A Phase 2 Clinical Study of REC-3964 in Adults for the Reduction of Recurrent Clostridioides Difficile Infection (CDI)
Phase: PHASE2
Conditions: Recurrent Clostridioides Difficile Infection
Sponsor: Recursion Pharmaceuticals Inc.

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CLINICAL TRIAL PROTOCOL 
Study Title: 
A Phase 2 Clinical Study of REC-3964 in Adults for the 
Reduction of Recurrent Clostridioides Difficile Infection 
Brief Study Title: 
The Clostridioides Difficile Trial of REC-3964 
Study Number: 
REC-3964-201 
Investigational Product: 
REC-3964 
IND: 
169641 
EU CT: 
2024-520223-81-00 
Sponsor: 
Recursion Pharmaceuticals, Inc. 
41 South Rio Grande St. 
Salt Lake City, UT 84101 
Responsible Medical Officer 
 
  
Recursion Pharmaceuticals, Inc. 
Protocol Version 
Version 7.0 
Date 
27 March 2025 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or under control of 
Recursion Pharmaceuticals, Inc., and is provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an applicable Institutional Review Board or Independent Ethics 
Committee. The information is only to be used by you in connection with authorized clinical studies of the 
investigational drug described in the protocol. You will not disclose any of the information to others without 
written authorization from Recursion Pharmaceuticals, Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 
NCT #: NCT06536465

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1. 
SIGNATURE PAGE 
Sponsor’s Approval 
The protocol has been approved by:  
 
{See appended electronic signature page} 
 
 
 
 
 
 
 
 
Date 
{See appended electronic signature page} 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 

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INVESTIGATOR’S AGREEMENT 
I have read the REC-3964-201 protocol and agree to conduct the study as outlined and in 
accordance with GCP. I agree to maintain the confidentiality of all information received or 
developed in connection with this protocol. 
 
 
 
Printed Name of Investigator 
 
Signature of Investigator 
 
Date 

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EMERGENCY CONTACT INFORMATION 
Name 
Contact Number 
Email Address 
 
 
 

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PROTOCOL AMENDMENT HISTORY 
The following amendments have been made to this protocol since the date of preparation: 

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2. 
SYNOPSIS 
Name of Sponsor / Company: Recursion Pharmaceuticals, Inc 
Name of Investigational Product: REC-3964 
Name of Active Ingredient: REC-3964 
Protocol Number: REC-3964-201 
Phase: 2 
Countries: Multi-site, 
multi-regional 
Title of Study 
A Phase 2 Clinical Study of REC-3964 in Adults for the Reduction of Recurrent 
Clostridioides Difficile Infection  
Study center(s): 
Approximately 40-50 centers 
Objectives: 
Primary 
• 
To evaluate the efficacy of REC-3964 as determined by survival without recurrence or requirement for 
additional CDI treatment for at least eight weeks following cure of preceding CDI with vancomycin or 
fidaxomicin  
• 
To evaluate the safety and tolerability of REC-3964 
Secondary 
• 
To assess the efficacy of REC-3964 as measured by other efficacy endpoints 
• 
To characterize the pharmacokinetics (PK) of REC-3964 
Methodology: This Phase 2, open-labeled, multi-center study is designed to characterize the safety, tolerability, 
PK, and efficacy of REC-3964 at doses of either 
 
 for the reduction of recurrent Clostridioides difficile 
infection (rCDI) after cure of preceding CDI with vancomycin or fidaxomicin. The study will enroll male and 
female participants who are 18 years of age or older. 
Study Schema 
Figure 1: 
 
 
Number of Participants (Planned): Approximately 80 participants 
 
 in the Observation arm) will be randomized. 

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Enrollment of participants initially treated with fidaxomicin will be capped at no more than 33% of the total 
study population. 
Diagnosis and Main Criteria for Eligibility: 
Inclusion Criteria 
To be enrolled, the participant must provide informed consent and meet ALL of the following criteria at the 
time of enrollment: 
• 
Be 18 years of age or older  
• 
Have CDI diarrhea, defined as 3 or more unformed stools per day (types 5-7 on the Bristol stool scale) for 
at least 2 consecutive days AND 
• 
Confirmed lab diagnosis through positive stool test for C. difficile toxin[s] prior to the preceding curative 
treatment  
• 
The CDI episode, severe or otherwise, must have resolved (two or less unformed stools for at least 24 
hours) after receiving a standard duration of vancomycin (or fidaxomicin) treatment for 10 – 14 days 
(+2 days). The standard initial curative treatment is vancomycin. Fidaxomicin is an optional alternative 
and may be chosen if deemed appropriate by the investigator, taking into account the participant’s 
condition, treatment history, and other relevant clinical factors. The participant must be randomized within 
2 days of completing the preceding curative treatment. 
• 
Have high risk for rCDI, defined as any of the following: 
o having had at least one prior CDI episode within the last 6 months 
o age ≥65 years 
o immunocompromised state 
o severe CDI with resolution prior to enrollment into the study 
• 
NOTE: Severe CDI is defined as CDI with white blood cell count >15,000 cells/mL and/or 
serum creatinine ≥1.5 mg/dL. Severe CDI must have resolved prior to enrollment into the 
study. 
 
Exclusion Criteria 
To participate, the participant must meet NONE of the following at the time of enrollment: 
• 
Have an active, symptomatic, chronic diarrheal illness from other causes such as ulcerative colitis or 
Crohn’s disease. 
• 
Have a life expectancy of less than 90 days. 
• 
Have surgery planned to manage severe CDI colitis during the study period. 
• 
Have fulminant CDI. 
• 
 
 
 
. 
• 
Chronic or recent use of laxatives, or anti-motility agents, such as loperamide. 
Investigational Product, Dosage, and Mode of Action 
REC-3964 
 
 
 
 
 
Duration of Treatment 
The duration of participation for each participant is up to 
, as follows: 
• Screening 
  

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• Treatment Period 
 
• Follow-up Period 
 
Statistical Methods: 
Sample Size 
Approximately 80 participants will be randomized to this study. No hypothesis testing will be conducted. This 
sample size is deemed appropriate to provide safety profile and preliminary efficacy information on the effect 
of treatment with REC-3964 in C. difficile participants. 
Statistical Analysis 
The primary efficacy endpoint is survival without recurrence or requirement for additional CDI treatment for at 
least eight weeks following cure of preceding CDI with initial curative treatment defined in Inclusion Criteria 
6.1.4. It will be analyzed as the rate of recurrent C. difficile infection after treatment with REC-3964 or 
observation at 8 weeks, upon resolution of the preceding CDI diarrheal episode with initial curative treatment. 
For secondary efficacy endpoints, rates/proportions will be calculated and summarized with 2-sided 95% CIs 
per treatment group using exact test while time to event endpoints will be analyzed using the KM method. 
Additional efficacy analyses will be conducted within stratum of prior antibiotic use (vancomycin versus 
fidaxomicin).  
Safety and tolerability will be assessed by the following endpoints: incidence, severity, and relatedness of AEs 
and SAEs; and incidence of treatment-emergent adverse events (TEAEs) leading to study drug discontinuation. 
Safety and tolerability will be summarized by treatment arm in terms of the frequency and percentage of AEs. 
All TEAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The frequency 
and severity of AEs will be summarized by treatment arm in particular, all TEAEs, SAEs and deaths, and AEs 
leading to discontinuation of study drug will be presented. AEs by relationship to study treatment will also be 
summarized by the MedDRA preferred term (PT) and system organ class (SOC). Laboratory data, physical 
examination, vital signs, and 12-lead ECG data will be summarized descriptively by treatment arm over time, 
including displays of change from baseline. Values outside normal ranges will be identified and summarized by 
treatment arms. Incidence of abnormal physical examination findings will also be summarized. Plasma 
concentrations of REC-3964 and PK parameters derived from plasma concentration will be summarized and 
analyzed on PK Analysis Set. 
Analyses of other endpoints and details will be provided in the Statistical Analysis Plan (SAP). 

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Table 1: 
 

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TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ....................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
EMERGENCY CONTACT INFORMATION ................................................................................4 
PROTOCOL AMENDMENT HISTORY .......................................................................................5 
2. 
SYNOPSIS ...................................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................17 
3. 
INTRODUCTION ......................................................................................................19 
3.1. 
Clostridioides Difficile Background ...........................................................................19 
3.2. 
Clostridioides Difficile Pathogenesis ..........................................................................19 
3.3. 
Treatment of Clostridioides Difficile ..........................................................................20 
3.4. 
 ......................20 
3.4.1. 
 ........................................................................20 
3.4.2. 
 ............................................................21 
3.4.3. 
Benefit / Risk Assessment ..........................................................................................22 
3.5. 
REC-3964 Dose Justification .....................................................................................23 
4. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................24 
5. 
INVESTIGATIONAL PLAN .....................................................................................25 
5.1. 
Overall Study Plan ......................................................................................................25 
5.1.1. 
Screening Period .........................................................................................................26 
5.1.2. 
Treatment / Observation Period ..................................................................................26 
5.1.2.1. 
Early Discontinuation Visit ........................................................................................26 
5.1.3. 
Follow-up Period ........................................................................................................26 
5.1.3.1. 
Recurrence Visit .........................................................................................................27 
5.1.3.2. 
Safety Follow-Up Visit ...............................................................................................27 
5.1.3.3. 
Final Assessment Visit ...............................................................................................27 
5.2. 
Number of Participants ...............................................................................................27 
5.3. 
Treatment Assignments ..............................................................................................27 
6. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.....................................28 
6.1. 
Inclusion Criteria ........................................................................................................28 
6.2. 
Exclusion Criteria .......................................................................................................29 
6.3. 
Removal of Therapy ...................................................................................................31 

