Clinical trial NCT05737433
Conditions: NASH With Fibrosis
Keywords: Nonalcoholic Steatohepatitis NASH NAFLD
Sponsor: Hepion Pharmaceuticals, Inc.
Start date: 2023-03-01; Completion date: 2023-08-04
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-center, single-period, single-dose, open-label, non-randomized study to assess the mass balance recovery, metabolite profile and metabolite identification of 14C- labelled rencofilstat (\[14C\] CRV431). It is planned to enroll 6 healthy male subjects in a single group. Each subject will receive a single 225 mg oral dose of \[14C\] CRV431 self-micro emulsifying drug delivery system (SMEDDS) oral emulsion.

Detailed description:
This is a single center, open-label, non-randomized, single period, single dose study in healthy male subjects designed to assess the mass balance recovery, pharmacokinetics (PK), metabolite profile and metabolite identification of rencofilstat. It is planned to enroll a single cohort of 6 subjects. All subjects will receive a single 225 mg oral dose of \[14C\]-rencofilstat, as a SMEDDS oral emulsion in the fasted state.

Subjects will undergo preliminary screening procedures for the study at the screening visit (Day -28 to Day -2). Subjects will be admitted in the evening on the day before dosing (Day-1).

Whole blood, plasma, urine and feces samples will be collected at regular intervals for PK analysis, total radioactivity analysis, metabolite profiling, mass balance and safety as applicable, from pre-dose to discharge from the clinical unit. Urine and feces samples may be collected at return visits or home visits if mass balance criteria have not been met by a subject.

Arms: arm 1: \[14C\]-rencofilstat, 225mg oral dose, self-micro-emulsifying drug delivery system, single dose
Interventions: intervention 1: [14C]-rencofilstat 225mg
Intervention descriptions: intervention 1: radio-labelled 225mg oral dose of rencofilstat

Protocol documents:
Prot_000.pdf: 
Doc No:DOC-61548    
  Doc Name:QSC204643 Clinical Protocol 
Project Number:204643        
   Version:3.0        
Status:Approved 
CLINICAL STUDY PROTOCOL 
An Open Label, Single-Dose, Single-Period Study Designed to 
Assess the Mass Balance Recovery, Metabolite Profile and 
Metabolite Identification of [14C]-Rencofilstat in Healthy Male 
Subjects  
Short Study Title: Single Dose ADME Study of [14C]-Rencofilstat 
in Healthy Male Subjects 
Quotient Sciences Study Number: 
QSC204643 
Sponsor Study Number: 
HEPA-CRV431-105 
EudraCT Number: 
2022-003789-20 
IRAS ID 
1007072 
Clinical Study Site: 
Quotient Sciences 
Mere Way 
Ruddington Fields 
Ruddington 
Nottingham NG11 6JS, UK 
Tel: +44 (0)115 974 9000 
Sponsor: 
Hepion Pharmaceuticals, Inc 
399 Thornall Street, First Floor 
Edison 
New Jersey 
08837 
Tel: +1 732-902-4000 
Date of Protocol: 
22 Mar 2023 
Status of Protocol: 
Version 3.0 
SPONSOR/QUOTIENT SCIENCES CONFIDENTIAL 
This clinical protocol may not be reproduced or communicated to a third party 
without the written permission of Hepion Pharmaceuticals, Inc. 


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Document History 
Protocol Version Number 
Classification 
Date  
Version 3.0 
Non-Substantial Amendment 
22 Mar 2023 
Version 2.0 
Non-Substantial Amendment 
10 Mar 2023 
Version 1.0 
Original Protocol 
21 Dec 2022 
Details of the amendments can be found in Appendix 3. 
 


