Clinical trial NCT04781387
Conditions: Clostridioides Difficile Infection
Keywords: CDI Cdiff Infection Clostridiodes difficile infection Cdiff
Sponsor: Crestone, Inc
Start date: 2021-01-05; Completion date: 2024-04-16
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research is 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 \> or equal to 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 endpoints as secondary objectives.

Detailed description:

Arms: arm 1: CRS3123 200 milligram dose (400 mg/day) given orally at approximately 6-hour intervals for 10 days.

Due to the difference in dosing schedules between CRS3123 (twice a day) and the standard of care vancomycin (four times a day) and appearance of study drugs used in the 3 Arms, placebo will be used to match the total number of capsules in each arm. arm 2: CRS3123 400 milligram dose (800 mg/day) given orally at approximately 6-hour intervals for 10 days.

Due to the difference in dosing schedules between CRS3123 (twice a day) and the standard of care vancomycin (four times a day) and appearance of study drugs used in the 3 Arms, placebo will be used to match the total number of capsules in each arm. arm 3: Vancomycin 125 milligram dose (500 mg/day) given orally at approximately 6-hour intervals for 10 days.
Interventions: intervention 1: CRS3123 intervention 2: Active Comparator
Intervention descriptions: intervention 1: Study drug dosed PO BID for a total of 10 days intervention 2: Active comparator dosed PO QID for 10 days

Protocol documents:
SAP_002.pdf: 
Crestone, Inc. 
 
Statistical Analysis Plan  
Protocol 19-0021  
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STATISTICAL ANALYSIS PLAN 
 
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 
 
Study: 19-0021 
 
 
 
 
 
 
 
 


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1.1 
Table 1.  Definitions of Terms  
Term 
Definition 
Dose 
Study intervention administered, where 4 doses a day are expected over a period of a 
treatment period of 10 days for a total number of 40 expected doses in the course of the 
study. 
EOT 
End of treatment visit (last day of study drug) 
Follow-up Period 
There will be a total of 3 Follow-up Visits (FUVs) after EOT and up to 60 days after 
EOT. FUV1 will be at least 2 days after the last dose of study drug and FUV2 will occur 
at Day 40 (± 3 days).  FUV3 is a telephone contact on Day 70 (± 3 days). 
Normalization of 
bowel movement / 
Resolution of 
diarrhea 
Is defined as the resolution of diarrhea, which is less than 3 unformed bowel movements 
[UBM] [Bristol Stool Scale score of 5, 6, or 7] per day for 2 consecutive days. 
Recurrence 
Is defined as a return of diarrhea (≥ 3 UBM per day) 
TOC 
Test of Cure visit which coincides with FUV1 
Subject  
An individual who participates in a clinical trial, either as a recipient of the 
investigational product(s) or as a control. 
Treatment Period 
Day 1 through Day 10 (+2 window allowed) 
Unformed bowel 
movements (UBM) / 
Diarrheal stools 
Stool with a Bristol Stool Scale score of 5, 6, or 7 
2 INTRODUCTION 
This document presents the Statistical Analysis Plan (SAP) for the Crestone protocol 19-
0021, “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.” The statistical plan described is an a priori plan and 
no analyses have been conducted prior to the preparation of this plan. This SAP summarizes 
the study design and objectives and provides details of the outcome definitions and statistical 
methods that will be used to analyze the data from protocol 19-0021. Changes made to the 
SAP after it has been signed but prior to study unblinding will be documented in an 
amendment. Any important changes made to the analyses will be described in the clinical 
study report (CSR). This SAP is based on amended protocol version 7.0 dated 23 August 
2023. 


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3 DATA MANAGEMENT 
Data management procedures, including database design, and coding of medical history, 
adverse events, and prior and concomitant medications, will be performed by the lead clinical 
data manager. Data will be entered into an electronic case report form (eCRF) at the study 
sites. A series of logic and consistency checks will be conducted to ensure accuracy and 
completeness of the clinical database. Safety laboratory results, microbiology (fecal), 
bioanalytical, toxin, and pharmacokinetic data will be electronically transmitted from 
external vendors. After database lock, randomization data will be provided electronically 
from the IRT vendor. Refer to the Data Management Plan for further Data Management 
details. 
4 DEFINITION OF ANALYSIS POPULATIONS 
The relationship between the analysis sets is shown in Figure 1. 
 
 


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Figure 1:  Overview of Analysis Populations 
EOT = end of treatment; ITT = intent-to-treat; ME = microbiologically evaluable; micro-
ITT = microbiological intent-to-treat; PK = pharmacokinetic; PP = Per Protocol; MRT= 
microbiota restoration therapy. 
4.1 
Enrolled Population 
All participants who signed the informed consent form will be included in the enrolled 
population.  Unless otherwise specified, data for subjects who are enrolled but are not 
randomized will be listed, but not included, in summary tables. 
4.2 
Intent-to-Treat (ITT) Population 
The ITT population will consist of all randomized participants regardless of whether study 
treatment is administered. Participants will be grouped by the treatment to which they were 
randomized. This will be the population for analysis of the primary efficacy endpoint. 


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4.3 
Microbiological Intent-to-Treat (Micro-ITT) Population 
The Micro-ITT population will consist of all participants in the ITT population who have C. 
difficile isolated in culture at the central laboratory and who are C. difficile toxin positive 
(either Toxin A or Toxin B) from the central laboratory or local laboratory from a screening 
or Day 1 fecal sample.  Day 1 fecal samples can include samples collected after the first dose 
of study drug. Subjects who have culture grown at JMI, have positive spore counts, or have a 
ribotype identified are considered as having C. difficile isolated in culture at the central 
laboratory. Analyses in this population will be presented in summary tables by the treatment 
arm to which the subject was randomized. 
4.4 
Per-Protocol (PP) Population 
The Per-Protocol population will consist of all randomized participants who: 
• Receive at least 32 of the planned doses (i.e., approximately 80%) of study treatment 
through EOT. Note, if vomiting occurs within 15 minutes of dosing, then that dose is 
considered a missed dose. 
• Receive no concomitant systemic antibiotics or MRT from randomization through TOC, 
and 
• Receive no concomitant prohibited probiotic or anti-diarrheal medication from 
randomization through TOC unless due to failure of study treatment and 
• Have an investigator assessment of clinical response at TOC and 
• No major protocol violations that impact the efficacy assessments. In particular, subjects 
who are toxin A or toxin B negative or who violate Inclusion Criteria 2 (More than 3 
diarrheal stools per day in the 24 hours prior to randomization) will be excluded from the 
PP population.  Any subjects who take the wrong study drug will also be excluded from 
the PP population. 
Analyses in this population will be grouped by the treatment received. 
4.5 
Microbiologically Evaluable Population (ME) 
The Microbiologically Evaluable population will consist of all participants in the Micro-ITT 
population who also meet all of the criteria for the PP population. 
Analyses in this population will be grouped by the treatment to which they were treated. 


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4.6 
Safety Population 
The Safety population will consist of all randomized participants who receive any amount of 
study drug. All safety analyses will be conducted in this population and will be presented in 
the summary tables by the treatment the participants actually received. If a participant 
received both CRS3123 and vancomycin then that participant will be included in the 
CRS3123 arm for summaries in the Safety population. If the participant received both doses 
of CRS3123, the participant will be included in the 400 mg group for summaries in the 
Safety population. 
4.7 
Pharmacokinetic Population (PK-Plasma and PK-Fecal) 
The Plasma Pharmacokinetic Population will consist of all participants who receive at least 1 
dose of CRS3123 and have at least 1 evaluable postdose plasma sample for analysis.  
The Fecal Pharmacokinetic Population will consist of all participants who receive at least 1 
dose of CRS3123 and have at least 1 evaluable postdose fecal sample for analysis.  
4.8 
Population Determination  
Inclusion into the ITT, Micro-ITT, Safety, PP and ME populations will be determined 
programmatically from the eCRF data. Inclusion into the PK populations will also be 
determined programmatically based on the presence of at least one evaluable record from the 
external PK plasma and fecal files. 
The Medical Monitor and/or other sponsor designees will review the programmatic 
population determinations used to confirm inclusion and exclusion of participants into each 
of the analysis populations. Reviewers will be blinded to treatment assignment and will 
review the data concurrent with the conduct of the study. All study populations will be 
identified and finalized after database lock, but prior to study unblinding. The only exception 
is if subjects are determined to have taken the wrong study drug after study unblinding, they 
will be excluded from the PP population.  
 
 
 


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5 DEFINITION OF OUTCOME MEASURES 
5.1 
Definition of Efficacy Endpoints 
A general overview of the efficacy endpoints is defined in Table 2.  
Table 1: Clinical Response – Primary and Secondary Endpoints 
Endpoints 
Definition 
Primary 
Rate of clinical cure at TOC in 
the ITT populationa 
Clinical cure is defined as survival through TOC and resolution of diarrhea 
(ie, < 3 unformed bowel movements [UBM] [Bristol Stool Scale score of 5, 
6, or 7] at EOT with maintenance of resolution through TOC and no further 
requirement (in the investigator’s judgment) for treatment for CDI through 
TOC. 
Clinical failure is defined as persistence of diarrhea (≥ 3 UBM per day), or 
treatment with anti-CDI standard of care at any time through TOC. Return 
of diarrhea after an initial response, or mortality prior to TOC is also 
considered a clinical failure.  
Note that this endpoint is based on Table 6 . 
Secondary 
Rate of clinical cure at TOC in 
the Micro-ITT, PP, and ME 
populationsa 
Same as for the primary endpoint, above. 
Rate of clinical cure at TOC as 
assessed by the investigator in 
the ITT, Micro-ITT, PP, and 
ME populationsb 
Investigator’s assessment of clinical response (See Table 4 for more 
details). 
Rate of total relief of 
symptoms of CDI at TOC in 
the Micro-ITT, PP, and ME 
populationsb 
Defined at TOC as resolution (< 3 per day) of UBMs (ie, return to Bristol 
Stool Scale scores 1-4 recorded on the Participant Daily Diary), an 
investigator’s assessment of clinical cure, and the resolution of signs or 
symptoms of CDI recorded at baseline (ie, including fever [>37.7 °C], 
abdominal pain (as assessed by the investigator), and 
WBC > 15,000 cells/mm3). 
Time to resolution of diarrhea 
(through TOC) in the 
Micro-ITT, PP, and ME 
populations  
 
 
 
 
The time to resolution of diarrhea is defined as the time elapsed from 
randomization to the last UBM before 2 consecutive days of < 3 UBM 
(Bristol Stool Scale score of 5, 6, or 7) per day through TOC. 