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6.4. 
Discontinuation / Withdrawal from Study ..................................................................31 
6.5. 
Study Termination ......................................................................................................32 
6.6. 
End of Study Definition ..............................................................................................33 
7. 
TREATMENT OF PARTICIPANTS .........................................................................34 
7.1. 
 ..........................................................................................34 
7.2. 
 ...........................................................................................34 
7.3. 
 ................................................................................................35 
7.4. 
Randomization and Blinding ......................................................................................35 
8. 
 ...........................................36 
8.1. 
 ..................................................................................................................36 
8.2. 
 ..........................................................................36 
8.3. 
 .....................................................................................................36 
8.4. 
 ..............................................................................................36 
8.5. 
Administration ............................................................................................................36 
8.6. 
Study Drug Accountability .........................................................................................37 
8.7. 
Study Drug Handling and Disposal ............................................................................37 
9. 
ASSESSMENT OF SAFETY .....................................................................................38 
9.1. 
Adverse and Serious Adverse Events .........................................................................38 
9.1.1. 
Adverse Event .............................................................................................................38 
9.1.2. 
Serious Adverse Event ................................................................................................39 
9.1.3. 
Clinically Significant Laboratory Findings ................................................................40 
9.2. 
Relationship to Study Drug ........................................................................................40 
9.3. 
Recording Adverse Events .........................................................................................40 
9.4. 
Reporting Serious Adverse Events .............................................................................42 
9.4.1. 
Reporting of SUSARs.................................................................................................43 
9.5. 
Pregnancies .................................................................................................................43 
9.6. 
Overdose .....................................................................................................................44 
9.7. 
Additional Safety Assessments...................................................................................44 
9.7.1. 
Vital Signs ..................................................................................................................44 
9.7.2. 
Physical Examination .................................................................................................44 
9.7.3. 
Electrocardiogram (ECG) ...........................................................................................44 
9.7.4. 
Clinical Laboratory Assessments ...............................................................................44 
10. 
ASSESSMENT OF EFFICACY ................................................................................46 

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10.1. 
Efficacy Assessments .................................................................................................46 
10.1.1. 
Survival without Recurrence or Additional Treatment ..............................................46 
10.1.2. 
Rate of Recurrence .....................................................................................................46 
10.1.3. 
Time to Recurrence .....................................................................................................46 
10.1.4. 
Proportion of Participants with Severe rCDI ..............................................................46 
10.1.5. 
rCDI-associated hospital admissions ..........................................................................46 
10.1.6. 
Evaluation of Diarrheal Episodes ...............................................................................46 
10.1.7. 
 ........................................................47 
10.1.8. 
 ...........................................47 
11. 
PHARMACOKINETIC ASSESSMENTS .................................................................48 
12. 
STATISTICAL METHODS .......................................................................................49 
12.1. 
Analysis Population ....................................................................................................49 
12.2. 
Statistical Analyses .....................................................................................................50 
12.2.1. 
General Consideration ................................................................................................50 
12.3. 
Efficacy Endpoints Analyses ......................................................................................50 
12.3.1. 
Primary Endpoint Analyses ........................................................................................50 
12.3.2. 
Secondary Endpoints Analyses ...................................................................................50 
12.3.3. 
Evaluation of Diarrheal Episodes ...............................................................................51 
12.3.4. 
 ................................................................................51 
12.3.4.1. 
 ...............................................................................51 
12.3.4.2. 
 .................................................................52 
12.4. 
Safety Endpoint Analyses ...........................................................................................52 
12.4.1. 
Adverse Events ...........................................................................................................52 
12.4.2. 
Clinical Laboratory, Vital Signs, Electrocardiograms, and Physical 
Examinations ..............................................................................................................52 
12.5. 
Statistical Analyses for Pharmacokinetic Data ...........................................................52 
12.5.1. 
Pharmacokinetic Evaluation .......................................................................................53 
12.6. 
Sample Size Evaluation ..............................................................................................53 
12.7. 
Interim Analyses .........................................................................................................53 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................54 
13.1. 
Case Report Form .......................................................................................................54 
13.2. 
Study Monitoring ........................................................................................................54 
13.3. 
Audits and Inspections ................................................................................................55 

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13.4. 
Institutional Review Board (IRB) ...............................................................................55 
13.5. 
Data Protection ...........................................................................................................56 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................57 
15. 
ETHICS ......................................................................................................................58 
15.1. 
Ethics Review .............................................................................................................58 
15.2. 
Ethical Conduct of the Study ......................................................................................58 
15.3. 
Written Informed Consent ..........................................................................................58 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................59 
16.1. 
Inspection of Records .................................................................................................59 
16.2. 
Retention of Records ..................................................................................................59 
17. 
PUBLICATION POLICY ..........................................................................................60 
18. 
LIST OF REFERENCES ............................................................................................61 
APPENDIX A. 
 ..............................................63 
APPENDIX B. 
 
 
...............................................................65 
 
 
 

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LIST OF TABLES 
Table 1: 
 ..............................................................................................9 
Table 2: 
..........22 
Table 3: 
Grading of Adverse Event Severity ............................................................................41 
Table 4: 
Laboratory Assessments .............................................................................................45 
Table 5: 
Analyses Population ...................................................................................................49 
Table 6: 
 ..........................................63 
Table 7: 
 ................................................................................................64 
Table 8: 
 .............................................................................65 
Table 9: 
 ...............................................................67 
Table 10: 
 ....................................................................................................68 
Table 11: 
 .......................................................................................................68 
Table 12: 
 ................................................................................69 
 
 

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LIST OF FIGURES 
Figure 1: 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABBREVIATION 
EXPLANATION 
AE 
Adverse event 
AUC 
Area under the curve 
AUCinf 
Area under the curve to infinity 
AUClast 
Area under the curve to the last timepoint measured 
BCRP 
Breast Cancer Resistance Protein 
BID 
twice a day 
C. difficile 
Clostridioides difficile 
Cmax 
Maximum Observed Plasma Concentration 
Ctrough 
Trough Plasma Concentration 
CA 
Competent authority 
CDI 
C. difficile infection 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECIS 
Electric Cell-substrate Impedance Sensing  
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOT 
End of Treatment 
ET 
Early Termination  
FDA 
Food and Drug Administration 
FMT 
Fecal Microbiota Transplantation 
GCP 
Good Clinical Practice 
GMR 
Geometric Mean Ratio 
IC 
Inclusion Criteria 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 

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ABBREVIATION 
EXPLANATION 
IL 
Interleukin 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
K-M 
Kaplan Meier  
ITT 
Intent-to-treat population 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
P-gp 
P-glycoprotein 
PBPK 
Physiologically-based Pharmacokinetic 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
 
 
PT 
Preferred Term 
QTcF 
Fridericia’s correction formula 
rCDI 
Recurrent Clostridioides Difficile Infection 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Assessments 
SOC 
System Organ Class 
TCdiffB 
C. difficile toxin B 
Tmax 
Time to Maximum Plasma Concentration 
TEAE 
Treatment-Emergent Adverse Event 
WBC 
White Blood Cell 
WOCBP 
Women of Childbearing Potential 
 
 
 
 

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3. 
INTRODUCTION 
Recursion Pharmaceuticals, Inc is proposing REC-3964 in this Investigational New Drug 
application for reduction of recurrent Clostridioides difficile (C. difficile) infections. 
3.1. 
Clostridioides Difficile Background 
C. difficile infection (CDI) is a worldwide disease affecting approximately half a million people 
in the United States and has been the leading cause of nosocomial infection and was responsible 
for 29,000 deaths in the United States in 2011 (Lessa, 2015). In North America, it is estimated 
that a cost of up to 4.8 billion dollars is associated with excess health care for CDI treatment 
(Lee, 2017; CDC, 2015) with endemic disease and outbreaks reported from all world regions 
including Asia, Western Pacific, Latin America, and Africa (Acuña-Amador, 2022; 
Rajabally, 2013; Chan, 2011; Ferguson, 2011; Camacho-Ortiz, 2009). 
C. difficile is a Gram-positive, anaerobic, bacillus in which pathogenic strains produce protein 
exotoxins. These cytotoxic, enterotoxin, and pro-inflammatory toxins induce colonic mucosal 
injury, diarrhea, and in severe cases, pseudomembranous colitis, colonic perforation, and/or toxic 
megacolon (Cole, 2015; Viswanathan, 2010; Pothoulakis, 2000). Although clinical overt 
infection from C. difficile requires both acquisition of the bacterium and disruption of the normal 
bacterial flora in the colon (Bagdasarian, 2015), most clinical and pathophysiological 
characteristics of CDI are related to C. difficile toxins. 
Often, CDI is precipitated by the use of antibiotics or other contributing factors 
(e.g., immunocompromised conditions), which affect normal gut flora and facilitate colonization 
by C. difficile spores in the gastrointestinal tract. The spores germinate in the gut after which 
C. difficile bacteria produce toxins that disrupt the normal architecture and function of the 
intestinal tract (Viswanathan, 2010). The main toxins produced by C. difficile are toxin A and 
toxin B which affect epithelial integrity via disruption of microtubules and cell-cell tight 
junctions, resulting in cytokine release such as interleukin (IL)-8 and other inflammatory factors 
(Bagdasarian, 2015; Pothoulakis, 2000). These actions promote pathogenic infiltration in the 
colonic mucosa, fluid shifts leading to diarrhea, and epithelial necrosis. Antibiotics alter normal 
microbiota, increasing CDI risk. Additional risk factors associated with the development of CDI 
include advanced age (>65 years), recent hospitalization, longer hospital duration, receipt of 
multiple antibiotics, longer antibiotic use duration, gastric acid suppression (e.g., with proton 
pump inhibitors), chemotherapy, chronic kidney disease, and the use of feeding-tubes 
(Cole, 2015; Viswanathan, 2010; Garey, 2008; Asha, 2006). 
3.2. 
Clostridioides Difficile Pathogenesis  
Rho family of guanosine triphosphatases has a pivotal role in cytoskeleton organization and 
rearrangements of intestinal cells. C. difficile mediate its pathogenicity via toxin-mediated 
glycosylation of the active form of the intracellular Rho GTPase. This leads to depolymerization 
of the actin cytoskeleton, followed by disruption of tight cellular junctions and ultimately results 
in apoptosis in colonic epithelial cells. 
REC-3964 is a novel chemical entity identified from Recursion’s unique artificial-intelligence 
platform. REC-3964 belongs to the diazepinedione chemical class and by inhibiting the C. 
difficile toxin effects on the glycosylation of the active form of the intracellular Rho GTPase, 

