Clinical trial NCT04247542
Conditions: Clostridium Difficile Infection
Keywords: Clostridioides difficile CDAD (Clostridioides difficile-associated diarrhea) DNA polymerase IIIC
Sponsor: Acurx Pharmaceuticals Inc.
Start date: 2020-03-06; Completion date: 2023-11-15
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Segments 2A and 2B of this trial evaluate the safety, efficacy, pharmacokinetics, fecal concentrations, and fecal microbiome effects of ACX-362E \[ibezapolstat\] in patients with C. difficile infection (CDI).

Detailed description:
This Phase 2, multicenter, open-label single-arm segment (2A) followed by a double-blind, randomized, active-controlled segment (2B) is designed to evaluate ACX-362E in the treatment of CDI. Segment 2A of this trial was an open-label study of up to 20 patients at 6 study centers and was terminated early at 10 patients based on the protocol-specified Trial Oversight Committee's assessment of the compelling efficacy and safety data. Patients were treated with 450 mg of oral ibezapolstat twice daily for 10 days. The trial will advance to Segment 2B which is a double-blind comparison of ibezapolstat to the standard of care, oral vancomycin, in approximately 64 subjects (1-1 randomization) at up to approximately 15 sites.

Subjects will be evaluated for cure, safety, and tolerability. All subjects in both segments will have stool samples tested for microbiome profiles. Pharmacokinetic (PK) testing for systemic exposure will be performed on blood samples. Stool samples will be tested for study drug concentration.

Arms: arm 1: Active investigational antibacterial agent: ibezapolstat 450 mg po Q12H x 10 days arm 2: Standard of care: Vancomycin 125 mg po Q6H x 10 days
Interventions: intervention 1: Ibezapolstat intervention 2: Vancomycin
Intervention descriptions: intervention 1: Investigational antibacterial agent intervention 2: Active comparator

Protocol documents:
Prot_000.pdf: 
1 
CLINICAL STUDY PROTOCOL 
 
 
 
 
Acurx Pharmaceuticals, Inc. 
Protocol Title: Ibezapolstat (ACX-362E) for Oral Treatment of Clostridioides difficile 
Infection: A Phase 2A Open-Label Segment Followed by a Phase 2B Double-Blind 
Vancomycin-Controlled Segment 
Protocol Number: ACX-362E-201 
 
Investigational New Drug Number: 
139236 
Name of Investigational Product 
Ibezapolstat (ACX-362E) 
Phase of Development: 
Phase 2 
Indication: 
Clostridioides difficile infection 
Sponsor: 
Robert J. DeLuccia 
Executive Chairman 
Acurx Pharmaceuticals, Inc. 
259 Liberty Ave. 
Staten Island, NY 10305 
Tel: 914-949-3898 
Email: rjdeluccia@acurxpharma.com 
NCT Number: 
04247542 
Protocol Version 1.0:  
10 Dec 2019 
Protocol Amendment 2.0 
09 Mar 2020 
Protocol Amendment 3.0 
18 Dec 2020 
Protocol Amendment 4.0 
01 Apr 2022 
Protocol Amendment 5.0 
30 Aug 2022 
Protocol Amendment 6.0 
03 Apr 2023 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Acurx Pharmaceuticals, Inc. 
Any unauthorized copying or use of this document is prohibited. 
 


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PROTOCOL APPROVAL SIGNATURES 
 
Protocol Title: 
Ibezapolstat (ACX-362E) for Oral Treatment of Clostridioides 
difficile Infection: A Phase 2A Open-Label Segment Followed by 
a Phase 2B Double-Blind Vancomycin-Controlled Segment  
Protocol Number: 
ACX-362E-201 
This study will be conducted in compliance with the clinical study protocol 
(and amendments), International Council for Harmonisation (ICH) guidelines for 
current Good Clinical Practice (GCP) and applicable regulatory requirements. 
Sponsor Signatory 
Robert J. DeLuccia 
Executive Chairman  
Acurx Pharmaceuticals, Inc. 
259 Liberty Ave. 
Staten Island, NY 10305 
Signature 
Date (DD-Mmm-YYYY) 
Medical Monitors 
Michael H. Silverman, MD, FACP 
BioStrategics Consulting Ltd. 
51 Intrepid Circle 
Marblehead, MA 01945 
Signature 
Date (DD-Mmm-YYYY) 
Gino Girardi, MD 
Sr Vice President 
Syneos Health 
100 Brandywine Boulevard, 2nd Floor 
Newtown, PA 18940 
Signature 
Date (DD-Mmm-YYYY) 
03-April-2023
05 April 2023
05-April-2023


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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
Ibezapolstat (ACX-362E) for Oral Treatment of Clostridioides difficile 
Infection: A Phase 2A Open-Label Segment Followed by a Phase 2B 
Double-Blind Vancomycin-Controlled Segment 
Protocol Number: 
ACX-362E-201 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance 
Statement 
• 
I, the undersigned, have reviewed this protocol, including appendices, and I will conduct 
the study as described in compliance with this protocol, GCP, and relevant International 
Council for Harmonisation (ICH) guidelines. 
• 
I am thoroughly familiar with the appropriate use of the study drug, as described in this 
protocol and any other information provided by Acurx Pharmaceuticals including, but not 
limited to, the current Investigator’s Brochure. 
• 
Once the protocol has been approved by the independent ethics committee 
(IEC)/institutional review board (IRB), I will not modify this protocol without obtaining 
prior approval of Acurx Pharmaceuticals and of the IEC/IRB. I will submit the protocol 
amendments and/or any informed consent form modifications to Acurx Pharmaceuticals 
and the IEC/IRB, and approval will be obtained before any amendments are 
implemented. 
• 
I ensure that all persons or party assisting me with the study are adequately qualified and 
informed about the Acurx Pharmaceuticals study drug and of their delegated study-
related duties and functions as described in the protocol. 
• 
I ensure that source documents and trial records that include all pertinent observations on 
each of the site’s trial subjects will be attributable, legible, contemporaneous, original, 
accurate, and complete. 
• 
I understand that all information obtained during the conduct of the study with regard to 
the subjects’ state of health will be regarded as confidential. No subjects’ names will be 
disclosed. All subjects will be identified by assigned numbers on all case report forms, 
laboratory samples, or source documents forwarded to the Sponsor. Clinical information 
may be reviewed by the Sponsor or its agents or regulatory agencies. Agreement must be 
obtained from the subject before disclosure of subject information to a third party. 
• 
Information developed in this clinical study may be disclosed by Acurx Pharmaceuticals 
to other clinical Investigators, regulatory agencies, or other health authority or 
government agencies as required. 
Printed Name of Investigator 
 
Signature of Investigator 
 
Date 
 
Institution 
 


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2 
SYNOPSIS 
Title of Study: 
Ibezapolstat (ACX-362E) for Oral Treatment of Clostridioides difficile 
Infection: A Phase 2A Open-Label Segment Followed by a Phase 2B Double-
Blind Vancomycin-Controlled Segment 
Protocol Number: 
ACX-362E-201 
Investigators/Study Sites: 
Up to 5 study centers in the United States (US) and Canada for Segment 2A 
and up to 30 study centers in United States and Canada for Segment 2B 
Phase of Development: 
Phase 2 
Objectives: 
Primary Objectives: 
1. Assess Clostridioides difficile infection (CDI) clinical cure rates 2 days after 
the end of treatment (EOT) (Segment 2A/2B) 
2. Evaluate the safety and tolerability of ibezapolstat (ACX-362E) 
administered every 12 hours for 10 days in the treatment of CDI (Segment 
2A/2B) 
Secondary Objectives: 
1. Determine the systemic exposure (Segment 2A) and fecal concentrations 
(Segment 2A/2B) of ibezapolstat in subjects with CDI during the course 
of treatment. 
2. Assess incidence of sustained clinical cure (SCC) at 28 ± 2 days after EOT 
(Segment 2A/2B) 
Exploratory Objectives: 
1. Compare the effects of ibezapolstat versus vancomycin on relative and 
quantitative changes to the fecal microbiome (Segment 2A/2B) 
2. Assess times to resolution of diarrhea during the treatment period 
(Segment 2A/2B) 
3. Assess times to hospital discharge during the treatment period (Segment 
2A/2B) 
4. Assess the impact of ibezapolstat treatment on subject reported quality of 
life and resource utilization (Segment 2B) 
5. Assess incidence of extended clinical cure (ECC) at 56 ± 2 days and 
84 ± 2 days after EOT in subjects participating in the extended follow-up 
period (Segment 2B) 


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Study Endpoints: 
Primary Endpoints: 
• 
Clinical cure at the test of cure (TOC) visit: defined as survival and the 
resolution of diarrhea in the 24-hour period immediately before EOT that 
is maintained for 48 hours post EOT without a requirement for additional 
CDI treatment. Diarrhea is defined as ≥ 3 unformed bowel movements 
(UBMs) in a 24-hour period; < 3 UBMs is considered as resolution of 
diarrhea. A UBM is defined as a Type 5, 6, or 7 bowel movement on the 
Bristol Stool Chart. 
• 
Safety endpoints for all subjects: These include the nature, frequency, and 
severity of adverse events (AEs), including serious adverse events (SAEs); 
changes from baseline in findings on physical examination, vital sign 
measurements, safety laboratory tests (hematology, biochemistry, 
urinalysis); and electrocardiogram (ECG) findings. 
Secondary Endpoint: 
• 
SCC: this is defined as a clinical cure at the TOC visit (ie, at least 
48 hours post EOT) and no recurrence of CDI within the 28 ± 2 days post 
EOT. Recurrence is defined as a new episode of diarrhea (≥ 3 UBMs in a 
24-hour period) with a positive toxin result, using a Sponsor-approved 
C. difficile free toxin test and, in the opinion of the Investigator, requiring 
retreatment with an antibacterial agent for C. difficile. 
Pharmacokinetic Endpoint: 
• 
Systemic exposure of ibezapolstat will be determined by measuring 
plasma ibezapolstat concentrations at specified time points following dose 
administration; fecal concentrations of ibezapolstat will be measured at 
specified study visits. 
Exploratory Endpoints: 
• 
Microbial endpoints: Quantitative changes in relevant fecal bacterial 
communities and microbial diversity will be assessed for 
ibezapolstat-treated subjects in both segments, and in comparison to those 
treated with vancomycin in Segment 2B. Changes will be assessed during 
the treatment period and post EOT. 
• 
Time to resolution of diarrhea, defined as the time from outset of 
treatment to the first formed bowel movement not followed within the 
next 24 hours by a UBM, will be recorded. 
• 
Time to hospital discharge (for hospitalized subjects only) is defined as 
time from outset of treatment to day of discharge, and not followed by 
readmission for treatment of CDI before the TOC visit. 
• 
Quality of life assessments including EuroQoL 5 Dimension 5 Level 
(EQ-5D-5L) and medical resource utilization data will be performed at 
designated time points during Segment 2B.  
• 
ECC: this is defined as a clinical cure at the TOC visit (ie, at least 
48 hours post EOT) and no recurrence of CDI within the 56 ± 2 days post 
EOT (ECC56) and 84 ± 2 days post EOT (ECC84). Recurrence is defined 


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as a new episode of diarrhea (≥ 3 UBMs in a 24-hour period) with a 
positive toxin result, using a Sponsor-approved C. difficile free toxin test 
and, in the opinion of the Investigator, requiring retreatment with an 
antibacterial agent for C. difficile. 
Study Design: 
This Phase 2, multicenter, open-label single-arm segment followed by a 
double-blind, randomized, active-controlled segment is designed to evaluate 
ibezapolstat in the treatment of CDI. Segment 2A of this trial is an open-label 
cohort of up to 20 subjects in up to 5 study centers in the United States and 
Canada. In Segment 2A, up to 20 subjects with diarrhea caused by C. difficile 
will be treated with ibezapolstat 450 mg orally for 10 days. All subjects will be 
followed for recurrence for 28 ± 2 days. After 10 subjects have completed 
treatment and again after all subjects have completed treatment, a Trial 
Oversight Committee will assess the safety and tolerability, and, as data allow, 
efficacy, to make recommendation regarding whether the study should 
continue. 
In Segment 2B, at least 72 additional subjects with CDI will be enrolled and 
randomized in a 1:1 ratio to either ibezapolstat 450 mg every 12 hours or 
vancomycin 125 mg orally every 6 hours for 10 days and followed for 28 ± 2 
days for recurrence. Additionally, approximately 16 subjects recruited from 
selected sites will participate in an extended follow-up period consisting of 
observation visits at 56 days and 84 days after treatment to evaluate the long-
term impact of ibezapolstat on the microbiome and on disease recurrence. The 
2 treatments will be identical in appearance, dosing times, and number of 
capsules administered to maintain the blind. 
Subjects in both segments will be evaluated for cure, safety, and tolerability. 
All subjects in both segments will have stool samples tested for microbiome 
profiles. Pharmacokinetic (PK) testing for systemic exposure will be 
performed on blood samples in Segment 2A and approximately 50% of 
subjects (ie, approximately 36 subjects) in Segment 2B. Stool samples will be 
tested for study drug concentration in Segment 2A and Segment 2B. 
Selection of Subjects: 
Inclusion Criteria: 
1. Male or female 18 to 90 years of age, inclusive, at the time of Screening. 
2. Capable of reading, understanding, and signing the written informed 
consent; able to adhere to all study procedures and attend all scheduled 
study visits. 
3. Confirmed diagnosis of mild or moderate CDI as defined by the Infectious 
Diseases Society of America/Society for Healthcare Epidemiology of 
America guidelines. Subjects will be diagnosed with CDI based on 
clinical and laboratory findings: 
a. 
The presence of diarrhea, defined as passage of ≥ 3 UBMs within 
24 hours before dosing; an unformed stool is defined as a Type 5, 6, 
or 7 on the Bristol Stool Chart. 
b. A stool test result positive for the presence of C. difficile free toxins 
using a test (approved by either the US Food and Drug 
Administration [FDA] or Health Canada) that detects toxins A/B 


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(and is prospectively agreed with the Sponsor). The Sponsor will 
provide a toxin A/B test kit if the site does not have it as part of 
standard of care testing. 
c. 
Mild or moderate CDI as defined as a white blood cell count of 
≤ 15,000 cells/mL and a serum creatinine level < 1.5 mg/dL. 
4. Agreement by subjects with reproductive potential to use two adequate 
methods of contraception during the study and for 4 weeks after the last 
study drug administration. A female subject is considered to be of 
reproductive potential following menarche and until she is in a 
postmenopausal state for 12 months or otherwise permanently sterile (for 
which acceptable methods include hysterectomy, bilateral salpingectomy, 
and bilateral oophorectomy). Female subjects must agree to the use of 
TWO reliable methods of contraception while receiving study drug and 
for 4 weeks after the last study drug administration if sexually active, 
which can include: condoms, spermicidal gel, diaphragm, hormonal or 
non-hormonal intrauterine device, surgical sterilization, oral contraceptive 
pill, and depot progesterone injections. If a male subject is sexually active, 
the subject and his partner will each use at least one of the listed 
contraceptive methods. 
5. Negative serum pregnancy test at Screening and/or a negative urine 
pregnancy test on the day of admittance to the inpatient phase for all 
female subjects of childbearing potential. 
6. Agreement in male subjects to not donate sperm starting at Screening and 
throughout the study period and for 90 days after the final study drug 
administration. 
Exclusion Criteria: 
1. Received more than 24 hours of dosing (> 4 doses) of oral vancomycin for 
the current episode of CDI before first dose of study drug. 
2. Received more than 24 hours of dosing (> 2 doses) of oral fidaxomicin for 
the current episode of CDI before first dose of study drug. 
3. Received more than 24 hours of dosing (> 3 doses) of oral/intravenous 
(IV) metronidazole for the current episode of CDI before first dose of 
study drug. 
4. Received any other antibacterial therapy for the current CDI episode 
within 48 hours before the first dose of study drug. 
5. Subjects considered treatment failures on prior antibiotics for their current 
episode of CDI will be excluded. 
6. More than 3 episodes of CDI in the previous 12 months or more than 1 
prior episode in the last 3 months, excluding the current episode. 
7. Severe, complicated, or life-threatening fulminant CDI with evidence of 
hypotension (systolic blood pressure less than 90 mmHg), septic shock, 
peritoneal signs or ileus, or toxic megacolon. 
8. Elevated liver transaminases (ALT, AST) greater than 2 times ULN. 
9. Active inflammatory bowel disease (Crohn’s disease, ulcerative colitis, 
Irritable Bowel Syndrome with chronic diarrhea). 
10. Any other non-C. difficile diarrhea. 


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11. Active gastroenteritis because of Salmonella, Shigella, Escherichia coli 
0157H7, Yersinia or Campylobacter, a parasite, or virus within the past 
2 weeks. 
12. Had a known positive diagnostic test for other relevant gastrointestinal 
(GI) pathogens in the 2 weeks before study drug treatment and/or 
colonization/infection by ova or parasites. 
13. Major GI surgery (ie, significant bowel resection) within 3 months of 
enrollment (does not include appendectomy or cholecystectomy). 
14. Prior or current use of anti-C. difficile toxin antibodies. 
15. Have received a vaccine against C. difficile or its toxins. 
16. Anticipated that systemic antibacterial therapy for a non-CDI infection 
will be required for > 7 days after start of study therapy. 
17. Actively taking anti-diarrheals, and unable to discontinue anti-diarrheal 
medication, or any medication with the potential to slow bowel movement 
(for opiates, a stable dose, including use as needed, is permitted). 
18. Actively taking Saccharomyces boulardii and unwilling to discontinue 
during the study period. 
19. Received a fecal transplant in the previous 3 months. 
20. Received laxatives in the last 48 hours. 
21. Unable or unwilling to stop taking oral probiotics for the duration of the 
study. 
22. Received IV immunoglobulin within 3 months before study drug 
treatment. 
23. Sepsis. 
24. Have a known current history of significantly compromised immune 
system such as: 
a. 
Subjects with a known history of human immunodeficiency virus 
infection and CD4 < 200 cells/mm3 within 6 months of start of study 
therapy. 
b. Severe neutropenia with neutrophil count < 500 cells/mL. 
c. 
Concurrent intensive induction chemotherapy, radiotherapy, or 
biologic treatment for active malignancy. 
25. Any specific condition that, in the judgment of the Investigator, precludes 
participation because it could affect subject safety. 
26. Active participation in other clinical research studies using an 
investigational product or received investigational antibacterial agent 
within one month before Screening. 
27. Pregnant or lactating women. 
28. Known hypersensitivity to any ibezapolstat excipient. 
29. Hypersensitivity or other contraindication to vancomycin. 
30. Prior treatment with study drug in this trial. 
Planned Sample Size: 
Up to 20 subjects are planned for Segment 2A and at least 72 subjects are 
planned for Segment 2B. 
Investigational Therapy: 
Ibezapolstat 450 mg oral capsules taken with food every 12 hours for 10 days. 
Reference Therapy: 
Vancomycin 125 mg every 6 hours for 10 days. 


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Treatment Duration: 
Subjects will receive study drug for 10 days. 
Efficacy 
Subjects will receive a diary and will be instructed to record in it each day of 
the study the date and time of dosing of study drug; date, time, and consistency 
of all bowel movements up to Day 12/TOC; and the date, time, and 
consistency of all UBMs from TOC to Day 38. 
Sustained clinical cure will be determined in the 24-hour period immediately 
before EOT that is maintained for 48 hours post EOT. 
SCC will be determined by following all subjects for 28 ± 2 days post 
treatment for recurrence of UBMs, although only subjects with clinical cure 
are eligible to be classified as SCC. 
Exploratory: 
The time to resolution of diarrhea will be determined by measuring the time 
from outset of treatment to the first formed bowel movement not followed 
within the next 24 hours by a UBM. 
Time to hospital discharge will be determined by measuring time from the 
outset of treatment to the day of discharge that is not followed by a 
readmission for treatment of CDI before the TOC visit (for hospitalized 
subjects only). 
Microbiome testing to determine the microbial content of stool samples will 
occur at specified time points during the study. 
Quality of life assessments including EQ-5D-5L and medical resource 
utilization data will be performed at designated time points during 
Segment 2B.  
ECC: this is defined as a clinical cure at the TOC visit (ie, at least 48 hours 
post EOT) and no recurrence of CDI within the 56 ± 2 days post EOT 
(ECC56) and 84 ± 2 days post EOT (ECC84). Recurrence is defined as a new 
episode of diarrhea (≥ 3 UBMs in a 24-hour period) with a positive toxin 
result, using a Sponsor-approved C. difficile free toxin test and, in the opinion 
of the Investigator, requiring retreatment with an antibacterial agent for 
C. difficile. 
Safety: 
Safety assessments include vital signs, physical examination, ECG recordings, 
collection of AEs, and clinical laboratory tests (hematology, biochemistry, and 
urinalysis). 
Pharmacokinetics: 
During Segment 2A and Segment 2B, stool samples will be collected to 
analyze ibezapolstat levels at designated time points. In Segment 2A and 
approximately 50% of subjects in Segment 2B, blood samples will be collected 
to analyze ibezapolstat levels at designated time points. 
Statistical Methods and 
Planned Analyses: 
Study Populations 
The Enrolled population includes all subjects who sign an informed consent 
form. 
The Intent-to-Treat (ITT) population includes all subjects who are enrolled and 
treated in Segment 2A or who are randomized in Segment 2B and will be used 
to analyze efficacy. In Segment 2B, subjects will be analyzed based on their 
randomized assignment. This population will be used for the primary analyses 
of efficacy. 
The Per Protocol (PP) population will consist of subjects in the ITT population 
with no major protocol deviations. The determination of which subjects have 
major protocol violations will be made in a blinded manner prior to database 
lock. For analyses based on the PP population, subjects will be grouped 


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according to the treatment to which they were randomized. This population 
will be used for a secondary analysis of the primary and secondary efficacy 
endpoints. 
The ITT Extension population will include all randomized Segment 2B 
subjects who participate in the extended follow-up period. Subjects will be 
analyzed based on their randomized assignment.  
The Safety population includes all subjects who receive at least 1 dose of study 
drug and will be used to analyze safety. Subjects will be analyzed based on the 
treatment actually received. 
The PK population includes all subjects who take at least 1 dose of active 
study treatment (ibezapolstat) and have at least 1 quantifiable plasma 
concentration collected post dose without any important protocol 
deviations/violations or events that would affect the PK. 
Efficacy 
The primary efficacy endpoint is clinical cure at the TOC visit defined as 
survival and the resolution of diarrhea in the 24-hour period immediately 
before the EOT and maintained for 48 hours after EOT without a requirement 
for additional CDI treatment. For Segment 2A, this endpoint will be 
summarized using frequencies and percentages, together with a 95% exact 
(Clopper-Pearson) confidence interval for the true cure percentage. For 
Segment 2B, the null and alternative hypotheses for this endpoint are: 
H0: π 1,T ≤ π1,C - δ and H1: π 1,T > π1,C - δ, 
where π1,T and π1,C are the true proportions of subjects with clinical cure at the 
TOC visit for the ibezapolstat 450 mg and vancomycin 125 mg treatments, 
respectively, and δ is the non-inferiority margin which is here taken to be 0.25. 
This endpoint will be summarized by treatment group using frequencies and 
percentages, together with an exact (Clopper-Pearson) 95% confidence interval 
for the true cure percentage. A 95% confidence interval based on the normal 
approximation will also be calculated for the difference between the 
2 population proportions. The null hypothesis will be tested using a one-sided 
normal approximation test of non-inferiority at the 0.03037 significance level 
(Pocock 1977) for an overall significance level of 0.05. In the event 
non-inferiority of ibezapolstat 450 mg is demonstrated, Fisher’s exact test 
(two-sided) will be used to conduct a test for superiority at the 0.05 
significance level. 
A single interim analysis will be performed when the first 36 Segment 2B 
subjects in the ITT Population (one half of the planned sample size) have data 
for the primary efficacy endpoint. The null hypothesis (see Section 14.3.1) will 
be tested using a one-sided normal approximation test of non-inferiority at a 
one-sided α=0.03037 level of significance (Pocock 1977) for an overall 
significance level of 0.05. If the p-value is less than or equal to 0.03037 at the 
time of the interim analysis, then the study will be stopped early for success. 
A secondary endpoint is SCC. For Segment 2A, this endpoint will be 
summarized using frequencies and percentages, together with an exact 
(Clopper-Pearson) 95% confidence interval for the true SCC percentage. For 
Segment 2B, this endpoint will be summarized by treatment group using 
frequencies and percentages, together with an exact (Clopper-Pearson) 95% 
confidence interval for the true SCC percentage. A 95% confidence interval 
based on the normal approximation will also be calculated for the difference 
between the 2 population proportions. The null hypothesis that the true 