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Endpoints 
Definition 
Rate of early recurrence of 
CDI through FUV2 in the 
Micro-ITT and ME 
populationsc 
Rate of early recurrence of CDI is defined as a new episode of diarrhea 
(≥ 3 UBM [Bristol Stool Scale score of 5, 6, or 7] in a 24-hour period) with 
a positive toxin result and requires retreatment for CDI before FUV2. 
Recurrence will be indicated as clinical failure by the investigator on the 
eCRF. 
Rate of late recurrence of CDI 
(between FUV2 [Day 40 Visit] 
and FUV3 [Day 70 Visit]) in 
the Micro-ITT and ME 
populationsc 
Rate of late recurrence of CDI is defined as a new episode of diarrhea (≥ 3 
UBM [Bristol Stool Scale score of 5, 6, or 7] in a 24-hour period), with a 
positive toxin result and requires retreatment of CDI between FUV2 (Day 
40 Visit) and FUV3 (Day 70 Visit). 
Recurrence will be indicated as clinical failure by the investigator on the 
eCRF. 
Rate of recurrence of CDI 
through FUV3 [Day 70 Visit] 
in the Micro-ITT and ME 
populationsc 
Rate of recurrence of CDI is defined as a new episode of diarrhea (≥3 
UBM [Bristol Stool Scale score of 5, 6, or 7] in a 24-hour period) with a 
positive toxin result and requires retreatment for CDI at any point between 
TOC/FUV1 and FUV3 [Day 70 Visit]. 
Recurrence will be indicated as clinical failure by the investigator on the 
eCRF. 
Time to recurrence of CDI 
though FUV3 [Day 70 Visit] 
in the Micro-ITT and ME 
populations 
Time to recurrence of CDI is defined as the number of days from clinical 
cure at TOC to a new episode of diarrhea (ie, ≥ 3 UBM [Bristol Stool Scale 
score of 5, 6, or 7] (as evaluated by the clinician at the unscheduled 
Suspected Recurrence Visit) in a 24-hour period with a positive toxin result 
and requires retreatment for CDI prior to FUV3 [Day 70 Visit]. 
Rate of global cure in the 
Micro-ITT, PP, and ME 
populationsc  
Global cure is defined as a clinical cure at TOC without recurrence through 
FUV2. 
a. Response will be determined programmatically according to Table 6.  
b. Investigator’s assessment of response will be determined according to Table 4.  
c. Response will be determined programmatically according to Table 6.  
5.2 
Clinical Response Definitions for Investigator Assessment of Responses 
The investigator’s assessment of clinical response at EOT, TOC, and post-TOC visits will be 
classified as defined in the following tables and will be recorded in the eCRF. Once the 
participant is classified as a failure at TOC or subsequent visits, this assessment is carried 
forward to subsequent assessments, and investigator assessments of response are no longer 
needed for this participant at subsequent visits.  
Table 2: Clinical Response – Investigator’s Assessment at EOT 
Assessment  
Definition  
Clinical Cure  
Clinical cure is defined as resolution of diarrhea (i.e., < 3 UBM 
[Bristol Stool Scale score of 5, 6, or 7]) and no treatment with non-
study medication (anti-CDI standard of care) through the EOT 
visit.  


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Clinical Failure  
Clinical failure is defined as persistence of diarrhea (≥ 3 UBM per 
day) or treatment with non-study medication (anti-CDI standard of 
care) through the EOT visit.  
Indeterminate  
Participants for whom study data are unavailable for evaluation of 
clinical response at EOT for any reason (e.g., missing data, lost to 
follow-up, did not attend the clinic appointment).  
Abbreviations: CDI = C. difficile infection; EOT = end of treatment; UBM = unformed bowel movements. 
Table 3: Clinical Response – Investigator’s Assessment at TOC (FUV1) 
Assessment 
Definition 
Clinical Cure 
Clinical cure is defined as survival through TOC and resolution of 
diarrhea (i.e., < 3 UBM [Bristol Stool Scale score of 5, 6, or 7] at 
EOT with maintenance of resolution through TOC and no further 
requirement (in the investigator’s judgement) for treatment for 
CDI.  
Clinical Failure 
Clinical failure is defined as persistence of diarrhea (≥ 3 UBM per 
day) after initial response, or the treatment with non-study 
medication (anti-CDI standard of care), or mortality through TOC.  
Indeterminate 
Participants for whom study data are unavailable for evaluation of 
clinical response at TOC for any reason (e.g., missing data, lost to 
follow-up, did not attend the clinic appointment). 
Abbreviations: CDI = C. difficile infection; TOC = test of cure (occurring at FUV1); UBM = unformed bowel 
movements. 
 
 
 


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Table 4: Clinical Response – Investigator’s Assessment post-TOC 
Assessment 
Definition 
Sustained Clinical Cure 
Investigator’s assessment of clinical cure at TOC (as defined in 
Table 4, above), no recurrence between TOC and specified visit. 
Recurrence is defined as the return of diarrhea (≥ 3 UBM [Bristol 
Stool Scale score of 5, 6, or 7] in a 24-hour period), with a positive 
toxin result and requires retreatment for CDI through the specified 
visit. 
Clinical Failure 
Investigator’s assessment of clinical failure at TOC (as defined in 
Table 4, above), or a recurrence between TOC and the specified 
visit.   
Indeterminate 
Participants for whom study data are unavailable at for the 
specified visit for any reason (e.g., missing data, lost to follow-up, 
did not attend the clinic appointment). 
Abbreviations: CDI = C. difficile infection; FUV = Follow-up Visit; TOC = test of cure (occurring at FUV1).  
Note: Recurrence will only be assessed for participants with clinical cure at TOC. 
5.3 
Programmatic Clinical Response Definitions - Primary Efficacy Endpoint at 
TOC 
The primary efficacy endpoint for the study is clinical cure at TOC in the ITT population. 
Clinical response for this endpoint will be determined programmatically based on the 
investigator’s assessment at TOC and as outlined in Table 6.  Note that once the participant is 
classified as a failure at TOC or subsequent visits, this assessment is carried forward to 
subsequent assessments and the participant will be classified as a failure, regardless of 
whether an investigator’s assessment is available at post-TOC visits. 


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Table 5: Programmatic Clinical Response at TOC 
Clinical Cure 
Clinical cure is defined as survival through TOC and resolution 
of diarrhea (i.e., < 3 UBM at EOT with maintenance of resolution 
through TOC and no treatment with non-study medication (anti-
CDI standard of care) through TOC. 
Clinical Failure 
Clinical failure is defined as persistence of diarrhea (≥ 3 UBM 
per day) or the need for additional (non-study) medication 
(anti-CDI standard of care through TOC) or mortality prior to 
TOC. 
Recurrence of diarrhea after an initial response at any point 
through TOC is also considered a clinical failure. Additionally, 
participants who are classified as clinical cure at TOC on the 
eCRF but take a potentially effective anti-CDI treatment through 
TOC (e.g., metronidazole, vancomycin, fidaxomicin, 
bezlotoxumab, or microbiota restoration therapy [MRT]) will be 
programmatically classified as clinical failure. 
Indeterminate 
Participants who meet any of the following criteria will also be 
programmatically classified as indeterminate: 
• 
Participants for whom study data are unavailable for 
evaluation of clinical response at TOC for any reason (e.g., 
missing data, lost to follow-up, did not attend the clinic 
appointment)  
• 
Participants who are classified as clinical failure on the eCRF 
at TOC, but take medication or receive therapy that can alter 
normal gastrointestinal (GI) flora (e.g., systemic antibiotics 
for infections other than CDI) or receive therapy that can 
cause diarrhea (e.g., laxatives or tube feeds) through TOC 
• 
Participants who are classified as clinical cure on the eCRF at 
TOC, but take medication that can cause constipation or 
decrease in stool frequency (e.g., Imodium) through TOC 
Abbreviations: CDI = Clostridioides difficile infection; TOC = test of cure; UBM = unformed 
bowel movements  
5.4 
Programmatic Clinical Response Definitions: EOT, FUV2, and FUV3 
The protocol also calls for the same programmatic clinical response definitions to be derived 
for EOT and FUV2; these are provided Table 7 and Table 8. 


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Table 6: Programmatic Clinical Response at EOT 
Clinical Cure  
Clinical cure is defined as survival through EOT and resolution 
of diarrhea (i.e., < 3 UBM [Bristol Stool Scale score of 5, 6, or 7] 
per day) with maintenance of resolution through EOT and no 
treatment with non-study medication (anti-CDI standard of care) 
through EOT. 
Clinical Failure 
Clinical failure is defined as persistence of diarrhea (≥ 3 UBM 
per day) or the need for additional (non-study) medication 
(anti-CDI standard of care through EOT) or mortality through 
EOT. 
Recurrence of diarrhea after an initial response at any point 
through EOT is also considered a clinical failure. Additionally, 
participants who are classified as clinical cure at EOT on the 
eCRF but take a potentially effective anti-CDI treatment through 
EOT (e.g., metronidazole, vancomycin, fidaxomicin, 
bezlotoxumab, or MRT) will be programmatically classified as 
clinical failure. 
Indeterminate 
Participants who meet any of the following criteria will also be 
programmatically classified as indeterminate: 
• 
Participants for whom study data are unavailable for 
evaluation of clinical response at EOT for any reason (e.g., 
missing data, lost to follow-up, did not attend the clinic 
appointment)  
• 
Participants who are classified as clinical failure on the eCRF 
at EOT, but take medication or receive therapy that can alter 
normal GI flora (e.g., systemic antibiotics for infections other 
than CDI) or receive therapy that can cause diarrhea (e.g., 
laxatives or tube feeds) through EOT 
• 
Participants who are classified as clinical cure on the eCRF at 
EOT, but take medication that can cause constipation or 
decrease in stool frequency (e.g., Imodium) through EOT 
Abbreviations: CDI = Clostridioides difficile infection; eCRF = electronic CRF; EOT = end of 
treatment; MRT= microbiota restoration therapy; GI = gastrointestinal; UBM = unformed bowel 
movements  


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Table 7: Programmatic Clinical Response post TOC/FUV1 
Sustained Clinical Cure 
Clinical cure at TOC, no recurrence between TOC and specified 
visit, and no further anti-CDI standard of care therapy through 
specified visit. 
Clinical failure 
All participants programmatically classified as a clinical failure at 
TOC, will be automatically classified as failures at the specified 
visit. Recurrence of diarrhea between the initial response and the 
specified visit is considered a clinical failure at the specified visit 
unless diarrhea has a proven cause other than C. difficile.  
Additionally, participants who are classified as clinical cure at the 
specified visit on the eCRF but take a potentially effective anti-
CDI standard of care treatment (e.g., metronidazole, vancomycin, 
fidaxomicin, bezlotoxumab, or MRT) at any point through the 
specified visit will be programmatically classified as clinical 
failure. 
Indeterminate 
Participants who meet any of the following criteria will be 
programmatically classified as indeterminate: 
• 
Participants for whom study data are unavailable for the 
specified visit for any reason (e.g., missing data, lost to 
follow-up, did not attend the clinic appointment)  
• 
Participants who are classified as indeterminate at TOC will 
be classified as indeterminate at the specified visit unless they 
have previously been classified as a failure, (in which case 
these subjects will classified as failure) 
• 
Participants who are classified as clinical failure on the eCRF 
at the specified visit, but take medication or receive therapy 
that can alter normal GI flora (e.g., systemic antibiotics for 
infections other than CDI) or receive therapy that can cause 
diarrhea (e.g., laxatives or tube feeds) through the specified 
follow-up visit 
• 
Participants who are classified as sustained clinical cure on 
the eCRF at the specified visit, but take medication that can 
cause constipation or decrease in stool frequency (e.g., 
Imodium) through the specified visit 
Abbreviations: CDI = Clostridioides difficile infection; eCRF = electronic CRF; MRT= 
microbiota restoration therapy; FUV1 = Follow-up Visit 1; GI = gastrointestinal; TOC = test of 
cure  
5.5 
CDI-DaySymsTM 
Health-Related Quality of Life will be assessed using the CDI-DaySymsTM instrument which 
is a valid measure of these patient-reported CDI symptoms (Kleinman et al., 2018 and also 
Talbot et al., 2019). The CDI-DaySymsTM questionnaire will be included as part of the 
Participant Daily Diary and will be filled out by the participant daily from screening through 