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prevents the disruption of cytoskeletal effects on the intestinal cells. REC-3964 has been 
formulated as an 
 active compound and has demonstrated antitoxin effects. REC-3964 
is expected to be effective in several forms of CDI including recurrent CDI (rCDI). 
3.3. 
Treatment of Clostridioides Difficile 
Several agents can be used for the treatment of CDI, including antibiotics such as vancomycin 
and fidaxomicin, while monoclonal antibodies such as bezlotoxumab, or fecal microbiota 
transplants can be used to prevent recurrent CDI (Lee, 2017; Mada, 2022). While current 
antibiotic treatments, such as vancomycin and fidaxomicin, provide symptomatic relief by killing 
C. difficile bacteria, C. difficile spores are not affected by such antibiotics and can quickly 
propagate into virulent toxin-producing bacteria after treatment discontinuation. A significant 
number of patients have frequent recurrence or reinfection, or inability to prevent the disease 
from advancing to a more debilitating condition (Smits, 2016). Indeed, primary recurrence of 
CDI (recurrence after initial treatment of CDI) is seen in 20% to 30% of patients, and up to 
45%--65% of these patients experience multiple recurrent episodes despite current available 
treatment (Kelly, 2010; Viswananthan, 2010; Kelly, 2012; Barbut, 2000). Recurrent CDI is 
associated with a 2.5-fold higher hospital readmission rate and a 33% higher mortality rate at 180 
days compared with primary CDI, thereby highlighting the critical need for additional effective 
treatments (Olsen, 2015A; Olsen, 2015B). 
Bezlotoxumab, a monoclonal antibody inhibitor to toxin B, reduced the rate of recurrence by 
14.2%, 14.2%, and 24.8% in individuals who have between 1, 2, and 3 risk factors for 
recurrence, respectively, such as patients who are 65 years or older, those who have severe CDI 
on presentation, those who are immunosuppressed, those who have a history of recurrent CDI 
within 6 months, and those with certain virulent ribotypes (ribotypes 027/078/244) (IDSA, 
2021). Bezlotoxumab injection has been discontinued as of January 31, 2025, according to the 
Food and Drug Administration (FDA) drug shortages tracker. Per guidance of Infectious 
Diseases Society of America (IDSA), fecal microbiota transplantation (FMT) is administered 
after initial cure with antibiotics to reduce the rate of recurrent CDI for patients with multiple 
recurrences of CDI who have failed appropriate antibiotics treatments. However, there are 
limitations of currently approved FMT treatments, including potential discomfort or difficulty 
with administration, possible transmission of pathogenic Escherichia coli from donor to FMT 
recipients, limited accessibility and gastrointestinal side effects, etc.. Given some of these 
limitations and the morbidity and mortality of recurrent Clostridioides difficile infection (rCDI), 
there is a significant unmet medical need for a highly effective, oral, toxin inhibitor that can be 
conveniently administered after initial cure with antibiotics to reduce the rate of recurrent CDI. 
3.4. 
 
3.4.1. 
 
 
 
 
 
 
 

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. 
3.4.2. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  

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Table 2: 
 
 
 
 
 
 
 
 
 
 
 
 
3.4.3. 
Benefit / Risk Assessment 
Both in vitro and in vivo nonclinical studies have been conducted to document the efficacy of 
REC-3964 to inhibit the effects of TCdiffB. Primary in vitro pharmacology studies conducted 
with REC-3964 demonstrate that it is a potent, effective inhibitor of the uridine 
diphosphate-glucose hydrolysis activity of TCdiffB in cell-free assays. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  

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Overall, it is considered that the potential benefit to patients, knowledge, and safety information 
derived from further investigation outweighs the potential risks derived from REC-3964 
administration and provides ample support for a positive benefit-risk assessment. 
3.5. 
 REC-3964 Dose Justification 
 
 
 
 
 
 
 
 
 
 
Participants in this study will receive REC-3964 for 
 after the end of initial curative 
treatment defined in Inclusion Criteria (IC) 6.1.4. REC-3964 is intended as a treatment to reduce 
the CDI recurrence rate by protecting the endothelial barrier from TCdiffB during recovery 
following antimicrobial treatment for CDI. REC-3964 was safe and well tolerated in healthy 
volunteers for multiple doses 
 and is not expected to impair the recolonization 
of the healthy enteric microbiota. A 
 regimen is expected to safely maximize the ability of 
REC-3964 to inhibit TCdiffB during the Follow-up Period. Additionally, since the risk of CDI 
recurrence is highest in the month following curative treatment (Feuerstadt, 2020), a 
 
regimen provides adequate coverage to help mitigate the heightened risk of recurrence during 
this critical period. 
 

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4. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
Efficacy of REC-3964 
• Survival without recurrence or requirement for 
additional CDI treatment for at least eight weeks 
following cure of preceding CDI with initial curative 
treatment defined in IC 6.1.4. Recurrent CDI is 
defined as a new episode of CDI associated with a 
new positive C. difficile stool toxin or requirement 
for additional CDI treatment during the 8-week 
Follow-up Period after cure of preceding CDI with 
initial curative treatment. 
Safety and Tolerability 
• Number, severity, and relatedness of adverse events 
(AEs), serious adverse events (SAEs), AEs leading to 
study drug discontinuation. 
Secondary 
 
Efficacy of REC-3964 
• Rate of rCDI 
• Time to recurrence 
• Proportion of participants with severe rCDI (severe 
CDI is defined as CDI with white blood cell count 
>15,000 cells/mL and/or serum creatinine 
≥1.5 mg/dL.) 
• rCDI-associated hospital admissions 
• Evaluation of diarrheal episodes (e.g., number of 
unformed bowel movements per day)  
Pharmacokinetics 
• Plasma concentrations of REC-3964  
• Plasma PK parameters including, but not limited to, 
maximum observed plasma concentration (Cmax), 
time to maximum plasma concentration (Tmax), and 
trough plasma concentration (Ctrough) 
Exploratory 
 
 
 
 
 
 

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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Study Plan 
This Phase 2, open-label, multi-center study is designed to characterize the safety, tolerability, 
PK, and efficacy of REC-3964 doses of 
 
 for the reduction of rCDI following 
cure of preceding CDI with treatment defined in IC 6.1.4. The study will enroll male and female 
participants who are 18 years of age or older. 
The study will consist of three periods: 
• Screening 
  
• Treatment / Observation Period 
 
• Follow-up Period 
 
Screening Period 
During the Screening Period 
 participants will undergo 
assessments as described in the Schedule of Assessments (Table 1) to ensure they meet the 
enrollment criteria of the study. Medical history will be reviewed, including a detailed review of 
the participant’s C. difficile history. 
Treatment / Observation Period 
Approximately 80 participants who have met the enrollment criteria will be randomized in the 
study and dosed 
 
. 
Follow-up Period 
Participants will be 
 
 after cure of preceding CDI with initial treatment. 
An overview of the study design is presented in Figure 1.  
 
 

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5.1.1. 
Screening Period 
During the Screening Period 
 participants will undergo assessments as 
described in the Schedule of Assessments (Table 1) to ensure they meet the Inclusion and 
Exclusion Criteria of the study. Medical history will be reviewed, including a detailed review of 
the participant’s C. difficile history. In addition, a pre-vancomycin (or pre-fidaxomicin treatment 
fecal sample will be collected, if possible, and analyzed for C. difficile toxins, gut bile acid 
composition, microbiome, and an antibiotic resistance gene profile. Review of stool sample 
reports, including analysis of C. difficile toxin, will also be performed if available.  
Individual assessments can be repeated once within the designated Screening Period window, 
and re-screening is possible with Sponsor approval in a circumstance for example, when a 
subject’s Screening Period has elapsed.  
5.1.2. 
Treatment / Observation Period 
Approximately 80 participants who have met the enrollment criteria will be randomized in the 
study. 
Participants will be stratified on prior antibiotic use (fidaxomicin versus vancomycin). Within 
each stratum participants are randomized 1:2:1 to receive REC-3964 
 or REC-3964 
 or observation, respectively, during the 
 Treatment Period of the study. 
Assessments to be performed during the Treatment Period are presented Table 1. 
The duration of REC-3964 dose in treatment period is planned for 
. However, the 
treatment period may vary if participants discontinue the study drug due to recurrence or other 
reasons. In such cases, the treatment period will be shorter than 
. Should two or more 
participants experience treatment-related ≥G3 AEs in the same cohort, further enrollment in the 
cohort will be discontinued. 
5.1.2.1. 
Early Discontinuation Visit  
The Early Discontinuation Visit is required for all participants assigned to REC-3964 who 
discontinue study drug for reasons other than recurrence prior to the end of their 
 
treatment cycle (Table 1). Participants in REC-3964 cohorts discontinued during the Treatment 
Period will be followed for 
 additional days for AEs, concomitant medications, and diarrheal 
symptoms (via stool diaries). 
Should a participant assigned to REC-3964 discontinue during their 
 treatment cycle due 
to recurrence, the Recurrence Visit should be performed in lieu of the Early Discontinuation 
Visit. 
5.1.3. 
Follow-up Period 
After completing the 
 Treatment / Observation Period, all participants who have not 
experienced recurrence will be followed for an additional 
 of observation to assess safety 
and tolerability, and recurrence. Participants who have recurrence shall participate in a 
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5.1.3.1. 
Recurrence Visit  
The Recurrence Visit is required for all participants who experience a recurrence of CDI during 
the study (Table 1). While the requirement for hospitalization for rCDI will be made per the 
discretion of the Investigator, all visit specific procedures will need to be performed. Participants 
in REC-3-964 cohorts who recur during the Treatment Period will be discontinued from 
treatment with REC-3964 and will be followed for 
 additional days for AEs and concomitant 
medications. For participants in the Observation cohort, the Recurrence Visit will be the last 
study visit. 
5.1.3.2. 
Safety Follow-Up Visit  
The Safety Follow-Up Visit is required for all participants assigned to REC-3964 who 
discontinue study drug prior to the completion of their 
 treatment cycle (Table 1). This 
Safety Follow-Up Visit should occur 
 after the cessation of study drug. 
5.1.3.3. 
Final Assessment Visit 
The Final Assessment Visit will be performed for all participants approximately 8 weeks 
following the cure of their preceding CDI with initial curative treatment defined in IC 6.1.4. 
(Table 1). The purpose of this visit is to assess safety for participants assigned to treatment with 
REC-3964 who complete their full 
 treatment course and to assess recurrence of all trial 
participants who do not experience recurrence prior to and including this visit. 
5.2. 
 Number of Participants 
Approximately 80 participants 
 
 will be enrolled. 
5.3. 
Treatment Assignments 
Participants will be randomized 1:2:1 to receive 
: REC-3964 
 
