptoms (see the following table 
for the number of questions and grading for belly pain, bowel incontinence, constipation, 
diarrhea, disrupted swallowing, gas/bloating, nausea/vomiting, and gastroesophageal reflux). To 
obtain an adequate baseline, questionnaires must be completed before the first dose of study drug 
on Day 1. Post-baseline questionnaires should be completed prior to study drug administration 
on Days 7 and 14. All attempts must be made to have questionnaires completed at approximately 
the same time of day at every time point. 


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Row 
GI symptoms 
# of Questions 
Each Question 
Grading 
Total Grading 
1 
Belly Pain (Tier 1) 
5 
1 to 5 
5 to 25 
2 
Diarrhea (Tier 1) 
6 
1 to 5 
6 to 30 
3 
Nausea and vomiting (Tier 1) 
4 
1 to 5 
4 to 20 
4 
GI incontinence 
4 
1 to 5 
4 to 20 
5 
Constipation 
9 
1 to 5 
9 to 45 
6 
Disrupted swallowing 
7 
1 to 5 
7 to 35 
7 
Gas and bloating 
13 
1 to 5 
13 to 65 
8 
Reflux 
13 
1 to 5 
13 to 65 
 
Two “Tier” domains will be used to summarize the PROMIS questionnaire data. Tier-1 will 
include grades from the GI symptom domains of Belly Pain, Diarrhea, and Nausea and 
Vomiting. These 3 domains have been selected for Tier-1 because they pertain to common 
clinical manifestations and symptoms of C. difficile infection and are often reported as AEs in 
association with C. difficile recurrences. Tier-2 domains will include grades from the other 5 GI 
symptom domains. 
For Tier-1 domains, both the total grading and grades for each individual question within each 
domain will be summarized descriptively as continuous variables at baseline and at Day 7 and 
Day 14 by treatment group for the SAS. For Tier-2 domains, grading will be summarized only 
for total grading and not presented for each individual question within each domain.  
For the Tier-1 domains only, a shift table from baseline grade to worst post-baseline grade for 
each question within a domain will be presented by treatment group. Baseline will be defined as 
the last non-missing assessment prior to the administration of study drug. Worst post-baseline 
grade will be defined as the highest grade observed at any post-baseline visit. Grading will be 
based on the response provided to each question. 
Box-and-whisker plots of the total grading for Belly Pain, Diarrhea, and Nausea and Vomiting 
over time will be presented by treatment group, presenting mean and +/- SD. 
If a response to any of the individual questions within a domain is missing, then the total grading 
for this domain will not be calculated and set to missing. The amount of missed PROMIS 
questionnaire data will be summarized over time by treatment group. 
All subject PROMIS questionnaire responses will be listed. 


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10. 
CHANGES FROM ANALYSIS PLANNED IN PROTOCOL 
Any changes from the SAP will be provided in the CSR. 


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11. 
PROGRAMMING CONSIDERATIONS 
All TLFs, and statistical analyses will be generated using SAS, Release 9.4 or later (SAS 
Institute Inc., Cary, NC, USA). Computer-generated table, listing and figure output will adhere 
to the following specifications. 
11.1. 
GENERAL CONSIDERATIONS 
• One SAS program can create several outputs, or a separate SAS program can be 
created for each output at the statistical programmer’s discretion. 
• Each output will be stored in a separate file. 
• Output files will be delivered in Word format / rtf format. 
• Numbering of TLFs will follow ICH E3 guidance. 
 