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TOC/FUV1.  The self-administered questionnaire measures a broad range of CDI symptoms 
that focus on the burden and/or impact of CDI on patients’ lives. The questionnaire consists 
of a total of 10 CDI symptoms categorized into 3 domains (diarrhea symptoms, abdominal 
symptoms, and systemic/other symptoms). Each item is scored on a 5-point Likert scale 
(none = 0, mild = 1, moderate = 2, severe = 3, and very severe = 4), and the scores within 
each domain are averaged to provide 3 separate domain scores.  
The Diarrhea Symptoms domain is calculated by averaging the scores from the first 3 
questions (diarrhea, need to empty bowels right away, need to go to the bathroom more than 
usual).  The Abdominal Symptoms domain is calculated by averaging the scores from items 
4 through 6 (abdominal cramping, abdominal pain, feeling bloated). The Systemic/Other 
Symptoms domain is calculated by averaging the scores from items 7-10 (feeling tired, lack 
of energy, lightheadedness, lack of appetite).  For the Diarrhea Symptoms domain, if Item 1 
(diarrhea) is available, then a domain score is calculated even if Items 2 and 3 are missing.  
In all other cases, if greater than 50% of the items are missing, then the Diarrhea Symptoms 
domain is marked as missing.  For the Systemic/Other Symptoms Domain Score, the domain 
score is only calculated if none of the 4 items are missing.  For the Abdominal Symptoms 
Domain, the domain score will be calculated as long as 2 of the 3 items are available. These 
missing data calculation rules are based on Talbot et al., 2019 and communication with the 
FDA. 
6 STATISTICAL METHODS AND GENERAL CONSIDERATIONS 
6.1 
Sample Size 
This study is not powered for a hypothesis test. Rather the sample size was chosen in order to 
provide a reasonable estimate of the rate of clinical cure at TOC to allow for planning of 
future studies. This study will provide an initial assessment of safety and efficacy data to 
inform the future development of CRS3123.  
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). Alternatively, if 12 participants are enrolled in each CRS3123 treatment arm and 
the true rate of clinical cure at TOC is 0.83, then the 95% exact CI for the rate is (0.52, 0.98). 
6.2 
Randomization and Masking 
Participants will be randomly assigned in a 1:1:1 ratio to one of three treatment arms: 
CRS3123 200 mg po bid (i.e., 400 mg/day), CRS3123 400 mg po bid (i.e., 800 mg/day), or 
vancomycin 125 mg po qid (i.e., 500 mg/day). Randomization will be stratified by first 
episode or by first recurrence of CDI. All participants will be centrally assigned to 
randomized study treatment with an IRT. Before the study is initiated, login information and 


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directions for the IRT will be provided to each site. Approximately 30 to 36 participants are 
planned per treatment arm, for a total of approximately 90 to 108 participants for the study.   
After informed consent has been obtained and study eligibility established, the IRT will 
assign a randomization number to that participant. The IRT will also assign an appropriate 
blister pack of double-blind study treatment that will be available at the site for that 
participant and visit. The blinded study site’s pharmacist or designee will obtain the 
randomization number from the IRT. Once the IRT provides the randomization number, the 
participant is considered randomized regardless of whether the participant ultimately receives 
the study treatment. 
Once a randomization number has been assigned to a participant, the number cannot be 
reused even if the participant discontinues the study early or withdraws prior to receiving any 
interventional treatment. Participants who discontinue from the study or who have been 
previously randomized in the study will not be permitted to re-enter and will not be replaced. 
Similarly, investigational product dispensed to the participant may not be reused during the 
study, even if the blister pack is returned unopened. 
Those blinded to study treatment assignment throughout the study include the sponsor, CRO, 
investigator, study monitor, study statistician, study pharmacist and personnel, clinical study 
personnel participating in direct participant care and those involved in all clinical 
evaluations. Those unblinded to study treatment assignment include the bioanalytical 
laboratory, unblinded statistician or programmer, and the designated investigational product 
distribution team. To minimize the potential for bias, treatment randomization information 
will be kept confidential by and from the sponsor personnel and will not be released to the 
investigator, investigational site personnel, CRO, or the study monitor until the conclusion of 
the study. 
If study treatment is determined not to be safe and/or not tolerated, the study treatment 
assignment for those participants with a significant safety concern may be unblinded. The 
investigator, Crestone medical monitor, and the InClin medical monitor will review the 
participant’s data, discuss the findings, and jointly decide to unblind the treatment 
assignment, continue, or terminate enrollment in the study. 
The blind may also be broken in the case of a medical emergency that requires the 
investigator to know the identity of the study treatment to appropriately guide the 
participant’s medical management. Before unblinding the treatment, the investigator is 
strongly advised to discuss options with the InClin medical monitor or appropriate sponsor 
study personnel. If the blind is broken for any reason and the investigator is unable to contact 
the sponsor before unblinding the treatment, the investigator must notify the sponsor as soon 
as possible, without revealing the participant’s study treatment assignment (unless important 
to the safety of participants remaining in the study). All instances of treatment unblinding 
will be thoroughly investigated and documented by a designated member of the sponsor team 
who, if they are unblinded during this process, will thereafter remain unblinded until the 
conclusion of the study. 


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In the event of a quality assurance audit, the auditor will be allowed access to unblinded 
study treatment records at the investigational product distribution sites to verify that 
randomization/dispensing has been done accurately. 
After the database is locked and the SAP is final, and all analysis populations have been 
determined, the study will be unblinded. 
6.3 
Interim Analysis 
There is no planned interim analysis of efficacy or safety for this study.   
As per the protocol, a Data Safety Monitoring Board (DSMB) will be established and 
managed in this study by the National Institute of Allergy and Infectious Diseases (NIAID); 
the DSMB will review all AEs and other safety information, as detailed in the DSMB 
charter. 
6.4 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
• Baseline – A baseline value is the last non-missing value recorded prior to the first dose 
of study drug. For subjects who never get dosed, the screening measurements will be the 
baseline. If an assessment has both a date and time that exactly match the date and time 
of first dose of study drug, this assessment will be counted as baseline.  
• Change from baseline – Change from baseline will be calculated for each subject at the 
specified time point as the value at the specified time point minus that subject’s baseline 
value. 
• Study day – For a given date (date), the study day is calculated as days since the date of 
first dose of study drug (firstdose). 
o Study day = date – firstdose + 1, where date ≥ firstdose  
o Study day = date – firstdose, where date < firstdose 
• Days – Durations, expressed in days, between one date (date1) and another later date 
(date2) are calculated using the following formula: duration in days = (date2-date1+1). 
• Body Mass Index – BMI (kg/m2) = weight (kg) / [[height (cm)/100]2]. 
• Age, in years, will be computed from the date of informed consent and the date of birth. 


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6.5 
Handling of Missing Dates / Times and Data: 
All missing data and missing and partial dates for events occurring after randomization or for 
medications received after randomization will be queried for a value.  If no value can be 
obtained missing data will be handled as outlined below.  
• All AEs with partial or missing dates and times will be considered treatment emergent 
unless a partial start date and/or time indicates the AE began prior to the start of study 
medication or a stop date indicates the AE ended prior to the start of study medication. 
• The severity and causality assessment for adverse events should not be missing and will 
be queried for a value. Should there be missing data, adverse events with missing severity 
will be considered severe and adverse events with missing relationship to study drug will 
be considered related to study drug. 
• All medications with partial or missing dates and times recorded on the concomitant 
medication eCRF will be considered concomitant unless a partial stop date and time 
clearly indicates it was stopped before the first dose of study treatment. 
• For the Investigator’s assessment of clinical response, subjects will be defined as 
indeterminate if the Investigator cannot determine whether the subject is a clinical 
cure/improvement or failure or if any data is missing to make a determination.  
• Missing values for other individual data points will remain as missing. Missing values 
will not be imputed and only observed values will be used in data analyses and 
presentations. 
• Where individual data points are missing, categorical data will be summarized based on 
reduced denominators (i.e., only subjects with available data will be included in the 
denominators). 
6.6 
Comments on Statistical Analysis 
The following general comments apply to all statistical analyses and data presentations: 
• All listings will be presented by treatment assigned and sorted by ascending subject 
number within these. All relevant data captured on the eCRFs and external data sources, 
including specific descriptions of ‘other’ and comments fields will be included on the 
listings. 
• All summary tables will be presented by treatment arm. Summary tables presenting 
results by study visit will include all scheduled study visits using informative visit labels. 
For baseline tables (excluding MIC tables) and safety tables, results will also be 
presented for both CRS3123 groups combined. 


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• Continuous variables will be summarized using number (n), mean, standard deviation 
(SD), median, minimum, and maximum. Summaries of PK plasma concentrations will 
also include the geometric mean (GM) and coefficient of variation (CV). 
• Frequency counts and percentages will be reported for all categorical data.  
• If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (e.g., a character string is reported for a parameter of the numerical type), 
a coded value must be appropriately determined and used in the statistical analyses. In 
general, a value or lower and upper limit of normal range such as ‘<10’ or ‘≤ 5’ will be 
treated as ‘10’ or ‘5’ respectively, and a value such as ‘>100’ will be treated as ’100’. 
However, the actual values as reported in the database will be presented in data listings. 
• For all “by visit” safety tables (e.g., laboratory values, vital signs, ECGs), nominal visits 
will be summarized. In addition, within tables that summarize changes from baseline, the 
minimum and maximum post-baseline values will be summarized to take unscheduled 
visits into account. 
• Version 9.4 (or higher) of SAS statistical software package will be used to provide all 
summaries, listings, graphs, and statistical analyses. 
• Exact confidence intervals around proportions will use the Clopper-Pearson method. 
• Confidence intervals around differences of proportions will use the Miettinen & 
Nurminen method. 
The analyses described in this plan are considered a priori, in that they have been defined 
prior to database lock. Any analyses performed subsequent to this will be considered post-
hoc and exploratory. Post-hoc analyses will be labeled as such on the output and identified in 
the CSR. 
 
 


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7 STATISTICAL ANALYSES 
7.1 
Screening, Analysis Populations, and Subject Disposition 
The number and percentage of subjects included in each of the analysis populations (ITT, PP, 
Safety, Micro-ITT, ME, PK-Plasma, PK-Fecal) will be summarized by treatment group in the 
Enrolled Analysis Set.  The number of subjects screened and the reasons for screen failures 
will also be summarized. A table will summarize the reasons for exclusion from each 
population and a listing will be provided that indicates each subject’s inclusion/exclusion 
from the analysis population and the reason for exclusion from each analysis population.  
The number and percentage of subjects completing the study, prematurely discontinuing 
from study drug, and prematurely withdrawing from the study will be presented for each 
treatment group for the ITT, Safety, and ME populations. Reasons for premature 
discontinuation of study drug, and/or premature withdrawal from the study, as recorded on 
the eCRF will be summarized (number and percentage) by treatment group. 
A listing of all subjects who prematurely discontinued from study drug or prematurely 
withdrew from the study will be presented, and the primary reason for discontinuation of 
study drug or withdrawal from the study will be provided. In addition, a listing will be 
provided for all subjects that shows inclusion into each of the analysis populations, as well as 
a listing of inclusion and exclusion findings. 
7.2 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics will be presented by treatment group in the 
ITT, Safety, Micro-ITT, and ME analysis populations. A table will present the subject 
demographics (e.g., gender, age, age category [18- <65, ≥65) ethnicity, and race) and 
baseline characteristics (height, weight, BMI, C-Reactive protein, and number of subjects 
with WBC >15,000 cells/mm3) collected before the start of study drug as well as the 
subject’s type of CDI episode (Primary versus First Recurrence), and the randomized “CDI 
episode” stratum (Primary versus First Recurrence). 
A demographic data listing, which includes the date the informed consent was signed, will 
also be provided. 
7.3 
Medical and Surgical History 
Medical history will be coded using the Medical Dictionary of Regulatory Activities 
(MedDRA) classification, version 23.1. Medical and surgical history will be summarized for 
the ITT Population and Safety population by system organ class, preferred term, and 
treatment group. Subjects reporting the same system organ class or preferred term more than 
once will be counted only once for that system organ class and preferred term.  
A listing of medical and surgical history will be provided. 