(N=20) or REC-3964 
 (N=40) or observation (N=20) within strata of prior 
antibiotic use (vancomycin or fidaxomicin), during the 
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6. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
6.1. 
Inclusion Criteria 
To be enrolled, the participant must provide informed consent and meet ALL of the following 
criteria at the time of enrollment: 
1. Be 18 years of age or older 
2. Have CDI diarrhea, defined as 3 or more unformed stools (types 5-7 on the Bristol stool 
scale) per day for at least 2 consecutive days AND 
3. Confirmed lab diagnosis through positive stool test for C. difficile toxin[s] prior to the 
preceding curative treatment 
4. The CDI episode, severe of otherwise, must have resolved (two or less unformed stools 
for at least 24 hours) after receiving a standard duration of vancomycin (or fidaxomicin) 
treatment for 10 – 14 days (+ 2 days). The standard initial curative treatment is 
vancomycin. Fidaxomicin is an optional alternative and may be chosen if deemed 
appropriate by the investigator, taking into account the participant’s condition, treatment 
history, and other relevant clinical factors. The participant must be randomized within 2 
days of completing the preceding curative treatment.  
5. Have high risk for rCDI, defined as any of the following: 
• having had at least one prior CDI episode within the last 6 months 
• age ≥65 years 
• immunocompromised state 
• severe CDI with resolution prior to enrollment into the study 
NOTE: Severe CDI is defined as CDI with white blood cell count >15,000 cells/mL 
and/or serum creatinine ≥1.5 mg/dL. Severe CDI must have resolved prior to 
enrollment into the study. 
6. Females must not be pregnant or lactating and either of non-childbearing potential 
(defined as having undergone surgical sterilization or being postmenopausal [i.e., greater 
than 40 years old with amenorrhea for at least 12 months prior to screening with follicle 
stimulating hormone (FSH) levels in the laboratory defined post-menopausal range])  
OR 
Using at least one of the following acceptable methods of contraception during the study 
and for up to 90 days after the last administration of study drug: 
a. Double-barrier method (e.g., condom plus spermicide, condom plus diaphragm with 
spermicide) 
b. Stable use of hormonal contraceptive treatment  
c. Intrauterine Device (IUD) 
d. Monogamous relationship with a vasectomized partner 

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e. Abstinence for 8 weeks prior to and throughout the study 
7. Men who are sexually active must use at least one of the following forms of medically 
acceptable birth control during the study drug Treatment Period and for 90 days after the 
last administration of study drug: 
a. Vasectomy with medical assessment of surgical success 
b. Consistent use of a condom with partner also using either stable hormonal 
contraceptive or IUD.  
Sperm donation is prohibited during the study and for up to 90 days after the last 
administration of study drug. 
8. Have NOT participated in a clinical study utilizing an investigational agent within 28 days 
or within 5 half-lives (if known) of the investigational drug (whichever is longer) prior to 
Day 1. 
9. Acceptable laboratory parameters: 
• Hemoglobin ≥8.0g/dL 
• Platelet count ≥100,000/µL 
• Absolute neutrophil count ≥500 cells/mm3 
6.2. 
 Exclusion Criteria 
To participate, the participant must meet NONE of the following at the time of enrollment: 
1. Have an active, symptomatic, chronic diarrheal illness from other causes, such as 
ulcerative colitis or Crohn’s disease. 
2. Have a life expectancy of less than 90 days. 
3. Have surgery planned to manage severe CDI colitis during the study period. 
4. Have liver dysfunction or active liver disease as defined by: 
• AST / ALT >2x ULN 
• Total bilirubin >2mg/dL 
5. Have estimated glomerular filtration rate <60ml/min/1.73m2, active renal disease or have 
previously received a kidney transplant. 
6. Have a history of alcohol or substance abuse within 1 year prior to screening for study 
participation, or is currently using alcohol, drugs of abuse, or any prescribed or 
over -the -counter medication in a manner, which, in the opinion of the Investigator, 
indicates abuse. 
7. Severe or uncontrolled intercurrent illness or clinically significant unrelated systemic 
illness that, in the opinion of the Investigator, could compromise participation in or the 
interpretation of the study or put the participant at risk. 

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8. Diarrhea that requires on-study treatment with agents that would confound the 
interpretation of the study results, including, but not limited to: bezlotoxumab, FMT, 
rifaximicin, nitazoxanide, loperamide, diphenoxylate/atropine, or cholestyramine.  
NOTE: bezlotoxumab and FMT use during the current episode is exclusionary whereas 
administration of rifaximicin, nitazoxanide, loperamide, diphenoxylate/atropine, or 
cholestyramine would be prohibited from Screening until the Safety Follow-up Visit.  
9. Diarrhea attributable to other enteropathogens identified laboratory evaluation such as 
stool cultures or gastrointestinal panel, including but not limited to, Salmonella, Shigella, 
and Campylobacter at the point of enrollment.  
10. Known stool studies positive for ova and/or parasites at the point of enrollment.  
11. 
 
 
 
  
12. 
 
 
 
 
13. 
 
 
 
 
 
 
 
 
14. Chronic or recent use of laxatives, or gastric anti-motility agents, such as loperamide. 
15. Have fulminant CDI. 
16. Immunocompromised participants with: 
• Uncontrolled infection with human immunodeficiency virus (HIV). Participants on 
stable highly active antiretroviral therapy with undetectable viral load and normal 
CD4 counts for at least six months prior to study entry are eligible. Serological testing 
for HIV at screening is not required. 
• Known to be positive for hepatitis B virus (HBV) surface antigen, or any other 
positive test for hepatitis B indicating acute or chronic infection. Participants who are 
or have received anti-HBV therapy and have undetectable HBV DNA for at least six 
months prior to study entry are eligible. Serological testing for HBV at screening is 
not required. 
• Known active hepatitis C virus (HCV) as determined by positive serology and 
confirmed by polymerase chain reaction (PCR). Participants on or having received 

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antiviral therapy are eligible provided they are virus-free by PCR for at least six 
months prior to study entry. Serological testing for HCV at screening is not required.  
• Known active or latent tuberculosis (testing at screening not required). 
6.3. 
Removal of Therapy  
Study medication may be discontinued at the discretion of the Investigator in consultation with 
the participant in the following instances:  
• Unacceptable AEs or toxicity, as defined in Section 9 of the protocol, or toxicity that, 
in the judgment of the Investigator, compromises the ability to continue 
study-specific procedures or is considered to not be in the participant’s best interest  
• Participant’s request to discontinue for any reason  
• Participant’s non-compliance  
• Pregnancy during the study  
• Dosing is interrupted for more than 7 days for any reason  
The reason for study medication discontinuation must be documented. In the case of 
discontinuation due to an AE, SAE, or laboratory toxicity, the event that led to discontinuation 
must be specified and recorded on the AE electronic case report form (eCRF). 
6.4. 
Discontinuation / Withdrawal from Study 
Participants considering withdrawing from the study should be informed that they can 
discontinue treatment or withdraw from the study at any time without having to justify the reason 
for doing so and without jeopardizing their future medical care by the physician or institution. 
Participants must be discontinued from study treatment and withdrawn from the study under the 
following circumstances:  
• Participant or participant’s legally authorized representative requests discontinuation 
from the study  
• Investigator advises that the participants safety and/or well-being could be 
compromised by further participation  
• A treatment-related AE ≥Grade 3 
• Sponsor request, for example, due to suspicion of fraud, multiple enrollments in 
clinical studies, lack of compliance  
In all cases, prior to the Investigator discontinuing the participant from the study, the Investigator 
should confer with the Sponsor or Medical Monitor. 
If a participant withdraws, or is withdrawn, from the study, the principal reason leading to the 
decision for withdrawal must be recorded in the appropriate section of the eCRF. The reasons for 
withdrawal from the study will be coded as:  
• AE (serious or non-serious; related or unrelated to study procedures / medication, as 
assessed by the Investigator)  

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• Disease progression or lack of efficacy  
• Non-compliance (participant fails to comply with protocol requirements)  
• Withdrawal of consent by participant  
• Lost to follow-up  
• Discretion of Investigator (the Investigator determines that continuation in the study 
would be detrimental to a participant’s well-being)  
• Discretion of Sponsor  
• Female participant becomes pregnant  
• Other (specify) 
For participants withdrawing due to AE(s), the Investigator should review the potential 
relationship of the AE to the study/study medication and record their assessment on the eCRF. If 
a participant withdraws due to an AE, the AE should be followed as described Section 9. 
All participants who discontinue treatment early for reasons other than recurrence will attend the 
early discontinuation visit. Participants assigned to study drug will also need to complete the 
Post-treatment Follow-up Visit which will be 
 after the last dose of REC-3964 and the 
Final Assessment Visit (see Table 1). 
6.5. 
Study Termination 
The study may also be terminated at the discretion of the Sponsor for any reason at any time. In 
addition, for reasonable cause, either the Investigator or the IRB/IEC may terminate the study at 
their center.  
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to:  
• Administrative decision by the Investigator (closure at a specific site) 
• New toxicological or pharmacological findings or safety issues that alter the 
risk-benefit assessment 
• Participant or Investigator noncompliance  
• Unsatisfactory participant enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Decision by the Sponsor to discontinue development of REC-3964 or modify the plan 
for its development 
• Decision by a regulatory authority 
• Local discontinuation of the study within a territory or at a specific site at the request 
of an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 

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6.6. 
End of Study Definition 
The end of the study is defined as the date of the last participant’s Final Assessment Visit, 
conducted approximately eight weeks following the cessation of initial curative treatment 
defined in IC 6.1.4. (unless superseded by a Recurrence Visit and subsequent Safety Follow-Up 
Visit). The study may be terminated at individual sites or in its entirety per the criteria listed in 
Section 6.5. The Investigator will be informed of additional procedures necessary to ensure the 
protection of participants’ interests. 
A participant is considered to have completed the study if he/she has completed all study visits 
per protocol as shown in the SoA (Table 1). 
 
 

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7. 
TREATMENT OF PARTICIPANTS 
7.1. 
 
 
 
  
 
 
7.2. 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.3. 
 
 
 
7.4. 
Randomization and Blinding 
Participants will be stratified on prior antibiotic use (fidaxomicin versus vancomycin). Within 
each stratum participants are randomized 1:2:1 to receive REC-3964 
 or REC-3964 
 or observation, respectively. The specific arm assigned will be done by IRT. The 
study is open-label and is unblinded.  
 

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8. 
 
8.1. 
 
 
 
 
 
  
 
 
 
  
8.2. 
 
 
 
8.3. 
 
 
 
 
 
 
8.4. 
  
 
 
8.5. 
Administration 
Randomized participants will receive their first 
 dose of study drug at the investigative site 
on Day 1. Participants will maintain 
 dosing with study drug throughout the Treatment 
Period, taking the drug at approximately the same time in the morning and the evening. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8.6. 
Study Drug Accountability 
The Investigator is responsible for the control of the study drug under investigation. Adequate 
records of the receipt and disposition of the study drug must be maintained as directed by the 
Sponsor. All records and study drug supplies must be available for inspection by the monitor at 
every monitoring visit. 
8.7. 
Study Drug Handling and Disposal 
Unused study drug will be returned to the clinical depot or will be locally destroyed according to 
the study site procedures and as per the study Pharmacy Manual. The completed Drug 
Dispensing Log and Drug Return Record(s) will be returned to the Sponsor. The Investigator’s 
copy of the Drug Return Record(s) must accurately document the return of all study drug 
supplies to the Sponsor, if applicable. 