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Study Contacts 
Principal Investigator: 
Litza McKenzie MBChB, BScMedSci (Hons)  
Quotient Sciences 
Mere Way 
Ruddington Fields 
Ruddington 
Nottingham NG11 6JS, UK 
Tel: +44 (0)115 974 9000 (day) 
Tel: +44 (0)7774 017236 (out of hours emergency) 
Sub-Investigators: 
Sharan Sidhu MBChB, BAO, MRCS, MFPM 
Philip Evans MBChB, MRCS (Ed) 
Stuart Mair MBChB, DRCOG, DCPSA, FFPM 
Nand Singh BSc, MD, DPM, MFPM 
Martina Fieldingova MUDr 
Elizabeth Maria van Niekerk MBChB, DipPalMed 
Somasekhara Menakuru MBBS, MS, MRCS, DPM, 
MFPM 
David Everton BSc, MBBS 
Courtney Krstic BMedSci, BMBS (Hons)  
Lena Chen BSc (Hons), MBBS, MRCGP 
Nicholas Akam BMedSci, BMBS, MRCGP  
Daniel Pickering BMBS, BMedSci, PhD 
Mohamed Abokhwat MBBCH 
Quotient Sciences Tel:  
+44 (0)115 974 9000 (day) 
Tel: +44 (0)7774 017236 (out of hours emergency) 
Project Manager: 
Kirsty Webster BSc (Hons) 
Quotient Sciences 
Tel: +44 (0)115 974 9000 
Study Monitor: 
Details will be provided in the Communication Plan 
Medical Monitor: 
Bionical Emas 
Suite 209 
Spirella Building 
Bridge Road 
Letchworth Garden City 
Hertfordshire, SG6 4ET, UK 
Tel: +44 (0)1462 424 400 
Pharmacovigilance 
Provider: 
Details will be provided in the Communication Plan 
ARSAC Practitioner: 
Stuart Mair MBChB, DRCOG, DCPSA, FFPM 
Tel: +44 (0)115 974 9000  
Email: stuart.mair@quotientsciences.com 
Central Laboratory: 
The Doctors Laboratory 
The Halo Building 
1 Mabledon Place 
London WC1H 9AX 
Tel: + 44 (0)207 3077 404 


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Bioanalytical Laboratory, 
Mass Balance and 
Metabolism Laboratory: 
Pharmaron UK   
Pegasus Way 
Crown Business Park 
Rushden  
Northamptonshire NN10 6ER, UK 
Tel: +44 (0)1933 319 900 