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7.4 
Prior and Concomitant Medications  
All other prescription medications and over-the-counter medications, including herbal, 
nutritional, and dietary supplements (e.g., any antacid, iron supplement, or multivitamin) or 
vaccines administered between randomization and the end of the study will be documented in 
the eCRF. All prior antibiotic therapies taken within 30 days prior to screening, and systemic 
corticosteroids taken within 2 weeks prior to screening will also be recorded. 
Verbatim terms on case report forms will be mapped to Anatomical/Therapeutic/Chemical 
(ATC) class and Generic Drug Names using the World Health Organization (WHO Drug–
WHO GLOBAL B3 2020-09-01) dictionary.  
Prior medications are those medications taken before the first dose of study drug.  
Concomitant medications are those medications taken at the start of study drug or initiated 
after the initial dose of study drug, or medications that were initiated prior to the start of 
study drug and continue to be taken after study drug is administered.  
The proportion of subjects who receive the following prior and concomitant medications will 
be summarized by ATC level 3 class, preferred term, and treatment group in the Safety and 
ITT populations: 
• Prior medications taken amongst All Subjects (ITT, Safety populations) 
• Prior CDI medications taken amongst All Subjects (ITT, mITT)  
• Concomitant medications taken amongst All Subjects (ITT, Safety Population) 
Subjects will be counted only once for an ATC class and preferred term. 
A listing will be provided of all prior and concomitant medications received, and will include 
the reason for receiving, dose, frequency, and route. A separate CDI history listing will be 
provided including the type of CDI episode, when the primary episode occurred, and the CDI 
medications. 
7.5 
Randomization, Study Drug Exposure and Compliance 
Subjects are randomly assigned to treatment in one of three treatment arms in a 1:1:1 ratio as 
per the following table. On the Participant Daily Diary, the subjects should record any 
missing doses. If vomiting occurs within 15 minutes of dosing, then that dose is considered a 
missed dose. 


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Table 8: Treatment Arms and Subject Dosing Regimen 
Arm 
Study Treatment, Dose, Duration 
Study Treatment Administration 
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 
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 
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 
Abbreviations: bid = twice daily; po = Oral; h = hours; qid = 4 times daily, q6h = every 6 hours. 
A listing of all randomized participants will be provided.  The listing will include the 
randomized CDI episode (Primary versus First Recurrence) as well as the participant’s actual 
type of CDI episode. The randomized and actual CDI episode should be identical unless 
there are errors in the randomization stratum.   
• The duration of treatment and study drug compliance will be summarized in the ITT and 
Safety populations.  The number of Oral Doses (i.e., capsules) taken over each 24-hour 
dosing period (maximum of 4 doses a day) for a total potential number of 60 capsules per 
subject will be summarized as well. 
• Duration of Treatment: ‘Defined as the number of calendar days from when the subject 
first received study treatment until the last data study treatment was received and is 
calculated as (date of last dose – date of first dose +1).   
• Compliance to Study Drug: ‘Calculated based on the total number of capsules taken for a 
subject, divided by the total number of expected capsules (60).  Compliance is calculated 
as follows: 
Compliance (%) = 100 x (Number of capsules taken)
60
. 
• Number of Subjects ≥80 % compliance 
• Number of Subjects < 80 % compliance 
 


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All exposure and dosing data will also be provided in by-subject listings. Drug accountability 
information will be listed. 
7.6 
Efficacy Analyses 
The primary and secondary efficacy endpoints are identified in Table 10. 
Table 9: Efficacy Endpoints 
 
Efficacy Populations 
 
ITT 
micro-
ITT 
PP 
ME 
Primary: 
 
 
 
 
Rate of clinical cure at TOC 
√ 
 
 
 
Secondary and Exploratory: 
 
 
 
 
Rate of clinical cure at TOC 
 
√ 
√ 
√ 
Rate of clinical cure at TOC as assessed by the 
investigator  
√ 
√ 
√ 
√ 
Rate of total relief of symptoms of CDI at TOC  
 
√ 
√ 
√ 
Time to resolution of diarrhea through TOC  
 
√ 
√ 
√ 
Rate of early recurrence of CDI through FUV2 (Day 40)  
 
√ 
 
√ 
Rate of late recurrence of CDI between FUV2 (Day 40) 
and FUV3 (Day 70) 
 
√ 
 
√ 
Rate of recurrence of CDI through FUV3 (Day 70) 
 
√ 
 
√ 
Time to recurrence of CDI though FUV3 (Day 70) 
 
√ 
 
√ 
Rate of global cure (clinical cure at TOC and no 
recurrence through FUV2 [Day 40]) 
 
√ 
√ 
√ 
CDI= Clostridioides difficile infection; EOT = end of treatment; FUV=follow-up visit; ITT = intent-to-treat; 
ME = microbiologically evaluable; micro-ITT = microbiological intent to treat; PP=per-protocol; TOC=test of 
cure 
7.6.1 
Primary Efficacy Analysis 
The primary efficacy analysis is an examination of the (programmatic) rate of clinical cure 
(Table 6) in the CRS3123 groups versus the rate of clinical cure in the vancomycin group at 
TOC in the ITT population. The number and percentage of clinical cure, clinical failure and 
indeterminate responses will be summarized by treatment group and an exact 95% CI and 
will be provided for the clinical cure rates in each treatment group. For each of the CRS3123 
dosing groups, 95% CIs for the difference between the clinical cure rates versus the 
vancomycin group will be calculated using the Miettinen & Nurminen method. A summary 


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of reasons for programmatic clinical failure and indeterminate response at the TOC Visit will 
also be provided in the ITT population. 
7.6.1.1 
Additional Analyses for Clinical Cure at TOC 
In addition, the rates of clinical cure at TOC will be summarized by randomization stratum in 
the ITT population. 
The following two sensitivity analyses will also be conducted in the ITT population. 
• Sensitivity analysis #1:  The primary efficacy analysis will be repeated but subjects 
whose TOC visit occurs less than 2 days from the last dose of study drug will categorized 
as indeterminate. 
• Sensitivity analysis #2: The primary efficacy analysis will be repeated but subjects who 
have >3 UBM as reported in the subject diary in any 24-hour period from the last dose of 
study drug date to the TOC visit date will be categorized as indeterminate.  
7.6.2 
Secondary Efficacy Analyses 
For all secondary endpoints that are rates, these will be summarized by treatment arm in the 
relevant populations and exact 95% CI will be provided for the rates in each treatment group. 
Additionally, for each of the CRS3123 dosing groups, 95% CIs for the difference between 
the clinical cure rates versus the vancomycin group, will be calculated using the Miettinen & 
Nurminen method. 
Additionally, all primary and secondary efficacy endpoints will be accompanied by subject 
listings. 
7.6.2.1 
Rate of (programmatic) clinical cure at TOC 
The rate of (programmatic) clinical cure will also be summarized in a similar manner as 
outlined in Section 7.6.1 for the micro-ITT, PP and ME populations. 
The rate of programmatic clinical cure will also be summarized in a similar manner by CDI 
Episode (Primary or First Recurrence) in the ITT population. 
7.6.2.2 
 Investigator’s assessment of clinical cure at TOC 
The Investigator’s assessment of clinical cure will be as described in Table 4. The number of 
subjects with an Investigator’s assessment of clinical cure, clinical failure, and indeterminate 
at TOC will be summarized at TOC for both treatment groups in the ITT, micro-ITT, PP and 
ME populations. Note subjects with an indeterminate response at TOC will be excluded from 
summaries in the ME populations.  


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7.6.2.3 
Rate of total relief of symptoms of CDI at TOC 
The total relief of symptoms of CDI at TOC is achieved when all the following criteria are 
met:  
• the resolution of UBMs (< 3 per day with Bristol Stool Scale scores 1-4 recorded on the 
Participant Daily Diary on the calendar day of the TOC visit)  
• an investigator’s assessment of clinical cure,  
• resolution of signs or symptoms of CDI recorded at baseline of: 
o no fever [>37.7 °C]  
o no abdominal pain 
o WBC <15,000 cells/mm3.  
The resolution of abdominal pain as assessed by the investigator will be used. If the 
investigator’s assessment of abdominal pain is missing, then the abdominal pain assessment 
from the patient diary will be used. Persistence of any parameter will be classified as non-
total relief. If the Bristol stool score reported on the patient diary is missing or is different 
from the Investigator’s assessment then only the Investigator’s assessment will be used to 
determine total relief of symptoms. If any of the other criteria listed above are missing, then 
these participants will be classified as indeterminate.   
The percentage of subjects with total relief of symptoms of CDI at TOC will be summarized 
by treatment group in the micro-ITT, PP, and ME populations. 
7.6.2.4 
Time to resolution of diarrhea through TOC  
The time to resolution of diarrhea is defined as, the time elapsed in (decimal) days, from the 
randomization to the last UBM before 2 consecutive days of < 3 UBM (Bristol Stool Scale 
score of 5, 6, or 7) per day through TOC. As an example: if a subject was randomized on Day 
1 at 10 AM and has their first 2 days of < 3 UBMs on Day 8 and Day 9, and if the last UBM 
on Day 8 was at 10 pm, then this subject would have a time to resolution of diarrhea of 180.0 
hours or 7.5 days.  If a subject never has resolution of diarrhea trough TOC, then the time to 
resolution of diarrhea is censored as the time of the last bowel movement on or prior to TOC. 
Kaplan-Meier, time to event analysis will be used to compare the treatment groups.  When 
the event is not observed, the last date and time the subject reported ‘no resolution’ (i.e.≥ 3 
UBM with a Bristol Stool Scale score of 5, 6, 7) will be used as the censored time 
measurement. The “no resolution” date and time will coincide with the last reported UBM 
date and time. The Investigator Assessment form and the Participant Daily Diary form will 
be used to assess the last available date without resolution through the TOC visit.  Kapan-


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Meier Survival figures will be produced displaying the survival (step-down) curves for the 3 
treatment groups. These KM figures and summaries will be completed for the micro-ITT, PP 
and ME populations. 
7.6.2.5 
Rate of early recurrence of CDI through FUV2 (Day 40 visit) 
Early recurrence of CDI is defined as the return of diarrhea (≥3 UBM [Bristol Stool Scale 
score of 5, 6, or 7] in a 24-hour period), a stool sample positive for C. difficile Toxin A 
and/or B, and requires retreatment for CDI before FUV2. Recurrence will be indicated as 
clinical failure by the investigator on the eCRF. Additionally, subjects who are treated with 
an anti-CDI medication prior to FUV2 will be programmatically classified as recurrences and 
failures, even if clinical failure is not indicated on the eCRF.  
Only subjects who were a clinical cure at TOC (programmatic clinical cure) and had no 
recurrence thorough FUV2 will be assessed for early recurrence. 
The number and percentage of subjects with early recurrence of CDI through FUV2 will be 
summarized by treatment groups in the micro-ITT and ME populations. 
7.6.2.6 
Rate of late recurrence of CDI between FUV2 (Day 40) and FUV3 (Day 70) 
Late recurrence of CDI is defined as the return of diarrhea (≥3 UBM [Bristol Stool Scale 
score of 5, 6, or 7] in a 24-hour period), a stool sample positive for C. difficile Toxin A 
and/or B, and requires retreatment of CDI between FUV2 (Day 40) and FUV3 (Day 70).  
Recurrence will be indicated as clinical failure by the investigator on the eCRF. Additionally, 
subjects who are treated with an anti-CDI medication between FUV2 and FUV3 will be 
programmatically classified as recurrences and failures. 
If a subject has an early recurrence, then late recurrence will be undefined. Only subjects 
who were a clinical cure at TOC (programmatic clinical cure based on the Investigator’s 
assessment) and had no recurrence thorough FUV2 will be assessed for late recurrence.  
The number and percentage of subjects with a late recurrence of CDI will be summarized by 
treatment groups in the micro-ITT and ME populations. 
7.6.2.7 
Rate of recurrence of CDI through FUV3 (Day 70 Visit) 
Recurrence of CDI is defined as the return of diarrhea (≥3 UBM [Bristol Stool Scale score of 
5, 6, or 7] in a 24-hour period), a stool sample positive for C. difficile Toxin A and/or B, and 
requires retreatment of CDI through FUV3 (Day 70 Visit). Recurrence will be indicated as 
clinical failure by the investigator on the eCRF. Additionally, subjects who are treated with 
an anti-CDI medication through FUV3 (Day 70 Visit) will be programmatically classified as 
recurrences and failures. 
Only subjects who were a clinical cure at TOC (programmatic clinical cure based on the 
Investigator’s assessment) will be assessed for recurrence through FUV3.  