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9. 
ASSESSMENT OF SAFETY 
9.1. 
Adverse and Serious Adverse Events  
9.1.1. 
Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. In clinical studies, an AE can include 
an undesirable medical condition occurring at any time, including baseline or safety Follow-up 
Periods, even if no study treatment has been administered. 
All AEs that occur after any participant has signed the full-study informed consent, before 
treatment, during treatment, or within 
 following the cessation of treatment, whether or 
not they are related to the study, must be recorded on forms provided by the Sponsor. AEs 
occurring in patients randomized to observation will be recorded up to 
 after the patient’s 
last day in the observation arm. 
This includes events that occur after obtaining consent and throughout the duration of the study, 
including the follow-up off-study medication period. For example,  
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedures (e.g., invasive procedures such as venipuncture) during or after screening 
(before the administration of study drug) 
• Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study drug phase of a human clinical study, will also be considered an 
AE. 
The following are not considered AEs: 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the Screening Visit is not an AE; it is considered to be pre-existing and should be 
documented on the medical history eCRF 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; the condition that leads to the procedure or the complication that occurs as a 
result of the procedure is an AE 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for planned elective surgery, social and / or convenience admissions for example, a 
pre-existing condition that is deemed clinically stable.) 
• An overdose without clinical sequelae 
For this protocol, an overdose is administration of study drug in an amount in excess of that 
intended for the participant according to this protocol. There is no information regarding 
overdose with REC-3964. Any overdose, with or without associated AEs, must be promptly 
communicated to the Medical Monitor. The overdose event does not need to be recorded as an 
AE in the eCRF. If an AE is associated with the overdose, the AE should be recorded on the 
relevant AE/SAE sections in the eCRF.  

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• Pre-treatment emergent AEs will be those recorded after the full-study informed consent is 
signed up to the time of the first administration of study drug. 
• Treatment-emergent adverse events (TEAEs) will be those recorded from the time of the 
first administration of study drug to the last dose of study drug taken by the participant 
during this study. 
• Post-treatment emergent AEs will be those recorded from the last dose of study drug taken 
by the participant through the last study-associated visit, end of the study, or early 
termination. 
All participants who receive at least one dose of study drug will be included in the analyses of 
safety. 
9.1.2. 
Serious Adverse Event 
A SAE is an AE occurring during any study phase (i.e., Screening, Treatment, or Follow-up 
Periods), and at any dose of the study drug that fulfills one or more of the following: 
• Results in death. The cause of death is the AE; death is an outcome, not the AE. 
• It is immediately life-threatening. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe 
• It requires in-participant hospitalization or prolongation of existing hospitalization. 
Hospitalization refers to an admission to the facility, not simply the amount of time that 
the participant may have been in the emergency department (rehospitalizations for the 
same AE within one week of discharge will not be considered as a new admission) 
• Results in persistent or significant disability or incapacity in conducting activities of daily 
living for at least 
 
• Results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the participant or may require medical 
intervention to prevent one of the outcomes listed above 
All SAEs that occur after any participant signed consent, before treatment, during treatment, or 
within 
 following the cessation of treatment, whether or not they are related to the study 
must be recorded on forms provided by the Sponsor. 
If clinical site personnel become aware of an event fulfilling the criteria of an SAE, the 
Investigator or clinical site personnel must notify Recursion Pharmacovigilance within 24 hours, 
regardless of assessment of relationship to the study drug. The site should report SAEs via the 
AE eCRF in the electronic data capture system (EDC) AND email a completed SAE report form 
to Recursion Pharmacovigilance at safety@recursionpharma.com within 24 hours of awareness. 
In addition, notification must be provided by the Investigator to the Institutional Review Board 
(IRB). 
Recursion is responsible for notifying the relevant regulatory authorities of certain events. It is 
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Investigators will also be notified of all unexpected, serious, drug-related events (7/15 Day 
Safety Reports) that occur during the clinical study. Each site is responsible for notifying its IRB 
or Independent Ethics Committee (IEC) of these SAEs. 
9.1.3. 
Clinically Significant Laboratory Findings 
Any clinically relevant deterioration in laboratory assessments or other clinical findings is 
considered an AE. In addition, an abnormal test finding will be classified as an AE if one or 
more of the following criteria are met: 
• The test finding is accompanied by clinical symptoms 
• The test finding necessitates additional diagnostic evaluations or medical / surgical 
intervention, including significant additional concomitant drug treatment or other drug. 
Note: Simply repeating a test finding, in the absence of any of the other listed criteria does 
not constitute an AE 
• The test finding leads to a change in study drug dosing or discontinuation of the 
participant in the clinical research study 
• The test finding is considered clinically significant by the Investigator based on his / her 
medical judgment. If an abnormal laboratory result is recorded as an AE, then the 
corresponding laboratory value must be marked clinically significant in the database. 
Similarly, if an abnormal laboratory value is marked clinically significant in the database, 
there should be a corresponding AE entered. 
In case of unexplained or unexpected clinical laboratory test values, the tests will be repeated as 
soon as possible and followed up until the results have returned to the normal range and/or an 
adequate explanation for the abnormality is found. The clinical laboratory will clearly mark all 
laboratory test values that are outside the normal range and the Investigator will indicate which 
of these deviations after treatment are clinically significant. These clinically significant deviating 
laboratory results will then be recorded as AEs and the relationship to the treatment will be 
indicated. 
9.2. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
study drug for each AE (unrelated or related). The Investigator should decide whether, in his or 
her medical judgment, there is a reasonable biological possibility that the event may have been 
caused by the study drug. If no valid reason exists for suggesting a relationship, then the AE 
should be classified as “not related.” If there is a valid biological basis for asserting that a causal 
relationship is present, then the AE should be considered “related.” 
9.3. 
Recording Adverse Events 
All AEs spontaneously reported by the participant and / or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic procedures 
will be recorded on the Adverse Event eCRF for that visit. All participants will be queried, using 
non-leading questions, about the occurrence of AEs at each study visit and throughout the study. 

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When possible, a constellation of signs and/or symptoms should be identified as 1 overall event 
or diagnosis. All AEs for randomized participants will be recorded in the eCRF and the 
participant's source documents. The following data should be documented for each AE: 
• Description of the event 
• Classification of "serious" or "not serious" 
• Date of first occurrence and date of resolution (if applicable) 
• Severity 
• Causal relationship to study drug 
• Action taken 
• Outcome  
• Concomitant medication or other treatment given. 
Abnormal laboratory values that constitute an AE or lead to discontinuation of administration of 
study drug must be reported and recorded as an AE. Information about AEs and SAEs will be 
collected from signing of consent form until 
 after the participant has received their last 
dose of study drug. The AE term should be reported using standard medical terminology when 
possible. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified. However, if an observed or reported sign or symptom is not 
considered a component of a specific disease or syndrome by the Investigator, it should be 
recorded as a separate AE. Clinical syndromes associated with laboratory abnormalities are to be 
recorded as appropriate (e.g., diabetes mellitus rather than hyperglycemia). 
For each AE, the Investigator will evaluate and report the onset (date), resolution (date), 
intensity, causality, action taken, serious outcome (if applicable), and whether or not it caused 
the participant to discontinue the study or study treatment. 
Table 3: 
Grading of Adverse Event Severity 
Classification 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living 
Grade 4 
Life-threatening consequences: urgent intervention required 
Grade 5 
Death related to an adverse event 
General rules for the grading of AEs are found in Table 3. Investigators seeking further guidance 
on the assessment of intensity may consult the CTCAE, v 5.0 (information, including a 
searchable spreadsheet) can be found at 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50.  