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proportions are equal for the 2 treatments will be tested using a two-sided 
Fisher’s exact test at the 0.05 significance level. 
Safety 
Treatment-emergent AEs (TEAEs) will be coded using the most recent version 
of the Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized. If a subject experiences more than 1 occurrence of the same AE, 
the occurrence with the greatest severity and the closest relationship with the 
study drug will be used in the summary tables. 
The number and percentage of subjects with at least one TEAE, at least one 
treatment-related TEAE, at least one serious TEAE, and at least one TEAE 
leading to study discontinuation will be presented by treatment group. AEs that 
are definitely, probably, or possibly related, or for which the relationship is 
missing, will be considered related. 
The number and percentage of subjects having a TEAE in each System Organ 
Class (SOC) and having each individual type of AE (Preferred Term) will be 
presented. TEAEs will also be summarized at the event level by SOC/Preferred 
Term and severity. This will be done for all TEAEs, all serious TEAEs, and all 
TEAEs leading to discontinuation from the study. 
All AEs will be listed by subject, along with information regarding onset, 
duration, relationship and severity to study drug, action taken with study drug, 
treatment of event, and outcome. 
Clinical laboratory data and vital signs data will be summarized by treatment 
group and time point using descriptive statistics, for both the actual values and 
the changes from baseline, as well as the numbers and percentages of subjects 
with values outside the limits of the normal range at each time point. 
Electrocardiogram data will be summarized by treatment group and time point 
using descriptive statistics for both the actual values and the changes from 
baseline. 
Concomitant medications initiated during the study period will be summarized 
by treatment group using frequencies and percentages. 
Exploratory Analyses 
Quantitative changes in relevant fecal bacterial communities and microbial 
diversity will be determined at designated time points during the study. 
Quantitative changes in relevant fecal bacterial communities and microbial 
diversity will be assessed for ibezapolstat-treated subjects in both segments, 
and in comparison to those treated with vancomycin in Segment 2B. Changes 
will be assessed during the treatment period and post EOT. 
For Segment 2A, time to resolution of diarrhea will be summarized using the 
Kaplan-Meier method, with estimates of the true resolution of diarrhea rate at 
Days 1, 5, 10, 12, and 40. The estimated median time to resolution of diarrhea, 
together with a 95% confidence interval, will also be presented. For Segment 
2B, the analysis will be the same as for Segment 2A, except that the results 
will be presented by treatment group. 
For Segment 2A, time to hospital discharge will be summarized using 
descriptive statistics. For Segment 2B, the analysis will be the same as for 
Segment A, except that the results will be presented by treatment group. 
Medical resource utilization data will be summarized by treatment group and 
time point using descriptive statistics for continuous variables and frequencies 
and percentages for categorical variables. 


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EQ-5D-5L scores for each of the 5 dimensions and the EQ-5D-5L visual 
analog scale score will be summarized by treatment group and time point using 
descriptive statistics. 
ECC56 and ECC84 will be summarized by treatment group using frequencies 
and percentages, together with an exact (Clopper-Pearson) 95% confidence 
interval for the true percentage. A 95% confidence interval based on the 
normal approximation will also be calculated for the difference between the 2 
population proportions. 
These analyses will be performed for Segment 2B only. 
Further details of the statistical analyses of the EQ-5D-5L and medical 
resource utilization will be described in the statistical analysis plan. 
Pharmacokinetic Analysis 
Systemic exposure of ibezapolstat will be determined by measuring plasma 
ibezapolstat concentrations at specified time points following dose 
administration. Fecal concentrations of ibezapolstat will be measured at 
specified study visits. Plasma and fecal ibezapolstat concentrations will be 
listed by study segment, treatment, study day and/or nominal time, and 
summarized using descriptive statistics. 
Summary statistics will be generated for ibezapolstat plasma and fecal 
concentrations. Given sufficient plasma and fecal levels over the lower limit of 
quantitation (LLOQ), the data will be analyzed as follows: Median (and range) 
and mean (and standard deviation) ibezapolstat plasma concentrations at each 
nominal time point will be calculated. Concentrations reported as below the 
LLOQ will be set to zero for descriptive statistics. 


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3 
TABLE OF CONTENTS 
1 
CLINICAL STUDY PROTOCOL ....................................................................................1 
2 
SYNOPSIS ........................................................................................................................4 
3 
TABLE OF CONTENTS ................................................................................................13 
3.1 
List of In-text Tables ..................................................................................................17 
3.2 
List of In-Text Figures................................................................................................17 
4 
LIST OF ABBREVIATIONS .........................................................................................18 
5 
INTRODUCTION ...........................................................................................................19 
5.1 
Background on Clostridioides Difficile......................................................................19 
5.2 
Background on Ibezapolstat .......................................................................................20 
5.2.1 
Nonclinical Studies ............................................................................................20 
5.2.2 
Clinical Studies ..................................................................................................21 
5.3 
Clinical Risks/Benefits of Ibezapolstat ......................................................................22 
5.4 
Study Rationale ..........................................................................................................22 
5.4.1 
Justification for Dose .........................................................................................24 
6 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................24 
6.1 
Study Objectives .........................................................................................................24 
6.1.1 
Primary Objectives .............................................................................................24 
6.1.2 
Secondary Objectives .........................................................................................24 
6.1.3 
Exploratory Objectives ......................................................................................24 
6.2 
Study Endpoints..........................................................................................................25 
6.2.1 
Primary Endpoint ...............................................................................................25 
6.2.2 
Secondary Endpoints ..........................................................................................25 
6.2.2.1 
Efficacy Endpoints .......................................................................................25 
6.2.2.2 
Pharmacokinetic Endpoint ...........................................................................25 
6.2.3 
Exploratory Endpoints .......................................................................................25 
7 
INVESTIGATIONAL PLAN .........................................................................................26 
7.1 
Description of Overall Study Design and Plan...........................................................26 
7.2 
Discussion of Study Design........................................................................................28 
7.3 
End of Study ...............................................................................................................29 
8 
SELECTION OF STUDY POPULATION .....................................................................29 
8.1 
Inclusion Criteria ........................................................................................................29 
8.2 
Exclusion Criteria .......................................................................................................30 
8.3 
Rescreening ................................................................................................................31 


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8.4 
Study Discontinuation, Removal, and Replacement of Subjects ...............................31 
8.4.1 
Lost to Follow-Up ..............................................................................................33 
9 
TREATMENTS ...............................................................................................................33 
9.1 
Ibezapolstat .................................................................................................................33 
9.1.1 
Description .........................................................................................................33 
9.1.2 
Manufacturing ....................................................................................................33 
9.1.3 
How Supplied .....................................................................................................33 
9.1.4 
Packaging and Labeling .....................................................................................33 
9.1.5 
Storage and Handling .........................................................................................33 
9.1.6 
Dietary and Lifestyle Restrictions ......................................................................33 
9.2 
Vancomycin ................................................................................................................34 
9.3 
Placebo .......................................................................................................................34 
9.4 
Dosage Schedule ........................................................................................................34 
9.5 
Measures to Minimize Bias: Study Treatment Assignment and Blinding .................35 
9.5.1 
Method of Study Treatment Assignment ...........................................................35 
9.5.2 
Blinding ..............................................................................................................36 
9.6 
Dosage Modification ..................................................................................................36 
9.7 
Treatment Accountability and Compliance ................................................................36 
9.8 
Prior and Concomitant Therapy .................................................................................37 
9.8.1 
Prior Medications ...............................................................................................37 
9.8.2 
Concomitant Medications ..................................................................................38 
10 
STUDY PROCEDURES .................................................................................................41 
10.1 Informed Consent .......................................................................................................45 
10.2 Study Procedures ........................................................................................................45 
11 
EFFICACY ASSESSMENTS .........................................................................................45 
11.1 Subject Diary ..............................................................................................................45 
11.2 Clinical Cure ...............................................................................................................46 
11.3 Sustained Clinical Cure ..............................................................................................47 
11.4 Extended Clinical Cure...............................................................................................47 
11.5 Microbial Assessments ...............................................................................................47 
11.6 Time to Resolution of Diarrhea ..................................................................................47 
11.7 Time to Hospital Discharge ........................................................................................47 
12 
SAFETY AND TOLERABILITY ASSESSMENTS ......................................................47 
12.1 Medical History ..........................................................................................................48 
12.2 Vital Signs ..................................................................................................................48 


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12.3 Physical Examination .................................................................................................48 
12.4 Electrocardiograms .....................................................................................................49 
12.5 Laboratory Assessments .............................................................................................49 
12.6 Adverse Events ...........................................................................................................50 
12.6.1 
Serious Adverse Events .....................................................................................51 
12.6.2 
Serious Adverse Event Reporting ......................................................................52 
12.6.3 
Suspected Unexpected Serious Adverse Reactions ...........................................52 
12.6.4 
Pregnancy ...........................................................................................................53 
12.6.5 
Overdose ............................................................................................................54 
12.7 EQ-5D-5L ...................................................................................................................54 
12.8 Medical Resource Utilization Questions ....................................................................54 
13 
PHARMACOKINETICS ................................................................................................54 
13.1 Pharmacokinetic Sampling .........................................................................................54 
13.1.1 
Blood Samples ...................................................................................................54 
13.1.2 
Stool Samples .....................................................................................................55 
13.2 Pharmacokinetic Bioanalytical Methodology ............................................................55 
13.3 Calculation of Pharmacokinetic Variables .................................................................55 
14 
STATISTICAL ANALYSIS ...........................................................................................55 
14.1 Determination of Sample Size ....................................................................................56 
14.2 Analysis Populations ..................................................................................................56 
14.2.1 
Enrolled Population ............................................................................................56 
14.2.2 
Intent-to-Treat Population ..................................................................................57 
14.2.3 
Per Protocol Population .....................................................................................57 
14.2.4 
ITT Extension Population ..................................................................................57 
14.2.5 
Safety Population ...............................................................................................57 
14.2.6 
Pharmacokinetic Population ..............................................................................57 
14.3 Efficacy Analysis........................................................................................................57 
14.3.1 
Analysis of Primary Efficacy Endpoint .............................................................57 
14.3.2 
Analysis of Secondary Efficacy Endpoint: Sustained Clinical Cure .................58 
14.3.3 
Analysis of Exploratory Endpoints ....................................................................58 
14.3.3.1 
Microbial Assessments .................................................................................58 
14.3.3.2 
Time to Resolution of Diarrhea ....................................................................59 
14.3.3.3 
Time to Hospital Discharge ..........................................................................59 
14.3.3.4 
Quality of Life Assessments ........................................................................59 


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14.3.3.5 
ECC56 and ECC84 .......................................................................................59 
14.4 Safety Analysis ...........................................................................................................59 
14.5 Pharmacokinetic Analysis ..........................................................................................60 
14.6 Interim Analysis .........................................................................................................60 
14.7 Trial Oversight Committee .........................................................................................61 
15 
STUDY MANAGEMENT ..............................................................................................61 
15.1 Approval and Consent ................................................................................................61 
15.1.1 
Regulatory Guidelines ........................................................................................61 
15.1.2 
Institutional Review Board/Independent Ethics Committee ..............................61 
15.1.3 
Informed Consent ...............................................................................................62 
15.2 Data Handling .............................................................................................................62 
15.3 Source Documents ......................................................................................................62 
15.4 Record Retention ........................................................................................................63 
15.5 Monitoring ..................................................................................................................63 
15.6 Quality Control and Quality Assurance .....................................................................63 
15.7 Protocol Amendment and Protocol Deviation ............................................................64 
15.7.1 
Protocol Amendment .........................................................................................64 
15.7.2 
Protocol Deviations ............................................................................................64 
15.8 Ethical Considerations ................................................................................................64 
15.9 Financing and Insurance .............................................................................................64 
15.10 Publication Policy/Disclosure of Data........................................................................64 
16 
REFERENCES ................................................................................................................66 
17 
APPENDICES .................................................................................................................68 
APPENDIX 1. CONTRACEPTION GUIDELINES ............................................................69 
APPENDIX 2. BRISTOL STOOL CHART .........................................................................72 
 


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3.1 
List of In-text Tables 
Table 1. Dose, Route, and Schedule of Study Medication for Segment 2B .........................35 
Table 2. Daily Dosing for Segment 2B .................................................................................35 
Table 3. Potentially Confounding Medications.....................................................................39 
Table 4. Schedule of Assessments ........................................................................................42 
Table 5. Laboratory Assessments..........................................................................................49 
Table 6. Classification of Adverse Events by Intensity ........................................................50 
Table 7. Classification of Adverse Events by Relationship to Study Drug ..........................51 
Table 8. Estimated Cure Rate and Associated 95% Confidence Intervals Based on the 
Normal Approximation ...........................................................................................56 
Table 9. Highly Effective Contraceptive Methods................................................................70 
 
 
3.2 
List of In-Text Figures 
Figure 1. Study Schematic ......................................................................................................28 
 
 
 


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4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
CDI 
Clostridioides difficile infection 
CFR 
Code of Federal Regulations 
ECC 
extended clinical cure 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PP 
Per protocol 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCC 
sustained clinical cure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TOC 
test of cure 
UBM 
unformed bowel movements 
US 
United States 
WOCBP 
women of childbearing potential 
 


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5 
INTRODUCTION 
5.1 
Background on Clostridioides Difficile 
Clostridioides difficile (C. difficile) is an anaerobic, spore-forming, Gram-positive bacterium. 
It is the causative agent of C. difficile infection (CDI), an increasingly common, potentially 
life-threatening disease. C. difficile can live harmlessly in the colon, but in the presence of an 
antibiotic administered for another condition, overgrowth may occur, replacing normal 
bacterial flora and resulting in CDI and or C. difficile-associated disease (Nelson, 2017). 
The epidemiology of C. difficile has changed with the emergence of the North American 
pulsed-field gel electrophoresis type 1 strain, and use of more sensitive assays (Lessa, 2015). 
CDI infection affects approximately 500,000 patients in the United States (US) each year, 
and is associated with 15,000 to 30,000 deaths (McDonald, 2018). In fact, 65,000 hospital 
acquired hospital-onset cases, 50,000 hospital acquired post-discharge cases, and 263,000 
nursing home-onset cases, result in $4 billion in excess costs to the healthcare system 
annually (Clostridium Infections – Pipeline Review, 2012). Hospitalizations for CDI 
among nonpregnant adults has doubled from 2000 through 2010 and are projected to 
continue to increase in 2011 and 2012 (Lessa, 2015). 
Although the discontinuation of predisposing antibiotic therapy and treatment with 
metronidazole, oral vancomycin, or the recently approved drug fidaxomicin (Dificid®), are 
effective in management of CDI, the development of new alternative therapeutic measures 
will be of great benefit. Not only is the incidence of hospitalizations and deaths associated 
with C. difficile rising (Lessa, 2015; Louie, 2012; Zilberberg, 2008), but some strains may 
become hypervirulent and increasingly resistant to cephalosporins and fluoroquinolones 
(Razavi, 2007). 
Current treatment strategy includes discontinuation of predisposing antibiotic and oral 
administration of vancomycin or fidaxomicin. If access to vancomycin or fidaxomicin is 
limited, metronidazole may be used for an initial episode of nonsevere CDI only (McDonald, 
2018). 
While vancomycin continues to show good clinical efficacy for C. difficile, there is an 
increasing incidence of serious illness because of vancomycin-resistant enterococci in the 
United States, and use of oral vancomycin (as well as oral metronidazole) has been shown to 
promote overgrowth of this pathogen (Al-Nassir, 2008). Use of vancomycin to treat C. 
difficile is also associated with unacceptably high recurrence rates. Fidaxomicin (Dificid), 
although newly approved for treatment of CDI, is a treatment option if the risk of recurrence 
is high, but not for complicated CDI (Smits, 2016). 
Several additional products are under development, and include small molecules, natural 
products, vaccines, and fecal transplants (Clostridium Infections – Pipeline Review, 2012; 
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Ibezapolstat (ACX-362E) has activity in vitro and in vivo against C. difficile (Xu, 2011; 
Dvoskin, 2012). The crisis in antibiotic resistance of Gram-positive bacteria prompted the 
development of novel antibacterials through structure–activity relationship studies of 
replication-specific DNA polymerase IIIC. It is from among these compounds that 
antibacterial compounds against C. difficile with potent in vitro activity have been 
discovered. Among these is ibezapolstat, which also shows potent in vivo activity in the 
established Syrian golden hamster model of CDI (Kokkotou, 2008; Dvoskin, 2012). 
Ibezapolstat is an inhibitor of the C. difficile DNA polymerase IIIC and is highly selective for 
C. difficile compared with other Gram-positive anaerobes and aerobic bacteria. Ibezapolstat, 
2-(3,4-dichlorobenzyl)-7-(2-[morpholinyl]ethyl)guanine, is a small molecule, poorly 
bioavailable and active orally in the hamster model. In vitro, ibezapolstat inhibited numerous 
C. difficile strains, with a minimum inhibitory concentration required to inhibit the growth of 
90% of organisms value of 4 µg/mL, and without inhibiting Bifidobacteria and Lactobacillus 
spp., important "good" intestinal anaerobic bacteria, or Gram-negative bacteria. These results 
suggest that development of ibezapolstat as an oral treatment for CDI in human patients will 
result in a novel, first-in-class drug to treat this emerging infectious disease. 
Subjects in this study will be administered 450 mg ibezapolstat orally every 12 hours for 
10 days. Ibezapolstat is administered orally because it has been shown that ibezapolstat has 
low oral availability with low systemic absorption, and also has a unique specificity for 
C. difficile that does not affect the normal good flora of the colon, an important advantage to 
prevent recurrence. 
5.2 
Background on Ibezapolstat 
5.2.1 Nonclinical Studies 
In 14-day multiple oral dose studies, doses of ibezapolstat were given orally at doses ranging 
from 60 to 600 mg/kg in dogs, and 100 to 2000 mg/kg/day in rats. Bioavailability appeared to 
be approximately 10% after comparing intravenous and oral dosing in both rats 
(approximately 8%) and dogs (approximately 11%). The apparent plasma clearance after 
single dosing appeared to be approximately 90 to 140 L/h in rats and 60 to 90 L/h in dogs 
after administration of oral doses ranging from 60 to 1000 mg/kg/day. No toxicity was seen 
in these studies so the no observed adverse effect level was > 600 mg/kg/day in dogs and 
> 2000 mg/kg/day in rats (data on file). 
Ibezapolstat was excreted in urine and feces after oral administration in rats. Approximately 
9% and 0.4% of the dose was excreted in feces and urine, respectively; considering the oral 
bioavailability is approximately 10%, and that ibezapolstat is metabolized to 11 different 
metabolites. Fecal concentrations after a 50 mg/kg oral dose in rats were 107 to 191 µg/g at 
10 to 24 hours post dose (data on file). 
For more information, refer to the Investigator’s Brochure. 


