A Phase 2, Randomized, Double-Blind, Comparator-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of CRS3123 Compared With Oral Vancomycin in Adults With Clostridioides Difficile Infection
Phase: PHASE2
Conditions: Clostridioides Difficile Infection
Sponsor: Crestone, Inc

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TITLE PAGE 
PROTOCOL TITLE: A PHASE 2, RANDOMIZED, DOUBLE-BLIND, 
COMPARATOR-CONTROLLED, MULTICENTER STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF CRS3123 
COMPARED WITH ORAL VANCOMYCIN IN ADULTS WITH 
CLOSTRIDIOIDES DIFFICILE INFECTION 
Protocol Number: 19-0021 
Compound Number: CRS3123 
Study Phase: 2 
Short Title: A Randomized, Double-blind Evaluation of CRS3123 Versus Oral 
Vancomycin in Adult Patients with Clostridioides difficile Infection 
Sponsor Name:  
 
Crestone, Inc. 
Legal Registered Address:  6075 Longbow Dr., Suite 130 
Boulder, CO 80301 
Phone: (303) 530-2100 
Regulatory Agency Identifier Number 
Regulatory Agency File 
Identifying # 
IND:  
146,348 
Protocol Version: Protocol Amendment 7  
Approval Date: 23 August 2023 
This document is the confidential property of Crestone, Inc. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written 
authorization from Crestone, Inc. 
 

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1 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Phase 2, Randomized, Double-Blind, Comparator-Controlled, 
Multicenter Study to Evaluate the Safety and Efficacy of CRS3123 Compared with Oral 
Vancomycin in Adults with Clostridioides difficile Infection 
Short Title: A Randomized, Double-blind Evaluation of CRS3123 Versus Oral 
Vancomycin in Adult Patients with Clostridioides difficile Infection 
Rationale: 
Clostridioides difficile (C. difficile) infection (CDI) is currently classified as an urgent 
threat by the Centers of Disease control and Prevention (CDC, 2015; CDC, 2019; 
McDonald et al, 2018), and is the most common cause of healthcare-associated infections 
in the US (Magill et al, 2014). Over approximately the last decade, the incidence of C. 
difficile in the US has ranged from approximately 200,000 to 500,000 cases per year and 
mortality rate has ranged from approximately 13,000 to 29,000 deaths per year (Lessa et 
al, 2015; CDC, 2019). Because C. difficile is more common and more severe in older 
patients (CDC, 2019) as the US population ages, the total numbers of patients may be 
expected to rise. 
CRS3123 is a novel narrow-spectrum small molecule antibiotic that selectively inhibits 
methionyl-tRNA synthetase of C. difficile. As a protein synthesis inhibitor, CRS3123 
inhibits C. difficile toxin production and spore formation with no cross-resistance to 
existing antibiotics. CRS3123 exhibited minimal disruption of commensal 
gastrointestinal microbiota, blocking toxin and spore formation and exhibiting low 
recurrence rates compared to vancomycin in preclinical studies. 
CRS3123 has been evaluated in Phase 1 trials to determine its safety and tolerability in 
healthy subjects following a single oral dose of 100, 200, 400, 800 and 1200 mg 
(Division of Microbiology and Infectious Diseases [DMID] 10-0008), or multiple 
ascending doses of 200, 400 and 600 mg orally twice daily (bid) for 10 days (DMID 10-
0009). CRS3123 was generally safe and well tolerated with no significant treatment-
emergent adverse events (TEAEs) reported. CRS3123 showed very limited systemic 
absorption in humans and the majority of the oral dose remained intraluminal. Fecal 
concentrations reached levels above 1000 μg/g, substantially above the minimum 
inhibitory concentration necessary for 90% inhibition (MIC90, 1 μg/ml) at all dosages 
tested, and more than 10-fold above mutation prevention concentration (MPC). CRS3123 
exhibited minimal perturbation of normal intestinal microbiota and had no effects against 
important commensal anaerobes including Bacteroides, Bifidobacteria, and commensal 
Clostridia. The results demonstrate the differentiating profile of CRS3123 from other 
agents and support its further development as an oral agent for the treatment of CDI. In 
this Phase 2, randomized, double-blind, comparator-controlled clinical study, CRS3123 

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will be compared with oral vancomycin in adult participants experiencing a primary 
episode or first recurrence of CDI. 
Objectives and Endpoints: 
This is the first study in which CRS3123 is administered to participants with a primary 
episode or first recurrence of CDI. The primary objectives of the study are the evaluation 
of safety and efficacy (rate of clinical cure at the test of cure [TOC] visit in the 
intent-to-treat [ITT] population). The secondary and exploratory objectives are additional 
evaluation of efficacy, assessment of plasma concentrations of CRS3123, outcomes of 
health-related quality of life (HRQoL), the effect of CRS3123 on the microbiology, fecal 
microbiome, fecal markers of inflammation, and metabolomics; and the assessment of 
fecal concentration of CRS3123. 
The study objectives and endpoints are presented in Table 1. Detailed schedules of study 
assessments are provided in Section 1.3. 