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It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 9.1.2. An AE of severe intensity may 
not be considered serious, and a mild AE that resulted in a hospitalization, for instance, is always 
considered serious as it meets at least one of the criteria given in Section 9.1.2 as constituting an 
SAE. 
9.4. 
Reporting Serious Adverse Events 
All SAEs (and AESIs, if specified) that occur after any participant signed consent, before 
treatment, during treatment, or within 
 following the cessation of treatment, whether or 
not they are related to the study must be recorded. Any SAEs or AESIs (if specified) considered 
related to the investigational product and discovered by the Investigator at any time after the 
study should also be reported to Recursion.  
All SAEs/AESIs must be reported to Recursion within 24 hours of the first awareness of the 
event by entering all known information into the electronic clinical database. If not entered into 
the database within the first 24 hours of awareness, the Investigator must complete, sign and date 
an SAE Report Form, verify the accuracy of the information recorded and email Recursion at 
safety@recursionpharma.com. The information must then be entered into the electronic clinical 
database as soon as possible. Should the SAE be entered into the database within the first 
24 hours of awareness, the SAE will be automatically reported, and a paper SAE form will not 
be required. 
Additional follow-up information, if required or available, must be sent to the Sponsor by 
entering all follow-up information into the electronic clinical database. If not entered into the 
database within the first 24 hours of awareness, the Investigator must complete, sign and date a 
follow-up SAE Report Form, verify the accuracy of the information recorded and email 
Recursion at safety@recursionpharma.com. The information must then be entered into the 
electronic clinical database as soon as possible. Should the follow-up information be entered into 
the database within the first 24 hours of awareness, the SAE will be automatically reported, and a 
paper SAE form will not be required. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up. 
The original documentation must be maintained by the study site with the participant’s study 
records. 
It is the Investigator’s responsibility to obtain, and redact of personal identifying information, 
any hospital discharge summaries, death certificates, autopsy reports, or birth certificates 
associated with any SAEs developing in a participant (or, in the case of pregnancy, a 
participant’s partner) in this study. Such documents should be submitted to the Sponsor as soon 
as possible when the Investigator has access to a copy of the document. 
The Sponsor is responsible for notifying the relevant regulatory authorities of certain events 
(SUSARs, etc.). It is the Principal Investigator’s responsibility to notify the IRB or IEC of all 
SAEs that occur at his or her site. Investigators will also be notified of all unexpected, serious, 
drug-related events (7 / 15 Day Safety Reports) that occur during this clinical study and in other 
clinical studies using the same IMP (REC-3964). Each site is responsible for notifying its IRB or 
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9.4.1. 
Reporting of SUSARs 
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the Competent 
authority (CA), EC and the European Medicines Agency EudraVigilance database as required. 
Also, the investigators must be informed. The following timelines should be followed: 
• The Sponsor will ensure that all relevant information about SUSARs that are fatal or 
life-threatening is recorded and reported as soon as possible to the CA concerned, the EC 
concerned and the EudraVigilance database but no later than seven days after first 
knowledge by the Sponsor. The sponsor shall submit a completed report within an 
additional eight days. 
• All other SUSARs will be reported to the CA concerned, the EC concerned and the 
EudraVigilance database as soon as possible but no later than 15 days of first knowledge 
by the Sponsor and updated as soon as possible. 
9.5. 
Pregnancies 
Investigators must record and report pregnancies occurring in either a study participant or the 
partner of a study participant within 24 hours of becoming aware of the pregnancy. A Pregnancy 
Reporting Form should be completed by the Investigator / Designee, dated, signed, and emailed 
to Recursion. Pregnancy in itself is not regarded as an AE unless there is a suspicion that a study 
drug may have interfered with the effectiveness of a contraceptive medication. 
Participants who become pregnant while on study should immediately cease using study drug. 
The participant should be monitored throughout the pregnancy up to its conclusion. If the 
pregnancy results in a live birth, the Investigator should report the results of the pregnancy on the 
Pregnancy Reporting Form. The infant should be followed (telephone follow-up is sufficient) for 
two months to ascertain any congenital anomalies. Any congenital anomalies and pregnancy 
conclusion other than a live infant should be reported using the SAE Report Form within 
24 hours of the Investigator’s learning of the information. Any delivery that is other than an 
unassisted (by a health care professional) vaginal one should also be reported as an SAE within 
24 hours of the Investigator learnings of the information with the event being whatever condition 
necessitated either a cesarian section or other operative (e.g., forceps) delivery.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the participant was 
discontinued from the study unless and until the participant has withdrawn informed consent. 
All reports of congenital abnormalities / birth defects are SAEs. Spontaneous miscarriages are 
also SAEs and should also be reported as such. 
The Investigator should obtain a copy of any vital statistics document filed at the conclusion of 
the pregnancy (e.g., birth certificate) and, if circumstances warranted, an autopsy report of the 
stillbirth or the deceased infant, redacted of personal identifying details.  
If during the pregnancy, the pregnant woman was hospitalized, unless the hospitalization had 
been planned prior to enrollment in the study, the Investigator should obtain and send to 
Recursion a copy of the redacted hospital discharge summary. At the conclusion of the 
pregnancy, the Investigator should obtain a copy of the discharge summary from the hospital or 
birthing center at which the delivery took place and send a redacted copy of it to Recursion. 

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Male participants with partners who become pregnant.  
The Investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study.  
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. The investigator should 
follow-up with the participant regarding any congenital anomalies diagnosed at 2 months 
following the birth of the child. Any termination of the pregnancy will be reported including fetal 
status (presence or absence of anomalies) and indication for the procedure. 
9.6. 
Overdose 
An overdose is defined for this study as any administration of study drug in an amount in excess 
of that intended according to this protocol. In-and-of-itself, an overdose is not an adverse event 
(an exception being an intentional overdose); any clinical development resulting from an 
overdose, however, is an adverse event and should be reported by the Investigator accordingly. 
Should an overdose occur, the Investigator should contact the Medical Monitor as soon as 
possible using the contact information provided on the cover sheet of this protocol. 
9.7. 
Additional Safety Assessments 
9.7.1. 
Vital Signs 
Vital signs including temperature, respiratory rate, heart rate, and blood pressure will be 
collected as outlined in the SOA (Table 1). Where applicable, vital signs will be collected 
pre-dose. 
9.7.2. 
Physical Examination  
A full physical examination is required 
. For 
all other time points, an abbreviated PE (limited to organ systems based on presenting clinical 
signs and symptoms) is sufficient. 
9.7.3. 
Electrocardiogram (ECG) 
All standard digital single 12-lead ECGs will be performed during Screening. Heart rate, PR 
duration, QRS duration, QT duration, QTcF (Fridericia’s correction), and the investigator’s 
overall interpretation will be recorded in the eCRF. 
9.7.4. 
Clinical Laboratory Assessments 
Local laboratory testing will be used in this study. Screening Period labs will be used for 
eligibility assessments according to the inclusion and exclusion criteria. Further assessments will 
be made as specified in Table 1. The full testing panel to be carried out by sites is presented in 
Table 4. The Sponsor must be notified of any exceptions due to local testing restrictions to 
ensure safety assessment is not jeopardized. 
 
 

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Table 4: 
Laboratory Assessments 
Hematology 
Serum Chemistry 
Urinalysis (dipstick) 
• 
hemoglobin  
• 
hematocrit  
• 
reticulocytes  
• 
platelets  
• 
erythrocytes  
• 
leukocytes  
• 
neutrophils  
• 
lymphocytes  
• 
monocytes  
• 
eosinophils  
• 
basophils  
• 
albumin  
• 
amylase  
• 
alkaline 
phosphatase  
• 
ALT  
• 
AST  
• 
bicarbonate  
• 
BUN / Urea  
• 
calcium  
• 
chloride  
• 
CPK  
• 
creatinine  
• 
GGT  
• 
glucose 
(random)  
• 
magnesium 
• 
phosphorous  
• 
potassium  
• 
sodium  
• 
total bilirubin  
• 
total protein  
• 
appearance  
• 
color  
• 
ketones  
• 
leukocytes  
• 
protein  
• 
glucose  
• 
bilirubin  
• 
urobilinogen  
• 
occult blood (microscopic 
examination of sediment 
will be performed per the 
discretion of the 
Investigator)  
Coagulation 
• 
INR  
• 
APTT  
 
 
 

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10. 
ASSESSMENT OF EFFICACY 
Efficacy assessments will be conducted as specified in the SOAs (Table 1). Efficacy endpoints of 
the study are listed in Section 4. 
10.1. 
Efficacy Assessments 
10.1.1. 
Survival without Recurrence or Additional Treatment 
The primary efficacy endpoint is survival without recurrence or requirement for additional CDI 
treatment for at least eight weeks following the cure of preceding CDI with initial curative 
treatment defined in IC 6.1.4. (see also Section 12.3.1). Recurrent CDI is defined as a new 
episode of CDI associated with a new positive C. difficile stool toxin or requirement for 
additional CDI treatment within 8 weeks of the cessation of initial curative treatment defined in 
IC 6.1.4. All new episodes of diarrhea will be tested for toxigenic C. difficile to confirm CDI 
recurrence. The primary efficacy endpoint will be analyzed as the rate of recurrent C. difficile 
infection or requirement of additional CDI treatment for at least 8 weeks, upon resolution of the 
initial preceding CDI diarrheal episode with vancomycin or fidaxomicin. 
 
10.1.2. 
Rate of Recurrence  
The rate of recurrence of CDI associated with a new positive C. difficile stool toxin after 
treatment with REC-3964 or observation will be evaluated for participants who have rCDI 
during the study. 
10.1.3. 
Time to Recurrence  
The time to recurrence of rCDI after treatment with REC-3964 or after Day 1 for participants in 
the Observation arm will be evaluated. 
10.1.4. 
Proportion of Participants with Severe rCDI 
The proportion of participants with severe rCDI after treatment with REC-3964 or after Day 1 
for participants in the Observation arm will be defined as CDI with white blood cell count 
>15,000 cells/mL and/or serum creatinine ≥1.5 mg/dL. 
10.1.5. 
rCDI-associated hospital admissions 
The incidence of rCDI associated hospital admissions will be evaluated for participants who 
have rCDI across the study arms during the study.  
10.1.6. 
Evaluation of Diarrheal Episodes 
The number of unformed [types 5-7 on the Bristol stool scale] bowel movements per day will be 
assessed as recorded by the participant in the stool diary, will be monitored through Day 57 in 
order to identify a new episode of diarrhea.  

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10.1.7. 
  
 
 
10.1.8. 
  
 

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11. 
PHARMACOKINETIC ASSESSMENTS 
Pharmacokinetic parameters of REC-3964 following 
 will be measured in 
plasma of the study as described below.  
• Plasma concentrations of REC-3964 will be assessed within 15 minutes pre-dose, 1 hour, 
3 hours, 6 hours at each clinic visit (Days 1 and 15. All post-dose PK time points have a 
window of +/- 30 minutes), and once (any time) during the Recurrence and Early 
Discontinuation visits. 
• Pharmacokinetic parameters to be assessed include, but are not limited to:  
− Cmax  
− Tmax 
− Ctrough 
REC-3974 is the S-enantiomer of REC-3964. Remaining PK samples may be used to measure 
REC-3974 concentrations. 
 

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12. 
STATISTICAL METHODS 
The statistical analysis plan (SAP) will be finalized prior to final database lock, and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints. The SAP will supersede the protocol 
should any differences arise. Any changes to the methods described in the final SAP will be 
described and justified in the clinical study report (CSR).  
12.1. 
Analysis Population 
For analyses, the following analyses population are defined in Table 5: 
Table 5: 
Analyses Population  
Analysis Population 
Description 
All Randomized 
All participants who finished the Screening Period, eligible to, 
and randomized to study Treatment Period. 
Intent-to-treat Population 
All randomized participants who received at least 1 dose of 
REC-3964 intervention or who are intended to be followed-up on 
in the Observational arm. Participants will be analyzed according 
to the treatment arm they were originally assigned to, regardless 
of the treatment received, or withdrawals. ITT will be the primary 
efficacy analyses population. 
Per-protocol Population 
All randomized participants who completed the study without 
major protocol deviations. Participants with protocol deviations 
that affect primary efficacy analysis may be included in the Per-
protocol population depending on the actual impact of the 
protocol deviation. Per-protocol Population will be used for 
sensitivity analysis. 
As-treated Population 
All randomized participants who received at least 1 dose of 
REC-3964 intervention or who are intended to be followed-up on 
in the Observation arm. Participants will be analyzed according to 
the treatment received, regardless of assigned treatment. The 
as-treated Population Set will be used for safety analysis. 
Pharmacokinetic (PK) 
Population 
All participants in the As-treated Population Set who provide at 
least 1 measurable post-dose PK sample with no protocol 
deviation affecting PK evaluation. 
 