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1 Table of Contents 
1 
Table of Contents ............................................................................................ 5 
2 
List of Tables and Figures ............................................................................... 9 
2.1 
Table of In-Text Tables ...................................................................... 9 
2.2 
Table of In-Text Figures ..................................................................... 9 
3 
Synopsis ....................................................................................................... 10 
4 
List of Abbreviations ...................................................................................... 14 
5 
Background Information ................................................................................ 16 
5.1 
Introduction ...................................................................................... 16 
5.2 
Investigational Medicinal Product .................................................... 17 
5.3 
Previous Study Findings .................................................................. 17 
5.3.1 
Non-clinical Findings ....................................................................... 18 
5.3.2 
Clinical Findings .............................................................................. 19 
6 
Rationale ....................................................................................................... 22 
6.1 
Study Rationale ............................................................................... 22 
6.2 
Dose Rationale ................................................................................ 22 
6.3 
Population Rationale ....................................................................... 22 
6.4 
Risks and Benefits ........................................................................... 23 
6.4.1 
Risks Associated with Rencofilstat Administration ........................... 23 
6.4.2 
Risks Associated with Administration of Radioactivity ...................... 25 
6.4.3 
COVID-19 Related Risks and Risk Mitigation Measures .................. 25 
6.4.4 
General Risks and Overall Risk-Benefit Assessment ....................... 26 
7 
Objectives and Endpoints .............................................................................. 27 
8 
Study Design ................................................................................................. 27 
8.1 
Study Plan ....................................................................................... 27 
8.2 
Criteria for In-Study Decisions ......................................................... 29 
8.3 
Subject Withdrawal .......................................................................... 29 
8.4 
Subject Replacement ...................................................................... 30 
8.5 
Stopping Criteria .............................................................................. 30 
8.6 
Study Termination ........................................................................... 31 
8.7 
Lost to Follow-up ............................................................................. 31 
8.8 
Treatment Assignment..................................................................... 32 
8.8.1 
Subject Numbers ............................................................................. 32 
8.8.2 
Blinding ........................................................................................... 32 
9 
Selection of Subjects ..................................................................................... 32 
9.1 
Informed Consent ............................................................................ 32 
9.2 
Inclusion Criteria .............................................................................. 32 
9.3 
Exclusion Criteria ............................................................................. 33 
9.4 
Contraception and Restrictions ........................................................ 34 
9.4.1 
Sperm Donation............................................................................... 35 
9.5 
Pregnancy ....................................................................................... 35 
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9.6 
Additional Study Restrictions ........................................................... 35 
10 
Study Procedures .......................................................................................... 36 
10.1 
Screening ........................................................................................ 36 
10.1.1 
Subject Re-Screening ...................................................................... 36 
10.2 
Admission and Pre-dose Procedures ............................................... 36 
10.3 
Study Day Procedures ..................................................................... 37 
10.3.1 
Blood Volume .................................................................................. 37 
10.3.2 
Timing of Procedures ...................................................................... 37 
10.3.3 
Discharge from the Clinical Unit ....................................................... 37 
10.3.4 
Return Visits .................................................................................... 38 
10.3.5 
Medical Supervision ........................................................................ 38 
11 
Dosing of Subjects ........................................................................................ 38 
11.1 
Food and Fluid Intake ...................................................................... 38 
11.2 
Administration of Test Preparations ................................................. 38 
11.3 
Dosing Compliance ......................................................................... 39 
11.4 
Prior and Concomitant Medications ................................................. 39 
12 
Assessment of Efficacy ................................................................................. 39 
13 
Assessment of Mass Balance, Pharmacokinetics, Metabolite Profiling 
and Identification, and Pharmacodynamics ................................................... 39 
13.1 
Assessment of Mass Balance, Pharmacokinetic, and 
Metabolite Profiling and Identification .............................................. 39 
13.1.1 
Pharmacokinetic and Metabolite Profiling and Identification 
Blood Sampling ............................................................................... 40 
13.1.2 
Mass Balance and Metabolite Profiling and Identification Urine 
Sampling ......................................................................................... 40 
13.1.3 
Mass Balance and Metabolite Profiling and Identification 
Faecal Sampling .............................................................................. 41 
13.1.4 
Unexpected Sources of Elimination ................................................. 41 
13.2 
Assessment of Pharmacodynamics ................................................. 41 
14 
Assessment of Safety ................................................................................... 41 
14.1 
Definition and Classification of Adverse Events ............................... 41 
14.2 
Assessment of Causality ................................................................. 42 
14.3 
Recording Adverse Events .............................................................. 42 
14.4 
Serious Adverse Events .................................................................. 42 
14.4.1 
Definition of Serious Adverse Events ............................................... 42 
14.4.2 
Definition of Suspected Unexpected Serious Adverse 
Reactions ........................................................................................ 43 
14.5 
Laboratory Measurements ............................................................... 43 
14.5.1 
Haematology and Clinical Chemistry ............................................... 43 
14.5.2 
Virology ........................................................................................... 43 
14.5.3 
Urinalysis ......................................................................................... 44 
14.5.4 
Drug Screen .................................................................................... 44 
14.5.5 
Alcohol Breath Test ......................................................................... 44 
14.5.6 
Carbon Monoxide Breath Test ......................................................... 44 
14.5.7 
SARS-CoV-2 Tests (If Required) ..................................................... 44 
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14.5.8 
Abnormal Laboratory Findings ......................................................... 44 
14.6 
Vital Signs Measurements ............................................................... 45 
14.7 
ECG Measurements ........................................................................ 45 
14.8 
Body Weight, Height and BMI .......................................................... 45 
14.9 
Physical Examination ...................................................................... 46 
14.10 
Additional Safety Procedures........................................................... 46 
15 
Statistics and Data Analysis .......................................................................... 46 
15.1 
Sample Size Justification ................................................................. 46 
15.2 
Data Management ........................................................................... 46 
15.3 
Mass Balance, Pharmacokinetic, and Metabolite Profiling and 
Identification Data Analysis .............................................................. 47 
15.3.1 
Mass Balance Data Analysis ........................................................... 47 
15.3.2 
Pharmacokinetic and Total Radioactivity Data Analysis ................... 47 
15.3.3 
Metabolite Profiling and Identification .............................................. 48 
15.4 
Statistical Data Analysis .................................................................. 48 
15.5 
Interim Analysis ............................................................................... 49 
16 
Safety Reporting to Regulatory Authorities and Ethics Committees............... 49 
16.1 
Events Requiring Expedited Reporting ............................................ 49 
16.2 
Urgent Safety Measures .................................................................. 49 
16.3 
Reporting ......................................................................................... 50 
16.3.1 
Reporting Serious Adverse Events .................................................. 50 
16.3.2 
Reporting of Suspected Unexpected Serious Adverse 
Reactions ........................................................................................ 50 
16.3.3 
Expedited Reporting of Events ........................................................ 50 
16.3.4 
Reporting of Urgent Safety Measures .............................................. 51 
16.3.5 
Reporting of COVID-19 Vaccine-Related Adverse Events ............... 51 
16.4 
Serious Breaches ............................................................................ 51 
17 
Protocol Amendments and Deviations ........................................................... 51 
17.1 
Amendments ................................................................................... 51 
17.2 
Protocol Deviations .......................................................................... 51 
18 
Regulatory ..................................................................................................... 52 
18.1 
Compliance ..................................................................................... 52 
18.2 
MHRA and Ethical Approval ............................................................ 52 
18.3 
Administration of Radiation .............................................................. 52 
18.4 
Source Data .................................................................................... 53 
18.5 
Declaration of the End of the Study ................................................. 53 
18.6 
Document Storage and Archiving .................................................... 53 
18.7 
Protection of Personal Data and Confidentiality ............................... 53 
18.8 
Data Security Breach ....................................................................... 54 
19 
Quality Control and Quality Assurance .......................................................... 54 
19.1 
Monitoring........................................................................................ 54 
20 
Finance and Insurance .................................................................................. 55 
21 
Publication .................................................................................................... 55 
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22 
References ..................................................................................................... 55 
Appendix 1 
Clinical Laboratory Parameters ......................................................... 58 
Appendix 2 
Schedule of Assessments ................................................................. 59 
Appendix 3 
Protocol Amendment Summary of Changes ..................................... 62 
 