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5.2.2 Clinical Studies 
A Phase 1 study of ibezapolstat in healthy subjects (ACX-362E-101) has been completed. 
Study ACX-362E-101 was a randomized, double-blind, placebo-controlled, 3-part, single-
ascending dose, multiple-ascending dose, food effect study in which ibezapolstat was 
administered in doses of 150 mg, 300 mg, 450 mg, 600 mg, and 900 mg. The primary 
objective of the study was to determine the safety of ibezapolstat in both single and multiple 
doses to healthy subjects. Secondary objectives of the study were to determine systemic and 
fecal pharmacokinetics (PK) of ibezapolstat after single and multiple doses and to compare 
fecal microbiome effects of ibezapolstat compared to those of vancomycin after multiple 
doses. The plasma and stool levels of ibezapolstat were also determined after a fed and fasted 
state. Part 1 (n = 6 ibezapolstat; n = 2 placebo) was a single-ascending dose, double-blind, 
randomized, placebo-controlled escalation study. Part 2 (n = 8 ibezapolstat) was a separate, 
single dose cohort at the dose determined in Part 1 and was a randomized, open-label, food 
effect, 2-period cross-over study in which subjects were assigned a single dose of 
ibezapolstat in either a high-fat, high-calorie, fed state followed by a fasted state, or in a 
fasted state followed by a high-fat, high-calorie fed state. Part 3 (n = 6 ibezapolstat; n = 2 
placebo) was a multiple-dose, double-blind, randomized, placebo-controlled dose escalation 
study in which tolerability, plasma PK, fecal concentrations, and fecal microbiome effects of 
ibezapolstat were evaluated. In addition, a positive-control subgroup was randomly assigned 
to dosing with vancomycin and tolerability, fecal concentrations, and fecal microbiome effect 
were evaluated for these subjects. 
Preliminary results from Study ACX-362E-101 showed a favorable safety profile. Adverse 
events (AEs) were well tolerated, similar to placebo, and transitory. AEs in subjects who 
received ibezapolstat included cough, cystitis-noninfective, dizziness, nasal congestion, 
twitching sensation, and headache that were considered by the Investigator to be unrelated to 
ibezapolstat and epigastric pain, headache (3 events), dyspepsia, nausea, prolonged PR 
interval, shortness of breath, and tachycardia that were considered by the Investigator to be 
possibly or probably related to ibezapolstat. All the events were mild in intensity except for 1 
of moderate intensity (headache). No AE required a change in therapy or intervention. 
Ibezapolstat was shown to have ideal PK for a C. difficile antibiotic. Systemic concentrations 
of ibezapolstat after administration showed low systemic absorption. Fecal levels were 
several orders of magnitude higher than the microbial inhibitory concentration of C. difficile 
(4000 to 6000 µg/g stool). Study results demonstrated that after ibezapolstat administration, 
there is a favorable microbiome profile remaining in the gut with less disruption to normal 
microbiota compared to vancomycin, which was largely driven by decreased killing of 
Bacteroidetes and Firmicutes bacteria, which constitute > 80% of normal microbiota. These 
results support continuing the development of ibezapolstat for the treatment of CDI. 
The food effect on ibezapolstat following a 300 mg single dose of ibezapolstat showed a 
peak plasma concentration of ibezapolstat of approximately 3 times greater in a fasting state 


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versus a fed state, although the ibezapolstat plasma concentration returned to zero sooner in 
the fasting state. 
Comparison of multiple doses of 300 mg and 450 mg dosing of ibezapolstat showed plasma 
concentrations peaking at approximately 2 times greater with the 450 mg dose compared to 
the 300 mg dose. Multiple dosing showed higher peaks of ibezapolstat in stool samples in 
subjects who received 450 mg ibezapolstat compared to 300 mg ibezapolstat. 
5.3 
Clinical Risks/Benefits of Ibezapolstat 
Based on the available nonclinical and clinical data to date, the conduct of the study, as 
specified in this protocol, is considered justifiable. The nonclinical data suggest an acceptable 
safety margin for the selected dose of ibezapolstat. 
All subjects will receive an active treatment for their CDI in the study. Subjects who fail to 
respond to study treatment will be offered treatment for CDI according to the standard of 
care antibiotic at the Investigator’s discretion. 
This study will be performed in compliance with the protocol, International Council for 
Harmonisation Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) and applicable regulatory requirements. Aspects of the study 
concerned with the study drug will meet the requirements of Good Manufacturing Practice. 
Subjects will be closely monitored for safety during the study. The study progresses in 
stages, only going to the next stage after the Trial Oversight Committee (Section 14.7) has 
fully assessed the safety and tolerability of the prior stage and recommends continuing the 
study. 
The Sponsor will immediately notify the Principal Investigator (PI) if any additional safety or 
toxicology information becomes available during the study. 
The collection of blood samples may be accompanied by mild bruising, but it is usually 
painless. 
As this is the first administration of ibezapolstat to subjects with CDI, all effects cannot be 
reliably predicted. Facilities and staff for resuscitation and the treatment of other medical 
emergencies will be provided. 
5.4 
Study Rationale 
The growing prevalence, epidemic nature, and health care burden of C. difficile diarrhea 
provides a strong rationale to discover and develop oral agents to treat the condition in 
addition to those in current use. To that end, purine derivatives with potent inhibition of the 
growth of C. difficile clinical isolates in culture have been identified. Based on the finding 
that these molecules, inhibitors of DNA polymerase IIIC (pol IIIC), are potent inhibitors of 
the growth of the anaerobic bacterium C. difficile, the gene for pol IIIC from this organism 
was cloned and expressed for testing. This showed that inhibition of this enzyme by these 
anti-C. difficile compounds is, as expected, the likely basis for their antibacterial effect. One 


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of these purine-based inhibitors of C. difficile pol IIIC, ibezapolstat, is highly active in vitro 
and in vivo, displaying excellent potential for further development as a clinical agent for the 
treatment of CDI (Torti, 2011). 
New anti-CDI agents are needed to supplement those in current use for at least 2 significant 
reasons: firstly, ibezapolstat selectively inhibits pol IIIC, a target heretofore unexploited in 
C. difficile drug development. This property gives ibezapolstat strong potential for bypassing 
the resistance mechanism that may emerge in C. difficile during the prolonged administration 
of the agents in current use. Secondly, undesirable clinical issues frequently develop with 
prolonged use of some therapies such as vancomycin. Recurrence of C. difficile with 
vancomycin is a problem because vancomycin disrupts the normal balance of “good” 
bacteria in the gut, allowing “bad” bacteria to take over. Ibezapolstat, with its limited 
spectrum of activity, does not appear to disrupt the normal gut microbiome, thus having the 
potential to prevent the development and takeover of resistant strains needed for recurrence. 
Data from Study ACX-362E-101 supports further rationale for advancing ibezapolstat into 
Phase 2 studies in the treatment of C. difficile. When administered to healthy subjects, 
ibezapolstat was well tolerated, with an AE profile similar to placebo. All AEs but 1 were 
mild, transient, and nonrecurrent despite continued dosing. No AE required a change in 
therapy or an intervention and there were no clinically important adverse changes in physical 
examinations, vital signs, laboratory testing results, or electrocardiograms (ECGs). 
Ibezapolstat was shown to be an ideal treatment for C. difficile; it has low systemic exposure 
after oral dosing and showed no accumulation following 10 days of repeat dosing, yet fecal 
concentrations rose rapidly and were sustained at 2 to 3 orders of magnitude above the 
minimum inhibitory concentration for C. difficile. Furthermore, after treatment with 
ibezapolstat, the fecal microbiome remained favorable, with less disruption to microbiota 
compared to vancomycin. Ibezapolstat treatment resulted in decreased killing of 
Bacteroidetes and Firmicutes, which generally comprise 80% to 90% of the healthy fecal 
microbiome. The 450 mg dose of ibezapolstat proved to result in higher fecal concentrations 
of ibezapolstat over the 300 mg dose, while also having an acceptable safety profile, and thus 
was chosen as the dose moving forward. Treatment with oral vancomycin is the standard of 
care for patients with CDI. Vancomycin treatment will be incorporated as a positive control 
into this study to allow accurate and sophisticated comparison of the respective effects of 
ibezapolstat and vancomycin on the fecal microbiome. Such data will provide valuable 
information regarding potential advantages of ibezapolstat over the current standard of care, 
such as preservation of “good” elements of the microbiome or quicker recovery to 
pretreatment profiles. Furthermore, comparative microbiome profiling may provide 
information on the benefits of ibezapolstat to maintain normal intestinal flora, which has the 
potential to improve the efficiency of future ibezapolstat efficacy studies. 


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5.4.1 Justification for Dose 
The ibezapolstat dose chosen for this study is 450 mg. The results from Study ACX-362E-
101 showed that after administration of ibezapolstat 450 mg every 12 hours, stool 
concentrations of ibezapolstat peak at higher concentrations compared to the 300 mg dose 
given every 12 hours and are consistently 2 to 3 orders of magnitude above the C. difficile 
minimum inhibitory concentration required to inhibit the growth of 90% of organisms. The 
450 mg dose had an acceptable safety and tolerability profile and thus was selected to ensure 
presumed therapeutic levels of ibezapolstat in the gastrointestinal (GI) tract of subjects with 
CDI, while minimally impacting normal gut microbiome composition. 
Vancomycin is a registered product and is commercially available. The usual adult total daily 
dose is 500 mg to 2 g administered orally in 3 or 4 divided doses for 7 to 10 days. For this 
study, 125 mg vancomycin will be administered approximately every 6 hours for 10 days, per 
current treatment guidelines for CDI (McDonald, 2018). 
The 10-day duration of treatment was selected because: (a) this is the recommended duration 
of therapy for all current standard of care oral CDI drugs, according to the most recent 
Infectious Diseases Society of America and Society for Healthcare Epidemiology of America 
Guidelines (McDonald, 2018); (b) by the same token, it is the standard regimen of oral 
vancomycin, which is being used as the active control agent in the Phase 2B segment of this 
trial; (c) Phase 1 data have established the safety of ibezapolstat over 10 days of oral dosing; 
and (d) no human data exist to indicate that a shorter course of therapy with ibezapolstat 
would achieve acceptable efficacy for the treatment of CDI. 
6 STUDY OBJECTIVES AND ENDPOINTS 
6.1 
Study Objectives 
6.1.1 Primary Objectives 
1. Access CDI clinical cure rates 2 days after the end of treatment (EOT) (Segment 
2A/2B) 
2. Evaluate the safety and tolerability of ibezapolstat administered every 12 hours for 
10 days in the treatment of CDI (Segment 2A/2B) 
6.1.2 Secondary Objectives 
1. Determine the systemic exposure (Segment 2A) and fecal concentrations 
(Segment 2A/2B) of ibezapolstat in subjects with CDI during the course of treatment 
2. Assess incidence of sustained clinical cure (SCC) at 28 ± 2 days after EOT 
(Segment 2A/2B) 
6.1.3 Exploratory Objectives 
1. Compare the effects of ibezapolstat versus vancomycin on relative and quantitative 
changes to the fecal microbiome (Segment 2A/2B) 
2. Assess times to resolution of diarrhea during the treatment period (Segment 2A/2B) 


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3. Assess times to hospital discharge during the treatment period (Segment 2A/2B) 
4. Assess the impact of ibezapolstat treatment on subject reported quality of life and 
resource utilization (Segment 2B) 
5. Assess the incidence of extended clinical cure (ECC) at 56 ± 2 days and 84 ± 2 days 
after EOT in subjects participating in the extended follow-up period (Segment 2B) 
6.2 
Study Endpoints 
6.2.1 Primary Endpoint 
The primary endpoints of this study are: 
• Clinical cure at the test of cure (TOC) visit: defined as survival and the resolution of 
diarrhea in the 24-hour period immediately before EOT that is maintained for 48 
hours post EOT without a requirement for additional CDI treatment. Diarrhea is 
defined as ≥ 3 unformed bowel movements (UBMs) in a 24-hour period; < 3 UBMs 
is considered as resolution of diarrhea. A UBM is defined as a Type 5, 6, or 7 bowel 
movement on the Bristol Stool Chart (Appendix 2). 
• Safety endpoints for all subjects: These include the nature, frequency, and severity of 
AEs, including serious adverse events (SAEs); changes from baseline in findings on 
physical examination, vital sign measurements, safety laboratory tests (hematology, 
biochemistry, urinalysis); and ECG findings. 
6.2.2 Secondary Endpoints 
6.2.2.1 Efficacy Endpoints 
The secondary efficacy endpoint of this study is: 
• SCC: this is defined as a clinical cure at the TOC visit (ie, at least 48 hours post EOT) 
and no recurrence of CDI within the 28 ± 2 days post EOT. Recurrence is defined as a 
new episode of diarrhea (≥ 3 UBMs in a 24-hour period) with a positive toxin result, 
using a Sponsor-approved C. difficile free toxin test and, in the opinion of the 
Investigator, requiring retreatment with an antibacterial agent for C. difficile. 
6.2.2.2 Pharmacokinetic Endpoint 
The secondary PK endpoint is as follows: 
• Systemic exposure of ibezapolstat will be determined by measuring plasma 
ibezapolstat concentrations at specified time points following dose administration; 
fecal concentrations of ibezapolstat will be measured at specified study visits. 
6.2.3 Exploratory Endpoints 
The exploratory endpoints of this study are as follows: 
• Microbial endpoints: Quantitative changes in relevant fecal bacterial communities 
and microbial diversity will be assessed for ibezapolstat-treated subjects in both 
segments, and in comparison to those treated with vancomycin in Segment 2B. 


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Changes will be assessed during the treatment period and post EOT. Details of the 
final microbiome analysis will be described in the statistical analysis plan (SAP) or 
relevant laboratory manual. 
• Time to resolution of diarrhea, defined as the time from outset of treatment to the first 
formed bowel movement not followed within the next 24 hours by a UBM, will be 
recorded. 
• Time to hospital discharge (for hospitalized subjects only) is defined as time from 
outset of treatment to day of discharge, and not followed by readmission for treatment 
of CDI before the TOC visit. 
• Quality of life assessments including EuroQol 5 Dimension 5 Level (EQ-5D-5L) and 
medical resource utilization data will be performed at designated time points during 
Segment 2B.  
• ECC: this is defined as a clinical cure at the TOC visit (ie, at least 48 hours post EOT) 
and no recurrence of CDI within the 56 ± 2 days post EOT (ECC56) and 84 ± 2 days 
post EOT (ECC84). Recurrence is defined as a new episode of diarrhea (≥ 3 UBMs in 
a 24-hour period) with a positive toxin result, using a Sponsor-approved C. difficile 
free toxin test and, in the opinion of the Investigator, requiring retreatment with an 
antibacterial agent for C. difficile. 
7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This Phase 2, multicenter, combined segment open-label single-arm segment followed by a 
double-blind, randomized, active-controlled clinical segment is designed to evaluate 
ibezapolstat in the treatment of CDI. 
Segment 2A of this trial is an open-label cohort of up to 20 subjects in up to 5 study centers 
in the United States and Canada. If safety, tolerability, and efficacy are considered acceptable 
by the Trial Oversight Committee, Segment 2A will be followed by a double-blind, 
randomized, active-controlled trial with an additional cohort of at least 72 subjects. 
In Segment 2A, up to 20 subjects with diarrhea caused by C. difficile will be enrolled and 
treated with ibezapolstat 450 mg orally every 12 hours for 10 days. All subjects will be 
followed for recurrence for 28 ± 2 days, regardless of response to ibezapolstat. After up to 
10 subjects have been enrolled in the study and completed the full course of treatment in 
Segment 2A, there will be an assessment of safety, tolerability, and, as data allow, efficacy, 
by the Trial Oversight Committee, which will make a recommendation regarding continued 
enrollment of Segment 2A. The Trial Oversight Committee will consist of both the Sponsor’s 
Medical Monitor (Chair), the Syneos Health Medical Monitor, and up to 2 PIs who enrolled 
subjects in Segment 2A. 


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Another assessment of safety, tolerability, and efficacy will be made by the Trial Oversight 
Committee after all subjects have been enrolled in Segment 2A and followed through at least 
the EOT visit. 
In Segment 2B, at least 72 additional subjects with CDI will be enrolled and randomly 
assigned in a 1:1 ratio to either ibezapolstat 450 mg orally every 12 hours with food or to 
vancomycin 125 mg orally every 6 hours in up to 30 centers in the United States and Canada. 
Treatment will be administered for 10 days, and subjects will be followed for 28 ± 2 days for 
recurrence. Blinding in Segment 2B will be maintained by over-encapsulation of both drugs 
and dosing every 6 hours in all subjects. Subjects randomized to ibezapolstat will receive 
2 doses per day of ibezapolstat and 2 doses per day of placebo. Additionally, subjects 
recruited from selected sites will participate in an extended follow-up period consisting of 
observation visits at 56 and 84 days after treatment to evaluate the long-term impact of 
ibezapolstat on the microbiome and on disease recurrence. At these selected sites, 
consecutive subjects will be offered the opportunity to participate in the extended follow-up 
period until approximately 16 subjects are recruited. 
For all subjects, the diagnosis of CDI will be based on unexplained and new onset of diarrhea 
(≥ 3 UBMs in a 24-hour period) and a positive result using a US Food and Drug 
Administration (FDA)-approved test to detect free C. difficile toxins A and B in stools. 
Baseline safety evaluations will consist of physical examination, vital signs, routine 
laboratory (hematology, biochemistry, and urinalysis) testing, and ECG. 
Subjects will be evaluated for treatment response and safety (AEs, physical examination, 
vital signs, laboratory tests, and ECG) at designated time points according to Table 4. 
Clinical cure of CDI will be defined as survival and the resolution of diarrhea in the 24-hour 
period immediately before EOT that is maintained for 48 hours post EOT without a 
requirement for additional CDI treatment. All subjects, regardless of outcome after 10 days 
of treatment, will be followed for recurrence until Day 38; recurrence is defined as a new 
episode of diarrhea (≥ 3 UBMs in a 24-hour period) with a positive free toxin test result 
(using a Sponsor-approved diagnostic test) that in the opinion of the Investigator requires 
retreatment with an antibacterial for C. difficile. 
Stool samples for microbiome testing in Segment A and Segment B will be collected at the 
time points outlined in Table 4, frozen, and sent to the central laboratory for analysis. An 
additional sample will be collected in the event of any suspected recurrence post TOC, 
regardless of the outcome from the 10 days of treatment. Samples will also be collected in 
the event of any suspected recurrence at 56 and 84 days after EOT for those subjects 
participating in the extended follow-up period. Evaluation of changes to the microbiome at 
the TOC visit as well as overgrowth by vancomycin-resistant Enterococcus and multi-drug 
resistant organisms will be performed using Next Gen metagenomics sequencing and 
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For PK analysis in Segment 2A and 2B, fecal concentrations of ibezapolstat will be 
determined for the stool samples collected at time points outlined in Table 4. Blood samples 
to measure plasma levels of ibezapolstat in Segment 2A and approximately 50% of subjects 
(ie, approximately 36 subjects) in Segment 2B will be drawn 2 hours and 4 hours after the 
morning dose at time points specified in Table 4. 
Figure 1 presents the study design. 
Figure 1. 
Study Schematic 
 
7.2 
Discussion of Study Design 
Ibezapolstat is under clinical development for the treatment of CDI. 
A 10-day treatment period was selected to support the primary endpoint of initial cure rate 
and the 28 ± 2 days post EOT is considered the most appropriate measure of efficacy for 
sustained cure for comparison to vancomycin, since it captures both cure of the initial 
infection and any onset of CDI recurrence. 
The open-label Segment 2A will allow an initial evaluation of the safety, tolerability, and 
efficacy of ibezapolstat in a limited number of subjects diagnosed with CDI, since there has 
been only limited clinical exposure in healthy subjects to date and no clinical exposure in 
subjects diagnosed with CDI. The randomized, double-blind Segment 2B allows an 
evaluation of the safety, tolerability, and efficacy of ibezapolstat in a blinded comparison to 
vancomycin, the current standard of care for CDI. The extended follow-up period allows an 
evaluation of the long-term impact of ibezapolstat on the microbiome and on the incidence of 
recurrent CDI. 
To ensure the randomized population has a true CDI, the diagnosis of CDI is confirmed by 
the presence of free toxins in stool, which is the most rigorous sign of true infection in 
accordance with treatment guidelines. 
Vancomycin 125 mg every 6 hours over 10 days is a standard therapy option for CDI. 
Segment 2A: Open-Label
Segment 2B: Double-Blind Active-Controlled
•
Recommended Phase 2 
ACX-362E dose 
(450 mg every 12 hours)
•
N = ~20
•
~ 5 sites
•
Decision point based on 
minimal efficacy threshold
Vancomycin 125 every 6 hours 
(n = 36)
ACX-362E 450 mg every 12 hours 
(n = 36)
End of 
Study


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7.3 
End of Study 
A subject will have fulfilled the requirements for study completion if/when the subject has 
completed all study periods, including the Follow-Up End of Study Day 38 visit, and for 
those Segment 2B subjects participating in the extended follow-up period, observation visits 
Day 66 (56 days post EOT) and Day 94 (84 days post EOT), as indicated in the Schedule of 
Assessments (Table 4). 
The end of the study will be the last subject’s last visit or the last subject’s scheduled 
visit/assessment as indicated in the Schedule of Assessments (Table 4). 
8 
SELECTION OF STUDY POPULATION 
Up to 20 evaluable subjects with mild or moderate CDI are planned to be enrolled in 
Segment 2A and at least 72 subjects with mild or moderate CDI are planned to be 
randomized for Segment 2B. Subjects must meet all of the inclusion criteria and none of the 
exclusion criteria to be eligible for the study. 
8.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in the study: 
1. Male or female 18 to 90 years of age, inclusive, at the time of Screening. 
2. Capable of reading, understanding, and signing the written informed consent; able to 
adhere to all study procedures and attend all scheduled study visits. 
3. Confirmed diagnosis of mild or moderate CDI as defined by the Infectious Diseases 
Society of America/Society for Healthcare Epidemiology of America guidelines 
(McDonald et al. 2018). Subjects will be diagnosed with CDI based on clinical and 
laboratory findings: 
a. The presence of diarrhea, defined as passage of ≥ 3 UBMs within 24 hours before 
dosing; an unformed stool is defined as a Type 5, 6, or 7 on the Bristol Stool Chart 
(Appendix 2). 
b. A stool test result positive for the presence of C. difficile free toxins using a test 
(approved by either the US FDA or Health Canada) that detects toxins A/B (and is 
prospectively agreed with the Sponsor). The Sponsor will provide a toxin A/B test kit 
if the site does not have it as part of standard of care testing. 
c. Mild or moderate CDI as defined as a white blood cell count of ≤ 15,000 cells/mL 
and a serum creatinine level < 1.5 mg/dL. 
4. Agreement by subjects with reproductive potential to use two adequate methods of 
contraception during the study and for 4 weeks after the last study drug administration. A 
female subject is considered to be of reproductive potential following menarche and until 
she is in a postmenopausal state for 12 months or otherwise permanently sterile (for 
which acceptable methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy). Female subjects must agree to the use of TWO reliable methods of 
contraception while receiving study drug and for 4 weeks after the last study drug 


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administration if sexually active, which can include: condoms, spermicidal gel, 
diaphragm, hormonal or non-hormonal intrauterine device, surgical sterilization, oral 
contraceptive pill, and depot progesterone injections. If a male subject is sexually active, 
the subject and his partner will each use at least one of the listed contraceptive methods. 
See Appendix 1 for contraception guidelines for the study. 
5. Negative serum pregnancy test at Screening and/or a negative urine pregnancy test on the 
day of admittance to the inpatient phase for all female subjects of childbearing potential. 
6. Agreement in male subjects to not donate sperm starting at Screening and throughout the 
study period and for 90 days after the final study drug administration. 
8.2 
Exclusion Criteria 
Subjects meeting any of the following criteria at Screening or baseline are ineligible to 
participate in this study: 
1. Received more than 24 hours of dosing (> 4 doses) of oral vancomycin for the current 
episode of CDI before first dose of study drug. 
2. Received more than 24 hours of dosing (> 2 doses) of oral fidaxomicin for the current 
episode of CDI before first dose of study drug. 
3. Received more than 24 hours of dosing (> 3 doses) of oral/intravenous (IV) 
metronidazole for the current episode of CDI before first dose of study drug. 
4. Received any other antibacterial therapy for the current CDI episode within 48 hours 
before the first dose of study drug. 
5. Subjects considered treatment failures on prior antibiotics for their current episode of 
CDI will be excluded. 
6. More than 3 episodes of CDI in the previous 12 months or more than 1 prior episode in 
the last 3 months, excluding the current episode. 
7. Severe, complicated, or life-threatening fulminant CDI with evidence of hypotension 
(systolic blood pressure less than 90 mmHg), septic shock, peritoneal signs or ileus, or 
toxic megacolon. 
8. Elevated liver transaminases (ALT, AST) greater than 2 times ULN. 
9. Active inflammatory bowel disease (Crohn’s disease, ulcerative colitis, Irritable Bowel 
Syndrome with chronic diarrhea). 
10. Any other non-C. difficile diarrhea. 
11. Active gastroenteritis because of Salmonella, Shigella, Escherichia coli 0157H7, Yersinia 
or Campylobacter, a parasite, or virus within the past 2 weeks. 
12. Had a known positive diagnostic test for other relevant GI pathogens in the 2 weeks 
before study drug treatment and/or colonization/infection by ova or parasites. 
13. Major GI surgery (ie, significant bowel resection) within 3 months of enrollment (does 
not include appendectomy or cholecystectomy). 
14. Prior or current use of anti-C. difficile toxin antibodies. 
15. Have received a vaccine against C. difficile or its toxins. 