11.2. 
TABLE, LISTING, AND FIGURE FORMAT 
11.2.1. 
General 
• All TLFs will be produced in landscape format, unless otherwise specified. 
• All TLFs will be produced using the Courier New font, size 8.  
• The data displays for all TLFs will have a 1.5-inch binding margin on top of a 
landscape 
• oriented page and a minimum 1-inch margin on the other 3 sides. 
• Headers and footers for figures will be in Courier New font, size 8. 
• Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• TLFs will be in black and white (no color), unless otherwise specified. 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
• Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they are 
appropriate to help display math symbols (e.g., μ). Certain subscripts and superscripts 
(e.g., cm2, Cmax) will be employed on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
 


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11.2.2. 
Headers 
• All output should have the following header at the top left of each page: 
Vedanta Biosciences, Inc. 
Protocol: VE303-002 Version #7 
Draft/Final 
  
• All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table). 
• The date (date output was generated) should appear along with program name and 
location as the last footer on each page. 
11.2.3. 
Display Titles 
• Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination. A decimal system (x.y and x.y.z) should be used 
to identify TLFs with related contents. The title is centered. The analysis set should 
be identified on the line immediately following the title. The title and table 
designation are single spaced. A solid line spanning the margins will separate the 
display titles from the column headers. There will be 1 blank line between the last 
title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Analysis Set 
 
11.2.4. 
Column Headers 
• Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
• For numeric variables, include “unit” in column or row heading when appropriate. 
• Analysis set sizes will be presented for each treatment group in the column heading as 
(N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for the 
descriptive statistics representing the number of subjects in the analysis set. 


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11.2.5. 
Body of the Data Display 
11.2.5.1. 
General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• alphanumeric values are left-justified 
• whole numbers (e.g., counts) are right-justified 
• numbers containing fractional portions are decimal aligned 
11.2.5.2. 
Table Conventions 
• Units will be included where available. 
• If the categories of a parameter are ordered, then all categories between the maximum 
and minimum category should be presented in the table, even if n=0 for all treatment 
groups in a given category that is between the minimum and maximum level for that 
parameter. For example, the frequency distribution for symptom severity would 
appear as: 
Severity Rating 
N 
Severe 
0 
Moderate 
8 
Mild 
3 
Where percentages are presented in these tables, zero percentages will not be presented and so 
any counts of 0 will be presented as 0 and not as 0 (0%). 
• If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 subject 
represented in 1 or more groups should be included. 
• An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
• Unless otherwise specified, the mean and median for a set of values should be printed 
out to 1 more significant digit than the original values, and standard deviations should 
be printed out to 2 more significant digits than the original values. The minimum and 
maximum should report the same significant digits as the original values. For 
example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
 X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 


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• P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 3 
decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value should be less than 0.0001 then present as <0.0001. If the p-value is returned as 
>0.999 then it will be presented as >0.999. 
• Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count [e.g., 7 (12.8%), 13 (5.4%)]. Values that round down 
to 0.0 will be displayed as '<0.1'. Unless otherwise noted, for all percentages, the 
number of subjects in the analysis set for the treatment group who have an 
observation will be the denominator. Percentages after zero counts should not be 
displayed and percentages equating to 100% should be presented as 100%.  
• Unless otherwise specified, tabular display of data for medical history, 
prior/concomitant medications, and all tabular displays of adverse event data should 
be presented by the body system, treatment class, or SoC in alphabetical order, 
assuming all terms are coded. Within the body system, drug class and SoC, medical 
history (by preferred term), drugs (by ATC1 code), and adverse events (by preferred 
term) should be displayed in decreasing order. If incidence for more than 1 term is 
identical, they should then be sorted alphabetically. Missing descriptive statistics or 
p-values which cannot be estimated should be reported as “-”. 
• The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. If applicable, denominator details will be described in footnotes or 
programming notes. 
• For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, a footnote or programming note will describe 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
• Where a category with a subheading (such as system organ class) needs to be split 
over more than one page, output the subheading followed by “(cont)” at the top of 
each subsequent page. The overall summary statistics for the subheading should only 
be output on the first relevant page. 
11.2.5.3. 
Listing Conventions 
• Listings will be sorted for presentation in order of treatment groups as above, subject 
number, visit/collection day, and visit/collection time. 
• Missing data should be represented on subject listings as either a hyphen (“-”) with a 
corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 