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12.2. 
Statistical Analyses 
12.2.1. 
General Consideration 
In general, participant characteristics, demographics data, and safety summary statistics will be 
presented by treatment arm and overall unless otherwise specified. 
Descriptive analyses and summary statistics will be provided for all data collected during the 
study, where applicable. Continuous data will be summarized in terms of the number of 
participants, mean, standard deviation, median, minimum, maximum and number of 
observations, unless otherwise stated, e.g., additional lower and upper quartiles. Categorical data 
will be summarized in terms of the number of participants providing data at the relevant time 
point (n), number of participants with missing data, frequency counts and percentages. Changes 
from baseline in categorical data will be summarized using shift tables where appropriate.  
In addition to the overall crude analyses, stratified analyses, as specified, will be performed on 
all randomized subjects on the following stratification factor (recorded at randomization as per 
IRT):  
• prior antibiotic use (vancomycin versus fidaxomicin) 
12.3. 
Efficacy Endpoints Analyses 
12.3.1. 
Primary Endpoint Analyses 
The primary endpoint is survival without recurrence or requirement for additional CDI treatment 
for at least eight weeks after the cure of preceding CDI with initial curative treatment defined in 
IC 6.1.4. 
The primary endpoint will be analyzed as the proportion of participants with recurrent C. difficile 
infection (rCDI) or requirement for additional CDI treatment among randomized participants.  
The proportion and 2-sided 95% confidence interval (CI) based on the Clopper-Pearson exact 
method will be calculated for each REC-3964 treatment group and the Observation group. The 
estimated difference and corresponding 2-sided 95% CI in recurrence rate between randomized 
groups will be provided using a binomial model. No hypothesis test will be conducted for 
comparison. In addition, analyses will be stratified on prior antibiotic use and stratum specific 
proportions and corresponding 95% CI’s will be reported for each REC-3964 treatment group 
and the Observation arm. 
12.3.2. 
Secondary Endpoints Analyses 
• Rate of recurrence 
The rate of recurrent C. difficile infection is defined as the proportion of participants who had the 
C. difficile recurrence among randomized participants.  
The rate of recurrence and 2-sided 95% confidence interval (CI) based on the Clopper-Pearson 
exact method will be calculated for each REC-3964 treatment group and the Observation group. 
The estimated difference and corresponding 2-sided 95% CI in recurrence rate between 

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randomized groups will be provided using a binomial model. No hypothesis test will be 
conducted for comparison. 
In addition, analyses will be stratified on prior antibiotic use and stratum specific proportions and 
corresponding 95% CI’s will be reported for each REC-3964 treatment group and the 
Observation arm. 
• Time to recurrence  
Time to recurrence is defined as the time from the date of randomization until the occurrence of 
rCDI. The rCDI date is determined by the start of a new episode of symptoms in conjunction 
with a new positive C. difficile stool toxin result, or the need for additional CDI treatment. The 
KM method will be used to analyze the time to recurrence for each of the study arms. 
Participants who did not have recurrence by the time of analysis cutoff date will be censored. 
The estimated median time to rCDI along with the respective 95% confidence interval will be 
provided. In addition, analyses will be stratified on prior antibiotic use and stratum specific KM 
medians and corresponding 95% CI’s will be reported for each REC-3964 treatment group and 
the Observation arm. 
• Severity of rCDI 
The proportion of participants with severe rCDI and 2-sided 95% CI based on the 
Clopper-Pearson exact method will be calculated for each REC-3964 treatment and the 
Observation arm. Analyses stratified on prior antibiotic use will also be performed and stratum 
specific proportions and corresponding 95% CI’s will be reported for each REC-3964 treatment 
group and the Observation arm. 
• The rCDI-associated hospital admissions 
The incidence of rCDI associated hospital admissions will be summarized for participants who 
have rCDI during the study for each REC-3964 treatment and the Observation arm. Analyses 
stratified on prior antibiotic use will also be performed and stratum specific incidences and 
corresponding 95% CI’s will be reported for each REC-3964 treatment group and the 
Observation arm. 
12.3.3. 
Evaluation of Diarrheal Episodes 
The number of unformed [types 5-7 on the Bristol stool scale] bowel movements per day will be 
assessed as recorded by the participant in the stool diary, will be monitored through Day 57 in 
order to identify a new episode of diarrhea. In addition, analyses will be stratified on prior 
antibiotic use. 
12.3.4. 
 
12.3.4.1. 
  
 
 

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12.3.4.2. 
  
 
12.4. 
Safety Endpoint Analyses 
Safety and tolerability will be assessed through AEs, clinical laboratory values (hematology 
including reticulocyte count, biochemistry, coagulation, urinalysis, hepatic enzymes, bilirubin, 
and complete blood count), vital signs, ECGs, and physical examination findings. 
Safety analysis will be conducted using data from the As-treated Population. No formal 
inferential analyses will be conducted for safety variables. Safety will be evaluated using 
descriptive statistics. 
12.4.1. 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as AEs that occur after the participant 
received first dose of study treatment or if a pre-existing condition worsens in severity or 
becomes serious after receiving the first dose of study treatment up to 
 after the last dose 
of study treatment. 
AEs will be graded by the Investigator according to the National Cancer Institute (NCI) CTCAE 
v5.0 or higher. 
The frequency and percentage of participants with TEAEs will be displayed by System Organ 
Class (SOC) and Preferred Term (PT). Summary of TEAEs by severity and relationship to study 
medication will also be provided. Serious AEs and TEAEs resulting in discontinuation of study 
medication will be summarized separately in a similar manner. 
12.4.2. 
Clinical Laboratory, Vital Signs, Electrocardiograms, and Physical 
Examinations 
Vital signs, ECG parameters, and clinical laboratory data (hematology including reticulocyte 
count, biochemistry, coagulation, urinalysis, hepatic enzymes, bilirubin, and complete blood 
count) will be described using raw data and changes from baseline (Day 1), where both baseline 
assessments are available. For clinical laboratory values, vital signs, ECG readings, and physical 
examination results, the values that are below, within, or above a defined normal range will be 
counted and tabulated by the number and percentage of participants with such values. 
12.5. 
Statistical Analyses for Pharmacokinetic Data 
The SAP for PK analysis will be a component of the clinical SAP and will be generated by 
Recursion PK group; the PK SAP will be finalized prior to database lock. Full details of the 
analyses to be performed will be included in the PK SAP. Any deviation from the SAP will be 
reported in the Section “Changes in Planned Analysis” in the CSR. 
Population PK and/or exposure-response analysis may be conducted for all endpoints in this 
study. If this analysis is conducted, a separate report may be prepared. 

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12.5.1. 
Pharmacokinetic Evaluation 
PK parameters will be derived from the plasma concentration-time data. 
A noncompartmental PK method, as appropriate, will be used to analyze the plasma 
concentrations of REC-3964 and its metabolites, if applicable. 
Individual and summary statistics of plasma concentrations at each sampling time point will be 
presented for each treatment and cohort. Individual and mean (±SD standard deviation where 
appropriate) plasma concentration-time profiles will be presented on linear and semi-logarithmic 
scales. 
Individual and summary statistics of all PK parameters will be presented for each treatment and 
cohort. Scatterplots of mean and median values will be presented by treatment and cohort for PK 
parameters. 
12.6. 
Sample Size Evaluation 
Approximately, 80 participants will be randomized to this study. No formal hypothesis testing 
will be conducted. The sample size is deemed appropriate to provide preliminary safety and 
efficacy profiles of REC-3964 on C. difficile participants. 
12.7. 
Interim Analyses 
No interim analyses are planned. 
 

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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The clinical research site will be monitored by the study monitor to ensure correct performance 
of the study procedures and assure that the study will be conducted according to the relevant 
regulatory requirements. The eCRF entries will be verified with the source documentation. 
Regulatory authorities, the IRB, and/or the Sponsor’s clinical quality assurance group may 
request access to all source documents, eCRFs, and other study documentation for on-site audit 
or inspection. Direct access to these documents must be guaranteed by the Investigator, who 
must provide support at all times for these activities. 
An explanation will be given for all missing, unused, and spurious data in the relevant sections of 
the CSR. 
13.1. 
Case Report Form 
The Study Data Management Plan will describe the methods used to collect, check and process 
clinical data in detail. It will also clarify the roles and responsibilities for the different functions 
and personnel involved in the data management process. Furthermore, the Study Data 
Management Plan will describe the data flow and timelines within the study. 
Data captured electronically will be immediately saved to a central database and changes tracked 
to provide an audit trail. When the principal investigator (PI) has signed the eCRF electronically 
as per eCRF instructions, then the participant’s data will be locked. 
An eCRF casebook will be completed by an authorized study personnel member whose training 
for this function is completed in the EDC system unless otherwise directed. The electronic case 
report form casebook will only capture the data required per the protocol schedule of 
assessments and procedures, unless collected by a non-EDC vendor system (e.g., central 
laboratory). The Inclusion/Exclusion Criteria and Enrollment electronic case report forms should 
be completed only after all data related to eligibility are available. Data entry should be 
performed in accordance with the case report form Completion Guidelines provided by the 
Sponsor. Subsequent to data entry, a study monitor may perform source data verification. 
System-generated or manual queries will be issued in the EDC system as data discrepancies are 
identified by the study monitor or CRO Monitor who routinely review the data for completeness, 
correctness, and consistency. The site investigator, site coordinator, or other designee is 
responsible for responding to the queries in a timely manner, within the system, either by 
confirming the data as correct or updating the original entry, and providing the reason for the 
update (e.g., data entry error). Original entries as well as any changes to data fields will be stored 
in the audit trail of the system. Regular oversight by the PI of the data entered into the EDC 
system is expected to occur on an ongoing basis throughout the study to ensure quality and 
completeness. At a minimum, before any interim, final, or other time points (as instructed by 
Recursion), the Investigator applies their electronic signature to confirm that the forms have been 
reviewed and that the entries accurately reflect the information in the source documents. 
13.2. 
Study Monitoring 
Before an investigational site can enter a participant into the study, a representative of Recursion 
Pharmaceuticals, Inc. will visit the investigational study site to: 

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• Determine the adequacy of the facilities and 
• Discuss with the Investigators and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Recursion Pharmaceuticals, Inc. or its 
representatives. This will be documented in a Clinical Study Agreement between 
Recursion Pharmaceuticals, Inc. and the Investigator. 
During the study, a monitor from Recursion Pharmaceuticals, Inc. or representative will have 
regular contacts with the investigational site, for the following: 
• Provide information and support to the Investigators, 
• Confirm that facilities remain acceptable, 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that study drug accountability checks are being 
performed, 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the participant’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
participant (e.g., clinic charts), 
• Record and report any protocol deviations not previously sent to Recursion 
Pharmaceuticals, Inc., and 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Recursion Pharmaceuticals, Inc. and those SAEs that met 
criteria for reporting have been forwarded to the IRB. 
The monitor will be available between visits if the Investigators or other staff needs information 
or advice. 
13.3. 
Audits and Inspections 
Authorized representatives of Recursion Pharmaceuticals, Inc., a regulatory authority, an IEC, or 
an IRB may visit the site to perform audits or inspections, including source data verification and 
drug accountability verification. The purpose of a Recursion Pharmaceuticals, Inc. audit or 
inspection is to systematically and independently examine all study-related activities and data to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP) guidelines of the 
ICH, and any applicable regulatory requirements. The Investigator should contact Recursion 
Pharmaceuticals, Inc. immediately if contacted by a regulatory agency about an inspection. 
13.4. 
Institutional Review Board (IRB) 
The Investigator must obtain IRB approval for the investigation. Copies of the initial IRB 
approval and all materials approved by the IRB for this study, including the participant consent 
form and recruitment materials, must be maintained by the Investigator, and be made available 
for inspection. 