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16. Anticipated that systemic antibacterial therapy for a non-CDI infection will be required 
for > 7 days after start of study therapy. 
17. Actively taking anti-diarrheals, and unable to discontinue anti-diarrheal medication, or 
any medication with the potential to slow bowel movement (for opiates, a stable dose, 
including use as needed, is permitted). 
18. Actively taking Saccharomyces boulardii and unwilling to discontinue during the study 
period. 
19. Received a fecal transplant in the previous 3 months. 
20. Received laxatives in the last 48 hours. 
21. Unable or unwilling to stop taking oral probiotics for the duration of the study. 
22. Received IV immunoglobulin within 3 months before study drug treatment. 
23. Sepsis. 
24. Have a known current history of significantly compromised immune system such as: 
a. Subjects with a known history of human immunodeficiency virus infection and CD4 
< 200 cells/mm3 within 6 months of start of study therapy. 
b. Severe neutropenia with neutrophil count < 500 cells/mL. 
c. Concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for 
active malignancy. 
25. Any specific condition that, in the judgment of the Investigator, precludes participation 
because it could affect subject safety. 
26. Active participation in other clinical research studies using an investigational product or 
received investigational antibacterial agent within one month before Screening. 
27. Pregnant or lactating women. 
28. Known hypersensitivity to any ibezapolstat excipient. 
29. Hypersensitivity or other contraindication to vancomycin. 
30. Prior treatment with study drug in this trial. 
8.3 
Rescreening 
Subjects who sign the informed consent form (ICF) to participate in the study but who do not 
subsequently meet all the requirements as outlined in the inclusion and exclusion criteria and 
therefore do not enroll (screen failures) may be rescreened. Such individuals may be allowed 
to rescreen up to 2 times. Subjects with a negative toxin text will not be rescreened, unless 
the subject is experiencing a new, separate diarrheal episode. 
8.4 
Study Discontinuation, Removal, and Replacement of Subjects 
Discontinuation of study treatment for a subject occurs when study treatment is stopped 
earlier than the protocol planned duration. Discontinuation of study treatment can be decided 
by either the subject or the Investigator. 
If a subject discontinues study treatment and is withdrawn from the study for any reason, the 
study site must immediately notify the Medical Monitor. The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF). Subjects who 


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complete or discontinue early from the study will be asked to return to the study site within 
10 days of the last administration of study drug to complete End of Study assessments as 
indicated in the Schedule of Assessments (Table 4). 
In the event that a subject discontinues prematurely from the study because of a 
treatment-emergent AE (TEAE) or serious TEAE, the TEAE or serious TEAE will be 
followed up until it resolves (returns to normal or baseline values) or stabilizes, or until it is 
judged by the Investigator to no longer be clinically significant. 
Once a subject is withdrawn from the study, the subject may not reenter the study. 
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons 
including, but not limited to, the following: 
• subject withdrawal of consent: at any time, a subject's participation in the study may 
be terminated at his/her request or on the basis of the Investigator’s clinical judgment 
for safety, behavioral, compliance or administrative reasons 
• unacceptable toxicity or AE/SAE 
• intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis 
that became apparent during treatment and necessitated the subject’s termination from 
the study 
• general or specific changes in the subject's condition that renders him/her ineligible 
for further treatment according to the inclusion/exclusion criteria 
• subject fails to adhere to the protocol requirements (eg, drug noncompliance, failure 
to return for defined number of visits) 
• lost to follow-up: the subject stopped coming for visits, and study personnel were 
unable to contact the subject 
• pregnancy, as indicated in Section 12.6.4. 
Additionally, the Sponsor may stop the study at any time for safety, regulatory, legal, or 
other reasons aligned with GCP studies. This study may be terminated at the discretion of the 
Sponsor or any regulatory agency. An Investigator may elect to discontinue or stop the study 
at his or her study site for any reason, including safety or low enrollment. 
Subjects who discontinue the study will not be replaced. Subjects who discontinue the study 
will be offered treatment for CDI according to the standard of care antibiotic, at the 
Investigator’s discretion. 
If the subject withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. In addition, if a 
subject withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the study center study records. 


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8.4.1 Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study center. 
Reasonable efforts will be made to contact subjects who are lost to follow-up. These efforts 
must be documented in the subject’s file. 
9 
TREATMENTS 
Study treatment includes ibezapolstat, vancomycin, and placebo. 
9.1 
Ibezapolstat 
9.1.1 Description 
Ibezapolstat is a white to pale yellow powder. It is formulated as a 150 mg neat (without 
excipients) powder in white opaque, hard, size 1 gelatin capsules for oral administration. 
9.1.2 Manufacturing 
Ibezapolstat is manufactured by Piramal Enterprises Limited Pharmaceutical Development 
Services in Ahmedabad, India. Ibezapolstat will be supplied by Acurx Pharmaceuticals. 
9.1.3 How Supplied 
Segment 2A: Approximately 30 capsules are supplied in 40 cc round, white, opaque, high-
density polyethylene bottles with integral seals and caps. Individual doses will be taken from 
these bottles according to the coded dosing schedule. 
Segment 2B: Individual gelatin capsules will be in blister packs and each dose labeled as 
“Day X (Day 1 to 10) Dose X (Dose 1 to 4)”. 
9.1.4 Packaging and Labeling 
All packaging and labeling will be done according to Good Manufacturing Practice and the 
relevant regulatory requirements. Packaging will be designed to maintain the double-blind 
nature of the trial. 
9.1.5 Storage and Handling 
Ibezapolstat is to be stored at ambient temperature (23 ºC, range 20 ºC to 25 ºC). Keep bottle 
tightly closed before and after each use. 
All study treatments must be stored in a secure, environmentally controlled and monitored 
area in accordance with the labeled storage conditions with access limited to the Investigator, 
appropriate pharmacists, and authorized study center staff. 
9.1.6 Dietary and Lifestyle Restrictions 
In the Phase 1 study, the food effect on ibezapolstat following a single dose of ibezapolstat 
showed a peak plasma concentration of ibezapolstat of approximately 3 times greater in a 
fasting state versus a fed state. Therefore, to minimize systemic absorption and maximize 
colonic concentrations, subjects in Segment 2B will be instructed to take their morning and 


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evening doses (every 12 hours) of study drug with food; subjects will record their fed or 
fasting status for each dose. The requirement to take study drug with food only affects 
ibezapolstat but not vancomycin or placebo; therefore, only morning and evening doses must 
be taken with food by all subjects in this blinded trial. There is no dietary requirement for the 
other two daily dosing times.  
9.2 
Vancomycin 
Vancomycin is commercially available as vancomycin hydrochloride 125-mg capsules. 
Vancomycin capsules will be over-encapsulated with gelatin capsules to be identical in 
appearance to ibezapolstat. 
Vancomycin will be packaged in blister packs identical to ibezapolstat with each dose 
labeled as “Day X Dose X.” 
Vancomycin will be administered according to instructions in the package insert. 
Vancomycin is administered orally as 125 mg every 6 hours. Although the requirement to 
take study drug with food only affects ibezapolstat, not vancomycin or placebo, to maintain 
the blind in Segment 2B, only morning and evening doses must be taken with food; subjects 
will record their fed or fasting status for each dose. There is no dietary requirement for the 
other 2 daily dosing times. 
9.3 
Placebo 
Placebo powder will be filled into gelatin capsules to be identical in appearance to 
ibezapolstat. See Section 9.4 for placebo dosing instructions. 
The placebo capsules are manufactured by Piramal Enterprises Limited Pharmaceutical 
Development Services in Ahmedabad, India and will be supplied by Acurx Pharmaceuticals. 
Packaging, labeling, storage, and handling of placebo will be the same as for ibezapolstat. 
9.4 
Dosage Schedule 
Segment 2A 
In this open-label segment, ibezapolstat will be administered to all enrolled subjects as 
450 mg (three 150 mg capsules) every 12 hours for 10 days. Study drug will be administered 
with 240 mL water. There are no dietary requirements for this part of the study. 
Segment 2B 
Subjects randomly assigned to ibezapolstat will receive 450 mg ibezapolstat (three 150 mg 
capsules) orally every 12 hours for 10 days. Blinding is maintained in Segment 2B by 
over-encapsulation of all study drugs to appear identical. Because ibezapolstat and 
vancomycin have different dosing regimens (every 12 hours versus every 6 hours, 
respectively), subjects randomized to ibezapolstat will receive a placebo twice a day opposite 
of ibezapolstat dosing to mimic vancomycin dosing every 6 hours in order to maintain the 
blind. Thus, subjects assigned to ibezapolstat will receive ibezapolstat every 12 hours (eg, 


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6 AM and 6 PM) and a placebo capsule (eg, 12 AM and 12 PM) every 12 hours. Subjects 
randomized to vancomycin will receive 1 vancomycin capsule and 2 placebo capsules to 
mimic the 3 ibezapolstat 150 mg capsules every 12 hours (eg, 6 AM and 6 PM) and a single 
vancomycin capsule (eg, 12 AM and 12 PM) every 12 hours. 
Study drug will be administered with 240 mL water.  The morning and evening doses (every 
12 hours) of study drug must be taken with food. Subjects will record their fed or fasting 
status for each dose in the subject diary. 
Table 1. 
Dose, Route, and Schedule of Study Medication for Segment 2B 
Randomized 
Study Arm 
Dosea 
Duration of 
Treatment 
(Days) 
Active 
Capsules per 
Day 
Placebo 
Capsules per 
Day 
Route 
Ibezapolstat 
450 mg 
10 
6 
2 
Oral 
Vancomycin 
125 mg 
10 
4 
4 
Oral 
a Subjects will take study drug 4 times per day (approximately every 6 hours) at breakfast, lunch, dinner, and 
bedtime. 
 
Table 2. 
Daily Dosing for Segment 2B 
Study Arm 
Dose 1a 
Dose 2 
Dose 3 a 
Dose 4 
Ibezapolstat 
Ibezapolstat 450 mg 
oral capsule (given as 
three 150 mg 
capsules) 
Placebo 
Ibezapolstat 450 mg 
oral capsules (given 
as three 150 mg 
capsules) 
Placebo 
Vancomycin 
Vancomycin 125 mg 
oral capsule (1 
vancomycin capsule 
+ 2 placebo capsules)  
Vancomycin 
125 mg oral 
capsule 
Vancomycin 
125 mg oral capsule 
(1 vancomycin 
capsule + 2 placebo 
capsules)  
Vancomycin 
125 mg oral 
capsule 
a Subjects will take study drug with food. 
 
9.5 
Measures to Minimize Bias: Study Treatment Assignment and Blinding 
9.5.1 Method of Study Treatment Assignment 
Segment 2A 
Subjects will be screened and enrolled in the order they present to the study centers and will 
be assigned the next available sequential subject number. Subject number will be assigned 
sequentially by electronic data capture (EDC). 
Segment 2B 
On Day 1, subjects will be randomly allocated to kits containing blister packs of either 
ibezapolstat or vancomycin and will be assigned a randomization number according to an 


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interactive web response system (IWRS). The randomization schedule will be produced by 
staff outside the study team and kept secure from blinded study staff until after the study 
database is locked. Site staff will give the kits containing the blister packs to hospital staff 
while the subject is in the hospital (if needed), or to the subject to take home for self-dosing. 
9.5.2 Blinding 
Segment 2A 
Segment 2A is an open-label study; therefore, blinding is not applicable. 
Segment 2B 
Segment 2B is a double-blind study. Ibezapolstat, placebo, and vancomycin capsules will be 
identical in physical appearance by over-encapsulation, packaged into blister packs with each 
dose labeled, and will be administered 4 times a day so that neither study staff nor the 
subjects will know to which treatment the subject was assigned. Subjects randomized to 
vancomycin will receive 3 capsules (1 vancomycin capsule and 2 placebo capsules) to mimic 
the 3 ibezapolstat 150 mg capsules every 12 hours (eg, 6 AM and 6 PM) and a single 
vancomycin capsule (eg, 12 AM and 12 PM) every 12 hours. The Investigator, study staff, 
Sponsor, Trial Oversight Committee, and the subject will remain blinded to study treatment 
throughout the study. 
According to the randomization schedule as indicated in the Schedule of Assessments 
(Table 4), the Investigator or designee will obtain the kit number from the IWRS for the 
subject. The pharmacist or designee will provide the assigned kit number to the subject. No 
study site personnel, subjects, Sponsor personnel, or Sponsor designees will be unblinded to 
treatment assignment throughout the duration of the study unless unblinding is required. If an 
Investigator becomes unblinded to a given subject’s study treatment, that subject will 
continue in the study and undergo all protocol-required procedures for the determination of 
safety and efficacy. 
In the event that emergency unblinding is required for a given subject because of AEs or 
concerns for the subject’s safety or wellbeing, the Investigator may break the randomization 
code for the subject via the IWRS, by which system the unblinding will be captured. The 
Investigator is responsible for notifying the Medical Monitor and/or Sponsor of such an event 
within 24 hours. The unblinding and its cause will also be documented in the eCRF. 
9.6 
Dosage Modification 
Doses of study drug may not be modified in this study. 
9.7 
Treatment Accountability and Compliance 
The pharmacist or other designated individual will maintain records of drug kit number 
delivered to the study site (including amounts and lot numbers received, and confirmation of 
appropriate temperature conditions during transit), the inventory at the study site, the 
distribution to and use by each subject, and the return of materials to the Sponsor for storage 


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or disposal. These records should include dates, quantities, batch/serial numbers, expiration 
dates, in-clinic temperature log, and unique code numbers assigned to the product and study 
subjects. 
If the subject is hospitalized, administration of all study drug will be supervised by study site 
personnel to ensure compliance. Only subjects enrolled in the study may receive study drug 
and only authorized study center staff may administer the study drug to the subject. The 
subject will enter the date and time of dose administration and indicate fed or fasting status 
for each dose in the subject diary. 
If the subject is discharged or not hospitalized, at each visit after initiation of treatment, study 
site personnel will record compliance of the subject with the subject’s assigned regimen. 
Subjects will receive a diary and are to record the time and date of each dose they take in the 
diary. Subjects will be instructed to bring their diaries and drug kits containing 
unused/partially used/empty blister packs back for inspection at each study visit, as 
compliance will be assessed by capsule counts and recorded in the eCRF. Subjects are to be 
reminded of the importance of compliance with their assigned regimen, with an emphasis on 
taking their study drug on schedule and maintaining the prescribed interval between doses. 
Discontinuation for noncompliance is at the Investigator’s discretion and is to be noted in the 
eCRF. 
Study site personnel will be instructed to keep unused study drug and empty study drug 
packaging for drug accountability. Investigational product will not be returned to the Sponsor 
until accountability has been fully monitored. Any unused study treatment material may be 
destroyed by the study center according to their standard operating procedures upon written 
approval of the Sponsor. 
Investigators will maintain records that adequately document that the subjects were 
administered study drug from the correct study treatment kits and reconcile the products 
received from the drug dispensing center. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
9.8 
Prior and Concomitant Therapy 
9.8.1 Prior Medications 
Restricted prior therapies are provided in Section 8.2. Any medication or vaccine (including 
over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that the 
subject took within 30 days before, or is currently receiving at the Screening visit, must be 
recorded in the eCRF along with: 
• Reasons for use 
• Dates of administration including start and end dates 


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• Dosage information including dose and frequency 
Because of the seriousness of CDI, subjects need to start on an anti-C. difficile antibacterial 
drug as soon as possible once a CDI is suspected. However, subjects cannot have received 
more than 24 hours of an anti-C. difficile antibacterial medication before study drug 
treatment. Subjects also cannot have received more than 48 hours of any anti-C. difficile 
antibacterial for the current CDI episode within 14 days before the first dose of study drug. 
Doing so may mask the treatment effect of ibezapolstat. 
9.8.2 Concomitant Medications 
All medications and other treatments taken by the subject during the study, including 
over-the-counter or prescription medicines, vitamins, and/or herbal supplements, must be 
recorded in the eCRF. The entry must include the dose, regimen, route, indication, and dates 
of use. 
Refer to Table 3 for a list of medications that may alter bowel motility or impact CDI status 
and hence have the potential to confound study results. Control over administration of these 
medications is necessary, considering the primary endpoint of the study, but it is understood 
that a medication should not be withheld for purposes of the study if an alternative and 
comparable treatment cannot be provided, and the subject’s health would otherwise be 
compromised. 
From baseline/Day 1 to Day 12/TOC visit, confounding medications are NOT permitted. 
Any confounding medications taken should be recorded in the eCRF. 
From the Day 12/TOC visit to Day 38, confounding medications, except for CDI medication 
for recurrence, should be AVOIDED. Any confounding medications taken during this time 
should be recorded in the eCRF. 
Throughout the study, if antimicrobial therapy is required for infections other than those 
because of C. difficile, antimicrobials without activity/efficacy against C. difficile should be 
prescribed where possible without compromising the medical care of the subject. 


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Table 3. 
Potentially Confounding Medications 
Confounding Medications 
Screening 
Treatment Segment 
Follow-Up Segment 
Recurrence Segment 
Antimicrobials for treatment of 
CDIa 
Maximum of 24 hrs for current 
episode of CDI 
Not allowed 
Not allowed 
Permitted for treatment 
of confirmed recurrence 
Antimicrobials that may be 
active against C. difficileb 
No more than 24 hrs immediately 
before study drug treatment 
Not allowed 
Not allowedc 
As medically required 
Antimicrobials NOT active 
against C. difficiled 
Allowed 
Allowed 
Allowed 
Allowed 
Anti-diarrheals, antiperistaltics 
Not allowed 
Not allowed 
As medically required 
As medically required 
Opiates 
Allowed if dose stable, decreasing or 
stopped 7 days before study drug 
treatment 
Allowed if dose stable, 
decreasing or stopping is 
likelye 
Allowed if dose 
stable, decreasing or 
stopping is likelye 
Allowed following 
confirmed recurrence 
Anti-toxin antibodies including 
bezlotoxumab 
No prior use 
Not allowed 
Not allowed 
Allowed following 
confirmed recurrence 
Probiotics and herbal products 
for treatment of CDI 
Not allowed 
Not allowed 
Not allowed 
Allowed following 
confirmed recurrence 
Fecal microbiota transplant 
If taken within 3 months before 
study drug treatment, subject is 
excluded 
Not allowed 
Not allowed 
Allowed following 
confirmed recurrence 
IMP for CDI 
If taken within 3 months before 
study drug treatment, subject is 
excluded 
Not allowed 
Not allowed 
Allowed following 
confirmed recurrence 
Intravenous immunoglobulin 
If taken within 3 months before 
study drug treatment, subject is 
excluded 
Not allowed 
Not allowed 
Allowed following 
confirmed recurrence 
Investigational vaccine for C. 
difficile 
Subject is excluded 
Not allowed 
Not allowed 
Allowed following 
confirmed recurrence 
IMP for non-CDI 
If taken within 1 month (or 5 half-
lives) before study drug treatment, 
subject is excluded 
Not allowed 
Not allowed 
Allowed following 
confirmed recurrence 
Treatment for active 
malignancyf 
If taken within 6 months before 
study drug treatment (or likely to be 
taken during study), subject is 
excluded 
Not allowed 
Not allowed 
Allowed following 
confirmed recurrence 
Chemotherapy 
If taken within 3 months before 
study drug treatment (or likely to be 
taken during study), subject is 
excluded 
Not allowed 
Not allowed 
Allowed following 
confirmed recurrence 


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Confounding Medications 
Screening 
Treatment Segment 
Follow-Up Segment 
Recurrence Segment 
Immunosuppressive therapyg 
If current or likely to be taken during 
study, subject is excluded 
Not allowed 
Not allowed 
Allowed following 
confirmed recurrence 
Abbreviations: CDI, C. difficile infection; eCRF, electronic case report form; hrs, hours; IMP, investigational medicinal product. 
a Includes but not limited to oral vancomycin, IV or oral metronidazole, fidaxomicin. 
b Includes but not limited to oral teicoplanin, tigecycline, oral rifamycins, fusidic acid, bacitracin. 
c If antibiotics are required for non-CDI infection prescribe antibiotics that are not active versus C. difficile. 
d Document all antibiotics given in eCRF. 
e Consult with Medical Monitor if required. 
f Chemotherapy, radiotherapy, or biological treatment. 
g Does not include the limited topical or inhaled use of steroids or a brief period of oral steroids equivalent to a daily dose of less than 40 mg of prednisone 
administered for less than 2 weeks. 
 
 


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Any potential confounding medications taken 4 weeks before study drug treatment should be 
recorded in the eCRF along with any potential confounding medications started, stopped, or 
changed during the study (up to Day 38). 
During the study, both the treatment period and follow-up period, subjects who take any 
confounding medications should not necessarily be discontinued from study treatment and 
should not be withdrawn from the study. 
Investigators should contact the Medical Monitor for any questions regarding concomitant or 
prior therapy. 
10 STUDY PROCEDURES 
Table 4 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 12.5 specifies laboratory assessment samples to be obtained. See Section 11 and 
Section 12 for additional details regarding efficacy assessments and safety assessments, 
respectively. 
 