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• Dates should be printed in SAS® DATE9.format (“DDMMMYYYY”: 01JUL2000). 
Missing portions of dates should be represented on subject listings as dashes (--
JUL2000). Dates that are missing because they are not applicable for the subject are 
output as “N/A”, unless otherwise specified. 
• All observed time values should be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
• Units will be included where available. 
11.2.5.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed on 
the Y-axis. 
11.2.6. 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• All footnotes will be left-justified with single line spacing immediately below the 
solid line underneath the data display. 
• Footnotes should begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line where possible. 
• Footnotes will be present on the page where they are first referenced and thereafter on 
each page of the table unless the footnote is specific only to certain pages. Subject 
specific footnotes should be avoided. 
• Footnotes will be used as needed, however, it must add value to the table, listing, or 
figure. If more than six lines of footnotes are planned, then a cover page may be used 
to display footnotes, and only those essential to comprehension of the data will be 
repeated on each page.  
• The last 2 lines of the footnote section will be a standard source that indicates the 
name of the program used to produce the data display, date the program was run, and 
the listing source (or data source for a listing) (i.e., ‘Program: myprogram.sas    
Listing source: 16.x.y.z’). 


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15 July 2021 
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12. 
QUALITY CONTROL 
Validation of analysis datasets and tables/listings/plots are conducted through independent 
parallel programming of the statistical output according to the agreed upon specifications defined 
in the protocol, SAP, table shells, and dataset specifications. In this process, two programmers 
working independently (i.e., without input from one another), program the same output and 
compare results (via SAS PROC COMPARE). Any discrepancies are discussed and resolved, 
and the validation cycle is repeated until no further differences are noted between the two 
outputs. Once the validation cycle is complete, the output is subjected to senior review by the 
statistician. All programs are submitted in batch mode to document the results of the PROC 
COMPARE indicating no unequal observations. In addition, tracking logs will be maintained 
which document all Quality Control and validation findings and their resolution. 
 


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15 July 2021 
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13. 
ADMINISTRATIVE INTERIM ANALYSES 
Since the estimate of the true underlying treatment effect is unknown, and since enrolment has 
been slow, the decision was made to change Study VE303-002 to a non-pivotal trial after the 
sponsor’s careful assessment. Consequently, the study objective to enroll up to 146 patients 
(124 evaluable), to increase the sample size as a result of the SSR, and the IA stated in the 
original protocol will not be performed.  
Instead, 3 administrative IAs will be performed to inform business decisions by the sponsor on 
whether to continue development of VE303 in the CDI indication. The administrative IAs will be 
performed after at least 24 randomized subjects complete 8 weeks of the study, after at least 39 
randomized subjects complete 8 weeks of the study, and after at least 54 randomized subjects 
complete 8 weeks of the study. The number of subjects selected for each of the administrative IA 
were selected based on the number of subjects possibly randomized on each of the 3 treatment 
arms. The total number of approximately 60 to 80 subjects was assessed to allow at least 20 
subjects per arm. 
13.1. 
EFFICACY ANALYSIS  
The administrative IAs will be performed on the FAS analysis set for efficacy endpoints. The 
PPS population might be included as a supportive analysis, if there is a sufficient number of 
patients in PPS population.  
13.1.1. 
Primary Variable: Recurrence Rate before or at Week 8 
The Bayesian posterior probability will be evaluated at each administrative IA, for each of the 
following 6 conditions of true underlying treatment difference in recurrence rate,  
1. TRUE underlying treatment effect is better than placebo, i.e., recurrence rates 
difference >0% reduction associated with VE303 
2. TRUE underlying treatment effect is at least 5% better than placebo, i.e., recurrence 
rates difference >5% reduction associated with VE303 
3. TRUE underlying treatment effect is at least 10% better than placebo, i.e., recurrence 
rates difference >10% reduction associated with VE303 
4.  TRUE underlying treatment effect is at least 15% better than placebo, i.e., recurrence 
rates difference >15% reduction associated with VE303 
5. TRUE underlying treatment effect is at least 20% better than placebo (i.e., recurrence 
rates difference >20% reduction associated with VE303 
6. TRUE underlying treatment effect is at least 30% better than placebo (i.e. recurrence 
rates difference >30% reduction associated with VE303) 