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Table 1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the safety and efficacy of 
CRS3123 administered at 200 mg and 
400 mg po bid and vancomycin 
administered 125 mg po qid in 
participants with CDI 
 
Efficacy (Primary Endpoint): 
Rate of clinical cure at TOC in the ITT population 
 
Safety: 
An overall assessment of safety and tolerability of CRS3123 
based on: 
• Incidence, severity, and relatedness of AEs 
• Assessment of vital signs, laboratory data, ECG findings, 
as well as clinical observations and physical examination 
Secondary  
To further assess the efficacy of 
CRS3123 administered at 200 mg and 
400 mg po bid and vancomycin 
administered 125 mg po qid in 
participants with CDI 
Efficacy (Secondary Endpoints): 
• Rate of clinical cure at TOC in the Micro-ITT, PP, and ME 
populations 
• Rate of clinical cure at TOC as assessed by the investigator 
in the ITT, Micro-ITT, PP, and ME populations 
• Rate of total relief of symptoms of CDI at TOC in the 
Micro-ITT, PP, and ME populations 
• Time to resolution of diarrhea through TOC in the 
Micro-ITT, PP, and ME populations 
• Rate of early recurrence of CDI through FUV2 in the 
Micro-ITT and ME populations 
• Rate of late recurrence of CDI (between FUV2 and FUV3) 
in the Micro-ITT and ME populations 
• Rate of recurrence of CDI through FUV3 in the Micro-ITT 
and ME populations 
• Time to recurrence of CDI though FUV3 in the Micro-ITT 
and ME populations 
• Rate of global cure (clinical cure at TOC and no 
recurrence through FUV2 in the Micro-ITT, PP, and ME 
populations  
 
To assess the plasma concentrations of 
CRS3123 following oral administration 
at 200 mg and 400 mg po bid 
The following will be assessed in the Plasma-PK 
population: 
• Plasma concentrations of CRS3123 will be measured by 
sparse PK sampling at selected timepoints. 
• If feasible, primary parameters will be estimated from 
concentration versus time data using a population PK 
approach. PK parameters may include Cmax, tmax, t1/2, 
AUC0-24, and CL/F, and accumulation ratio calculated 
using the estimated AUC0-24 at EOT vs Day 1. 
To assess the health-related quality of 
life (HRQoL) outcomes in participants 
with CDI receiving CRS3123 
administered at 200 mg and 400 mg po 
bid and vancomycin administered at 
125 mg po qid 
 
HRQoL: 
• Clostridium difficile Infection-Daily Symptoms 
(CDI-DaySymsTM) change from baseline to each post-
baseline visit in domain scores (diarrhea symptoms, 
abdominal symptoms, and systemic/other symptoms) in 
the Micro-ITT and ME populations 

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Objectives 
Endpoints 
Exploratory 
 
To assess the effect of CRS3123 on the 
microbiology, fecal microbiome, and 
fecal biomarkers of inflammation, to 
assess microbiological effect, and to 
evaluate metabolomics 
The following parameters will be evaluated in the Micro-ITT 
and ME populations: 
• Quantitative C. difficile toxin production 
• Vancomycin-resistant enterococcus (VRE) culture and 
identification 
• C. difficile spore enumeration 
• Antimicrobial susceptibility testing 
• C. difficile culture 
• PCR Ribotyping 
• Toxin A/Toxin B titer 
 
Additional exploratory evaluations will includea 
• Effects of treatment on fecal inflammation biomarkers 
(calprotectin, lactoferrin, IL-1β, IL-2, IL-8, IL-15, IL-17, 
and GM-CSF) 
• Effects of treatment on fecal microbiome 
• Metabolomics 
To assess the fecal concentrations of 
CRS3123 in the CRS3123 200 mg and 
400 mg dose groups 
Fecal concentrations of CRS3123 in the PK-Fecal population 
Abbreviations:  AE = adverse event; AUC = area under the concentration-time curve; bid = twice daily; CDI = 
Clostridioides difficile infection; CL/F = apparent clearance; Cmax = maximum concentration; 
ECG = electrocardiogram; EOT = end of treatment; GM-CSF = granulocyte macrophage colony-stimulating factor; 
ITT = intent-to-treat; FUV = follow-up visit; Micro-ITT = microbiological ITT; ME = microbiologically evaluable; PD 
= pharmacodynamics; PK = pharmacokinetics; po = oral; PP = per-protocol; qid = 4 times daily; t1/2 = terminal half-
life; tmax = time to maximum concentration; TOC = test of cure visit (occurring at FUV1); VRE = vancomycin-resistant 
enterococcus 
a. 
Population for analysis of the fecal microbiome, fecal biomarkers of inflammation, and metabolomics will be 
defined separately in a standalone analysis plan(s). 
Overall Design: 
This Phase 2, randomized, double-blind, comparator-controlled, multicenter study will be 
conducted to evaluate the primary objectives of safety and efficacy (rate of clinical cure) 
of 2 dosages of CRS3123 (200 mg and 400 mg) administered orally (po) twice daily (bid) 
and vancomycin administered 125 mg po 4 times daily (qid) in adults ≥ 18 years of age 
with a primary episode or first recurrence of CDI. The study will investigate the plasma 
concentrations and HRQoL outcomes of CRS3123 and additional efficacy and 
microbiology endpoints as well as the effect of CRS3123 on the fecal microbiome, fecal 
biomarkers of inflammation, and metabolomics in participants with CDI, and an 
assessment of fecal concentration of CRS3123 after dosing. 