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The number and percentage of subjects with recurrence of CDI through FUV3 will be 
summarized by treatment groups in the micro-ITT and ME populations. 
7.6.2.8 
Time to recurrence of CDI though FUV3 (Day 70 Visit)  
Time to recurrence of CDI is defined as the number of days from clinical cure at TOC to 
recurrence of symptoms (i.e., ≥3 UBM [Bristol Stool Scale score of 5, 6, or 7] per day, as 
evaluated by the clinician on the unscheduled Suspected Recurrence Visit), AND a stool 
sample positive for C. difficile Toxin A and/or B.  Alternatively, the criteria for recurrence 
will also be met if the subject is treated with anti-CDI standard of care prior to FUV3 (Day 
70 Visit). As an example: if a subject has clinical cure at TOC (Day 12) and suspected 
recurrence occurs at Day 25, then this will trigger a Suspected Recurrence Visit 
(unscheduled).  If the assessment at this visit confirms the presence of ≥3 UBM for 2 or more 
days, then the time to recurrence would be 13 days (25-12). Only subjects who were a 
clinical cure at TOC (programmatic clinical cure based on the Investigator’s assessment at 
TOC) will be assessed for time to recurrence of CDI through FUV3. If a subject never has 
recurrence of CDI through FUV3 then the time to recurrence of CDI is censored as the last 
available date without recurrence through the FUV3 visit.   
Time to recurrence will be assessed in the Micro-ITT and ME analysis sets. Only subjects 
with clinical cure at TOC will be included in the analysis. The analysis for this time to 
recurrence of CDI through FUV3 will be similar to the KM analysis proposed for the time to 
resolution of diarrhea (through TOC), which is detailed in Section 7.6.2.4. The methods of 
analysis are the same except that, for this secondary outcome, should recurrence of CDI 
through FUV3 not occur, then the latest date and time the participant reported ≥3 UBM or 
the Investigator specified no recurrence will be used as the censored value. The date and time 
of the first of ≥3 UBM or the investigator identified a recurrence will be used as the time of 
recurrence.  
7.6.2.9 
Rate of global cure  
Global cure (sustained clinical response) is defined as a clinical cure at TOC without 
recurrence through FUV2 (Day 40 Visit) and will be derived from the combination of the 
primary endpoint of (programmatic) ‘Rate of Clinical Cure’ and the secondary endpoint of 
the ‘Recurrence of CDI (between TOC and FUV2)’.  Any subject with a ‘clinical cure’ result 
for the former and no recurrence on the latter will be defined as a ‘global cure’. Additionally, 
subjects who are treated with an anti-CDI medication through FUV2 (Day 40 Visit) will be 
included as a subject with recurrence. The rate of global cure will be calculated as follows: 
=
(subjects with programmatic clinical cure at TOC AND no recurrence through FUV2)
(All Subjects in Analysis Set)
*100. 
The percentage of subjects with global cure will be summarized by treatment group in the 
micro-ITT, PP, and ME populations. 


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7.6.2.10 
CDI-DaySymsTM 
The CDI-DaySymsTM domain scores of: Diarrhea symptoms, Abdominal symptoms and 
Systemic/Other for 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 in the Micro-ITT and ME populations.   
All CDI-DaySymsTM question responses and domain scores will also be provided in by-
subject listings.  
 
7.7 
Microbiology Assessments 
For all patients, the central microbiology laboratory will attempt to isolate and quantitate C. 
difficile (from the initial, TOC, and recurrence episode stool samples, including early 
discontinuation due to clinical failure), and perform antimicrobial susceptibility testing.  
The number of subjects with C. difficile isolated at baseline via culture and the number who 
are toxin positive (either local laboratory or central laboratory) at each relevant visit will be 
summarized in the micro-ITT population. 
The minimum inhibitory concentrations (MICs) to CRS3123 and vancomycin will be 
summarized at baseline and each visit for subjects in the Micro-ITT and ME populations. 
MICs to CRS3123 and vancomycin will also be summarized separately at baseline and each 
visit.  MIC summary statistics.  In addition, the MIC50, MIC90 and MIC Range of CRS3123 
and vancomycin for C. difficile will be summarized by study drug for the mITT and ME 
populations. MIC50 and MIC90 are the antibiotic concentration that would inhibit the growth 
of 50% and 90% of tested isolates, respectively.   
The number of isolates with each MIC will be summarized for all collected C. difficile 
isolates for CRS3123, fidaxomicin, metronidazole, moxifloxacin, and vancomycin. 
All microbiology data will also be listed. Subjects with an MIC increase ≥4-fold over the 
baseline MIC for either CRS3123 or vancomycin will be listed. 
7.8 
Safety Analyses 
All safety analyses will be conducted in the Safety population.   
7.8.1 
Adverse Events 
Adverse events will be coded to System Organ Class (SOC) and preferred term using 
Version 23.1 of MedDRA.  
Summary tables will be provided for all treatment-emergent adverse events (TEAEs).  A 
treatment-emergent AE is defined as any AE that newly appeared, increased in frequency, or 


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worsened in severity following initiation of study drug and up through the last study visit 
(FUV3) or evaluation, or an SAE that occurs during or after the first administration of study 
drug up through 60 days after the final administration of study drug.  
The following summaries for TEAEs will be provided by treatment group: 
• An overall summary of AEs will include number and percentage of subjects in each 
treatment group who experienced at least one AE of the following categories: any AE, 
any TEAE, any drug-related TEAE (defined as possibly related and or related to study 
drug), any severe or life-threatening TEAE, any serious TEAE (SAE), any drug-related 
SAE, any SAE leading to death, and any TEAE or SAE leading to premature 
discontinuation of study drug. 
• Subject incidence of TEAEs by MedDRA system organ class and preferred term.   
• Subject incidence of TEAEs by MedDRA system organ class, preferred term, and worst 
severity/intensity (grade). 
• Subject incidence of TEAEs related to study drug by MedDRA system organ class and 
preferred term. 
• Subject incidence of serious TEAEs (SAEs) by MedDRA system organ class and 
preferred term 
Summary tables will be presented alphabetically by system organ class and preferred term 
within system organ class. For all analyses of TEAEs, if the same AE (based on preferred 
term) is reported for the same subject more than once, the AE is counted only once for that 
preferred term and at the highest severity and strongest relationship to study drug.  
In addition, all AEs (including non-TEAEs), serious AEs (SAEs), fatal SAEs, SAEs leading 
to hospitalization, and TEAEs leading to study drug discontinuation or study discontinuation 
will be provided in listings.  
7.8.2 
Laboratory Values 
Laboratory assessments for hematology, serum chemistry, and/or urinalysis will be 
performed at each visit indicated in the Schedule of Activities. Coagulation will be 
performed at screening and EOT. Assessments will be performed by a local laboratory at 
screening to ensure inclusion/ exclusion criteria are met and at the central laboratory for the 
remainder of the study. All summaries will be based on the central lab data and local 
laboratory data will only be listed. 
All laboratory parameters will be converted to the conventional units prior to summarization. 
Descriptive statistics for hematology, coagulation, chemistry, and creatinine clearance results 
and the change from baseline will be summarized for baseline and post-baseline visits.  The 


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highest and lowest post-baseline values and changes to these values will also be summarized 
for each parameter to allow for summarization of high and low values collected at 
unscheduled visits.  Change from baseline will be calculated for each subject at the specified 
visit as the value at the specified visit minus the baseline value.   
The grade of a laboratory measurement will be assigned programmatically using the CTCAE 
V5.0 (NCI-CTCAE version 5.0). Shift tables, from baseline to post-baseline visits will be 
provided by CTCAE V5.0 toxicity grade for selected chemistry, hematology, and coagulation 
parameters.  The shift to highest grade post-baseline will also be included.  
General detailed subject listings for all relevant laboratory data collected during the study 
will be provided.  All CTCAE grades will be included in the listing and laboratory values 
outside normal limits will be identified in the subject data listings with flags for low (L) and 
high (H).  
7.8.3 
Vital Signs 
Blood pressure (systolic and diastolic), respiration rate, heart rate, and temperature will be 
summarized using descriptive statistics by treatment group at each time point at which they 
were measured. Descriptive statistics of the change from baseline to each post-baseline time 
visit will also be provided as well as the change to the maximum and minimum post-baseline 
values.  
The number and percentage of subjects with abnormal values as identified by the threshold 
values provided in the table below, will be summarized by treatment group.  Only subjects 
with both baseline and post-baseline values will be summarized for diastolic blood pressure 
increases. 
All vital signs will also be provided in by-subject listings.  
7.8.4 
Electrocardiogram 
12-lead ECG recordings will be obtained at screening and EOT (after resting in a supine 
position for 10 minutes) and before collection of blood for laboratory and PK assessments.  
Additional ECGs may be performed for any participant who experienced a cardiovascular-
related significant medical event (e.g., tachyarrhythmia) during the course of the study. 
Descriptive statistics for central ECG parameters of RR interval, PR interval, QRS duration, 
QT interval, and QTcF (using the Frederica’s formula for correction) interval, as well as the 
changes from baseline will be presented by treatment group at each scheduled visit. 
In cases where QTcF is not available from an ECG machine at the study site, the eCRF value 
for QTcF will be left blank and QTcF will be calculated programmatically as follows: (QT 
interval)/(RR) 1/3. 


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For QTcF values, a distribution showing counts and percentages for the increase from 
baseline to EOT will be provided using the following categories:  <0, ≥1 - <30 msec, ≥30 - 
<60 msec, ≥60 - <90 msec, >=90 msec. Actual QTcF visit values will also be summarized 
using counts and percentages for the following categories: ≤ 450, > 450 - ≤ 480, >480 - ≤ 
500, and >500 msec). 
A listing of ECG data will also be provided and will include the tracing results of normal, 
abnormal and clinically significant status for these measurements as well as any linked AE or 
Medical History event. 
7.8.5 
Physical Examinations 
Abnormal physical examination results in each treatment group will be tabulated by body 
system for each time point at which they were measured and will be listed.   
7.8.6 
Pharmacokinetic Analyses 
Characterization of the plasma exposure by sparse sampling during the 10-day CRS3123 
course of treatment for CDI is secondary objective for this study. Additionally, fecal 
concentrations of CRS3123 will be assessed as an exploratory endpoint at selected timepoints 
as described in the Schedule of Activities. Only blood and fecal PK samples collected from 
participants randomized to CSR3123 will be analyzed. 
Plasma concentrations of CRS3123 (parent) and CRS3123-GLU3 (metabolite) will be 
measured in the collected blood samples at selected timepoints. Fecal concentrations of 
CRS3123 will also be measured. Plasma concentrations of CRS3123 and CRS3123-GLU3 
and fecal concentrations of CRS3123 will be summarized in the PK-Plasma and PK-Fecal 
populations, respectively.  These concentrations will be summarized by treatment arm using 
descriptive statistics and will be graphically displayed.  
If feasible, primary parameters will be estimated from concentration versus time data using a 
population PK approach. These parameters include Cmax, tmax, t1/2, AUC0-24, and CL/F, and 
accumulation ratio calculated using the estimated AUC0-24 on Day 10 vs. Day 1.  
Methods and analysis for the population PK analysis will be provided in separate reports. 
 