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The number and percentage of subjects with CDI recurrence will be presented by treatment 
group, and the treatment difference from placebo group will be presented along with the odds 
ratio (treatment/placebo) of recurrence rates. The 80% CI (i.e., α= 0.2, 2-sided) and the 90% CI 
(i.e., α= 0.10, 2-sided) based on the asymptotic Wald CI will be constructed for the difference of 
the proportions of 2 treatments and associated 1-sided exact p-value. Bayesian posterior 
probability for each of the above conditions will be calculated by using 
 Go/No-Go 
software.  
The number of subjects and the number of subjects with recurrence by treatment by 
randomization stratum at each administrative IA will be summarized for demonstrating the 
degree of balance of number of subjects between treatments by stratum.  
The comparison between each treatment group and placebo will be analyzed using a stratified 
CMH method for treatment stratified by the stratification factors used in randomization at 
α= 0.05, 1-sided. The 90% CI based on the asymptotic Wald CI will be constructed for the 
difference of the proportions of 2 treatments. P-value from CMH test will be presented. The 
Breslow-Day chi-square test for homogeneity of the odds ratios across strata will also be used to 
check the assumption. If the assumption test fails, the nature of the difference may be further 
explored.  
13.1.2. 
Sensitivity Efficacy Analysis on Primary Variable 
The same analysis method that will be performed on the primary endpoint as described above 
will be repeated on 2 additional efficacy variables, which are defined as follows (see also Section 
8.1.1): 
• CDI recurrences using PCR-positive (with no confirmation using toxin positive) 
diarrhea episodes treated with an antibiotic that targets C. difficile 
• Diarrhea episodes treated with an antibiotic that targets C. difficile in the absence of a 
positive toxin assay or a positive PCR result 
13.1.3. 
Secondary Variable: Time to CDI Recurrence Before or at Week 8 
Time to CDI recurrence will be summarized by treatment group using the median and 25th and 
75th percentiles from the KM analysis. The 2-sided 90% CIs by using Greenwood’s formula for 
the median will also be presented. Subjects who are lost to follow-up or who terminated the 
study prematurely before experiencing a CDI recurrence will be censored on the date of last 
contact. Subjects who die before having a CDI recurrence will be censored on the date of death. 
The percentage of censored observations will also be presented.   
Kaplan-Meier plots of Time to CDI recurrence will be presented by treatment group. 


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Statistical Analysis Plan v2.0 
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15 July 2021 
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13.2. 
SAFETY ANALYSIS 
Safety data are reviewed over the course of the study on an ongoing basis in blinded manner. 
There are no safety concerns expected; however, a safety summary might be presented if needed.  
13.3. 
UNBLINDING AND BLINDING 
The IA analyses will be performed according the Unblinding Plan v1.0 by a separate set of 
unblinded statisticians and programmers at 
 who will 
have access to individual treatment assignments and will not be involved in subsequent trial 
conduct. The delegated members at Vedanta will have access to the group level unblinded results 
and will remain blinded to the individual treatment assignments. The remaining personnel (not 
mentioned before) involved in the conduct of the trial, including those at Vedanta, the CRO, and 
the trial sites, will remain blinded to the individual subject treatment assignment until unblinding 
after trial completion.  
13.4. 
STOPPING RULE 
The study enrollment may be stopped after each of the 3 IAs if the VE303 High-dose arm 
recurrence rate is ≥ 50%.  
At the 3rd administrative IA, when approximately 60 to 80 evaluable subjects complete 8 weeks 
of the study, the study may be stopped for futility if the reduction of the recurrence rate in the 
High-dose arm compared to the placebo arm either has a relative reduction of <33% (e.g., the 
odds ratio of treatment/control), or if the absolute reduction of recurrence rate is <10% (placebo 
minus high-dose arm).