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Table 4. 
Schedule of Assessments 
Study Phase 
Screening 
Treatment 
Follow-Up 
Recurrence 
Extended 
Follow-Upi 
Assessment 
Screening 
Visita 
Baselinea 
Check 
In 
Check 
In 
Check 
In 
End of 
Treatment 
Test 
of 
Cure 
Check 
In 
Check 
In 
End 
of 
Study 
Suspected 
Recurrence 
Obs 
Visit 
Obs 
Visit 
Day 
Day -2 to 
Day 1 
Day 1 
Day 3 
Day 5 
Day 8 
Day 10 
Day 
12 
(≥ 48 
hrs 
post 
last 
dose) 
Day 
20 
Day 
30 
Day 
38 
Test of 
Cure to 
End of 
Studyj 
Day 
66 
Day 
94 
Visit Window 
 
 
±1 
Day 
±1 
Day 
±1 
Day 
±1 Day 
+1 
Days 
±2 
Days 
±2 
Days 
±2 
Days 
<48 hrs of 
Reporting 
±2 
Days 
±2 
Days 
Visit Format 
Clinic 
Clinic 
Tel. 
Clinic 
Tel. 
Tel. 
Clinic 
Tel. 
Tel. 
Clinic 
Clinic 
Clinic 
Clinic 
Segment 2A/2B 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
CDI diagnosis 
including free 
toxin testb 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & 
medication 
histories including 
detailed CDI 
history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Vital signs 
 
X 
 
X 
 
 
Xd 
 
 
Safety laboratory 
testse 
 
X 
 
X 
 
 
X 
 
 
 
Pregnancy testf 
X 
 
 
 
 
 
X 
 
 
 
 
 
 


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Study Phase 
Screening 
Treatment 
Follow-Up 
Recurrence 
Extended 
Follow-Upi 
Assessment 
Screening 
Visita 
Baselinea 
Check 
In 
Check 
In 
Check 
In 
End of 
Treatment 
Test 
of 
Cure 
Check 
In 
Check 
In 
End 
of 
Study 
Suspected 
Recurrence 
Obs 
Visit 
Obs 
Visit 
Day 
Day -2 to 
Day 1 
Day 1 
Day 3 
Day 5 
Day 8 
Day 10 
Day 
12 
(≥ 48 
hrs 
post 
last 
dose) 
Day 
20 
Day 
30 
Day 
38 
Test of 
Cure to 
End of 
Studyj 
Day 
66 
Day 
94 
Visit Window 
 
 
±1 
Day 
±1 
Day 
±1 
Day 
±1 Day 
+1 
Days 
±2 
Days 
±2 
Days 
±2 
Days 
<48 hrs of 
Reporting 
±2 
Days 
±2 
Days 
Visit Format 
Clinic 
Clinic 
Tel. 
Clinic 
Tel. 
Tel. 
Clinic 
Tel. 
Tel. 
Clinic 
Clinic 
Clinic 
Clinic 
Electrocardiogram 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator 
assessment of 
clinical response 
 
 
X 
 
 
X 
 
 
 
Concomitant 
medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
Subject diary  
 
 
 
 
 
 
 
 
 
 
 
 
Stool samples for 
future analysesg 
(microbiome and 
fecal drug 
concentration 
analyses) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood sample for 
pharmacokineticsh 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Segment 2B only 
 
 
 
 
Randomization per 
IWRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 


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Study Phase 
Screening 
Treatment 
Follow-Up 
Recurrence 
Extended 
Follow-Upi 
Assessment 
Screening 
Visita 
Baselinea 
Check 
In 
Check 
In 
Check 
In 
End of 
Treatment 
Test 
of 
Cure 
Check 
In 
Check 
In 
End 
of 
Study 
Suspected 
Recurrence 
Obs 
Visit 
Obs 
Visit 
Day 
Day -2 to 
Day 1 
Day 1 
Day 3 
Day 5 
Day 8 
Day 10 
Day 
12 
(≥ 48 
hrs 
post 
last 
dose) 
Day 
20 
Day 
30 
Day 
38 
Test of 
Cure to 
End of 
Studyj 
Day 
66 
Day 
94 
Visit Window 
 
 
±1 
Day 
±1 
Day 
±1 
Day 
±1 Day 
+1 
Days 
±2 
Days 
±2 
Days 
±2 
Days 
<48 hrs of 
Reporting 
±2 
Days 
±2 
Days 
Visit Format 
Clinic 
Clinic 
Tel. 
Clinic 
Tel. 
Tel. 
Clinic 
Tel. 
Tel. 
Clinic 
Clinic 
Clinic 
Clinic 
Medical Resource 
Utilization 
Questions 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Stool samples for 
future analyses 
(microbiome 
analyses) 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: CDI, Clostridioides difficile infection; IWRS, Interactive Web Response System; Obs, observation; Tel., telephone. 
a May occur the same day as the baseline visit. Written informed consent for the study will be obtained from all subjects before any protocol specific 
procedures are performed. 
b Any Sponsor-approved free toxin test may be used. 
c A complete physical at screening; limited physical examination at other times as clinically indicated. 
d Perform at Day 38 or earlier (at an unscheduled visit) if subject experiences a confirmed recurrence. 
e Safety laboratory tests will include biochemistry, hematology, and urinalysis. 
f Only in women of childbearing potential. Serum test will be done at Screening; urine test will be done at the site at other specified time points. 
g If subject does not attend clinic then arrangements must be made to collect stool sample from subject’s home. Sample must be collected before first dose 
of study drug. Stool samples should be kept cool and brought to the clinic within 24 hours after collection. 
h Pharmacokinetic blood samples will be collected 2 hours (± 15 minutes) and 4 hours (± 30 minutes) after first dose of the day. In Segment 2B, 
pharmacokinetic blood samples will be collected in approximately 50% of subjects (ie, approximately 36 subjects). 
i Randomized Segment 2B subjects recruited from selected sites will have the opportunity to participate in an extended follow-up period to Day 94 
j End of study includes observation visits Day 66 and Day 94 for those subjects participating in the extended follow-up period 
 
 


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10.1 Informed Consent 
Before performing any study-related procedures, the Investigator (or designee) will obtain 
written informed consent from the subject. 
In the event that rescreening occurs, the individual is required to sign a new ICF and must be 
assigned a new identification number. 
10.2 Study Procedures 
Assessments and their timing are to be performed as outlined in the Schedule of Assessments 
(Table 4). Section 12.5 specifies laboratory assessment samples to be obtained. 
Assessments and procedures scheduled at a visit where study drug is administered should be 
performed before administration of treatment unless otherwise indicated in the Schedule of 
Assessments (Table 4). 
Efficacy assessments are described in Section 11 and include provision of subject diaries, 
assessment of clinical response, measurements of plasma and fecal ibezapolstat concentrations at 
specific concentrations, characterization of the fecal microbiome, assessment of recurrence, 
measurement of time to resolution of diarrhea, and measurement of time to hospital discharge. 
Safety assessments are described in Section 12 and include vital signs, physical examinations, 
ECGs, clinical laboratory assessments, pregnancy tests, concomitant medications, and AEs. 
The Investigator may, at his/her discretion, arrange for a subject to have an unscheduled 
assessment, especially in the case of AEs that require follow-up or are considered by the 
Investigator to be possibly related to the use of study drug. The unscheduled visit page in the 
eCRF must be completed. 
Study discontinuation procedures are described in Section 8.4. 
Follow-up of AEs and SAEs leading to study discontinuation is discussed in Section 8.4. 
11 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 4) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
11.1 Subject Diary 
Subjects will be provided with a diary and completion instruction at the baseline visit (Day 1). 
Adequate time should be allocated on Day 1 to ensure that the subject understands how to 
complete the diary and is willing and able to do so every day throughout the study through 
Day 38/end of study visit. NOTE: The primary objective and endpoint for this study relies on 
subject reported data collected via the diary. It is critical that the Investigator and subject 
understand that accurate, complete, and contemporaneous diary data is required to meet the study 
primary objective. It is particularly important to ensure that each subject completes the diary 


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every day. The diary will have reminders for subjects to take the study drug and to complete the 
diary daily. 
Subjects will be asked to record the following details in their diary: 
• Date and time of each dose of study drug and if it was taken with food 
• Date, time, and consistency (using the Bristol Stool Chart) of all bowel movements (up to 
Day 12/TOC) 
• Date, time, and consistency of all UBMs from TOC to Day 38. Subjects will be required 
to answer a question every day in the diary to indicate if UBMs were experienced and to 
record the details of the UBMs if they occurred. 
Information from the diary will be used directly for analysis of the primary and secondary 
endpoints. The Investigator or designee will be required to monitor the subject’s diary entries 
and contact the subject to discuss any omissions or inaccurate entries. 
Data changes that constitute subject reported data are not permitted. Changes to diary data will 
be limited to administrative corrections such as erroneous subject number, visit date, subject 
status, and elimination of duplicate data or merging of data for the same subject. 
Subject reported diary errors will be reported as protocol deviations. 
Investigators or designated site staff will be responsible to have a missed diary entry completed 
by asking the subject about the missed data when the subject brings the diary to study visits. 
Subjects who have difficulty completing the diary may be supported by a care provider either 
temporarily or for the duration of the study. This is permitted as long as the Investigator is 
confident that the support provided is adequate to ensure accurate entries into the diary on the 
subject’s behalf. The Investigator must document agreement for a care provider to enter 
information into the diary on behalf of the subject and the rationale. 
11.2 Clinical Cure 
Clinical cure: survival and the resolution of diarrhea in the 24-hour period immediately before 
EOT that is maintained for 48 hours post EOT without a requirement for additional CDI 
treatment. 
Treatment failures are defined as those subjects: 
• Who do not respond with reduced diarrhea; or 
• Whose diarrhea worsens during therapy; or 
• Who do not remain free of diarrhea for at least 2 days after the end of therapy; or 
• Who require an additional treatment for CDI before the TOC visit; or 
• Who do not survive until the TOC visit. 
Subjects who failed study treatment will be offered treatment for CDI according to standard of 
care antibiotic at the Investigator’s discretion. 


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After EOT, all subjects will be followed for up to an additional 28 ± 2 days to assess the 
recurrence of CDI. There also will be post treatment observation visits on Day 66 and Day 94 for 
those subjects participating in the extended follow-up period. 
11.3 Sustained Clinical Cure 
Sustained clinical cure: no recurrence of diarrhea from TOC to Day 38 among the subset of 
subjects who achieved an initial clinical cure. Recurrence is defined as ≥ 3 UBMs in any 24-hour 
period with free C. difficile toxin A or B (or both) detected in a stool sample and, in the opinion 
of the Investigator, there is a need for CDI retreatment. 
The Investigator’s assessment of SCC will be based on the Investigator’s decision that there is no 
need for further treatment for CDI based on post treatment symptoms and signs during the 
28 ± 2 days post treatment. 
11.4 Extended Clinical Cure 
Extended clinical cure: no recurrence of diarrhea from TOC to Day 56 (ECC56) and Day 84 
(ECC84) among the subset of subjects who achieved an initial clinical cure. Recurrence is 
defined as ≥ 3 UBMs in any 24-hour period with free C. difficile toxin A or B (or both) detected 
in a stool sample and, in the opinion of the Investigator, there is a need for CDI retreatment. 
The Investigator’s assessment of ECC will be based on the Investigator’s decision that there is 
no need for further treatment for CDI based on post treatment symptoms and signs during the 
28 ± 2 days post treatment. 
11.5 Microbial Assessments 
Microbiome testing: Stool samples will be collected at the time points outlined in Table 4 and 
analyzed for microbial quantity and diversity by polymerase chain reaction and Next Gen 
sequencing. 
Subjects will be provided with kits for collecting stool samples at home. A cooling device will be 
included to preserve the sample during transport to the study clinic. Stool samples must be 
brought to the study clinic within 24 hours of collection. 
11.6 Time to Resolution of Diarrhea 
Time to resolution of diarrhea: the time from outset of treatment to the first formed bowel 
movement not followed within the next 24 hours by a UBM. 
11.7 Time to Hospital Discharge 
Time from outset of treatment to the day of discharge, and not followed by readmission for 
treatment of CDI before the TOC visit (for hospitalized subjects only). 
12 SAFETY AND TOLERABILITY ASSESSMENTS 
Safety and tolerability assessments (vital signs, physical examinations, ECG recording, AEs, 
clinical laboratory results [routine hematology, biochemistry, and urinalysis]), pregnancy tests, 


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and concomitant medications are to be performed at protocol-specified visits, as specified in the 
Schedule of Assessments (Table 4). Study subjects will be monitored carefully throughout each 
dosing period for adverse experiences. A qualified physician will assess the relationship of AEs 
to study drug and in general based on such considerations as temporal relationship to study drug 
administration, subject’s relevant medical history, and whether the finding is likely because of a 
pre-existing condition. 
12.1 Medical History 
Medical history will be recorded at Screening. Investigators should document the occurrence, 
signs, and symptoms of the subject’s pre-existing conditions, including all prior significant 
illnesses, up to and including 1 year before Screening. Additional pre-existing conditions present 
at the time when informed consent is given and up to the time of first dosing (Day 1) are to be 
regarded as concomitant. Medical history will include alcohol consumption and smoking history. 
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs in the eCRF in accordance with Section 12.6. All 
changes not present at baseline or described in the past medical history and identified as 
clinically noteworthy must be recorded as AEs. 
Additionally, demographic data will be collected for all subjects and include age, sex, race, 
ethnicity, and CDI history. 
12.2 Vital Signs 
Vital signs (body temperature, respiration rate, heart rate, and systolic and diastolic blood 
pressure measurements) will be evaluated at the visits indicated in the Schedule of Assessments 
(Table 4). All vital signs will be measured after the subject has been resting in a sitting or supine 
position for at least 5 minutes. Blood pressure measurements are to be taken in the same arm for 
the duration of the study. Either an automated or manual measurement of blood pressure is 
acceptable; however, the same method should be used for the duration of the study. Body weight 
(without shoes) will be recorded whenever vital signs are recorded; height (without shoes) will 
be recorded at Screening only. 
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range blood pressure, respiratory rate, or heart rate measurements will be repeated 
at the Investigator’s discretion. Any confirmed, clinically significant vital sign measurements 
must be recorded as AEs. 
12.3 Physical Examination 
A complete physical examination (head, eyes, ears, nose and throat; heart; lungs; abdomen; skin; 
cervical and axillary lymph nodes; and neurological and musculoskeletal systems) will be 
performed at Screening (Visit 1). Physical examinations will be performed by a physician. 
A limited physical examination to verify continued subject eligibility and to follow-up regarding 
any change in medical history will be performed at the visits indicated in the Schedule of 


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Assessments (Table 4). Symptom-driven, limited physical examinations will be performed as 
clinically indicated at any study visit. 
12.4 Electrocardiograms 
A 12-lead, resting (sitting or supine for at least 10 minutes) ECG will be obtained at the visits 
indicated in the Schedule of Assessments (Table 4). Study sites may use their standard operating 
procedures for detailed instructions on conducting the ECG. 
At Screening, the Investigator will examine the ECG traces for signs of cardiac disease that 
could exclude the subject from the study. An assessment of normal or abnormal will be recorded; 
if the ECG is considered abnormal, the abnormality will be documented in the eCRF. ECGs will 
be repeated if clinically significant abnormalities are observed or artifacts are present. 
12.5 Laboratory Assessments 
Laboratory assessment samples (Table 5) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 4). 
Table 5. 
Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis (Dipstick) 
Full and differential blood count 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
 
Albumin 
ALT 
ALP 
AST 
BUN 
Creatinine 
Electrolytes (sodium, 
potassium, chloride, calcium, 
phosphorus) 
Glucose 
LDH 
Total bilirubin 
Direct bilirubin 
Uric acid 
Appearance 
pH 
Protein 
Glucose 
Ketones (dipstick) 
RBCs (dipstick) 
Specific gravity 
Urine HCG (premenopausal women only) 
Microscopy (if needed) 
Pregnancy test: A pregnancy HCG test will be performed on all women of childbearing potential at 
Screening. 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
BUN, blood urea nitrogen; Hb, hemoglobin; HCG, human chorionic gonadotropin; Hct, hematocrit; LDH, 
lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin 
concentration; MCV, mean corpuscular volume; RBC, red blood cell; WBC, white blood cell. 
Local laboratories will be used in Segment 2A. A central laboratory will be used for 
Segment 2B. Urine samples will be analyzed by dipstick, and a microscopic analysis will be 
performed if the results of dipstick indicate abnormalities to be further investigated. All 
laboratory reports must be reviewed, signed, and dated by the Investigator. A legible copy of all 
reports must be included in the subject’s medical record (source document) for that visit and the 
site must enter laboratory results manually into EDC for each subject. Any laboratory test result 


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considered by the Investigator to be clinically significant should be considered an AE (clinically 
significant AEs include those that require an intervention). Clinically significant abnormal values 
occurring during the study will be followed up until repeat test results return to normal, stabilize, 
or are no longer clinically significant. 
12.6 Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at Screening, worsens during the study, regardless of the suspected cause of the 
event. All medical and psychiatric conditions (except those related to the indication under study) 
present at Screening will be documented in the medical history eCRF. Changes in these 
conditions and new symptoms, physical signs, syndromes, or diseases should be noted on the AE 
eCRF during the rest of the study. Clinically significant laboratory abnormalities should also be 
recorded as AEs. Surgical procedures that were planned before the subject enrolled in the study 
are not considered AEs if the conditions were known before study inclusion; the medical 
condition should be reported in the subject’s medical history. 
Recurrence of CDI is a disease-related event that is common in subjects with CDI and can be 
serious/life threatening. Because recurrent CDI is an important medical event, all recurrences of 
CDI will be reported to the Sponsor per the standard process for expedited reporting of SAEs. 
Subjects will be instructed to report AEs at each study visit. All AEs are to be followed up until 
resolution or a stable clinical endpoint is reached. 
Each AE is to be documented in the eCRF with reference to date of onset, duration, frequency, 
severity, relationship to study drug, action taken with study drug, treatment of event, and 
outcome. Furthermore, each AE is to be classified as being serious or nonserious. Changes in 
AEs and resolution dates are to be documented in the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time the subject gives informed consent through study completion, as indicated in the Schedule 
of Assessments (Table 4). Follow-up of the AE, even after the date of therapy discontinuation, is 
required if the AE persists until the event resolves or stabilizes at a level acceptable to the 
Investigator. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately (with distinct onset dates). 
Specific guidelines for classifying AEs by intensity and relationship to study drug are given in 
Table 6 and Table 7. 
Table 6. 
Classification of Adverse Events by Intensity 
MILD: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An event that is sufficiently discomforting to interfere with normal everyday activities. 


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SEVERE: An event that prevents normal everyday activities. 
 
Table 7. 
Classification of Adverse Events by Relationship to Study Drug 
UNRELATED: This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc.). 
POSSIBLY: This category applies to those AEs for which a connection with the test drug administration 
appears unlikely but cannot be ruled out with certainty. An AE may be considered possibly related if or when 
it meets 2 of the following criteria: (1) it follows a reasonable temporal sequence from administration of the 
drug; (2) it could not readily have been produced by the subject’s clinical state, environmental or toxic factors, 
or other modes of therapy administered to the subject; or (3) it follows a known pattern of response to the test 
drug. 
PROBABLY: This category applies to those AEs that the Investigator feels with a high degree of certainty are 
related to the test drug. An AE may be considered probably related if or when it meets 3 of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose (note that there are exceptions when an AE does not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists; for example, as in bone marrow depression, fixed drug eruptions, or 
tardive dyskinesia); or (4) it follows a known pattern of response to the test drug. 
DEFINITELY: This category applies to those AEs that the Investigator feels are incontrovertibly related to test 
drug. An AE may be assigned an attribution of definitely related if or when it meets all of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose and recurs with reexposure to drug (if rechallenge occurs); and (4) it follows a known pattern 
of response to the test drug. 
Abbreviation: AE, adverse event. 
12.6.1 Serious Adverse Events 
An SAE is any untoward medical occurrence, in the view of either the Investigator or Sponsor, 
that: 
• results in death, 
• is life-threatening, 
• results in inpatient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, and/or 
• is a congenital anomaly/birth defect. 
• Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization, based upon appropriate medical judgment, are considered SAEs 
if they are thought to jeopardize the subject and/or require medical or surgical 
intervention to prevent one of the outcomes defining an SAE.  
SAEs are critically important for the identification of significant safety problems; therefore, it is 
important to take into account both the Investigator’s and the Sponsor’s assessment. If either the 
Sponsor or the Investigator believes that an event is serious, the event must be considered serious 
and evaluated by the Sponsor for expedited reporting. 


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12.6.2 Serious Adverse Event Reporting 
An SAE occurring from the time informed consent is obtained, during the study, or within 
30 days of stopping the treatment must be reported to the Syneos Health Safety and 
Pharmacovigilance group and will be communicated to the Sponsor. Any such SAE because of 
any cause, whether or not related to the study drug, must be reported within 24 hours of 
occurrence or when the Investigator becomes aware of the event. Notification can be made using 
the dedicated fax line or email for the Syneos Health pharmacovigilance group: 
Syneos Health Safety and Pharmacovigilance fax number: 1-877-464-7787 
Syneos Health Safety and Pharmacovigilance email address: safetyreporting@syneoshealth.com 
If the Investigator contacts the Syneos Health pharmacovigilance group by telephone, then a 
written report must follow within 24 hours and is to include a full description of the event and 
sequelae in the format detailed in the SAE reporting form. 
The event must also be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable. SAE reports must be made whether or not the Investigator considers the event to 
be related to the investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded. Clinical, laboratory, and diagnostic measures should be employed as needed in order to 
determine the etiology of the problem. The Investigator must report all additional follow-up 
evaluations to the Syneos Health Safety and Pharmacovigilance group within 24 hours of 
becoming aware of the additional information or as soon as is practicable. All SAEs will be 
followed up until the Investigator and Sponsor agree the event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the subject’s 
participation in the study is to be followed up until it either resolves, stabilizes, returns to 
baseline values (if a baseline value is available), or is shown to not be attributable to the study 
drug or procedures. 
12.6.3 Suspected Unexpected Serious Adverse Reactions 
AEs that meet all of the following criteria will be classified as suspected unexpected serious 
adverse reactions (SUSARs) and reported to the appropriate regulatory authorities in accordance 
with applicable regulatory requirements for expedited reporting: 
• serious 
• unexpected (ie, the event is not consistent with the safety information in the 
Investigator’s Brochure) 
• there is at least a reasonable possibility that there is a causal relationship between the 
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The Investigator will assess whether an event is causally related to study treatment. The Sponsor 
(or Syneos Health) will consider the Investigator’s assessment and determine whether the event 
meets the criteria for being reportable as a 7-day or 15-day safety report. SUSARs that are fatal 
or life-threatening must be reported to the regulatory authorities and the independent ethics 
committee (IEC)/institutional review board (IRB) (where required) within 7 days after the 
Sponsor (or Syneos Health) has first knowledge of them, with a follow-up report submitted 
within a further 8 calendar days. Other SUSARs must be reported to the relevant regulatory 
authorities and the IEC/IRBs within 15 calendar days after the Sponsor (or Syneos Health) first 
has knowledge of them. 
The Sponsor (or Syneos Health) is responsible for reporting SUSARs and any other events 
required to be reported in an expedited manner to the regulatory authorities and for informing 
investigators of reportable events, in compliance with applicable regulatory requirements within 
specific timeframes. Investigators will notify the relevant IEC/IRBs of reportable events within 
the applicable timeframes. 
12.6.4 Pregnancy 
Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening. 
Following administration of study drug, any known cases of pregnancy in female subjects will be 
reported until the subject completes or withdraws from the study. The pregnancy will be reported 
immediately by faxing/emailing a completed pregnancy report to the Sponsor (or designee) 
within 24 hours of knowledge of the event. The pregnancy will not be processed as an SAE; 
however, the Investigator will follow-up with the subject until completion of the pregnancy and 
must assess the outcome in the shortest possible time but not more than 30 days after completion 
of the pregnancy. The Investigator should notify the Sponsor (or designee) of the pregnancy 
outcome by submitting a follow-up pregnancy report. If the outcome of the pregnancy involved 
spontaneous or therapeutic abortion (any congenital anomaly detected in an aborted fetus is to be 
documented), stillbirth, neonatal death, or congenital anomaly, the Investigator will report the 
event by faxing/emailing a completed pregnancy report form to the Sponsor (or designee) within 
24 hours of knowledge of the event. 
If the Investigator becomes aware of a pregnancy occurring in the partner of a subject 
participating in the study, the pregnancy should be reported to the Sponsor (or designee) within 
24 hours of knowledge of the event. Information regarding the pregnancy must only be 
submitted after obtaining written consent from the pregnant partner. The Investigator will 
arrange counseling for the pregnant partner by a specialist to discuss the risks of continuing with 
the pregnancy and the possible effects on the fetus. 
Upon discontinuation from the study, only those procedures that would not expose the subject to 
undue risk will be performed. The Investigator should also be notified of pregnancy occurring 
during the study but confirmed after completion of the study. In the event that a subject is 
subsequently found to be pregnant after inclusion in the study, any pregnancy will be followed to 
term, and the status of mother and child will be reported to the Sponsor after delivery. 