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13.5. 
Data Protection 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
The Sponsor or its representative will not provide individual genotype results to participants, any 
insurance company, any employer, their family members, general physician, or any other third 
party, unless required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the participant. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a participant. For example, in the case of 
a medical emergency, the Sponsor or representative physician or an Investigator might know a 
participant’s identity and also have access to his or her genetic data. Also, regulatory authorities 
may require access to the relevant files. 
Any required notifications (e.g., serious breaches, other reports relevant for participant safety) 
will be completed, as per the applicable laws and regulations. 

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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, Recursion 
Pharmaceuticals, Inc. may conduct a quality assurance audit. See Section 13.3 for more details 
regarding the audit process. 
 

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15. 
ETHICS 
15.1. 
Ethics Review 
The final study protocol, including the final version of the full study Informed Consent Forms, 
must be approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
Investigator must submit written approval to Recursion Pharmaceuticals, Inc. before he or she 
can enroll any participant into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB or IEC must approve all advertising 
used to recruit participants for the study. The protocol must be re-approved by the IRB or IEC 
upon receipt of amendments and annually, as local regulations require. 
The Investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the study drug. Recursion 
Pharmaceuticals, Inc. will provide this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
15.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (World of Medical Association, 2013) and are consistent with ICH/GCP 
(ICH E6, 2016), applicable regulatory requirements and Recursion Pharmaceuticals, Inc.’s policy 
on bioethics. 
15.3. 
Written Informed Consent 
The Investigators at each center will ensure that the participant is given full and adequate oral 
and written information about the nature, purpose, possible risk, expectations, responsibilities, 
and benefit of the study. Participation is voluntary, refusal to participate will involve no penalty 
or loss of benefits to which the individual is otherwise entitled, and the participant may 
discontinue at any time without penalty or loss of benefits. The participant should be given the 
opportunity to ask questions and allowed time to consider the information provided. 
The participant’s signed and dated informed consent must be obtained before conducting any 
study procedures. 
The Investigators must maintain the original, signed informed consent forms. A copy of the 
signed informed consent forms must be given to the participant. 
 

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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Inspection of Records 
Recursion Pharmaceuticals, Inc. will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
participant charts and study source documents, and other records relative to study conduct. 
16.2. 
Retention of Records 
An Investigator shall retain all documentation relating to the study for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified.  
If it becomes necessary for Recursion Pharmaceuticals, Inc., or the regulatory authority to review 
any documentation relating to the study, the Investigator must permit access to such records. 
 

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17. 
PUBLICATION POLICY 
By signing this clinical study protocol, the Investigator reaffirms to the Sponsor that he or she 
will maintain in confidence all information furnished to him or her or resulting from this study. 
The Investigator and designees will only divulge such information as may be necessary to the 
IRB, the members of the staff, and the participants who are involved in this study. 
 

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18. 
LIST OF REFERENCES 
1. Acuña-Amador L, Quesada-Gómez C, Rodríguez C. Clostridioides difficile in Latin 
America: A comprehensive review of literature (1984-2021). Anaerobe. 2022;74:102547. 
doi:10.1016/j.anaerobe.2022.102547 
2. Asha NJ, Tompkins D, Wilcox MH. Comparative analysis of prevalence, risk factors, and 
molecular epidemiology of antibiotic-associated diarrhea due to Clostridium difficile, 
Clostridium perfringens, and Staphylococcus aureus. J Clin Microbiol. 2006;44(8):2785-
2791. doi:10.1128/JCM.00165-06 
3. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in 
adults: a systematic review. JAMA. 2015;313(4):398-408. doi:10.1001/jama.2014.17103 
4. Barbut F, Richard A, Hamadi K, Chomette V, Burghoffer B, Petit JC. Epidemiology of 
recurrences or reinfections of Clostridium difficile-associated diarrhea. J Clin 
Microbiol. 2000;38:2386–2388. 
5. Camacho-Ortiz A, Galindo-Fraga A, Rancel-Cordero A, et al. Factores asociados con el 
desarrollo de la enfermedad por Clostridium difficile en un hospital de tercer nivel en 
México: estudio de casos y controles [Factors associated with Clostridium difficile 
disease in a tertiary-care medical institution in Mexico: a case-control study]. Rev Invest 
Clin. 2009;61(5):371-377. 
6. Centers for Disease Control and Prevention. Nearly half a million Americans suffered 
from Clostridium difficile infections in a single year. February 25, 2015. Available from: 
https://www.cdc.gov/media/releases/2015/p0225-clostridium-difficile.html. Accessed 
April 26, 2022. 
7. Chan M, Lim PL, Chow A, Win MK, Barkham TM. Surveillance for Clostridium 
difficile infection: ICD-9 coding has poor sensitivity compared to laboratory diagnosis in 
hospital patients, Singapore. PLoS One. 2011;6(1):e15603. 
doi: 10.1371/journal.pone.0015603 
8. Cole SA, Stahl TJ. Persistent and Recurrent Clostridium difficile Colitis. Clin Colon 
Rectal Surg. 2015; 28(2):65-69. doi:10.1055/s-0035-1547333 
9. Ferguson JK, Cheng AC, Gilbert GL, et al. Clostridium difficile laboratory testing in 
Australia and New Zealand: national survey results and Australasian Society for 
Infectious Diseases recommendations for best practice. Pathology. 2011;43(5):482-487. 
doi:10.1097/PAT.0b013e328348c9b4 
10. Feuerstadt P, Stong L, Dahdal DN, Sacks N, Lang K, Nelson WW. Healthcare resource 
utilization and direct medical costs associated with index and recurrent Clostridioides 
difficile infection: a real-world data analysis. J Med Econ. 2020 Jun;23(6):603-609. 
11. Food and Drug Administration. (May 9, 2017). FY2015 Regulatory Science Research 
Report: Narrow Therapeutic Index Drugs. https://www.fda.gov/industry/generic-drug-
user-fee-amendments/fy2015-regulatory-science-research-report-narrow-therapeutic-
index-drugs. Accessed on March 26, 2025. 
 

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12. Garey KW, Sethi S, Yadav Y, DuPont HL. Meta-analysis to assess risk factors for 
recurrent Clostridium difficile infection. J Hosp Infect. 2008;70(4):298-304. 
doi:10.1016/j.jhin.2008.08.012 
13. Johnson S. Lavergne V, Skinner AM et al. Clinical Practice Guideline by the Infectious 
Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of 
America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides 
difficile Infection in Adults. Clinical Infectious Diseases. 2021. DOI: 
10.1093/cid/ciab549 
14. Kelly CP, LaMont JT. Clostridium difficile-more difficult than ever [published correction 
appears in N Engl J Med. 2010 Oct 14;363(16):1585]. N Engl J Med. 2008;359(18):1932-
1940. doi:10.1056/NEJMra0707500 
15. Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile 
infection? Clin Microbiol Infect. 2012;18(Suppl 6):21-27. doi: 10.1111/1469-
0691.12046. 
16. Lee Y, Lim WI, Bloom CI, Moore S, Chung E, Marzella N. Bezlotoxumab (Zinplava) for 
Clostridium Difficile Infection: The First Monoclonal Antibody Approved to Prevent the 
Recurrence of a Bacterial Infection. P T. 2017;42(12):735-738. 
17. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the 
United States. N Engl J Med. 2015;372(9):825-834. doi:10.1056/NEJMoa1408913 
18. Mada PK, Alam MU. Clostridioides Difficile. [Updated 2022 Jan 31]. In: StatPearls 
[Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK431054 
19. Olsen MA, Yan Y, Reske KA, Zilberberg MD, Dubberke ER. Recurrent Clostridium 
difficile infection is associated with increased mortality. Clin Microbiol Infect. 
2015;21(2):164–70. 
20. Olsen MA, Yan Y, Reske KA, Zilberberg M, Dubberke ER. Impact of Clostridium 
difficile recurrence on hospital readmissions. Am J Infect Control. 2015;43(4):318–22. 
21. Pothoulakis C. Effects of Clostridium difficile toxins on epithelial cell barrier. Ann N Y 
Acad Sci. 2000;915:347-56. doi: 10.1111/j.1749-6632.2000.tb05263.x. PMID: 11193598. 
22. Rajabally NM, Pentecost M, Pretorius G, Whitelaw A, Mendelson M, Watermeyer G. 
The Clostridium difficile problem: a South African tertiary institution's prospective 
perspective. S Afr Med J. 2013;103(3):168-172. doi:10.7196/samj.6012 
23. 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 
24. Viswanathan VK, Mallozzi MJ, Vedantam G. Clostridium difficile infection: An 
overview of the disease and its pathogenesis, epidemiology and interventions. Gut 
Microbes. 2010;1(4):234-242. doi:10.4161/gmic.1.4.12706 
 

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APPENDIX A. 
 
 
 
 
 
 
 
 
 
 
Table 6: 
 

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. 
Table 7: 
 

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APPENDIX B. 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
Table 8: 
 

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Table 9: 
 

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Table 10: 
 
Table 11: 
 
 
 
 

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Table 12: 
 
 
 
 

Signature Page for: REC-3964-201 Protocol_Version 7_03252025
VV-CLIN-000585
Signature Page for: REC-3964-201 Protocol_Version 7_03252025
VV-CLIN-000585
Approval Task
Verdict: Approved
Medical
27-Mar-2025 19:27:12 GMT+0000
Approval Task
Verdict: Approved
Biostats
27-Mar-2025 21:42:36 GMT+0000