 
 


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8 REFERENCE LIST 
1. 
https://www.alere.com/en/home/about/stories/putting_c_diff_to_test-
us.html?gclid=EAIaIQobChMIlIe84sOj5QIVQdbACh2RiQVXEAAYASAAEgJn2_
D_BwE. Abbott Laboratories, Waukegan, IL. Accessed 17 October 2019. 
2. 
Kleinman, L., Talbot, G. H., Hunsche, E., Schüler, R., & Nord, C. E. (2018). The 
CDI-DaySyms: Content Development of a New Patient-Reported Outcome 
Questionnaire for Symptoms of Clostridium difficile Infection. Value in Health, 
21(4), 441–448. https://doi.org/10.1016/j.jval.2017.08.3017 
3. 
Talbot, G. H., Kleinman, L., Davies, E., Hunsche, E., Revicki, D., Roberts, L., 
Rosenberg, D., & Nord, C. E. (2019). Clostridium difficile Infection–Daily 
Symptoms (CDI-DaySymsTM) questionnaire: psychometric characteristics and 
responder thresholds. Health and Quality of Life Outcomes, 17(1). 
https://doi.org/10.1186/s12955-019-1142-9 
4. 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 5.0. National Institutes of Health, US Department of Health and 
Human Services. Published 27 Nov 2017. Available at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v
5_Quick_Reference_8.5x11.pdf  
5. 
Miettinen, O., & Nurminen, M. (1985). Comparative analysis of two rates. Statistics 
in Medicine, 4(2), 213–226. https://doi.org/10.1002/sim.4780040211 
6. 
Goorhuis, A., Bakker, D., Corver, J., et al (2008). Emergence of Clostridium difficile 
infection due to a new hypervirulent strain, polymerase chain reaction ribotype 078. Clin 
Infect Dis 47, 1162-1170. 
7. 
Merrigan, M., Venugopal, A., Mallozzi, M et al (2010). Human hypervirulent 
Clostridium difficile strains exhibit increased sporulation as well as robust toxin 
production. J Bacteriol 192, 49 
8. 
Sponsor Responses to FDA Type C Meeting (IND 146348, SN0021, 4 May 2023). 
 
 

Prot_001.pdf: 
Protocol 19-0021 
        Confidential 
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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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Protocol Amendment 7 
  
                          23 August 2023 
 
 
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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Protocol Amendment 7 
  
                          23 August 2023 
 
 
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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Protocol Amendment 7 
                                                  23 August 2023 
 
 
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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Protocol Amendment 7 
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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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Protocol Amendment 7 
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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. 

ICF_004.pdf: 
Crestone, Inc. / Protocol Number 19-0021 
Page 1 of 19   
 
 
«PiFullName» 
Advarra IRB Approved Version 3 Aug 2023 
Revised «PIApprovalDate» 
 
INFORMED CONSENT FORM 
and 
AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION 
 
 
Sponsor / Study Title: 
  
Crestone, Inc. / “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 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
This form is for use in a research study that may involve subjects who may or may not have the 
capacity to consent to take part in the study.  When the subject cannot legally consent to take 
part, pronouns “you” and “your” should be read as referring to the subject rather than the person 
(legally authorized representative) who is signing and dating this form for the subject. In cases 
where the subject’s representative gives consent, the subject should be informed about the study 
to the extent possible given his/her understanding. During the course of the study, if the subject 
regains the capacity to consent, informed consent will be obtained from the subject and the 
subject offered the ability to leave the study if desired. 
 
KEY INFORMATION 
The purpose of this research study is to test if an investigational study drug (not approved by 
the United States Food & Drug Administration) (CRS3123) is a safe and effective study 
treatment of an infection due to a bacteria called Clostridioides difficile.  This infection is 
sometimes referred to as CDI which is short for Clostridioides difficile infection (CDI).  Crestone, 
Inc. is the company sponsoring this research study with support from the National Institutes of 
Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID). 
 
The study will test two different doses of CRS3123 compared to a standard antibiotic treatment 
for this infection called vancomycin.  CRS3123 is a drug with a new way of attacking the 
bacteria that causes Clostridioides difficile infection. It is effective against many types of 


Crestone, Inc. / Protocol Number 19-0021 
Page 2 of 19   
 
 
«PiFullName» 
Advarra IRB Approved Version 3 Aug 2023 
Revised «PIApprovalDate» 
 
bacteria that cause CDI.  If enrolled, you will be asked to complete up to 5 outpatient study 
visits over 70 days. 
 
The study has a screening period to determine if you meet the required criteria to enroll in the 
study. During the study treatment period, each subject will receive capsules of study drug 
(containing CRS3123, vancomycin, or placebo) four times a day (at approximately 6-hour 
intervals) for 10 days.  The study treatment will last 10 days.  Then there will be a follow-up 
period from day 11 through day 70. 
 
Since CRS3123 has only been tested in healthy subjects, the side effects are relatively unknown 
in patients with CDI. The healthy volunteers who received either a single dose or multiple doses 
had the following most reported adverse events including: 
 
• Headache 
• Abdominal pain 
• Upset stomach 
• Diarrhea 
• Taste disturbance 
• Some changes in laboratory tests including decreased hemoglobin, liver function, 
decreased blood calcium, and blood tests that may indicate altered function of the 
pancreas. 
 
Your participation in this research study is completely voluntary, meaning that you may or may 
not choose to participate. To decide whether or not you want to be part of this research, the 
risks and possible benefits of the study are described in this form so that you can make an 
informed decision. This consent form describes the purpose, procedures, possible benefits and 
risks of the study. This form explains how your medical information will be used and who may 
see it. You may have a copy of this form to review at your convenience or to ask advice from 
others before signing and dating it. 
 
Please read this form carefully. Take your time to ask the Investigator or study staff as many 
questions about the study as you would like. The Investigator or study staff can explain words 
or information that you do not understand. Reading this form and talking to the Investigator or 
study staff may help you decide whether to take part in the study or not. If you decide to take 
part in this study, you must sign your name at the end of this form and date it. 
 
BACKGROUND AND PURPOSE 
You are being invited to participate in this research study because you have primary episode or 
first recurrence of Clostridioides difficile (C. difficile) infection referred to as CDI.  This means it 
is your first episode or that you have been treated for this infection in the past no more than 
one time before this current infection you have now. 
 


Crestone, Inc. / Protocol Number 19-0021 
Page 3 of 19   
 
 
«PiFullName» 
Advarra IRB Approved Version 3 Aug 2023 
Revised «PIApprovalDate» 
 
C. difficile is a type of bacteria, which lives in the intestines of many people and animals and is 
also present in the environment in places such as soil and water.  Diarrhea, the most common 
symptom of CDI, may be caused by the use of some antibiotic therapies causing a change to the 
normal balance of the microflora (a complex community of naturally occurring bacteria that live 
in your intestines).  When the intestinal microflora is out of balance, the C. difficile bacteria 
begin to grow and produce toxins causing diarrhea and other symptoms such as abdominal pain 
or tenderness, loss of appetite, low-grade fever, nausea and vomiting.  Sometimes CDI can 
become severe causing bloody diarrhea and even death.  It is for this reason that new 
treatments are being discovered and tested. 
 
The purpose of this research study is to: 
• 
Test the safety and effectiveness of the 2 dosages of the study drug, CRS3123, 
compared with vancomycin. 
• 
Test the amount of CRS3123 in your blood; this tells researchers how much time it takes 
for the study drug to be absorbed. 
• 
To see how well this study treatment is impacting your symptoms and the quality of 
your life by using a Health-related quality of life (HRQoL) questionnaire. 
 
This is a research study to test a new investigational drug (CRS3123). An investigational drug is 
one that is not approved by the United States Food and Drug Administration (FDA). It is being 
compared to vancomycin; this study drug may be available by prescription for CDI. 
 
A total of 30-36 subjects are planned per study treatment type, for a total of 90-108 total 
subjects for the study. 
 
WHAT WILL HAPPEN DURING THE STUDY 
Your participation in this study will last approximately 70 days and will include approximately 
up to 5 study visits to the study center. 
 
The sponsor anticipates that the total amount of blood taken for study assessments will not 
exceed 129 mL (milliliters), or about half a cup. 
 
Screening: 
Before any study-related tests and procedures are performed, you will be asked to read and 
sign and date this consent document. The following screening tests and procedures will then be 
performed to determine if you qualify to take part in this study: 
• 
An interview to collect information on your current and past medical history; current 
and recent medications you take; and information about your CDI. 
• 
You will be asked to have your temperature, blood pressure, heart rate, breathing rate, 
weight and height taken. 


Crestone, Inc. / Protocol Number 19-0021 
Page 4 of 19   
 
 
«PiFullName» 
Advarra IRB Approved Version 3 Aug 2023 
Revised «PIApprovalDate» 
 
• 
A complete physical examination evaluation will be performed and includes evaluation 
of the head, eyes, ears, nose, and throat, neck, lungs, heart, chest, abdomen, 
extremities, neurological status, and skin. 
• 
You will be asked to have an electrocardiogram (ECG) done, which is a recording of the 
electrical activity of your heart.  
• 
Blood and urine samples will be collected to test the function of your major organ 
systems. These tests will be compared to the same blood tests that are done at a later 
visit, after taking study drug. 
• 
Urine pregnancy testing will be done for all women of childbearing potential. Women 
who are post-menopausal less than one year will have a urine pregnancy test. 
• 
You will receive your Daily Diary that will capture details for each of your bowel 
movements, any missed doses of the study drug, other new medications, and the 
questions about your CDI symptoms.  The study staff will train you on how to use that 
paper booklet every day. 
• 
A stool sample will be collected at screening to determine if you have the infection and 
the type of CDI you have.  The stool sample will also be sent for cultures and analysis at 
a designated lab. 
 
If you qualify to take part in this study and go on to receive the study treatment, then the 
following will happen: 
 
Study Treatment: 
During the study treatment period, each subject will receive capsules of study drug (containing 
CRS3123, vancomycin, or placebo) four times a day (at approximately 6-hour intervals), by 
mouth, for 10 days.  Everyone will get an active study drug (either vancomycin or CRS3123).  No 
one will receive placebo alone. 
 
If you agree to participate in this study, you will be randomly assigned (like the flip of a coin) to 
receive one of the following study treatments: 
 
Arm A: CRS3123 200 milligram dose (400 mg/day) given orally at approximately 6-hour 
intervals for 10 days. 
or 
 
Arm B: CRS3123 400 milligram dose (800 mg/day) given orally at approximately 6-hour 
intervals for 10 days. 
or 
 
Arm C: Vancomycin 125 milligram dose (500 mg/day) given orally at approximately 6-
hour intervals for 10 days. 
This random assignment to a study treatment is called “randomization.”  The study treatment 
randomization will be in a 1:1:1 ratio, which means there is a 1 out of 3 chance of being 
randomized to any of the 3 arms. 
This is a “double-blind study” which means that you and your Investigator will not know which 


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study treatment you are receiving. In case of an emergency, however, the Investigator can get 
this information. 
 
Due to the difference in dosing schedules between CRS3123 (twice a day) and the standard of 
care vancomycin (four times a day) and appearance of study drugs used in the 3 Arms, placebo 
will be used to match the total number of capsules in each arm. A placebo study treatment is 
designed to appear very similar to the active study drug treatment being tested. In this study, 
the placebo looks exactly like the real study drug, but it does not have any active ingredients in 
it. When we talk about “study drug” or “study treatment” we are talking about both the 
placebo and the active study drug. 
 