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2 List of Tables and Figures  
2.1 
Table of In-Text Tables 
Table 1 
Investigational Medicinal Product ............................................................... 17 
Table 2 
Summary of Whole Blood Rencofilstat Pharmacokinetic Parameters 
Following Single Oral Doses (SAD, PK Population) .................................. 21 
Table 3 
Mass Balance Parameters ......................................................................... 47 
Table 4 
Whole Blood Pharmacokinetic Parameters ................................................ 47 
 
2.2 
Table of In-Text Figures 
Figure 1 
Study Sequence ......................................................................................... 29 
 
 


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3 Synopsis 
 
Sponsor:  
Hepion 
Pharmaceuticals, Inc. 
 
Drug Substance:  
[14C]-rencofilstat 
EudraCT No.: 
2022-003789-20 
IRAS ID: 
1007072 
Title of Study: 
An Open Label, Single-Dose, Single-Period Study Designed to Assess the Mass Balance 
Recovery, Metabolite Profile and Metabolite Identification of [14C]-Rencofilstat in Healthy 
Male Subjects. 
Principal Investigator:  
Litza McKenzie MBChB, BScMedSci (Hons) 
Study Centre: 
Quotient Sciences, Mere Way, Ruddington Fields, Ruddington, Nottingham, NG11 6JS, 
UK 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary  
 
To determine the mass balance recovery after a 
single oral dose of carbon-14 ([14C])-rencofilstat 
 
Mass balance recovery of total radioactivity (TR) in 
all excreta (urine and faeces): CumAe and 
Cum%Ae 
To determine % parent drug unchanged versus 
metabolites 
Parent to total radioactivity ratio for whole blood 
based on AUC 
To perform metabolite profiling and structural 
identification from whole blood, urine and faecal 
samplesa 
Collection of whole blood, urine and faeces 
samples 
for 
metabolite 
profiling, 
structural 
identification, and quantification analysis 
Secondary 
To determine the routes and rates of elimination of 
[14C]-rencofilstat 
 
Mass balance recovery of TR in urine and faeces 
separately: Ae, %Ae, CumAe and Cum%Ae by 
interval 
To identify the chemical structure of each metabolite 
accounting for more than 10% of circulating TR or 
accounting for 10% or more of the dose in excreta 
Identification of the chemical structure of each 
metabolite accounting for more than 10% by AUC 
of circulating TR or accounting for 10% or more of 
the dose in excreta 
To evaluate the extent of distribution of TR into blood 
cells 
Evaluation of whole blood:plasma concentration 
ratios for TR 
To provide 
additional safety and tolerability 
information for rencofilstat 
To provide additional safety and tolerability 
information for rencofilstat by assessing: incidence 
of adverse events (AEs), physical examinations 
and change from baseline for vital signs, 
electrocardiograms (ECGs), and laboratory safety 
tests 
To further explore the oral pharmacokinetics (PK) of 
rencofilstat 
PK parameters for rencofilstat in whole blood and 
TR in plasma and whole blood following a single 
oral dose, including but not limited to: Tlag, Tmax, 
Cmax, 
AUC(0-last), 
AUC(0-inf), 
AUC(0-24), 
Lambda-z, T1/2, CL/F, Vz/F, MRT(0-last) and 
MRT(0-inf) as applicable 
a Metabolite profiling and identification will be reported separately from the clinical study report as a 
standalone document. 
Methodology: 
This is a single centre, open-label, non-randomised, single period, single dose study in 
healthy male subjects. It is planned to enrol a single cohort of 6 subjects.  