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12.6.5 Overdose 
There is no specific antidote for ibezapolstat. The Investigator must immediately notify the 
Sponsor of any occurrence of overdose with study drug. Overdosage should be managed with 
symptomatic and supportive care. 
12.7 EQ-5D-5L 
The EQ-5D-5L is a questionnaire, which has been developed as a standardized measure of health 
status, which can provide a simple, generic measure of health for clinical and economic 
appraisal. It is cognitively undemanding, taking only a few minutes to complete. Subjects will be 
asked to complete the EQ-5D-5L at certain intervals in Segment 2B throughout the study, as 
specified in Table 4. Instructions to respondents are included in the questionnaire. The EQ-5D-
5L essentially consists of 2 pages – the EQ-5D descriptive system (page 2) and the EQ visual 
analog scale (page 3). The EQ-5D-5L descriptive system comprises the following 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
If, at any visit, the subject is unable to complete the EQ-5D-5L independently, then it should not 
be completed for that visit. 
12.8 Medical Resource Utilization Questions 
Medical resource utilization data, associated with medical encounters, will be collected in the 
eCRF by the Investigator and study site personnel for all subjects throughout the study. Protocol-
mandated procedures, tests, and encounters are excluded. Data collected will include: 
• Length of hospital stay 
• Hospital admissions and readmissions, and reasons for admission 
• Subject location at admission and discharge 
13 PHARMACOKINETICS 
13.1 Pharmacokinetic Sampling 
Instructions for the collection and handling of biological samples will be provided separately by 
the Sponsor or Sponsor designee and will be detailed in the Sample Processing Instructions.  
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member(s) and then archived in the 
Sponsor and study center study files but will not constitute a protocol amendment. The IRB will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF. 
13.1.1 Blood Samples 
For Segment 2A and approximately 50% of subjects in Segment 2B: Blood samples for PK 
analysis of ibezapolstat plasma levels will be collected at the time points indicated in the 
Schedule of Assessments (Table 4). The actual date and time of each blood sample collection 
will be recorded. The actual date and time of study treatment administration will also be 


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recorded. The timing of PK samples may be altered, and/or PK samples may be obtained at 
additional time points to ensure thorough PK monitoring. Blood samples will be taken either by 
direct venipuncture or an indwelling cannula inserted in a forearm vein. 
Details of PK blood sample collection, processing, labeling, freezing and storage, and shipping 
procedures are provided in a separate laboratory manual. 
13.1.2 Stool Samples 
In conjunction with the drawing of multiple blood samples, multiple stool samples will be 
collected at the time points in Segment 2A and 2B indicated in the Schedule of Assessments 
(Table 4) for fecal concentrations of ibezapolstat through the TOC visit. The actual date and time 
of each fecal void will be recorded. 
Subjects will be provided with kits for collecting stool samples at home. A cooling device will be 
included to preserve the sample. Stool samples must be brought to the study clinic within 
24 hours of collection. 
Details of stool sample collection, processing, labeling, storage, and shipping procedures are 
provided in the Sample Processing Instructions. 
13.2 Pharmacokinetic Bioanalytical Methodology 
The concentration of study drug will be determined from the plasma and stool samples using a 
validated bioanalytical method. Details of the method validation and sample analysis will be 
included with a separate bioanalytical report. PK samples will be collected in Segment 2A and 
approximately 50% of subjects in Segment 2B. 
13.3 Calculation of Pharmacokinetic Variables 
A population PK analysis may be conducted using plasma and fecal ibezapolstat concentrations. 
The model developed using this approach will be used to predict parameters such as, but not 
limited to, Cmax and AUC0-inf for each subject. This analysis will be described in a separate PK 
analysis plan and results from the population PK analysis will also be presented in a separate 
report. 
14 STATISTICAL ANALYSIS 
The SAP will be prepared after the protocol is approved. This document will provide further 
details regarding the definition of analysis variables and analysis methodology to address all 
study objectives. The SAP will serve as a complement to the protocol and supersedes it in case of 
differences. The SAP will describe the subject analysis sets to be included in the analyses and 
procedures for handling missing data. This section is a summary of the planned statistical 
analyses of the endpoints. 
The statistical analyses will be performed using SAS® software version 9.4 or higher. All data 
will be listed, and summary tables will be provided. Summary statistics will be presented by 
treatment group.  


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The following descriptive statistics will be used as applicable to summarize the study data unless 
otherwise specified: 
• Continuous variables: sample size, mean, standard deviation, median, minimum, and 
maximum. Geometric mean and coefficient of variation will be included for relevant PK 
parameter summaries. 
• Categorical variables: frequencies and percentages. 
14.1 Determination of Sample Size 
Segment 2A is considered a proof-of-principle substudy and is not hypothesis driven; the sample 
size of up to 20 subjects was selected to provide some degree of precision for the estimated cure 
rate, as shown in the table below: 
Table 8. 
Estimated Cure Rate and Associated 95% Confidence Intervals Based on the 
Normal Approximation 
Estimated Cure Rate (%) 
95% Confidence Interval (%) 
75 
(56.0, 94.0) 
80 
(62.5, 97.5) 
85 
(69.4, 100.0) 
90 
(76.9, 100.0) 
Sample size for Segment 2B was calculated based on the following assumptions: 
1. Non-inferiority study 
2. Endpoint is clinical cure at the TOC visit 
3. One-sided normal approximation test 
4. Overall alpha = 0.05 
5. Allocation to treatment = 1:1 
6. True cure rate = 0.80 in both arms 
7. Non-inferiority margin = 0.25 
8. Power = 80% 
9. Sample size adjusted for one interim analysis (Pocock 1977). 
A sample size of 36 subjects per treatment group, or 72 subjects total, will satisfy these criteria. 
Further, subjects at selected sites will undergo extended follow-up to Day 94. At these selected 
sites, consecutive subjects will be offered the opportunity to participate in the extended 
follow-up period until approximately 16 subjects are recruited. 
14.2 Analysis Populations 
14.2.1 Enrolled Population 
The Enrolled population will include all subjects who sign the ICF. 


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14.2.2 Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all subjects who are enrolled and treated in 
Segment 2A or who are randomized in Segment 2B. In Segment 2B, subjects will be analyzed 
based on their randomized assignment. The ITT population will be used as the primary analysis 
of efficacy. 
14.2.3 Per Protocol Population 
The PP population will consist of patients in the ITT population with no major protocol 
deviations. The determination of which subjects have major protocol violations will be made in a 
blinded manner before the database lock. For analyses based on the PP population, subjects will 
be grouped according to the treatment to which they were randomized. This population will be 
used for a secondary analysis of the primary and secondary efficacy endpoints. 
14.2.4 ITT Extension Population 
The ITT Extension population will include all randomized Segment 2B subjects who participate 
in the extended follow-up period. Subjects will be analyzed based on their randomized 
assignment. The ITT Extension population will be used for the analysis of the ECC56 and 
ECC84 exploratory endpoints.  
14.2.5 Safety Population 
The Safety population will include all subjects who receive at least 1 dose of study drug. 
Subjects will be analyzed based on the treatment actually received. This population will be used 
for the analysis of safety. 
14.2.6 Pharmacokinetic Population 
The PK population will include all subjects who take at least 1 dose of active study treatment and 
have at least 1 quantifiable plasma concentration collected post dose without important protocol 
deviations/violations or events thought to affect the PK. 
14.3 Efficacy Analysis 
14.3.1 Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is clinical cure at the TOC visit, defined as survival and resolution 
of diarrhea in the 24-hour period immediately before EOT that is maintained for 48 hours post 
EOT without a requirement for additional CDI treatment. 
After EOT, subjects with initial clinical cure will be followed for up to an additional 28 ± 2 days 
to assess the recurrence of CDI. 
For Segment 2A, this endpoint will be summarized using frequencies and percentages, together 
with a 95% exact (Clopper-Pearson) confidence interval for the true cure percentage. 
For Segment 2B, the null and alternative hypotheses for this endpoint are as follows: 
H0: π 1,T ≤ π1,C - δ      
  and 


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H1: π 1,T > π1,C - δ, 
where π1,T and π1,C are the true proportions of subjects with clinical cure at the TOC visit for the 
ibezapolstat 450 mg and vancomycin 125 mg treatments, respectively, and δ is the non-
inferiority margin which is here taken to be 0.25. 
This endpoint will be summarized by treatment group using frequencies and percentages, 
together with an exact (Clopper-Pearson) 95% confidence interval for the true cure percentage. 
The 95% confidence interval based on the normal approximation will also be calculated for the 
difference between the 2 population proportions (π1,C – π1,T). The null hypothesis will be tested 
using a one-sided normal approximation test non-inferiority at the 0.03037 significance level 
(Pocock 1977) for an overall significance level of 0.05. In the event non-inferiority of 
ibezapolstat 450 mg is demonstrated, Fisher’s exact test (two-sided) will be used to conduct a 
test for superiority at the 0.05 significance level. 
14.3.2 Analysis of Secondary Efficacy Endpoint: Sustained Clinical Cure 
The secondary efficacy endpoint is SCC, which is defined below, and is determined for subjects 
who achieve initial clinical cure. The determination will be made at the Day 38 follow-up visit. 
1. Recurrence is defined as ≥ 3 bowel movements with unformed stools in any 24-hour 
period with free C. difficile toxin A or B (or both) detected in a stool sample and in the 
opinion of the Investigator, there is a need for CDI retreatment. 
2. SCC is defined as initial clinical cure without subsequent recurrence within 28 ± 2 days 
post EOT. 
For Segment 2A, this endpoint will be summarized using frequencies and percentages, together 
with an exact (Clopper-Pearson) 95% confidence interval for the true cure percentage. 
For Segment 2B, this endpoint will be summarized by treatment group using frequencies and 
percentages, together with an exact (Clopper-Pearson) 95% confidence interval for the true SCC 
percentage. A 95% confidence interval based on the normal approximation will also be 
calculated for the difference between the 2 population proportions (π1,C – π1,T). The null 
hypothesis that the true proportions are equal for the 2 treatments will be tested using a two-sided 
Fisher’s exact test at the 0.05 significance level. 
14.3.3 Analysis of Exploratory Endpoints 
14.3.3.1 Microbial Assessments 
Microbiome testing: Stool samples will be collected at the time points outlined in Table 4 and 
analyzed for microbial quantity and diversity by polymerase chain reaction and Next Gen 
sequencing. 
Changes in the total fecal bacterial quantity and microbial diversity will be assessed for 
ibezapolstat-treated subjects in both segments, and in comparison to those treated with 
vancomycin in Segment 2B. Changes will be assessed during the treatment period and post EOT. 


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Details of the final microbiome analysis will be described in the SAP or relevant laboratory 
manual. 
14.3.3.2 Time to Resolution of Diarrhea 
For Segment 2A, time to resolution of diarrhea, defined as the time from onset of treatment to 
the first formed bowel movement not followed within the next 24 hours by a UBM, will be 
summarized using the Kaplan-Meier method, with estimates of the true resolution of diarrhea 
rate at Days 1, 5, 10, 12, and 40. The estimated median time to resolution of diarrhea, together 
with a 95% confidence interval, will also be presented. For Segment 2B, the analysis will be the 
same as for Segment 2A, except that the results will be presented by treatment group. 
14.3.3.3 Time to Hospital Discharge 
For Segment 2A, time to hospital discharge, defined as the time from onset of treatment to the 
day of discharge, and not followed by readmission for treatment of CDI before the TOC visit (for 
hospitalized subjects only), will be summarized using descriptive statistics. For Segment 2B, the 
analysis will be the same as for Segment A, except that the results will be presented by treatment 
group. 
14.3.3.4 Quality of Life Assessments 
The EQ-5D-5L scores for each of the 5 dimensions and the EQ-5D-5L visual analog scale score 
will be summarized by treatment group and time point using descriptive statistics. 
Medical resource utilization data will be summarized by treatment group and time point using 
descriptive statistics for continuous variables and frequencies and percentages for categorical 
variables.  
These analyses will be performed for Segment 2B only. 
Further details of the statistical analyses of the EQ-5D-5L and Medical Resource Utilization will 
be described in the SAP. 
14.3.3.5 ECC56 and ECC84 
These endpoints will be summarized by treatment group using frequencies and percentages, 
together with exact (Clopper-Pearson) 95% confidence intervals for the true percentages. Also, 
95% confidence intervals based on the normal approximation will be calculated for the 
differences between the 2 population proportions. These endpoints will be analyzed based on the 
ITT Extension Population. 
14.4 Safety Analysis 
TEAEs are defined as any AE with onset date on or after the date of the start of the study drug or 
any AE already present at baseline that worsens in severity. All reported AEs will be coded using 
the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA). Events 
with missing onset dates will be considered to be treatment-emergent unless there is additional 
information indicating that the AE started before study treatment. Only TEAEs will be 


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summarized. If a subject experiences more than 1 occurrence of the same AE, the occurrence 
with the greatest severity and the closest relationship with the study drug will be used in the 
summary tables. 
The number and percentage of subjects with at least one TEAE, at least one treatment-related 
TEAE, at least one serious TEAE, and at least one TEAE leading to study discontinuation will be 
presented by treatment group. AEs that are definitely, probably, or possibly related, or for which 
the relationship is missing, will be considered related. 
The number and percentage of subjects having a TEAE in each System Organ Class (SOC) and 
having each individual type of AE (Preferred Term) will be presented. TEAEs will also be 
summarized at the event level by SOC/Preferred Term and severity. This will be done for all 
TEAEs, all serious TEAEs, and all TEAEs leading to discontinuation from the study. 
All AEs will be listed by subject, along with information regarding onset, duration, relationship 
and severity to study drug, action taken with study drug, treatment of event, and outcome. 
Clinical laboratory data and vital signs data will be summarized by treatment group and time 
point using descriptive statistics for both the actual values and the changes from baseline, as well 
as numbers and percentages of subjects with values outside the limits of the normal range at each 
time point. Electrocardiogram data will be summarized by treatment group and time point using 
descriptive statistics for both the actual values and the changes from baseline. 
Concomitant medications initiated during the study period will be summarized by treatment 
group using frequencies and percentages. 
14.5 Pharmacokinetic Analysis 
The PK Analysis Set will be used for all summaries and exploratory analyses of PK data. 
Systemic exposure of ibezapolstat will be determined by measuring plasma ibezapolstat 
concentrations at specified time points following dose administration. Fecal concentrations of 
ibezapolstat will be measured at specified study visits. Plasma and fecal ibezapolstat 
concentrations will be listed by study segment, treatment, study day and/or nominal time, and 
summarized using descriptive statistics. 
Summary statistics will be generated for ibezapolstat plasma and fecal concentrations. Given 
sufficient plasma and fecal levels over the lower limit of quantitation (LLOQ), the data will be 
analyzed as follows. Median (and range) and mean (and standard deviation) ibezapolstat plasma 
concentrations at each nominal time point will be calculated, as appropriate. Concentrations 
reported as below the LLOQ will be set to zero for descriptive statistics. 
14.6 Interim Analysis 
A single interim analysis will be performed when the first 36 Segment 2B subjects in the ITT 
Population (one half of the planned sample size) have data for the primary efficacy endpoint of 
clinical cure at the TOC visit. The null hypothesis (see Section 14.3.1) will be tested with a 


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one-sided normal approximation test of non-inferiority at a one-sided α=0.03037 level of 
significance (Pocock 1977) for an overall significance level of 0.05. If the p-value is less than or 
equal to 0.03037 at the time of the interim analysis, then the study may be stopped early for 
success. 
14.7 Trial Oversight Committee 
A Trial Oversight Committee will be established by the Sponsor to review accumulating safety 
data at regular intervals throughout the study and monitor overall study conduct. Members will 
include the Sponsor’s Medical Monitor, Clinical Research Organization Medical Monitor, a 
biostatistician, and 1 PI who has enrolled subjects in Segment 2A. The Trial Oversight 
Committee can recommend in writing to the Sponsor whether to continue, modify, or stop the 
clinical study on the basis of efficacy and safety considerations. The Trial Oversight 
Committee’s specific duties as well as statistical monitoring guidelines and procedures will be 
governed by a Trial Oversight Committee Charter. 
After up to 10 subjects have been enrolled and completed the full course of treatment in Segment 
2A, the Trial Oversight Committee will assess safety, tolerability, and as data allow, efficacy and 
will make a recommendation to the Sponsor regarding continued enrollment of Segment 2A. 
Another assessment of safety, tolerability, and efficacy will be made by the Trial Oversight 
Committee after all subjects have been enrolled in Segment 2A and followed through at least the 
EOT visit. If the Trial Oversight Committee judges the results to be favorable, it will recommend 
to the Sponsor that Segment 2B commence, or alternatively may make other recommendations to 
the Sponsor to modify Segment 2A or the entire study, such as, for example, expanding 
Segment 2A, adding another open-label dose group, and/or prospectively adjusting the sample 
size of Segment 2B. 
15 STUDY MANAGEMENT 
15.1 Approval and Consent 
15.1.1 Regulatory Guidelines 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of 
the US Code of Federal Regulations (CFR), in compliance with ICH and GCP guidelines and 
according to the appropriate regulatory requirements in the countries where the study was 
conducted. 
15.1.2 Institutional Review Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted IEC/IRB. Approval is 
required for the study protocol, protocol amendments (if applicable), Investigator’s Brochure, 
ICFs, recruitment material and subject information sheets, and other subject-facing material. 


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15.1.3 Informed Consent 
For each study subject, written informed consent will be obtained before any protocol-related 
activities. As part of this procedure, the PI or designee must explain orally and in writing the 
nature of the study, its purpose, procedures, expected duration, alternative therapy available, and 
the benefits and risks involved in study participation. The subject should be informed that he/she 
may withdraw from the study at any time, and the subject will receive all information that is 
required by local regulations and guidelines for ICH. The PI will provide the Sponsor or its 
representative with a copy of the IEC/IRB-approved ICF before the start of the study. 
15.2 Data Handling 
Any data to be recorded directly in the eCRFs (to be considered as source data) will be identified 
at the start of the study. Data reported in the eCRF that are derived from source documents 
should be consistent with the source documents, or the discrepancies must be explained. See also 
Section 15.3. 
Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained. In such cases, the 
study site should document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by direct data entry. 
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based EDC system maintained by Syneos Health. Access to 
the EDC system is available to only authorized users via the study’s internet web site, where a 
user unique assigned username and password are required for access. 
Any changes made to data after collection will be made through the use of the EDC system. 
eCRFs will be considered complete when all missing and/or incorrect data have been resolved. 
15.3 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The Investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The Investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 


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15.4 Record Retention 
Study records and source documents must be preserved for at least 15 years after the completion 
or discontinuation of/withdrawal from the study, at least 2 years after the drug being studied has 
received its last approval for sale, or at least 2 years after the drug development has stopped, and 
in accordance with the applicable local privacy laws, whichever is the longer time period. 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
Health Insurance Portability Accountability Act of 1996 Privacy Regulation). The Investigator 
shall ensure that study subjects authorize the use and disclosure of protected health information 
in accordance with Health Insurance Portability Accountability Act of 1996 Privacy Regulation 
and in a form satisfactory to the Sponsor. 
15.5 Monitoring 
The study will be monitored according to the study’s monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. 
On-site monitoring visits and contacts will be made at appropriate times during the study. The PI 
will assure he/she and adequate site personnel are available throughout the study to collaborate 
with clinical monitors. Clinical monitors must have direct access to source documentation in 
order to check the completeness, clarity, and consistency of the data recorded in the eCRFs for 
each subject. 
The Investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the Investigator will 
work closely with the clinical monitor and, as needed, provide them appropriate evidence that the 
study is being conducted in accordance with the protocol, applicable regulations, and GCP 
guidelines. 
15.6 Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the Investigator generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, standard operating procedures, 
GCP, and all applicable regulatory requirements. Audits will be independent of and separate 
from the routine monitoring and quality control functions. Quality assurance procedures will be 
performed at study sites and during data management to assure that safety and efficacy data are 
adequate and well documented. 


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15.7 Protocol Amendment and Protocol Deviation 
15.7.1 Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect on 
the safety of subjects or the conduct of the study will be classed as administrative amendments 
and will be submitted to the IEC/IRB for information only. The Sponsor will ensure that 
acknowledgment is received and filed. Amendments that are classed as substantial amendments 
must be submitted to the appropriate regulatory authorities and the IECs/IRBs for approval and 
will not be implemented at sites until such approvals are received other than in the case of an 
urgent safety measure. 
15.7.2 Protocol Deviations 
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical study 
report. Reporting of protocol deviations to the IRB/IEC and in accordance with applicable 
regulatory authority mandates is an Investigator’s responsibility. 
15.8 Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; EU 536/2014, Annex 1, D, 17 (a); in compliance with GCP 
guidelines; and according to the appropriate regulatory requirements in the countries where the 
study is conducted. 
IECs/IRBs will review and approve this protocol and the ICF. All subjects are required to give 
written informed consent before participation in the study. 
15.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the Investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the Investigator (or the institution 
signatory) and the Sponsor (or its designee). 
The Investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice. The Sponsor will provide no-exclusion insurance coverage for the clinical 
study as required by national regulations. 
15.10 Publication Policy/Disclosure of Data 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the Investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the institution and the Sponsor or their designee. With respect to such rights, 
the Sponsor or its designee will solely own all rights and interests in any materials, data, and 


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intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions either to their institution or 
directly to the Sponsor or its designee, as will be set forth in the clinical study agreement. 


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16 REFERENCES 
Acurx. ACX-362E. Investigator’s Brochure Edition 1. White Plains, NY: Acurx; 12 October 
2018. 
Al-Nassir WN, Sethi AK, Nerandzic MM, Bobulsky GS, Jump RL, Donskey CJ. Comparison of 
clinical and microbiological response to treatment of Clostridium difficile-associated disease 
with metronidazole and vancomycin. Clin Infect Dis. 2008;47(1):56-62. 
Global Markets Direct. Clostridium Infections – Pipeline Review, H2 2012, July 2012. 
Dvoskin S, Xu WC, Brown NC, Yanachkov IB, Yanachkova M, Wright GE. A novel agent 
effective against Clostridium difficile infection. Antimicrob Agents Chemother. 
2012;56(3):1624-6. 
Kokkotou E, Moss AC, Michos A, Espinoza D, Cloud JW, Mustafa N, et al. Comparative 
efﬁcacies of rifaximin and vancomycin for treatment of Clostridium difﬁcile-associated diarrhea 
and prevention of disease recurrence in hamsters. Antimicrob Agents Chemother. 
2008;52(3):1121-6. 
Lessa FC, Winston LG, McDonald LC; Emerging Infections Program C, difficile Surveillance 
Team. Burden of Clostridium difficile infection in the United States. N Engl J Med. 
2015;372(24):825-34. 
Louie TJ, Cannon K, Byrne B, Emery J, Ward L, Eyben M, et al. Fidaxomicin preserves the 
intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and 
reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis. 2012;55(Suppl 2):S132-
42. 
McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, et al. Clinical 
Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update 
by the Infectious Diseases Society of America (IDSA) and Society for Healthcare 
Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):987-94. 
Nelson RL, Suda KJ, Evans CT. Antibiotic treatment for Clostridium difficile-associated 
diarrhoea in adults. Cochrane Database Syst Rev. 2017;3:CD004610. doi: 
10.1002/14651858.CD004610.pub5. 
Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika. 
1977;64 (2):191-199. doi.org/10.2307/2335684. 
Razavi B, Apisarnthanarak A, Mundy LM. Clostridium difficile: emergence of hypervirulence 
and fluoroquinolone resistance. Infection. 2007;35(5):300-7. 
Smits WK, Lyras D, Lacy DB, Wilcox MH, Kuijper EJ. Clostridium difficile infection. Nat Rev 
Dis Primers. 2016;2:16020. doi: 10.1038/nrdp.2016.20. 


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Torti A, Lossani A, Savi L, Focher F, Wright GE, Brown NC, et al. Clostridium difficile DNA 
polymerase IIIC: basis for activity of antibacterial compounds. Curr Enzym Inhib. 
2011;7(3):147-53. 
Xu WC, Wright GE, Brown NC, Long ZY, Zhi CX, Dvoskin S, et al. 7-Alkyl-N2-substituted-3-
deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity. Bioorg Med 
Chem Lett. 2011;21(14):4197-202. 
Zilberberg MD, Shorr AF, Kollef MH. Increase in adult Clostridium difficile-related 
hospitalizations and case-fatality rate, United States, 2000-2005. Emerg Infect Dis. 
2008;14(6):929-31. 


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17 APPENDICES 
APPENDIX 1 describes the contraception guidelines applicable for this study. 
APPENDIX 2 contains the Bristol Stool Chart. 