You will have the following study visits and undergo the following procedures: 
 
Day 1 (Before taking Study Drug) 
• 
Vital signs including temperature, pulse rate, respiratory rate, and blood pressure. 
• 
Review of your current medications: you will be asked to list any medications that you 
have taken since your last visit. 
• 
You will be asked to give a stool sample.  Part of the stool sample will be stored for 
future analyses. 
• 
Blood samples will be collected for pharmacokinetic (PK) tests.  PK tests are research 
tests done to see how long the study drug remains in your body. 
• 
Randomization - all inclusion and exclusion criteria need to be met before 
randomization to a study treatment arm.  All participants will be randomized by a 
computer system. 
 
Day 1 (After taking Study Drug) 
• 
Routine blood tests to check your overall health. 
• 
You will be asked to give a stool sample.  Part of the stool sample will be stored for 
future analysis. 
• 
Blood samples will be collected for pharmacokinetic (PK) tests.  PK tests are research 
tests done to see how long the study drug remains in your body. The samples will be 
taken approximately 1 hour and 3 hours after taking the study drug. 
• 
You will receive your Daily Diary that will capture details for each of your bowel 
movements, date and time of study drug dosing, concomitant medications, and the 
questions about your CDI symptoms and how much of a burden they are to you.  The 
study staff will train you on how to use that paper booklet every day. 
• 
The study staff will review clinical observations during your study site visit. 
• 
You will be given enough study drug at enrollment for all ten days of dosing.  You will 
take your dose with water approximately every 6 hours as instructed by the study site 
staff. 
 
Day 2, Day 5, Day 7, Day 8, and Day 9 
• 
Complete your Daily Diary as instructed by the study site staff. 


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• 
You will take your study drug approximately every 6 hours with water and you will 
record if you missed any of the study drug in your Daily Diary. 
 
Day 3 and Day 6 – phone contact 
• 
The study site staff will contact you on the phone to capture an update on your 
symptoms, new or ongoing health problems. 
• 
Complete your Daily Diary as instructed by the study site staff. 
• 
Study drug will be taken approximately every 6 hours with water and any doses missed 
will be recorded in your Daily Diary. 
 
Day 10/day of last dose - clinic visit 
• 
Blood samples will be collected for pharmacokinetic (PK) tests.  PK tests are research 
tests done to see how long the study drug remains in your body. The samples will be 
taken pre-dose, about 2-hours post-dose, and about 4 hours post-dose. 
• 
You will be asked to have your temperature, blood pressure, heart rate, and breathing 
rate taken. 
• 
An interview to capture an update on your symptoms, new or ongoing health problems. 
• 
You will be asked to have an electrocardiogram (ECG) done, which is a recording of the 
electrical activity of your heart.  
• 
Daily Diary completion and review with study site staff.   
• 
Routine blood tests to check your overall health (about 10.5 mL [about 2 teaspoons] of 
blood will be drawn for these tests). 
• 
You will be asked to give a stool sample pre-dose and another pre-dose or post-dose.  
Part of the stool sample will be stored for future analysis. 
• 
You will return your empty study drug wallets or unused study drug to the study site 
staff. 
 
After Study Treatment: 
Because this is a research study, the study drug will be given to you only during this study and 
not after the study is over. 
 
Follow Up Visit-1, two days after last dose- clinic visit 
Height and weight will be measured 
• 
You will be asked to have your temperature, blood pressure, heart rate, and breathing 
rate taken. 
• 
A complete physical examination evaluation will be performed and include evaluation of 
the head, eyes, ears, nose, and throat, neck, lungs, heart, chest, abdomen, extremities, 
neurological status, and skin. 
• 
An interview to capture an update on your symptoms, new or ongoing health problems. 
• 
Daily Diary completion and review with study site staff.  This is the final day the diary 
will be completed unless there is suspected reoccurrence of CDI during the follow up 
period. 


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• 
Routine blood test to check your overall health. 
• 
You will be asked to give a stool sample.  Part of the stool sample will be stored for 
future analysis. 
 
Day 20 and Day 27 – phone contact 
• 
The study site staff will contact you on the phone to capture an update on your 
symptoms, new or ongoing health problems. 
 
Follow Up Visit-2, Day 40 - clinic visit 
• 
You will be asked to have your temperature, blood pressure, heart rate, and breathing 
rate  taken. 
• 
A complete physical examination evaluation will be performed and include evaluation of 
the head, eyes, ears, nose, and throat, neck, lungs, heart, chest, abdomen, extremities, 
neurological status, and skin. 
• 
An interview to capture an update on your symptoms, new or ongoing health problems. 
• 
Routine blood tests to check your overall health. 
• 
Urine pregnancy testing will be done for all women of childbearing potential. Women 
who are post-menopausal less than one year will have a urine pregnancy test. 
• 
You will be asked to give a stool sample.  Part of the stool sample will be stored for 
future analysis 
 
Follow Up Visit-3, Day 70 – phone contact 
• 
The study site staff will contact you on the phone to capture an update on your 
symptoms, new or ongoing health problems. 
 
Unscheduled Visit, Suspected Recurrence 
 
If signs and symptoms of CDI recurrences are suspected at any point in the study prior to 
Follow up Visit-3 on Day 70, you will be asked to return for an unscheduled clinic visit. 
 
• 
You will be asked to have your temperature, blood pressure, heart rate, and breathing 
rate taken. 
• 
A complete physical examination evaluation will be performed and include evaluation of 
the head, eyes, ears, nose, and throat, neck, lungs, heart, chest, abdomen, extremities, 
neurological status, and skin. 
• 
An interview to capture an update on your symptoms, new or ongoing health problems. 
• 
Daily Diary completion and review with study site staff. 
• 
Routine blood tests to check your overall health. 
• 
You will be asked to give a stool sample.  Part of the stool sample will be re-tested for C. 
difficile, and part will be stored for future analysis. 
 
EXPECTATIONS 
If you participate in this study, you will be expected to: 


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• 
Complete a Daily Diary that will capture details for each of your bowel movements, date 
and time of study drug dosing, concomitant medications, and the questions about your 
CDI symptoms. 
• 
Take your study drug as directed by the Investigator or his/her designee. Return to the 
study site for all study procedures. Continue taking all other medications as told to you 
by your doctor. 
• 
Call the study site if you are hospitalized, visit an emergency room or urgent care, your 
diarrhea returns for more than one day, or you do not feel well. 
• 
Refrain from consuming non-dietary probiotics include capsules, powders, or liquids 
that are nutraceutical probiotics [primary ingredient is bacteria or yeast]. Yogurt, 
kombucha, kimchi, kefir, brine pickles, cheese, and other foods that are considered 
“dietary probiotics” are permitted.) 
• 
Refrain from consumption of grapefruit and its juices as well as nutraceutical 
supplements containing curcumin (i.e., turmeric) until 24 hours after the last dose of 
study medication 
• 
Females: if of childbearing potential and sexually active use 2 methods of birth control 
from the screening period until 60 days after taking last dose of study drug. 
• Males: use highly effective method of birth control if female partner is of childbearing 
potential and refrain from sperm donation for 2 months after your last dose of the study 
drug. 
 
RISKS, SIDE EFFECTS, AND/OR DISCOMFORTS 
 
For CRS3123: 
CRS3123 and placebo were tested in normal healthy volunteers who received either a single 
dose or multiple doses and the most common reported adverse events included: 
• 
Headache 
• 
Abdominal pain 
• 
Upset stomach 
• 
Diarrhea  
• 
Taste disturbance 
• 
Some changes in laboratory tests including deceased hemoglobin, liver function, and 
decreased blood calcium function of the pancreas 
 
As with any drug, allergic reaction is possible which can sometimes be severe or potentially life-
threatening.  This is a possibility but, to date, no reports of allergic reactions have occurred.  
Some symptoms of allergic reactions are rash, wheezing, difficulty breathing, dizziness, fainting, 
swelling around the mouth or throat or eyes, a fast pulse, and sweating. Please seek treatment 
immediately and tell the Investigator and study staff if you have any of these symptoms, or any 
other side effects, during the study. 
 


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For Vancomycin 
Vancomycin capsules have been approved by the US Food and Drug Administration for the 
planned use and at the planned dose in this study. In studies done in humans, the most 
common side effects, occurring in at least 5% of people treated included: 
• Nausea 
• Stomach Pain 
• Vomiting 
• Diarrhea 
• Flatulence 
• Fever 
• Swelling of the legs 
• Tiredness 
• Urinary Tract Infection 
• Low blood levels of potassium 
• Back pain 
• Headache 
 
In people over the age of 65 years, there is a chance that the kidneys can be injured. This may 
be as serious as kidney failure; it may also be milder kidney impairment or just an increase in 
the blood level of creatinine, a substance that is an indicator of how the kidneys are working. 
 
There have also been cases of hearing loss or loss of balance and infections caused by bacteria 
that are resistant to vancomycin. 
 
As with any drug, allergic reaction is possible which can sometimes be severe. While this is 
possible, it is not common with vancomycin. 
 
RISKS OF STUDY PROCEDURES 
• 
Blood samples:  Possible side effects from blood drawing include faintness, 
inflammation of the vein, pain, bruising, or bleeding at the site of puncture. There is also 
a slight possibility of infection. 
• 
Electrocardiogram (ECG):  Skin irritation is rare but could occur during an ECG from the 
electrodes or gel that is used. 
• 
Stool Sample:  When you need to take a stool sample at home, there may be a 
possibility that you soil your skin with stool from the collection container if you do not 
handle your stool collection according to the instructions. 
If you are taking antidiarrheals you will be asked to stop taking these medicines (washout 
period) from randomization until after Follow up Visit 3 (day 70). During this time, your 
symptoms may not improve or may get worse. If your symptoms get worse, tell the Investigator 
immediately. 
 


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UNFORESEEN RISKS 
Since the study drug is investigational, there may be other risks that are unknown. Additionally, 
there may be unknown risks to a pregnancy or unborn child if you or your female partner 
become pregnant. 
CRS3123 may interfere with how some medications are processed by your body. If you are 
taking medications, it is important to inform your doctor to discuss if these medications might 
be impacted by CRS3123.  He or she might make adjustments to your medication. 
 
BIRTH CONTROL RESTRICTIONS 
Taking the study drug may involve risks to a pregnant woman, an embryo, fetus (unborn baby) 
or nursing infant. Therefore, if you are pregnant, planning to become pregnant, planning to 
father a child, or are breastfeeding a child, you cannot participate in this study. 
 
Females: 
 In order to reduce the risk of pregnancy, you should use an effective method of birth 
control while you are participating in this study and for 2 months after your last dose of 
the study drug. Acceptable methods of birth control for use in this study are Abstinence, 
Oral contraceptives ("the pill") or other prescription hormonal contraceptive method, 
Birth control injections, Birth control patch, Intrauterine device, Double-barrier method 
(condoms, diaphragm, or cervical cap plus spermicidal foam, cream, or gel), or if female, 
male partner sterilization. The Investigator or study staff will discuss this with you. The 
use of contraception does not apply if the male partner has been vasectomized at least 
6 months prior to dosing. 
If you become pregnant while you are participating in this study or within 2 months after you 
have stopped taking the study drug, tell your Investigator or study staff immediately. The study 
drug will be stopped and your participation in this study will be ended. The Investigator will ask 
to follow the pregnancy to its outcome and for up to 6-8 weeks after delivery. 
 