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The duration of the treatment period for all study treatment arms is 10 days (40 doses; 
administration of last dose may occur on Day 11). 
The Schedule of Activities is presented in Table 3 (Section 1.3). 
Participants must meet the entry criteria, including the diagnosis of CDI by having 
≥ 3 diarrheal (Bristol Stool Scale scores 5, 6, or 7) stools/day in 24 hours prior to 
randomization and in the judgment of the investigator that C. difficile is the causative 
agent for the diarrhea. Stool must be positive for C. difficile Toxin A and/or B antigen 
using an FDA or Health Canada approved/cleared EIA or ELISA laboratory test (e.g., 
Abbott/Alere QUIK CHEK COMPLETE®, Premier® Toxins A&B, etc.).  A non-CLIA 
certified site may perform an Abbott/Alere QUIK CHEK COMPLETE® stool test 
provided by TechLabs, and if the test is positive for toxin A and/or B antigen, the subject 
may randomize while the local standard of care test is pending (i.e., NAAT, PCR, other 
toxin testing via EIA or ELISA). 
Participants will be randomized (1:1:1) to 1 of 3 treatment arms as shown below. The 
treatment period for each arm will be 10 days. Randomization will be stratified by CDI 
type (first episode of CDI or first recurrence of CDI) to ensure proper balance among 
treatment arms. 
• Treatment Arm A (n = 30-36): CRS3123 200 mg po bid (i.e., 400 mg/day) 
• Treatment Arm B (n = 30-36): CRS3123 400 mg po bid (i.e., 800 mg/day) 
• Treatment Arm C (n = 30-36): Vancomycin 125 mg po qid (i.e., 500 mg/day) 
Study procedures will be completed at the following visits: 
Screening Visit, Day -3 to Day 1: This is the pretreatment screening/baseline visit to 
determine study eligibility. 
Treatment Period: Day 1 through EOT: Participants will receive study treatment qid at 
approximately 6-hour intervals for a total of 4 doses per day. During the treatment period, 
in Treatment Arm C, vancomycin comparator will be given as 125 mg capsules po qid; in 
Treatment Arms A and B, CRS3123 (200 mg and 400 mg, respectively) will be given po 
bid as doses 1 and 3, with placebos being given as doses 2 and 4. All study treatment 
(CRS3123, vancomycin, and placebo) will have an identical appearance. Study treatment 
will be administered for a total of 10 days for a total of 40 doses in each Treatment Arm. 
The first dose of study treatment may occur on the same calendar day as the screening 
visit. The participants will be instructed to take all study treatment doses with water. 
Participants, regardless of treatment arm, should make every attempt to maintain the qid 
(approximately every 6 hours (q6h) [± 1.5 h]) schedule. If they slip outside of this 
schedule, the participants should take their dose as soon as possible and should not skip 
the dose. On the Participant Daily Diary, the participants should record any missed doses. 