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Each subject will receive a single 225 mg oral dose of [14C]-rencofilstat 
self-microemulsifying drug delivery system oral emulsion (not more than [NMT] 
6.4 MBq), in the fasted state. 
Study Design: 
Subjects will undergo preliminary screening procedures for the study at the screening 
visit (Day -28 to Day -2). Subjects will be admitted in the evening on the day before 
dosing (Day -1). 
Whole blood, plasma, urine and faeces samples will be collected at regular intervals for 
PK analysis, TR analysis, metabolite profiling, mass balance and safety as applicable, 
from pre-dose to discharge from the clinical unit. Urine and faeces samples may be 
collected at return visits or home visits if mass balance criteria has not been met by a 
subject.  
Subjects will be dosed on the morning of Day 1 following an overnight fast (minimum 8 h) 
and will remain resident in the clinical unit until up to 504 h after dosing (up to Day 22).  
It is planned that subjects will be released as a group when all subjects have achieved a 
mass balance cumulative recovery of >90% or if <1% of the dose administered has been 
collected in urine and faeces within two separate, consecutive 24 h periods. This may 
result in the subjects being discharged as a group prior to completion of the planned 
residency period.  
If the mass balance criteria are achieved during the planned residency period, collection 
of all samples (blood, urine and faeces) will be stopped once the current 24 h collection 
period is complete, and subjects will undergo discharge assessments. 
If the mass balance criteria have not been met by all subjects on the morning of Day 22, 
the residency period for the subjects not achieving the mass balance criteria may be 
extended up to a maximum of 96 h (Day 26; 600 h post-dose). Only urine and/or faecal 
samples will be collected during the extended residency period.  
If the mass balance criteria have not been met by all subjects on the morning of Day 26, 
subjects not achieving the release criteria may be required to make up to 2 return visits 
(each of 24 h duration) at (nominally) Day 28 (+2 days) and Day 35 (±2 days) for 
additional collection of excreta samples (urine and/or faecal samples). 
If the mass balance criteria have not been met following the return visits, then home 
collections of urine and/or faeces may be requested at the discretion of the investigator 
for individual subjects. 
Number of Subjects Planned: 
It is planned to enrol 6 healthy male subjects to ensure data in a minimum of 4 subjects. 
No replacement subjects are planned for this study.  
Duration of Study: 
Subjects will receive 1 single administration on a single occasion. The estimated time 
from screening until the end of the study is approximately up to 8 weeks (9 weeks if 
return visits are required). 
Main Inclusion Criteria: 
Healthy males aged 30 to 65 years inclusive at the time of signing informed consent. 
Body mass index of 18.0 to 35.0 kg/m2 as measured at screening. 
Investigational Medicinal Product, Dose and Mode of Administration: 
The following IMP will be used in this clinical study. 
IMP Name 
Dose 
Route of Administration 
[14C]CRV431 SMEDDS Concentrate for 
Oral Emulsion, 225 mg (NMT 6.4 MBq) 
225 mg 
Oral administration, Fasted 
14C: carbon-14, MBq: megabecquerel, NMT: not more than 