Males: 
In order to reduce the risk of pregnancy, you should use an effective method of birth control 
while you are participating in this study and for 2 months after your last dose of the study drug. 
Acceptable methods of birth control for use in this study are complete abstinence, male 
vasectomy, or double barrier method (condoms plus spermicidal foam, cream, or gel).  The 
Investigator or study staff will discuss this with you. 
 
If your female partner becomes pregnant while you are participating in this study or within 2 
months after you have stopped taking the study drug, tell your Investigator or study staff 
immediately.  The Investigator will ask for permission to follow up with your partner and, with 
her consent, will follow the pregnancy to its outcome and for up to 6-8 weeks after delivery.  
Your partner will be provided with a consent form for this pregnancy follow-up. 
 


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ALTERNATIVES TO PARTICIPATION 
You do not have to be in this study to receive treatment for your CDI.  Your options may 
include: 
• 
There may be other clinical research studies available to you. 
• 
Standard antibiotic treatment with Vancomycin, Fidaxomicin, or Metronidazole or 
treatment with Microbiota Restoration Therapy. 
Please talk to the Investigator about your options before you decide whether or not you will 
take part in this study. 
 
NEW FINDINGS 
Any new important information that is discovered during the study and which may influence 
your willingness to continue participation in the study will be provided to you by the 
Investigator or study staff. 
 
BENEFITS 
You may benefit as a result of your participation in this study. There is, however, no guarantee 
that you will benefit from your participation in this study. Information learned from the study 
may help other people in the future. 
 
COMPENSATION FOR PARTICIPATION 
«Compensation» 
You will be paid up to a total of $_____ if you complete this study. You will be paid for the visits 
you complete according to the following schedule: 
• 
$_____ for Visits Day 1, Day 10, Follow up Visit 1, Follow up Visit 2, and Follow Up Visit 
3. 
• 
$_____ for Visits Day 3, Day 6, Day 20, and Day 27 
If you do not complete the study, for any reason, you will be paid for each study visit you do 
complete. 
 
You will be paid ___________ [“after each visit,” “at the end of study participation,” etc.]. 
 
Transportation assistance to and from clinical visits may be available to you.  If you have any 
questions regarding your compensation for participation, please contact the study staff. 
 
CONFIDENTIALITY 
Records of your participation in this study will be held confidential except when sharing the 
information is required by law or as described in this informed consent. The Investigator, the 
sponsor or persons working on behalf of the sponsor, and under certain circumstances, the 
United States Food and Drug Administration (FDA) and the Institutional Review Board (IRB) will 


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be able to inspect and copy confidential study-related records which identify you by name. This 
means that absolute confidentiality cannot be guaranteed. If the results of this study are 
published or presented at meetings, you will not be identified. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you.  At most, the Web site 
will include a summary of the results.  You can search this Web site at any time. 
 
Certificate of Confidentiality 
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. This means that the researchers cannot release or use information, documents, or 
samples that may identify you in any action or suit unless you say it is okay. They also cannot 
provide them as evidence unless you have agreed.  This protection includes federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings. An example would be a 
court subpoena. 
 
There are some important things that you need to know.  The Certificate DOES NOT stop 
reporting that federal, state or local laws require. Some examples are laws that require 
reporting of child or elder abuse, some communicable diseases, and threats to harm yourself or 
others.  The Certificate CANNOT BE USED to stop a sponsoring United States federal or state 
government agency from checking records or evaluating programs. The Certificate DOES NOT 
stop disclosures required by the U.S. Food and Drug Administration (FDA).  The Certificate also 
DOES NOT prevent your information from being used for other research if allowed by federal 
regulations. 
 
Researchers may release information about you when you say it is okay. For example, you may 
give them permission to release information to insurers, medical providers or any other 
persons not connected with the research.  The Certificate of Confidentiality does not stop you 
from willingly releasing information about your involvement in this research. It also does not 
prevent you from having access to your own information. 
 
COMPENSATION FOR INJURY 
If you become ill or are injured while you are in the study, get the medical care that you need 
right away. You should inform the healthcare professional treating you that you are 
participating in this study. If you tell the study staff that you think you have been injured, then 
they will help you get the care you need. 
 
If you are injured as a result of taking the study drug(s) or from procedures done for the 
purpose of this study, the sponsor will pay for those medical expenses necessary to treat your 
injury that are not covered by your medical insurance or any other third-party coverage. You 
will not lose any of your legal rights or release the sponsor, the Investigator, the study staff, or 
study site from liability for mistakes by signing this consent document. To pay medical 
expenses, the sponsor will need to know some information about you like your name, date of 


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birth, and Medicare Beneficiary Identifier (MBI). This is because the sponsor has to check to see 
if you receive Medicare and if you do, report the payment it makes to Medicare. 
 
In general, no long-term medical care or financial compensation for research-related injuries 
will be provided by the NIH or the Federal Government. 
 
COSTS 
There will be no charge to you for your participation in this study. The study drug, study-related 
procedures, and study visits will be provided at no charge to you or your insurance company. 
 
FUTURE RESEARCH STUDIES 
Identifiers will be removed from your identifiable private information or identifiable 
biospecimens collected during this study and could then be used for future research studies or 
distributed to another investigator for future research studies. You may change your mind 
about secondary research and withdraw consent for the storage and use of your coded samples 
or information at any time. You will need to contact the Investigator using the contact 
information listed on page 1 of this form. We will do our best to follow your wishes but cannot 
promise that we will always be able to destroy your samples or data. For example, if your 
samples were already used, we would not be able to destroy them. 
 
Blood and urine specimens remaining after clinical safety assessments are performed will not 
be stored for future use. 
 
Excess/leftover blood and fecal specimens remaining after pharmacokinetic tests may be stored 
for up to 5 years for future analyses. 
 
No human genetic (DNA) tests will be done on these samples. The results of any future testing 
will be kept confidential in the same way as the results of other testing done for this study. 
______ 
YES, you may store my excess/leftover blood and fecal samples for up to 5 years 
and use them for future research. 
______ 
NO, you may not store my excess/leftover blood and fecal samples for up to 5 
years and use them for future research. 
 
COMMERCIAL PROFIT 
Your biospecimens collected during this study may be used for commercial profit (even if 
identifiers are removed) and you will not share in this profit. 
 
CONFLICTS OF INTEREST 
The policy of the NIH is to evaluate investigators at least yearly for any conflicts of interest. You 
may review the system for assessing conflicts of interest by checking the web site link: 


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http://ethics.od.nih.gov/forms/Protocol-Review-Guide.pdf.  Copies of the standards may also 
be requested by research subjects.  Crestone, Inc., the company that makes CRS3123 and NIH 
are providing funding for this study. 
 
CLINICALLY RELEVANT RESULTS 
Research results that are clinically relevant, including individual research results, will not be 
disclosed to you. 
 
GENOME SEQUENCING 
Researchers will only look at the genetic information of the microbes found in your stool 
sample.  The research will not include study of any of your genetic information by sequencing, 
or “reading,” every letter in your DNA (your genome). 
 
WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the Investigator at the 
telephone number listed on the first page of this consent document. If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in this 
research study. 
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects. If you have any questions about your rights as a research subject, 
and/or concerns or complaints regarding this research study, contact: 
• By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Drive, Suite 600 
Columbia, MD 21044 
• or call toll free:    877-992-4724 
• or by email:          adviser@advarra.com 
Please reference the following number when contacting the Study Subject Adviser: Pro00046367. 
 
VOLUNTARY PARTICIPATION / WITHDRAWAL 
Your decision to participate in this study is voluntary. You may choose to not participate, or you 
may withdraw from the study for any reason without penalty or loss of benefits to which you 
are otherwise entitled and without any effect on your future medical care. However, please 
note that the FDA requires that any information collected up to the point of your withdrawal 
cannot be removed from the study. 
 
For participants who discontinue prematurely during the study treatment period, an end of 
study treatment visit will be conducted as soon as possible after discontinuation of study and 


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the Investigator and study staff will subsequently perform all assessments as specified for 
follow up visits. 
 
The Investigator or the sponsor can stop your participation at any time without your consent 
for the following reasons: 
• 
If it appears to be medically harmful to you; 
• 
If you fail to follow directions for participating in the study; 
• 
If it is discovered that you do not meet the study requirements; 
• 
If the study is canceled; or  
• 
For administrative reasons. 
If you leave the study for any reason, the Investigator may ask you to have some end-of-study 
tests for your safety. 
 
PRIMARY HEALTH CARE PROVIDER NOTIFICATION OPTION 
I consent to having my family doctor or primary health care provider notified by the study site 
of my participation in this study and/or any significant findings related to my health (please 
check yes or no). 
 
YES (If yes, please complete the information below) 
NO 
 
Name and address of family 
doctor or primary health care 
provider: 
Name: 
Address: 
 
Telephone and Fax Number: 
Tel: 
Fax: 
 
CONSENT 
I have read and understand the information in this informed consent document. I have had an 
opportunity to ask questions and all of my questions have been answered to my satisfaction. I 
voluntarily agree to participate in this study until I decide otherwise. I do not give up any of my 
legal rights by signing and dating this consent document. I will receive a copy of this signed and 
dated consent document. 
 
 
 
 
Subject’s Printed Name 
 
 
 
 
 
 
Subject’s Signature 
Date 


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Signature of the Person Conducting the Consent Discussion 
Date 
 
 
 
 


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AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
If you decide to be in this study, the Investigator and research team will use and 
share health data about you to conduct the study. Health data may include: 
• Your name. 
• Address. 
• Phone number. 
• Date of birth. 
• Medical history. 
• Information from your study visits, including all test results. 
 
Health data may come from your study records or from existing records kept by 
your doctor or other health care workers. 
 
For this study, the research team may share health data about you with 
authorized users. Authorized users may include: 
• Representatives of Crestone, Inc. 
• Representatives of InClin. 
• Representatives of National Institutes of Health (NIH). 
• Representatives of Division of Microbiology and Infectious Disease (DMID). 
• Representatives of Advarra IRB (an Institutional Review Board that reviews 
this study). 
• The United States Food and Drug Administration (FDA) and other U.S. 
federal and state agencies. 
• Governmental agencies of other countries. 
• Outside individuals and companies, such as laboratories and data storage 
companies, that work with the researchers and sponsor and need to access 
your information to conduct this study. 
• Other research doctors and medical centers participating in this research, if 
applicable. 
• A data safety monitoring board which oversees this research, if applicable. 
 
Your health data will be used to conduct and oversee the research, including for 
instance: 
• To see if the study drug works and is safe. 


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• To compare the study drug to other drugs. 
• For other research activities related to the study drug. 
 
Once your health data has been shared with authorized users, it may no longer be 
protected by federal privacy law and could possibly be used or disclosed in ways 
other than those listed here. 
 
Your permission to use and share health data about you will end in 50 years 
unless you revoke it (take it back) sooner. 
 
You may revoke (take back) your permission to use and share health data about 
you at any time by writing to the Investigator at the address listed on the first 
page of this form. If you do this, you will not be able to stay in this study. No new 
health data that identifies you will be gathered after your written request is 
received. However, health data about you that has already been gathered may 
still be used and given to others as described in this form. 
 
Your right to access your health data in the study records will be suspended 
during the study to keep from changing the study results. When the study is over, 
you can access your study health data. 
 
If you decide not to sign and date this form, you will not be able to take part in 
the study. 
 
STATEMENT OF AUTHORIZATION 
I have read this form and its contents were explained. My questions have been 
answered. I voluntarily agree to allow study staff to collect, use and share my 
health data as specified in this form. I will receive a signed and dated copy of this 
form for my records. I am not giving up any of my legal rights by signing and 
dating this form. 
 
 
 
Printed Name of Subject 
 
 
  
 
Signature of Subject 
Date 


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Printed Name of the Person Obtaining the Authorization 
 
 
  
 
Signature of the Person Obtaining the Authorization 
Date