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If participants miss a dose of study treatment, the participants should record which dose 
of study treatment they missed in the Participant Daily Diary. 
The end of treatment (EOT) assessments (described in Section 1.3) will be performed on 
the last calendar day that the participants receive the 40th dose of study treatment. For 
participants who prematurely discontinue study treatment, the EOT visit should occur as 
soon as possible after discontinuation of study treatment; these participants should 
continue to follow the Schedule of Activities for all subsequent planned visits. 
Participants may be either inpatient (at the clinical site) or outpatient (this group may also 
include patients residing at skilled nursing facilities and rehabilitation facilities) based on 
investigator’s discretion, but regardless of status, all must comply with all study 
requirements, including visits, follow-up visits, and suspected recurrence visits during the 
follow-up period. 
Telephone contact during the treatment period will occur on Days 3 and 6 as described in 
Schedule of Activities (Section 1.3) to assess symptoms of clinical response or new or 
ongoing adverse events (AEs)/serious adverse events (SAEs) and will comprise a scripted 
interview with a questionnaire capturing the severity of GI symptoms/resolution of 
symptoms. 
Participants will complete the Participant Daily Diary from Day -1 (≤24 hours prior to 
randomization) through the test of cure /Follow-up Visit 1 (TOC/FUV1, described 
below), as well as for episodes of recurrence during the follow-up period, as specified in 
the Schedule of Activities (Section 1.3). The Participant Daily Diary will include the 
date, time, and the Bristol Stool Scale score of each bowel movement and concomitant 
medications through TOC/FUV1 and at suspected recurrence, and adherence to study 
treatment through the EOT visit. The Participant Daily Diary will also include the 
patient-reported outcome (PRO) questionnaire (CDI-DaySyms), which will be used to 
assess CDI symptoms as well as quality of life parameters from screening through 
TOC/FUV1 (Kleinman et al, 2018; Talbot et al, 2019).  The Daily Diary must be 
reconciled by study staff at every visit to ensure it is congruent with the eligibility 
criteria, the Investigator’s assessment of clinical response, or diagnosis of recurrence. 
Safety assessments will be performed at each visit from screening to FUV2 as indicated 
in the Schedule of Activities (Section 1.3). Safety will be assessed by Aes, physical 
examinations, vital signs, laboratory evaluations (hematology, chemistry, and/or 
urinalysis at most visits and coagulation at screening and EOT visit only), and 
electrocardiogram (ECG) parameters. Plasma concentrations will be assessed by 
collecting blood samples on Day 1 and the EOT visit (Section 1.3).  Exploratory 
pharmacokinetic (PK) fecal concentration analysis will be assessed by collecting fecal 
samples at the Day 1 and EOT visit.  
Follow-up Period: There will be a total of 3 Follow-up Visits (FUVs). The TOC/FUV1 
will be at least 2 full days after last dose, FUV2 (early recurrence visit), and FUV3 (late 
recurrence visit). The TOC/FUV1 and FUV2 follow-up visits will be conducted as direct 

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site visits and include stool and blood sample submission as well as clinical assessments 
and ascertainment for recurrence of CDI. Telephone contact, using a scripted interview, 
will occur on Day 20 (± 3 days), Day 27 (± 3 days), and FUV3 (± 3 days) of the follow-
up period to assess symptoms of clinical recurrence and new or ongoing Aes/SAEs, and 
capture the severity of gastrointestinal (GI) symptoms/resolution of symptoms. 
If signs and symptoms of CDI recurrence are suspected, participants must come in for an 
unscheduled Suspected Recurrence Visit earlier than the next planned visit, as applicable. 
Following the Suspected Recurrence Visit, participants will be treated per standard of 
care and continue to follow the Schedule of Activities for all subsequent planned visits 
and telephone calls. A test for C. difficile Toxin A and/or B antigen using an FDA or 
Health Canada approved/cleared EIA or ELISA laboratory test must be performed at the 
unscheduled Recurrence Visit.   
The study participant is expected to complete all study visits unless the participant dies or 
withdraws consent. 
A Data Safety Monitoring Board (DSMB) will be established and managed in this study 
by The National Institute of Allergy and Infectious Diseases (NIAID) to analyze aEs and 
other safety data. 
Number of Participants: 
This protocol plans to enroll approximately 90 to 108 participants who meet study entry 
criteria, who will be randomly assigned to treatment in 1 of 3 treatment arms in a 1:1:1 
ratio as presented in Table 2. This study will provide an initial assessment of safety and 
efficacy data to inform the future development of CRS3123. This study is not powered to 
detect a difference between the treatment groups or for non-inferiority testing. 
If 36 participants are enrolled in each CRS3123 treatment arm and the true rate of clinical 
cure at TOC is 0.83 in each group, then the exact 95% confidence interval for the 
treatment of cure rate is (0.67, 0.94). Alternatively, if 30 participants are enrolled in each 
CRS3123 treatment arm and true rate of clinical cure at TOC is 0.83, then the 95% CI for 
the rate is (0.65, 0.94). 
Number of Sites and Duration of Study: 
Up to 50 sites will be used to recruit participants, based on published CDI enrollment rate 
of 2.4 participants per site per year for fidaxomicin Phase 3 study (Cornely et al, 2012). 
The study will be conducted in United States and Canada. 
The duration of study will be approximately 36 months. 
 