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APPENDIX 1. 
CONTRACEPTION GUIDELINES 
Definitions: 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below) 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the subject’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
a. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient. 
b. Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
 
Contraception Guidance: 
Male Subjects 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (total 
abstinence on a long-term and persistent basis) and agree to remain abstinent. 
In addition, male subjects must refrain from donating sperm for 30 days after the last dose of 
study treatment. 
Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration for 
30 days after the last dose of study treatment. 


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Female Subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use two 
highly effective methods of contraception consistently and correctly as described in Table 9. 
Table 9. 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly Effective Contraceptive Methods That Are User Independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method if the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. 
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the treatment period and continuing for 30 days after the End of Study visit. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the subject. 
NOTES: 
• 
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for subjects participating in 
clinical studies. 
• 
Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce 
the efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should 
be utilized during the treatment period and for at least 30 days after the last dose of study treatment. 
 


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Pregnancy Testing: 
• WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test (a urine test will be provided by the 
Central Laboratory) 
• Pregnancy testing will be performed at Day 12, Day 38, and whenever a menstrual 
cycle is missed or when pregnancy is otherwise suspected up to 30 days after the last 
dose of study treatment. 
Collection of Pregnancy Information: 
Male Subjects With Partners Who Become Pregnant 
The Investigator will attempt to collect pregnancy information on any male subject’s female 
partner who becomes pregnant while the male subject is in this study up to 30 days following the 
last dose of study treatment. 
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the Investigator will record pregnancy information on the appropriate form and submit it to the 
Sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 8 
weeks following the estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female Subjects Who Become Pregnant 
The Investigator will collect pregnancy information on any female subject who becomes 
pregnant up to 30 days after the last dose of study treatment. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a subject's 
pregnancy. The subject will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will 
be reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion is 
always considered to be an SAE and will be reported as such. Any post-study pregnancy related 
SAE considered reasonably related to the study treatment by the Investigator will be reported to 
the Sponsor as described in Section 12.6.4. While the Investigator is not obligated to actively 
seek this information in former study subjects, he or she may learn of an SAE through 
spontaneous reporting. 


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APPENDIX 2. 
BRISTOL STOOL CHART 
 
 

SAP_001.pdf: 
 
 
 
 
STATISTICAL ANALYSIS PLAN  
 
Protocol Number: ACX-362E-201  
 
ACX-362E for Oral Treatment of Clostridioides 
difficile Infection: A Phase 2A Open-Label Segment 
Followed by a Phase 2B Double-Blind Vancomycin-
Controlled Segment 
 
Phase 2B 
 
October 25, 2023 
 
NCT: 04247542 
 
 
 
Prepared for 
Acurx Pharmaceuticals, Inc.  
259 Liberty Ave. 
Staten Island, NY 10305 
 
Prepared by 
Roger B. Johnson, Ph.D. 
Director, Biostatistics 
 
Reviewed by 
Susan Paadre, M.P.H. 
Associate Director, Biostatistics 
 
1 Hartwell Place 
Lexington, MA 02421 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                2 
Signature Page for Analysis Plan 
 
 
 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                3 
 
Table of Contents 
 
Signature Page for Analysis Plan .................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
List of Tables .................................................................................................................................. 5 
List of Listings ................................................................................................................................ 7 
List of Abbreviations ...................................................................................................................... 8 
1.0 
INTRODUCTION ................................................................................................................ 9 
2.0 
STUDY OBJECTIVES ....................................................................................................... 11 
2.1 
Primary Objectives ................................................................................................... 12 
2.2 
Secondary Objectives ............................................................................................... 17 
2.3 
Exploratory Objectives ............................................................................................. 17 
3.0 
STUDY DESIGN ............................................................................................................... 12 
3.1 
Overview ................................................................................................................... 12 
3.2 
Method of Assigning Subjects to Treatment ............................................................ 17 
3.3 
Blinding .................................................................................................................... 17 
3.4 
Determination of Sample Size .................................................................................. 17 
3.5 
Changes to the Protocol-Specified Analyses ............................................................ 18 
4.0 
EFFICACY AND SAFETY ENDPOINTS ........................................................................ 19 
4.1 
Primary Efficacy Endpoint ....................................................................................... 19 
4.2 
Secondary Efficacy Endpoint ................................................................................... 19 
4.3 
Exploratory Endpoints .............................................................................................. 19 
4.4 
Safety Endpoints ....................................................................................................... 19 
4.5 
Pharmacokinetic (PK) Endpoints ............................................................................. 19 
5.0 
STATISTICAL CONSIDERATIONS ............................................................................... 20 
5.1 
General Methodology ............................................................................................... 20 
5.2 
Adjustments for Covariates ...................................................................................... 20 
5.3 
Handling of Dropouts and Missing Data .................................................................. 20 
5.4 
Interim Analyses and Data Monitoring .................................................................... 20 
5.5 
Multicenter Study ..................................................................................................... 20 
5.6 
Multiple Comparisons / Multiplicity ........................................................................ 20 
5.7 
Examination of Subgroups ....................................................................................... 20 
5.8 
Baseline ..................................................................................................................... 21 
6.0 
ANALYSIS POPULATIONS ............................................................................................ 22 
6.1 
Enrolled Population .................................................................................................. 22 
6.2 
Intent-to-Treat Population ........................................................................................ 22 
6.3 
Per Protocol (PP) Population .................................................................................... 22 
6.4 
ITT Extension Population ......................................................................................... 22 


 
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6.5 
Safety Population ...................................................................................................... 22 
7.0 
SUBJECT DISPOSITION .................................................................................................. 23 
8.0 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................ 23 
9.0 
EFFICACY ANALYSES ................................................................................................... 24 
9.1 
Primary Efficacy Endpoint ....................................................................................... 25 
9.2 
Secondary Efficacy Endpoint ................................................................................... 25 
9.3     Exploratory Endpoints .............................................................................................. 25 
10.0 SAFETY ANALYSES ....................................................................................................... 27 
10.1 Adverse Events ......................................................................................................... 27 
10.2 Clinical Laboratory Tests ......................................................................................... 27 
10.3 Vital Signs ................................................................................................................ 27 
10.4 12-Lead ECG ............................................................................................................ 28 
10.5 Concomitant Medications ......................................................................................... 28 
11.0 OTHER ANALYSES ......................................................................................................... 27 
12.0 REFERENCES ................................................................................................................... 30 
 
Appendix A: TABLE SHELLS 
Appendix B:  LISTING SHELLS 
 
 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                5 
List of Tables 
 
Number 
Title 
1.1             
Subject Accountability (Enrolled Population) 
1.2 
 
Reason for Screen Failure (Screen Failures) 
2.1 
 
Demography and Height (ITT Population) 
2.2 
 
Medical History (ITT Population) 
2.3 
 
Current Episode of CDI (ITT Population) 
2.4 
 
Treatment of Current Episode of CDI (ITT Population) 
2.5 
 
Previous Episodes of CDI (Prior to Current Episode) (ITT Population) 
2.6  
 
Day 1 Limited Physical Examination (ITT Population) 
3.1.1  
Primary Efficacy Endpoint: Clinical Cure at the TOC Visit (Per Protocol   
 
 
Population) 
3.1.2 
Primary Efficacy Endpoint: Clinical Cure at the TOC Visit (ITT Population) 
3.2.1  
Secondary Efficacy Endpoint: Sustained Clinical Cure (Per Protocol Population) 
3.2.2  
Secondary Efficacy Endpoint: Sustained Clinical Cure (ITT Population) 
3.3.1  
Primary and Secondary Efficacy Endpoints for ACX-362E from Phases A and B  
(Per Protocol Population) 
3.3.2  
Primary and Secondary Efficacy Endpoints for ACX-362E from Phases A and B  
(ITT Population) 
3.4 
 
Exploratory Endpoint: Time to Resolution of Diarrhea (Per Protocol Population) 
3.5 
 
Exploratory Endpoint: EQ-5D-5L (Per Protocol Population) 
3.6 
 
Exploratory Endpoints: ECC56 and ECC84 (ITT Extension Population) 
3.7 
 
Investigator Assessment of Clinical Response (Per Protocol Population) 
4.1 
 
Treatment Emergent Adverse Events (TEAEs): Overview (Subject Level) (Safety  
Population) 
4.2 
 
Treatment Emergent Adverse Events (TEAEs): Incidence by System Organ Class  
and Preferred Term (Subject Level) (Safety Population) 
4.3 
 
Treatment Emergent Adverse Events (TEAEs) by System Organ Class/  
Preferred Term and Severity (Event Level) (Safety Population) 
4.4 
 
Treatment Emergent Adverse Events (TEAEs) by System Organ Class/  
Preferred Term and Relationship to the Study Drug (Event Level) (Safety  
Population) 
5.1 
 
Laboratory Tests: Hematology – Change from Baseline (Safety Population) 
5.2 
 
Laboratory Tests: Hematology – Lab Values Outside the Normal Range with  
Clinical Significance (Safety Population) 
5.3 
 
Laboratory Tests: Serum Chemistry – Change from Baseline (Safety Population) 
5.4 
Laboratory Tests: Serum Chemistry – Lab Values Outside the Normal Range with 
Clinical Significance (Safety Population) 
5.5 
 
Laboratory Tests: Urinalysis – Change from Baseline for Continuous Variables  
(Safety Population) 
5.6 
 
Laboratory Tests: Urinalysis – Categorical Variables (Safety Population) 
5.7 
 
Laboratory Tests: Urinalysis - Shifts in Status from Baseline (Day 1) to Days 5  
and 12 (Safety Population) 
6.1.1  
Vital Signs – Change from Baseline (Safety Population) 
6.1.2  
Vital Signs – Values Outside the Normal Range (Safety Population) 


 
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Number 
Title 
6.2.1  
12-Lead ECG (Safety Population) 
6.2.2  
12-Lead ECG: Shifts in Status from Baseline (Day 1) to Day 5 (Safety  
Population) 
7.1 
 
Pregnancy Tests (Safety Population) 
7.2 
 
Concomitant Medications (Safety Population) 
7.3 
 
Concomitant Procedures (Safety Population) 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                7 
List of Listings 
 
Number 
Title 
1.1 
Subject Enrollment, Informed Consent, and Analysis Populations (Enrolled 
Population) 
1.2 
 
Visits (ITT Population) 
1.3 
 
Eligibility Review (Enrolled Population) 
1.4 
 
Randomization per IWRS (Enrolled Population) 
1.5 
 
Subjects Excluded from the Per Protocol Population (ITT Population) 
1.6 
 
Unscheduled Visits (ITT Population) 
2.1 
 
Demography (ITT Population) 
2.2 
 
Subject Height (ITT Population) 
2.3 
 
Medical History (ITT Population) 
2.4 
 
Limited Physical Examination (ITT Population) 
 
3.1 
 
Study Drug Accountability and Compliance (ITT Population) 
3.2 
 
Dosing (ITT Population) 
4.1 
 
Current Episode of CDI (ITT Population) 
 
 
4.2 
 
Treatment of Current Episode of CDI (ITT Population) 
 
 
4.3 
 
Previous Episodes of CDI (Prior to Current Episode) (ITT Population) 
4.4 
 
Investigator Assessment of Clinical Response (ITT Population) 
 
 
4.5 
 
Suspected Recurrence of CDI (ITT Population) 
 
 
4.6 
 
Suspected Recurrence of CDI_2 (ITT Population)  
 
4.7 
 
Suspected Recurrence of CDI_3 (ITT Population)  
 
4.8 
 
Investigator Assessment - Recurrence Follow-up (ITT Population)  
 
4.9 
 
Subject Diary (ITT Population) 
 
 
4.10 
 
Subject Diary Review (ITT Population) 
 
 
4.11 
 
Stool Sample (ITT Population) 
 
 
4.12 
 
Subject Diary Bristol Stool Chart (ITT Population)  
 
4.13 
 
EQ-5D-5L (ITT Population) 
5.1 
 
Adverse Events (Safety Population) 
5.2 
 
Serious Adverse Events (SAEs) (Safety Population) 
6.1 
 
Central Laboratory Testing (Safety Population) 
6.2 
 
Laboratory Tests: Hematology (Safety Population) 
6.3 
 
Laboratory Tests: Serum Chemistry (Safety Population) 
6.4 
 
Laboratory Tests: Urinalysis (Safety Population) 
7.1 
 
Vital Signs (Safety Population) 
7.2 
 
12-Lead ECG (Safety Population) 
8.1 
 
Serum Pregnancy Test (Safety Population) 
8.2 
 
Urine Pregnancy Test (Safety Population) 
9.1 
 
Prior and Concomitant Medications (Safety Population) 
9.2 
 
Concomitant Procedures (Safety Population) 
10.1 
 
Medical Resource Utilization (ITT Population) 
10.2 
 
End of Treatment (ITT Population)  
 
10.3 
 
End of Study (ITT Population) 
 
 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                8 
List of Abbreviations 
 
Abbreviation 
Definition 
AE 
Adverse Event 
CDI 
Clostridioides difficile Infection 
ECC 
Extended Clinical Cure 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
EQ-5D-5L 
European Quality of Life - Five Dimension 
ICF 
Informed Consent Form 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCC 
Sustained Clinical Cure 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TOC 
Test of Cure 
UBM 
Unformed Bowel Movement 
US 
United States 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                9 
1.0 
INTRODUCTION 
This document details the analysis plan for the study entitled “ACX-362E for Oral Treatment of 
Clostridioides difficile Infection: A Phase 2A Open-Label Segment Followed by a Phase 2B 
Double-Blind Vancomycin-Controlled Segment”. It describes the proposed efficacy and safety 
analyses, including planned summary tables and by-subject data listings. This statistical analysis 
plan (SAP) concerns Phase 2B.  An earlier SAP describes the analyses of Phase 2A. 
 
Clostridioides difficile (C. difficile) is an anaerobic, spore-forming, Gram-positive bacterium. It 
is the causative agent of C. difficile infection (CDI), an increasingly common, potentially life-
threatening disease. C. difficile can live harmlessly in the colon, but in the presence of an 
antibiotic administered for another condition, overgrowth may occur, replacing normal bacterial 
flora and resulting in CDI and or C. difficile-associated disease (Nelson et al., 2017). 
 
The epidemiology of C. difficile has changed with the emergence of the North American 
pulsed-field gel electrophoresis type 1 strain, and use of more sensitive assays (Lessa et al., 
2015). Clostridioides difficile infection affects approximately 500,000 patients in the United 
States (US) each year, and is associated with 15,000 to 30,000 deaths (McDonald et al., 2018). In 
fact, 65,000 hospital acquired hospital-onset cases, 50,000 hospital acquired post-discharge 
cases, and 263,000 nursing home-onset cases, result in $4 billion in excess costs to the healthcare 
system annually (Clostridium Infections – Pipeline Review, 2012). Hospitalizations for CDI 
among nonpregnant adults has doubled from 2000 through 2010 and are projected to continue to 
increase in 2011 and 2012 (Lessa et al., 2015). 
 
Although the discontinuation of predisposing antibiotic therapy and treatment with 
metronidazole, oral vancomycin, or the recently approved drug fidaxomicin (Dificid®), are 
effective in management of CDI, the development of new alternative therapeutic measures will 
be of great benefit. Not only is the incidence of hospitalizations and deaths associated with 
C. difficile rising (Lessa et al., 2015; Louie et al., 2012; Zilberberg et al., 2008), but some strains 
may become hypervirulent and increasingly resistant to cephalosporins and fluoroquinolones 
(Razavi et al., 2007). 
 
Current treatment strategy includes discontinuation of predisposing antibiotic and oral 
administration of vancomycin or fidaxomicin. If access to vancomycin or fidaxomicin is limited, 
metronidazole may be used for an initial episode of non-severe CDI only (McDonald et al., 
2018).  
 
While vancomycin continues to show good clinical efficacy for C. difficile, there is an increasing 
incidence of serious illness because of vancomycin-resistant enterococci in the US, and use of 
oral vancomycin (as well as oral metronidazole) has been shown to promote overgrowth of this 
pathogen (Al-Nassir et al., 2008). Use of vancomycin to treat C. difficile is also associated with 
unacceptably high recurrence rates. Fidaxomicin (Dificid®), although newly approved for 
treatment of CDI, is a treatment option if the risk of recurrence is high, but not for complicated 
CDI (Smits et al., 2016). 
 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                10 
Several additional products are under development, and include small molecules, natural 
products, vaccines, and fecal transplants (Clostridium Infections – Pipeline Review, 2012; 
McDonald et al., 2018). 
 
Ibezapolstat (ACX-362E) has activity in vitro and in vivo against C. difficile (Xu et al., 2011; 
Dvoskin et al., 2012). The crisis in antibiotic resistance of Gram-positive bacteria prompted the 
development of novel antibacterials through structure–activity relationship studies of replication-
specific DNA polymerase IIIC. It is from among these compounds that antibacterial compounds 
against C. difficile with potent in vitro activity have been discovered. Among these is 
ibezapolstat, which also shows potent in vivo activity in the established Syrian golden hamster 
model of CDI (Kokkotou et al., 2008; Dvoskin et al., 2012). 
 
ACX-362E is an inhibitor of the C. difficile DNA polymerase IIIC and is highly selective for 
C. difficile compared with other Gram-positive anaerobes and aerobic bacteria. ACX-362E, 2-
(3,4-dichlorobenzyl)-7-(2-[morpholinyl]ethyl)guanine, is a small molecule, poorly bioavailable 
and active orally in the hamster model. In vitro, ACX-362E inhibited numerous C. difficile 
strains, with a minimum inhibitory concentration required to inhibit the growth of 90% of 
organisms value of 4 µg/mL, and without inhibiting Bifidobacteria and Lactobacillus spp., 
important "good" intestinal anaerobic bacteria, or Gram-negative bacteria. These results suggest 
that development of ACX-362E as an oral treatment for CDI in human patients will result in a 
novel, first-in-class drug to treat this emerging infectious disease.  
 
Subjects in this study who receive ACX-362E will be administered 450 mg orally every 12 hours 
for 10 days. ACX-362E is administered orally because it has been shown that ACX-362E has 
low oral availability with low systemic absorption and also has a unique specificity for 
C. difficile that does not affect the normal good flora of the colon, an important advantage to 
prevent recurrence.  
 
 
 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                11 
2.0 STUDY OBJECTIVES 
The objectives for Phase 2B of this study are as follows: 
2.1 
Primary Objectives 
1. Assess CDI clinical cure rates 2 days after the end of treatment (EOT) 
2. Evaluate the safety and tolerability of ACX-362E administered every 12 hours for 10 days in 
the treatment of CDI 
2.2  
Secondary Objectives 
1. Determine the fecal concentrations of ACX-362E in subjects with CDI during the course of 
treatment 
2. Assess incidence of sustained clinical cure (SCC) at 28 ± 2 days after EOT 
2.3 
Exploratory Objectives 
1. Compare the effects of ACX-362E versus vancomycin on relative and quantitative changes 
to the fecal microbiome 
2. Assess times to resolution of diarrhea during the treatment period 
3. Assess times to hospital discharge during the treatment period 
4. Assess the impact of ACX-362E treatment on subject reported quality of life and resource 
utilization 
5. Assess the incidence of extended clinical cure (ECC) at 56 ± 2 days and 84 ± 2 days after 
EOT in subjects participating in the extended follow-up period 
 
 
 
 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                12 
3.0 
STUDY DESIGN 
3.1 
Overview 
This Phase 2, multicenter, combined segment open-label single-arm segment followed by a 
double-blind, randomized, active-controlled clinical segment is designed to evaluate ACX-362E 
in the treatment of CDI. 
 
Segment 2A of this trial is an open-label cohort of approximately 20 subjects in approximately 
5 study centers in the US and Canada. If safety, tolerability, and efficacy are considered 
acceptable by the Trial Oversight Committee, Segment 2A will be followed by a double-blind, 
randomized, active-controlled trial (Segment 2B) with an additional cohort of at least 
72 subjects.  
 
In Segment 2B, subjects with CDI will be enrolled and randomly assigned in a 1:1 ratio to either 
ibezapolstat 450 mg orally every 12 hours with food or to vancomycin 125 mg orally every 6 
hours in up to 30 centers in the United States and Canada. Treatment will be administered for 
10 days and subjects will be followed for 28 ± 2 days for recurrence. Blinding in Segment 2B 
will be maintained by over-encapsulation of both drugs and dosing every 6 hours in all subjects. 
Subjects randomized to ibezapolstat will receive 2 doses per day of ibezapolstat and 2 doses per 
day of placebo. Additionally, subjects recruited from selected sites will participate in an 
extended follow-up period consisting of observation visits at 56 and 84 days after treatment to 
evaluate the long-term impact of ibezapolstat on the microbiome and on disease recurrence. At 
these selected sites, consecutive subjects will be offered the opportunity to participate in the 
extended follow-up period until approximately 16 subjects are recruited. 
 
For all subjects, the diagnosis of CDI will be based on unexplained and new onset of diarrhea 
(≥ 3 unformed bowel movements (UBMs) in a 24-hour period) and a positive result using a US 
Food and Drug Administration-approved test to detect free (C. difficile) toxins in stools. Baseline 
safety evaluations will consist of physical examination, vital signs, routine laboratory 
(hematology, clinical chemistry, and urinalysis) testing, and ECG. 
 
Subjects will be evaluated for treatment response and safety (adverse events (AEs), physical 
examination, vital signs, laboratory tests, and 12-lead ECG) at designated time points according 
to Table 1. Clinical cure of CDI will be defined as survival and the resolution of diarrhea in the 
24-hour period immediately before EOT that is maintained for 48 hours post EOT without a 
requirement for additional CDI treatment. All subjects, regardless of outcome after 10 days of 
treatment, will be followed for recurrence until Day 38; recurrence is defined as a new episode of 
diarrhea (≥ 3 UBMs in a 24-hour period) with a positive free toxin test result (using a Sponsor-
approved diagnostic test) that in the opinion of the Investigator requires retreatment with an 
antibacterial for C. difficile. 
 
Stool samples for microbiome testing will be collected at the time points outlined in Table 1, 
frozen, and sent to the central laboratory for analysis. An additional sample will be collected in 
the event of any suspected recurrence post test of cure (TOC), regardless of the outcome from 
the 10 days of treatment. Samples will also be collected in the event of any suspected recurrence 
at 56 and 84 days after EOT for those subjects participating in the extended follow-up period. 
Evaluation of changes to the microbiome at the TOC visit as well as overgrowth by vancomycin-


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                13 
resistant Enterococcus and multi-drug resistant organisms will be performed using Next Gen 
metagenomics sequencing and quantitative polymerase chain reaction.  
 
For pharmacokinetic (PK) analysis, fecal concentrations of ACX-362E will be determined for 
the stool samples collected at time points outlined in Table 1. Blood samples to measure plasma 
levels of ACX-362E in approximately 50% of subjects (i.e., approximately 36 subjects) in 
Segment 2B will be drawn 2 hours and 4 hours after the morning dose at time points specified in 
Table 1.   
 
The schedule of assessments for this study is presented in Table 1.  