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Treatment Arms and Duration: 
The estimated duration of study participation is approximately 70 days from the 
screening visit to FUV3; see Table 3 Schedule of Activities footnote ‘a’.  
The screening period will be up to 72 hours in duration before treatment, followed by a 
treatment period of 10 days, with an EOT visit on the day of last dose or as soon as 
possible after early study treatment discontinuation, and 3 follow-up visits (FUV1, 
FUV2, and FUV3). Additionally, phone calls during the treatment period (on Days 3 and 
6) and during the follow-up period (Day 20, Day 27, and FUV3) will be conducted, as 
described above and shown in Figure 1. 
The 3 treatment arms are presented in Table 2. 
Table 2 
Treatment Arms 
Treatment 
Arm 
Study Treatment, Dose, Duration 
Study Treatment 
Administration 
Approximate 
Planned 
Number of 
Participants 
A 
CRS3123, 200 mg po bid 
(i.e., 400 mg/day) (daily doses 1 and 
3) and placebo bid (daily doses 1 to 4) 
given approximately q6h (± 1.5 h) for 
10 days  
CRS3123 (1 capsule of 200 mg + 
1 capsule of placebo) at daily 
doses 1 and 3 
1 capsule of placebo at daily 
doses 2 and 4) 
30-36 
B 
CRS3123, 400 mg po bid 
(i.e., 800 mg/day) (daily doses 1 and 
3) and placebo bid (daily doses 2 and 
4) given approximately q6h (± 1.5 h) 
for 10 days 
CRS3123 (2 capsules of 200 mg) 
at daily doses 1 and 3 
1 capsule of placebo at daily 
doses 2 and 4 
30-36 
C 
Vancomycin, 125 mg po qid 
(i.e., 500 mg/day) given 
approximately q6h (± 1.5 h) for 10 
days  
Vancomycin (1 capsule of 
125 mg + 1 capsule of placebo) 
at daily doses 1 and 3 
Vancomycin (1 capsule of 
125 mg) at daily doses 2 and 4 
30-36 
Abbreviations: bid = twice daily; h = hours; qid = 4 times daily, q6h = every 6 hours 
Note: Vancomycin will be over-encapsulated to match the appearance of CRS3123 and placebo capsules. 
Summary of Statistical Methods 
Baseline data including demographic information (age, sex, race), medical history, and 
baseline signs and symptoms will be summarized by treatment arm using descriptive 
statistics. 
Safety will be assessed in the Safety population. The number and percentage of 
participants with TEAEs will be tabulated by system organ class, preferred term, and 
treatment arm. TEAEs will also be summarized by relationship to study treatment, system 

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organ class, and preferred term, and also by maximum severity, system organ class, and 
preferred term. Serious adverse events will be summarized similarly. Clinical laboratory 
test results, ECG parameters, and vital signs will be summarized by visit as will changes 
from baseline for each treatment arm.  
For the following efficacy endpoints, rates will be summarized by treatment arm and 
exact confidence intervals will be created to compare the difference in rates in the each of 
the CRS3123 groups versus the vancomycin group: 
• Clinical cure at TOC (primary endpoint in ITT population)  
• Clinical cure at TOC (secondary endpoints in Micro-ITT, PP, and ME populations) 
• Clinical cure at TOC as assessed by the investigator 
• Total relief of symptoms of CDI at TOC 
• Early recurrence of CDI through FUV2 
• Late recurrence of CDI through FUV3 
• Recurrence of CDI though FUV3 
• Global cure (clinical cure at TOC) and no recurrence through FUV2 
Kaplan-Meier analyses of time to resolution of diarrhea through TOC as well as time to 
recurrence through FUV3 will be provided by treatment arm. 
For the HRQoL CDI-DaySyms analysis, domain scores will be summarized by visit and 
treatment arm using summary statistics. Changes from baseline in domain scores to each 
post-baseline visit will also be summarized by visit and treatment arm. 
If feasible, primary parameters will be estimated from concentration versus time data 
using a population PK approach (plasma PK only). Plasma PK parameters may include 
maximum concentration (Cmax), time to maximum concentration (tmax), terminal half-life 
(t1/2), area under the concentration-time curve from 0 to 24 hours (AUC0-24) and apparent 
clearance (CL/F), and accumulation ratio calculated using the estimated AUC0-24 at EOT 
vs Day 1. 
All data collected during the study will be analysed and presented in the clinical study 
report. If possible, subjects determined to be immunosuppressed under Protocol 
Amendment 6 will be subject to a sensitivity analysis. 
The Statistical Analysis Plan will be developed and finalized before the database is locked 
and will provide additional details regarding statistical procedures. 

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1.2 
Schema 
An overview of the study design is presented in Figure 1. 
Figure 1: 
Overview of Study Design 
 
Abbreviations: bid = twice daily; CDI = Clostridioides difficile infection; EOT = end of treatment; FUV = 
Follow-up Visit; po = oral, qid = 4 times daily; TOC = test of cure 
Note: Red arrows indicate follow-up phone contact: Days 3 and 6 during the treatment period, and Day 20, 
Day 27, and FUV3 during the follow-up period. Screening/Day 1, EOT, TOC/FUV1, and FUV2 are in-
person visits. 
* Screening and randomization may both occur on Day 1. 
** The EOT assessments will be performed on the last calendar day that the participants receive the 40th 
dose of study treatment. TOC assessments will be performed on FUV1. TOC/FUV1 should occur at least 2 
days after the last dose of study drug. For participants who discontinue study treatment prematurely, EOT 
should occur as soon as possible after study treatment discontinuation; these participants should continue to 
follow the Schedule of Activities for all subsequent planned visits and telephone follow-up calls, including 
TOC1/FUV1 through FUV3. 
*** If signs and symptoms of CDI recur at any point in the study between FUV1 and FUV3 following 
clinical cure, participants must come in for an unscheduled Suspected Recurrence Visit. 
1.3 Schedule of Activities 
A Schedule of Activities is presented in Table 3. 

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Table 3 
Schedule of Activities 
 
 
Treatment Period (Days 1-10) 
Follow-up Period  
(Days 11-70) 
Suspected 
Recurrence 
Visit 
(Unscheduled) 
Study Visit 
Screening 
 
 
 
 
 
 
 
 
 
EOT 
TOC/FUV1 
Phone 
Contact 
FUV2 
 
FUV3 
(Phone 
Contact) 
Study Day 
D-3 to 
D1a 
D1a,b D2 
D3 
D4 D5 
D6 D7 D8 
D9 
D10b,c 
(Last dose 
+2b,c) 
D20+ D27d 
D40b,e 
 
D70d 
Post-TOC to 
FUV3b,d,e 
Study Windows 
(days) 
-- 
-- 
-- 
(±1) 
-- 
-- 
(±1) 
-- 
-- 
-- 
(+2) 
(+3) 
(±3) 
(±3) 
 
(±3) 
 
Informed consentf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fecal sample for C. 
difficile Toxin A or 
Be,f antigen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Inclusion/exclusion 
criteriaf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weightg 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Physical 
examinationg 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Vital signsh 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
12-lead ECG 
(supine)i 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Local lab for 
screening eligibilityj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(urine)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Randomizationl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatmentm 
 
Xm 
X 
X 
Xm 
X 
X 
X 
X 
X 
Xm 
 
 
 
 
 
Scripted telephone 
interviewd 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Concomitant 
medicationsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Adverse eventso 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Treatment Period (Days 1-10) 
Follow-up Period  
(Days 11-70) 
Suspected 
Recurrence 
Visit 
(Unscheduled) 
Study Visit 
Screening 
 
 
 
 
 
 
 
 
 
EOT 
TOC/FUV1 
Phone 
Contact 
FUV2 
 
FUV3 
(Phone 
Contact) 
Study Day 
D-3 to 
D1a 
D1a,b D2 
D3 
D4 D5 
D6 D7 D8 
D9 
D10b,c 
(Last dose 
+2b,c) 
D20+ D27d 
D40b,e 
 
D70d 
Post-TOC to 
FUV3b,d,e 
Study Windows 
(days) 
-- 
-- 
-- 
(±1) 
-- 
-- 
(±1) 
-- 
-- 
-- 
(+2) 
(+3) 
(±3) 
(±3) 
 
(±3) 
 
Safety lab 
assessments (central 
lab)p 
 
X 
 
 
 
 
 
 
 
 
Xp 
Xp 
 
X 
 
X 
Participant Daily 
Diary, 
CDI-DaySyms, 
review by 
investigatorq 
X 
X 
Xq 
X 
X 
Xq 
X 
Xq 
X 
X 
X 
X 
 
 
 
Xq 
Investigator 
assessment of 
clinical responser 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
Blood and fecal 
samples for PKs,v 
Xv 
Xv 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Fecal sample for 
microbiologyt, v 
Xv 
Xv 
 
 
 
 
 
 
 
 
Xw 
Xw 
 
 
 
Xt 
Fecal sample for 
microbiome and 
host biomarkers 
testingt, v 
Xv 
Xv 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Xt 
Metabolomicsu, v 
Xv 
Xv 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Abbreviations: aEs = adverse events, ALT = alanine aminotransferase, AST = aspartate aminotransferase, β-HCG = beta-human chorionic gonadotropin; 
BUN = blood urea nitrogen; CBC = complete blood count; CDI = C. difficile infection; CDI-DaySyms = C. difficile Infection-Daily Symptoms questionnaire; 
CPK = creatine phosphokinase; CRP = C-reactive protein; D = Day; ECG = electrocardiogram; EOT = end of treatment; FUV = Follow-up Visit; 
GDH = glutamate dehydrogenase; h = hours; IRT = interactive response technology; PD = pharmacodynamic; PK = pharmacokinetic; po = orally; PRO = 
patient-reported outcomes; qid = 4 times daily; SAE = serious adverse events; TOC = test of cure; VRE = vancomycin-resistant enterococcus  
a 
Screening and Day 1: Screening assessments for study eligibility can occur within 72 hours of the administration of the first dose of study treatment. 
Screening and Day 1 can occur on the same calendar day.  For instances when the study run-in period for study eligibility may be delayed (e.g., weekends, 
holidays, etc.), the screening period can be extended up to 72 hours (all eligibility criteria still apply including the requirement for ≥3 diarrheal (Bristol Stool 
Scale scores 5, 6, or 7) stools/day within in a 24-hour period prior to randomization).  