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                14 
Table 1: 
Schedule of Assessments 
Study Phase 
Screening 
Treatment 
Follow-Up 
Recurrence 
Extended 
Follow-Upi 
Assessment 
Screening 
Visita 
Baselinea 
Check 
In 
Check 
In 
Check 
In 
End of 
Treatment 
Test 
of 
Cure 
Check 
In 
Check 
In 
End 
of 
Study 
Suspected 
Recurrence 
Obs 
Visit 
Obs 
Visit 
Day 
Day -2 to 
Day 1 
Day 1 
Day 3 
Day 5 
Day 8 
Day 10 
Day 
12 
(≥ 48 
hrs 
post 
last 
dose) 
Day 20 
Day 30 
Day 
38 
Test of Cure 
to End of 
Studyj 
Day 66 
Day 
94 
Visit Window 
 
 
±1 Day 
±1 Day 
±1 Day 
±1 Day 
+1 
Days 
±2 
Days 
±2 
Days 
±2 
Days 
<48 hrs of 
Reporting 
±2 
Days 
±2 
Days 
Visit Format 
Clinic 
Clinic 
Tel. 
Clinic 
Tel. 
Tel. 
Clinic 
Tel. 
Tel. 
Clinic 
Clinic 
Clinic 
Clinic 
Segment 2A/2B 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
CDI diagnosis 
including free toxin 
testb 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & 
medication histories 
including detailed 
CDI history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Vital signs 
 
X 
 
X 
 
 
Xd 
 
 
Safety laboratory 
testse 
 
X 
 
X 
 
 
X 
 
 
 
Pregnancy testf 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Electrocardiogram 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator 
assessment of clinical 
response 
 
 
X 
 
 
X 
 
 
 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                15 
Study Phase 
Screening 
Treatment 
Follow-Up 
Recurrence 
Extended 
Follow-Upi 
Assessment 
Screening 
Visita 
Baselinea 
Check 
In 
Check 
In 
Check 
In 
End of 
Treatment 
Test 
of 
Cure 
Check 
In 
Check 
In 
End 
of 
Study 
Suspected 
Recurrence 
Obs 
Visit 
Obs 
Visit 
Day 
Day -2 to 
Day 1 
Day 1 
Day 3 
Day 5 
Day 8 
Day 10 
Day 
12 
(≥ 48 
hrs 
post 
last 
dose) 
Day 20 
Day 30 
Day 
38 
Test of Cure 
to End of 
Studyj 
Day 66 
Day 
94 
Visit Window 
 
 
±1 Day 
±1 Day 
±1 Day 
±1 Day 
+1 
Days 
±2 
Days 
±2 
Days 
±2 
Days 
<48 hrs of 
Reporting 
±2 
Days 
±2 
Days 
Visit Format 
Clinic 
Clinic 
Tel. 
Clinic 
Tel. 
Tel. 
Clinic 
Tel. 
Tel. 
Clinic 
Clinic 
Clinic 
Clinic 
Concomitant 
medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
Subject diary  
 
 
 
 
 
 
 
 
 
 
 
 
Stool samples for 
future analysesg 
(microbiome and 
fecal drug 
concentration 
analyses) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood sample for 
pharmacokineticsh 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Segment 2B only 
 
 
 
 
Randomization per 
IWRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Medical Resource 
Utilization Questions 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Stool samples for 
future analyses 
(microbiome 
analyses) 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: CDI, Clostridioides difficile infection; IWRS, Interactive Web Response System; Obs, observation; Tel., telephone. 
a May occur the same day as the baseline visit. Written informed consent for the study will be obtained from all subjects before any protocol specific procedures are performed. 
b Any Sponsor-approved free toxin test may be used. 
c A complete physical at screening; limited physical examination at other times as clinically indicated. 
d Perform at Day 38 or earlier (at an unscheduled visit) if subject experiences a confirmed recurrence. 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                16 
e Safety laboratory tests will include biochemistry, hematology, and urinalysis. 
f Only in women of childbearing potential. Serum test will be done at Screening; urine test will be done at the site at other specified time points. 
g If subject does not attend clinic then arrangements must be made to collect stool sample from subject’s home. Sample must be collected before first dose of study drug. Stool 
samples should be kept cool and brought to the clinic within 24 hours after collection. 
h Pharmacokinetic blood samples will be collected 2 hours (± 15 minutes) and 4 hours (± 30 minutes) after first dose of the day. In Segment 2B, pharmacokinetic blood samples 
will be collected in approximately 50% of subjects (i.e., approximately 36 subjects). 
i Randomized Segment 2B subjects recruited from selected sites will have the opportunity to participate in an extended follow-up period to Day 94. 
j     EOS includes observation visits Day 66 and Day 94 for those subjects participating in the extended follow-up period. 
 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                17 
3.2 
Method of Assigning Subjects to Treatment 
On Day 1, subjects will be randomly allocated to kits containing blister packs of either 
ibezapolstat or vancomycin and will be assigned a randomization number according to an 
interactive web response system (IWRS). The randomization schedule will be produced by staff 
outside the study team and kept secure from blinded study staff until after the study database is 
locked. Site staff will give the kits containing the blister packs to hospital staff while the subject 
is in the hospital (if needed), or to the subject to take home for self-dosing. 
3.3 
Blinding 
Segment 2B is a double-blind study. Ibezapolstat, placebo, and vancomycin capsules will be 
identical in physical appearance by over-encapsulation, packaged into blister packs with each 
dose labeled, and will be administered 4 times a day so that neither study staff nor the subjects 
will know to which treatment the subject was assigned. Subjects randomized to vancomycin will 
receive 3 capsules (1 vancomycin capsule and 2 placebo capsules) to mimic the 3 ibezapolstat 
150 mg capsules every 12 hours (e.g., 12 AM and 12 PM) and a single vancomycin capsule (e.g., 
6 AM and 6 PM) every 12 hours. The Investigator, study staff, Sponsor, Trial Oversight 
Committee, and the subject will remain blinded to study treatment throughout the study. 
According to the randomization schedule as indicated in the Schedule of Assessments (Table 1), 
the Investigator or designee will obtain the kit number from the IWRS for the subject. The 
pharmacist or designee will provide the assigned kit number to the subject. No study site 
personnel, subjects, Sponsor personnel, or Sponsor designees will be unblinded to treatment 
assignment throughout the duration of the study unless unblinding is required. If an Investigator 
becomes unblinded to a given subject’s study treatment, that subject will continue in the study 
and undergo all protocol-required procedures for the determination of safety and efficacy. 
In the event that emergency unblinding is required for a given subject because of AEs or 
concerns for the subject’s safety or wellbeing, the Investigator may break the randomization code 
for the subject via the IWRS, by which system the unblinding will be captured. The Investigator 
is responsible for notifying the Medical Monitor and/or Sponsor of such an event within 24 
hours. The unblinding and its cause will also be documented in the eCRF. 
 
3.4 
Determination of Sample Size 
Sample size for Segment 2B was calculated based on the following specifications: 
1. Non-inferiority study 
2. Endpoint is clinical cure at the TOC visit 
3. One-sided normal approximation test 
4. Alpha = 0.05 
5. Allocation to treatment = 1:1 
6. True cure rate = 0.80 in both arms 
7. Non-inferiority margin = 0.25 
8. Power = 80% 
9. Sample size adjusted for one interim analysis based on the method of Pocock 
 
A sample size of 36 subjects per treatment group, or 72 subjects total, will satisfy these 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                18 
specifications. 
3.5 
Changes to the Protocol-Specified Analyses 
The protocol states that at least 72 subjects are planned for Segment 2B of this study; however, 
study enrollment was stopped after 32 subjects were enrolled and randomized.  
The protocol indicates that the primary analysis of efficacy will be based on the Intent-to-Treat 
(ITT) Population and that a secondary analysis of the primary and secondary efficacy endpoints 
will be based on the Per Protocol Population. Instead, the primary analysis of efficacy will be 
based on the Per Protocol Population, and a secondary analysis of the primary and secondary 
efficacy endpoints will be based on the ITT Population. 
The protocol specifies that time to hospital discharge (for hospitalized subjects only) and medical 
resource utilization data are exploratory efficacy endpoints. These proposed endpoints are being 
dropped.  
The protocol states that a single interim analysis will be performed when the first 36 Segment 2B 
subjects in the ITT Population (one half of the planned sample size) have data for the primary 
efficacy endpoint of clinical cure at the TOC visit. This will not be done.  
The protocol indicates that the null and alternative hypotheses for the primary efficacy endpoint 
are as follows: 
 
H0: π 1,T ≤ π1,C - δ      
  and 
H1: π 1,T > π1,C - δ, 
 
where π1,T and π1,C are the true proportions of subjects with clinical cure at the TOC visit for the 
ibezapolstat 450 mg and vancomycin 125 mg treatments, respectively, and δ is the non-
inferiority margin, which was to be 0.25. No hypothesis test will be performed. 
 
The protocol states that, for the secondary efficacy endpoint, the null hypothesis that the true 
proportions are equal for the 2 treatments will be tested using a two-sided Fisher’s exact test at 
the 0.05 significance level. No hypothesis will be performed. 
The protocol states “The number and percentage of subjects having a treatment emergent AE 
(TEAE) in each System Organ Class (SOC) and having each individual type of AE (Preferred 
Term) will be presented. TEAEs will also be summarized at the event level by SOC/Preferred 
Term and severity. This will be done for all TEAEs, all serious TEAEs, and all TEAEs leading to 
discontinuation from the study.” However, this will be done only for TEAEs and not for serious 
TEAEs or TEAEs leading to discontinuation from the study. 
 
 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                19 
4.0 
EFFICACY AND SAFETY ENDPOINTS 
 
4.1 
Primary Efficacy Endpoint 
The primary endpoint of this study is clinical cure at the test of cure (TOC) visit, which is 
defined as survival and the resolution of diarrhea in the 24-hour period immediately before EOT 
that is maintained for 48 hours post EOT without a requirement for additional CDI treatment. 
Diarrhea is defined as ≥ 3 unformed bowel movements (UBMs) in a 24-hour period; < 3 UBMs 
is considered as resolution of diarrhea. A UBM is defined as a Type 5, 6, or 7 bowel movement 
on the Bristol Stool Chart. 
4.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint of this study is sustained clinical cure (SCC), which is defined 
as a clinical cure at the TOC visit (i.e., at least 48 hours post EOT) and no recurrence of CDI 
within the 28 ± 2 days post EOT. Recurrence is defined as a new episode of diarrhea (≥ 3 UBMs 
in a 24-hour period) with a positive toxin result, using a Sponsor-approved C. difficile free toxin 
test and, in the opinion of the Investigator, requiring retreatment with an antibacterial agent for 
C. difficile. 
 
4.3 
Exploratory Endpoints 
The exploratory endpoints of this study are as follows: 
 
• Microbial endpoints: Quantitative changes in relevant fecal bacterial communities and 
microbial diversity will be assessed. Changes will be assessed during the treatment period 
and post EOT.  
• Time to resolution of diarrhea, defined as the time from outset of treatment to the first 
formed bowel movement not followed within the next 24 hours by a UBM. 
• Quality of life assessments including EQ-5D-5L.  
• ECC, defined as a clinical cure at the TOC visit (i.e., at least 48 hours post EOT) and no 
recurrence of CDI within the 56 ± 2 days post EOT (ECC56) and 84 ± 2 days post EOT 
(ECC84). Recurrence is as defined for the secondary efficacy endpoint. 
 
This statistical analysis plan does not address the analysis of microbial endpoints. 
 
4.4 
Safety Endpoints 
Safety endpoints for all subjects include the nature, frequency, and severity of AEs, including 
serious adverse events (SAEs); changes from baseline in findings on physical examination, vital 
sign measurements, safety laboratory tests (hematology, chemistry, urinalysis); and ECG 
findings.  
4.5 
Pharmacokinetic (PK) Endpoints 
The secondary PK endpoint is systemic exposure of ACX-362E, which will be determined by 
measuring plasma ACX-362E concentrations at specified time points following dose 
administration; fecal concentrations of ACX-362E will be measured at specified study visits.  
The PK analysis is not part of this analysis plan. 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                20 
5.0 
STATISTICAL CONSIDERATIONS 
5.1 
General Methodology 
The statistical analysis of the data obtained from this study will be performed using SAS® 
version 9.4 or higher.    
Data collected in this study will be documented using summary tables and subject data listings. 
Continuous variables will be summarized using descriptive statistics, specifically the sample 
size, mean, median, standard deviation, minimum and maximum. Categorical variables will be 
summarized using frequencies and percentages.  For continuous data, the minimum and the 
maximum will use the same decimal accuracy as the raw data.  The mean, median, and standard 
deviation will use one more decimal place than the raw data.  For categorical data, percentages 
will be reported to one decimal place.  Summary statistics will be presented by treatment group.  
Data listings will be sorted by treatment group and patient ID.  
5.2 
Adjustments for Covariates 
No adjustments for covariates will be made.  
5.3 
Handling of Dropouts and Missing Data 
Multiple imputation methods will be used for the imputation of missing data for the primary and 
secondary efficacy endpoints for the ITT Population. For each treatment group and each imputed 
dataset, subjects with missing data will have a value for the endpoint imputed randomly based on 
the Bernoulli probability distribution with probability of success equal to the observed 
probability of success for the endpoint (clinical cure or sustained clinical cure) in the given 
treatment group.  PROC MIANALYZE of SAS® will be used to combine the results from the 
imputed datasets to produce an overall estimate of the true success rate for each treatment group 
and the other desired statistics as specified in Section 9.1 and 9.2.  Based on what is known to 
date for the observed, blinded data, there is one subject who has missing values for the primary 
and secondary efficacy endpoints. This subject dropped out of the study without receiving any 
study drug and has no follow-up data.   
No other imputation for missing data will be performed. 
5.4 
Interim Analyses and Data Monitoring 
No interim analyses will be performed.   
 
5.5 
Multicenter Study 
This is a multicenter study. It is planned to enroll at least 72 subjects at up to 30 study centers in 
the United States (US) and Canada for Segment 2B. 
5.6 
Multiple Comparisons / Multiplicity 
No adjustment for multiple comparisons/multiplicity is needed since no hypothesis testing is to 
be done.   
5.7 
Examination of Subgroups 
No subgroup analyses will be performed.  
 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                21 
5.8 
Baseline 
Baseline is defined as the last value prior to the start of study medication.   


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                22 
6.0 
ANALYSIS POPULATIONS 
6.1 
Enrolled Population 
The Enrolled population will include all subjects in Segment 2B who sign the informed consent 
form (ICF). 
 
6.2 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all subjects who are randomized. Subjects will 
be analyzed based on their randomized assignment. The ITT population will be used for a 
secondary analysis of the primary and secondary efficacy endpoints. 
 
6.3 
Per Protocol (PP) Population 
The PP Population will consist of patients in the ITT Population with no major protocol 
deviations. The determination of which patients have major protocol violations will be made in a 
blinded manner prior to database lock. For analyses based on the PP Population, patients will be 
grouped according to the treatment to which they were randomized. This population will be used 
for the primary analysis of the efficacy endpoints.  
 
6.4 
ITT Extension Population 
 
The ITT Extension population will include all randomized subjects who participate in the 
extended follow-up period. Subjects will be analyzed based on their randomized assignment. The 
ITT Extension population will be used for the analysis of the ECC56 and ECC84 exploratory 
endpoints. 
 
6.5 
Safety Population 
The Safety population will include all subjects who receive at least 1 dose of study drug. 
Subjects will be analyzed based on the treatment actually received. This population will be used 
for the analysis of safety. 


 
Acurx Pharmaceuticals, Inc.: Protocol Number ACX-362E-201 Phase 2B SAP, October 25, 2023                23 
7.0 
SUBJECT DISPOSITION 
The number of enrolled subjects, re-screened subjects, and screen failures will be presented. The 
number of randomized subjects (ITT Population) and the number and percentage of randomized 
subjects who are in the Per Protocol Population, the ITT Extension Population, and the Safety 
Population; who completed study treatment; who withdrew from study treatment, and their 
primary reason for early withdrawal; who completed the study; who withdrew early from the 
study treatment, and their primary reason for early withdrawal, will be summarized by treatment 
group.  
The reason for screen failure will be summarized using frequencies and percentages for screen 
failures. 
 
 


 
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8.0 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Descriptive statistics will be presented by treatment group and overall for the continuous 
variables of age and height; frequencies and percentages will be presented for the categorical 
variables of sex, whether the patient is of child bearing potential (females only), race, and 
ethnicity.  
The following data will each be summarized by treatment group using descriptive statistics for 
continuous variables and frequencies and percentages for categorical variables: medical history, 
current episode of CDI, treatment of current episode of CDI, previous episodes of CDI (prior to 
the current episode), and the Day 1 limited physical examination.  


 
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9.0 
EFFICACY ANALYSES 
9.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is clinical cure at the TOC visit, defined as survival and resolution 
of diarrhea in the 24-hour period immediately before EOT that is maintained for 48 hours post 
EOT without a requirement for additional CDI treatment.  
After EOT, subjects with initial clinical cure will be followed for an additional 28 ± 2 days to 
assess the recurrence of CDI. 
 
This endpoint will be summarized by treatment group using frequencies and percentages, 
together with an exact (Clopper-Pearson) 95% confidence interval for the true cure percentage. 
The 95% exact unconditional confidence interval will also be calculated for the difference 
between the 2 population proportions (π1,C – π1,T, where π1,C and π1,T are the true proportions of 
subjects with clinical cure at the TOC visit for the vancomycin 125 mg and ibezapolstat 450 mg 
treatments, respectively. 
 
In addition, the rate of clinical cure will also be summarized for ibezapolstat by frequency and 
percentage along with an exact 95% confidence interval pooling data from Phases A and B. 
 
9.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is sustained clinical cure (SCC), which is defined below, and is 
determined for subjects who achieve initial clinical cure. The determination will be made at the 
Day 38 follow-up visit. 
1. Recurrence is defined as ≥ 3 bowel movements with unformed stools in any 24-hour 
period with free C. difficile toxin A or B (or both) detected in a stool sample and, in the 
opinion of the Investigator, there is a need for CDI retreatment. 
2. SCC is defined as initial clinical cure without subsequent recurrence within 28 ± 2 days 
post EOT. 
This endpoint will be summarized by treatment group using frequencies and percentages, 
together with an exact (Clopper-Pearson) 95% confidence interval for the true SCC percentage. 
A 95% exact unconditional confidence interval will also be calculated for the difference between 
the 2 population proportions (π2,C – π2,T), where π2,C and π2,T are the true proportions of subjects 
with SCC for the vancomycin 125 mg and ibezapolstat 450 mg treatments, respectively.   
In addition, the rate of sustained clinical cure will also be summarized for ibezapolstat by 
frequency and percentage along with an exact 95% confidence interval pooling data from Phases 
A and B. 
 
9.3  Exploratory Endpoints  
9.3.1    Time to Resolution of Diarrhea 
Time to resolution of diarrhea, defined as the time from onset of treatment to the first formed 
bowel movement not followed within the next 24 hours by a UBM, will be summarized by 
treatment group using the Kaplan-Meier method, with estimates of the true resolution of diarrhea 
rate at Days 1, 5, 10, 12, and 40. The estimated median time to resolution of diarrhea, together 
with a 95% confidence interval, will also be presented.  


 
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9.3.2      Quality of Life Assessments 
The EQ-5D-5L scores and the changes from baseline (screening) for each of the 5 dimensions 
and the EQ-5D-5L visual analog scale score will be summarized by treatment group and time 
point using descriptive statistics. 
Medical resource utilization data will be listed.  
9.3.3     ECC56 and ECC84 
These endpoints will be summarized by treatment group using frequencies and percentages, 
together with exact (Clopper-Pearson) 95% confidence intervals for the true percentages.  Also, 
95% confidence intervals based on the normal approximation will be calculated for the 
differences between the 2 population proportions. These endpoints will be analyzed based on the 
ITT Extension Population. 
 


 
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10.0 
SAFETY ANALYSES 
Safety endpoints for all subjects include the nature, frequency, and severity of AEs; changes 
from baseline in findings on physical examination, vital sign measurements, safety laboratory 
tests (hematology, chemistry, urinalysis); and ECG findings.  
10.1 
Adverse Events 
Treatment-emergent AEs (TEAEs) are defined as any AE with onset date after the date of the 
start of the study drug or any AE already present at baseline that worsens in severity. All 
reported AEs will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Events with missing onset dates will be considered to be 
treatment-emergent unless there is additional information indicating that the AE started before 
study treatment. Only TEAEs will be summarized.  
 
The number and percentage of subjects with at least one TEAE, at least one treatment-related 
TEAE, at least one serious TEAE, and at least one TEAE leading to discontinuation from the 
study will be presented by treatment group. AEs that are definitely, probably, or possibly related, 
or for which the relationship is missing, will be considered treatment-related. 
 
The number and percentage of subjects having a TEAE in each System Organ Class (SOC) and 
having each individual type of AE (Preferred Term) will be presented. TEAEs will also be 
summarized at the event level by SOC/Preferred Term and severity and by SOC/Preferred Term 
and relationship to the study drug.  
 
SAEs will be listed. 
 
10.2 
Clinical Laboratory Tests 
Clinical laboratory data (hematology and serum chemistry) will be summarized by treatment 
group and time point using descriptive statistics for both the actual values and the changes from 
baseline (Day 1). Also, the number and percentage of subjects with lab values in the normal 
range, outside the normal range without clinical significance, and outside the normal range with 
clinical significance will be presented. 
 
Urinalysis data will be summarized by treatment group and time point using frequencies and 
percentages for categorical variables and descriptive statistics for continuous variables. A shift 
table will be presented showing changes in status (normal, abnormal without clinical 
significance, abnormal with clinical significance) from Baseline (Day 1) to Days 5 and 12. 
 
10.3 
Vital Signs 
Vital signs data will be summarized by treatment group and time point using descriptive statistics 
for both the actual values and the changes from baseline (Day 1). Also, the number and 
percentage of subjects with vital sign values in the normal range and outside the normal range 
will be presented. 
 
 


 
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10.4 
12-Lead ECG  
Electrocardiogram data will be summarized by treatment group and time point using descriptive 
statistics for both the actual values and the changes from baseline. A shift table will be presented 
showing changes in status (normal, abnormal without clinical significance, abnormal with 
clinical significance) from Baseline (Day 1) to Day 5. 
10.5 
Concomitant Medications 
Concomitant medications (medications initiated during the study period and medications 
initiated prior to the study period but continuing in the study period) will be summarized by 
treatment group using frequencies and percentages of subjects having a medication in each 
ATC3 class and having a medication with the given preferred term. 


 
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11.0 
OTHER ANALYSES 
Serum and urine pregnancy data will be summarized by treatment group using counts and 
percentages. 
The investigator assessment of clinical response at Days 12 and 38 will be summarized by 
treatment group using frequencies and percentages.  
Study drug compliance and accountability data will be provided in Listing 3.1. 
 
 
 
 
 
 


 
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12.0 
REFERENCES 
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Pocock, S. J. (1977). Group Sequential Methods in the Design and Analysis of Clinical 
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Razavi B, Apisarnthanarak A, Mundy LM. Clostridium difficile: emergence of hypervirulence and 
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Smits WK, Lyras D, Lacy DB, Wilcox MH, Kuijper EJ. Clostridium difficile infection. Nat Rev Dis 
Primers. 2016;2:16020. doi: 10.1038/nrdp.2016.20.  
Xu WC, Wright GE, Brown NC, Long ZY, Zhi CX, Dvoskin S, et al. 7-Alkyl-N2-substituted-3-
deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity. Bioorg Med 
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Appendix A: TABLE SHELLS 
 


 
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Appendix B: LISTING SHELLS