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b 
Mandatory clinical site visits occur on Day 1, EOT, TOC/FUV1, and FUV2, and at suspected recurrence, as shown in the Table of Activities. For 
participants who are inpatient at the clinical site, all safety assessments during the treatment period are performed in person daily. Participants will attend 
EOT, TOC/FUV1, and FUV2 for collection of safety and efficacy data.  Fecal samples for PK, microbiology, microbiome, host biomarkers of inflammation, 
and/or metabolome testing will occur at all in-person visits based on the Schedule of Activities. If signs and symptoms of CDI recur at any point in the study 
between TOC/FUV1 and FUV3 following clinical cure, participants must come in for an unscheduled Suspected Recurrence Visit. 
c 
EOT assessments will be performed on the last calendar day that the participants receive the 40th dose of study treatment (ostensibly Day 10; with a +2 day 
window.  Record the date and time of the last previous dose associated with the EOT plasma PK sample. TOC/FUV1 assessments will occur at least 2 full 
days after the day of the last administered study drug. Note: Participants who discontinue study treatment prematurely should come in for an EOT visit as 
soon as possible after study treatment discontinuation, and then continue to follow the Schedule of Activities for all subsequent planned visits and telephone 
calls, including TOC/FUV1 through FUV3 (telephone contact scheduled for Days 3 and 6 that fall after early EOT do not need to take place). 
d 
Telephone contact will occur on Days 3 and 6 during the treatment period to assess clinical response as well as on Day 20, Day 27, and FUV3 of the follow-
up period to assess symptoms of clinical recurrence, or new or ongoing AEs/SAEs. A scripted interview capturing the severity of gastrointestinal 
symptoms/resolution of symptoms, including resolution of diarrhea, will be administered during the call and participants will be reminded of any upcoming 
clinical site visits. If signs and symptoms of CDI recurrence are suspected at any point between FUV1/TOC and FUV3, participants must come in for an 
unscheduled Suspected Recurrence Visit. Note: In the event a participant is an inpatient at the clinical site at the time of a scheduled Telephone Contact, the 
Telephone Contact will be conducted as an in-person visit during the treatment period.  
e 
Participants who have a recurrence after TOC/FUV1 should be treated per standard of care and continue to follow the Schedule of Activities for FUV2 and 
FUV3. C. difficile culture as well as a stool evaluation for Toxin A and/or B antigen should be performed at suspected recurrence. A non-CLIA certified site 
may also perform an Abbott/Alere QUIK CHEK COMPLETE® test according to the package insert with results verified by a second individual and a 
photograph of the result recorded with the date and time of the result.  
f 
Written informed consent must be obtained before any nonstandard of care screening assessments are performed. All inclusion and exclusion criteria need to 
be met before randomization on Day 1. 
g 
A complete physical examination evaluation will be performed at screening and include evaluation of the head, eyes, ears, nose, and throat (HEENT), neck, 
lungs, heart, chest, abdomen, extremities, neurological status, and skin, as well as height, and weight. A focused physical examination and measurement of 
weight will be performed on subsequent indicated visits and at Suspected Recurrence Visit (if applicable). 
h 
Vital signs include temperature, pulse rate, respiratory rate, and blood pressure. 
i 
12-lead ECG will be performed in a supine position. 
j 
CBC with differential, chemistry (including sodium, potassium, bicarbonate, chloride, BUN, serum creatinine, glucose, total protein, albumin, alkaline 
phosphatase, total bilirubin, ALT, AST, lipase, amylase, and CPK), coagulation, and CRP will be performed in the local laboratory at screening with a 
subset of tests used to evaluate eligibility. It is not necessary for all labs to be resulted prior to randomization except those that would affect eligibility. 
Results that affect eligibility are confirmation of C. difficile toxin A and/or B antigen in stool, pregnancy test.  Labs drawn within 48 h prior to screening are 
acceptable for screening eligibility purposes.  However eligible subjects cannot have received anti-CDI therapy for longer than 24 hours.  When the turn-
around time of laboratory results affecting study eligibility may be delayed (e.g., weekends, holidays, etc.), the screening period is up to 72 hours (all 
eligibility criteria still apply including the requirement for ≥3 diarrheal (Bristol Stool Scale scores 5, 6, or 7) stools/day in 24 hours prior to randomization). 
k 
Female participants of childbearing potential must have a urine pregnancy test (β-HCG) at screening and FUV2 performed at the local laboratory. Women of 
non-childbearing potential include women who are postmenopausal as demonstrated by amenorrhea for ≥ 12 months or surgical sterilization (ie., tubal 

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ligation, bilateral salpingectomy, bilateral oophorectomy, or hysterectomy). Provision of documentation is not required for female sterilization; verbal 
confirmation is adequate. 
l 
All inclusion and exclusion criteria need to be met before randomization on Day 1. All participants will be centrally assigned to randomized study treatment 
via IRT. 
m Day 1 is the first day for administration of study treatment and subsequent days are calendar days. Blister packs (each containing 20 doses) will be dispensed 
on Day 1. Participants will receive study treatment on Days 1 through 10, qid, at approximately 6-hour intervals (± 1.5 h), for a total of 4 doses per day. 
Study treatment comprises vancomycin 125 mg po qid and CRS3123 capsules 200 mg or 400 mg po bid. Identical placebo capsules will be given as the 
second and final daily dose in participants randomized to CRS3123. On Day 1, the first dose of study treatment should be administered as quickly as 
possible after eligibility criteria are met. If the participant discontinues study treatment prematurely, an EOT visit should occur as soon as possible after 
study treatment discontinuation. NOTE: All doses should be taken with water. Participants, regardless of treatment arm, should make every attempt to 
maintain the qid (approximately every 6 hours (q6h) [± 1.5 h]) schedule. If they slip outside of this schedule, the participants should take their dose as soon 
as possible and should not skip the dose. On the Participant Daily Diary, the participants should record any missed doses. Dose 1 will be administered on site 
to facilitate plasma PK sample collection. 
n 
All medications taken within 30-days prior to screening as well as medications taken during the study period (randomization through FUV3) should be 
recorded. 
o 
All adverse events, including serious adverse events, will be collected from randomization through FUV3 at the timepoints indicated in the Schedule of 
Activities, above. 
p 
Safety laboratory assessments performed by the central laboratory will include CBC with differential, chemistry, CRP, coagulation parameters, and 
urinalysis at the indicated timepoints. Coagulation will be assessed only at screening (local laboratory) and EOT visit (central laboratory).  
q 
The Participant Daily Diary will be completed from D-1 (≤24h prior to randomization) daily through TOC/FUV1 and at suspected recurrence and reviewed 
by study staff at each visit. The Participant Daily Diary includes details for each bowel movement and concomitant medications through TOC/FUV1 and at 
suspected recurrence; any missed doses of study treatment through EOT, and the CDI-DaySyms PRO questionnaire through TOC/FUV1. For participants 
treated as outpatients, the Participant Daily Diary will be reviewed during visits at the clinical site and phone call days during the treatment period (i.e., Days 
3 and 6). For participants treated in the hospital, Participant Daily Diary review will occur daily.  
r 
Patients that are clinical failures at TOC or at any subsequent visit do not need to complete further investigator’s assessments beyond that visit; however, 
patients will continue visits per the Schedule of Activities for all other assessments. 
s 
Blood and fecal samples for assessment of plasma and fecal concentrations will be collected at the clinical site and provided to the bioanalytical laboratory 
for CRS3123 concentration analysis.  The date and time of each study treatment dose for each respective PK sampling, and the date and time of each sample 
collection (not processing), must be captured in the clinic.   
t 
Fecal samples for microbiology, microbiome, and host biomarkers of inflammation testing must be collected at the clinical site prior to first dose of study 
treatment (as described in footnote “v”) and at subsequent post-Day 1 visits shown in the Schedule of Activities, including at time of suspected recurrence if 
applicable. Of note, the culturing of toxigenic C. difficile and microbial susceptibility testing will be performed only from the initial, TOC, and recurrence 
episode stool samples (including early discontinuation due to clinical failure). 
u 
A portion of the collected fecal sample will also be used for metabolomics analysis prior to first dose of study treatment (as described in footnote “v”) and 
subsequent post-Day 1 timepoints indicated in the Schedule of Activities. 

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v 
Fecal sample collection: Fecal samples of ≥ 6 g will be collected at all timepoints requiring a fecal assessment. A fecal sample for PK, microbiology, 
microbiome, host biomarkers testing, and metabolomics will be collected at the clinical site prior to first dose of study treatment. This sample can be 
collected at Screening or on Day 1 (predose). For fecal PK analysis only, an additional fecal sample will be taken on Day 1 postdose (first bowel movement 
after dose). Fecal samples collected on subsequent visits will be used only for the analyses planned for that specific visit as indicated in the Schedule of 
Activities. (Note: The date and time of each study treatment dose and the date and time of each sample collection (not processing) must be captured in the 
clinic. Fecal samples will be processed by the central laboratory and portions of each sample will be provided to the relevant designated laboratories for 
analysis.  Stool samples may be collected as early as 24-hours prior to each study visit and up to 24-hours after each study visit.  Stool samples collected 
within 24-hours of the desired collection day will not constitute a protocol deviation.  
w    Microbiology samples should be collected at both the EOT visit and TOC/FUV1 visit; however, the EOT visit sample will be analyzed if the TOC/FUV1 
sample is missing or if the participant discontinues study treatment prematurely.