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Immediately after administration of the oral solution, the dosing vessel will be rinsed with 
water and subjects will consume the rinse solution. Subjects will then consume further 
water to a total volume of 240 mL (including the dosing volume and volume used to rinse 
the dosing vessel). 
Mass Balance Assessments: 
Mass balance of TR in urine and faeces (and emesis, if applicable) will be calculated by 
Quotient Sciences for the parameters below. 
Parameter 
Definition 
Ae(urine) 
amount of TR excreted in urine 
%Ae(urine) 
amount of TR excreted in urine expressed as a percentage of the radioactive dose 
administered 
CumAe(urine) 
cumulative amount of TR excreted in urine 
Cum%Ae(urine) 
cumulative amount of TR excreted in urine expressed as a percentage of the 
radioactive dose administered 
Ae(faeces) 
amount of TR eliminated in faeces 
%Ae(faeces) 
amount of TR eliminated in faeces expressed as a percentage of the radioactive 
dose administered 
CumAe(faeces) 
cumulative amount of TR eliminated in faeces 
Cum%Ae(faeces) 
cumulative amount of TR eliminated in faeces expressed as a percentage of the 
radioactive dose administered 
Ae(total) 
amount of TR excreted in urine and faeces combined 
%Ae(total) 
amount of TR excreted in urine and faeces combined expressed as a percentage of 
the radioactive dose administered 
CumAe(total) 
cumulative amount of TR excreted in urine and faeces combined 
Cum%Ae(total) 
cumulative amount of TR excreted in urine and faeces combined expressed as a 
percentage of the radioactive dose administered 
Pharmacokinetic and Total Radioactivity Assessments: 
Whole blood concentration-time data for rencofilstat will be analysed by Quotient 
Sciences using Phoenix WinNonlin v8.3 or a more recent version (Certara USA, Inc., 
USA) and appropriate non-compartmental techniques to obtain estimates of the following 
PK parameters, where possible and appropriate. 
Parameter 
Definition 
Tlag 
Time prior to the first measurable concentration 
Tmax 
Time of maximum observed concentration 
Cmax 
Maximum observed concentration 
AUC(0-24) 
Area under the curve from time 0 to 24 h post-dose 
AUC(0-last) 
Area under the curve from time 0 to the time of last measurable 
concentration 
AUC(0-inf) 
Area under the curve from time 0 extrapolated to infinity 
AUCextrap 
Area under the curve from time of the last measurable concentration to 
infinity as a percentage of the area under the curve extrapolated to infinity 
AUC ratio 
Parent to total radioactivity ratio for whole blood based on AUC 
T1/2  
Terminal elimination half-life 
Lambda-z 
First order rate constant associated with the terminal (log-linear) portion of 
the curve 
CL/F 
Total body clearance calculated after a single extravascular administration 
where F (fraction of dose bioavailable) is unknown 
Vz/F 
Apparent volume of distribution based on the terminal phase calculated using 
AUC(0-inf) after a single extravascular administration where F (fraction of 
dose bioavailable) is unknown 
MRT(0-last) 
Mean residence time from time 0 to time of the last measurable 
concentration  


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Parameter
Definition
MRT(0-inf)
Mean residence time from time 0 extrapolated to infinity 
In addition, whole blood-to-plasma TR concentration ratios will be calculated. 
Metabolite Profiling and Identification Assessment: 
Metabolite profiling of whole blood, urine and faeces will be performed using liquid 
chromatography-radio-detection with subsequent mass spectrometry where appropriate. 
Identification of the chemical structure of each metabolite accounting for greater than 
10% of circulating radioactivity in whole blood (“AUC pool”) and accounting for greater 
than 10% of the dose in the urine and faeces (from urine pools and faeces homogenate 
pools) will be performed. These aspects will be reported separately from the clinical study 
report as a standalone document. 
Safety Assessments: 
The safety assessments to be conducted are: 
•
AE monitoring
•
Single 12-lead ECGs
•
Vital signs
•
Clinical laboratory tests (clinical chemistry, haematology and urinalysis)
•
Physical examinations
Statistical Methodology: 
No formal statistical analysis will be performed for this study. Descriptive statistics 
(eg mean, median, standard deviation, minimum, maximum and number of subjects with 
an observation [n]) are considered adequate for a study of this type. Additional statistics 
will be provided for PK-related data, including coefficient of variation (CV%), geometric 
mean and geometric CV%. 
Sample Size and Power: 
The study is exploratory and no formal sample size calculation has been made. Based 
on experience from previous studies of a similar design, a total of 6 subjects are to be 
enrolled and a minimum of 4 evaluable subjects are considered sufficient. An evaluable 
subject is defined as a subject who has provided mass balance and PK samples for up 
to 21 days after drug administration or have demonstrated >90% mass balance recovery 
or have <1% of the administered dose eliminated in excreta for two consecutive days, 
whichever is sooner. 


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4 List of Abbreviations 
Abbreviation 
Definition 
14C 
carbon-14 
ADME 
absorption, metabolism, distribution and elimination 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARSAC 
Administration of Radioactive Substances Advisory 
Committee 
BCRP 
breast cancer resistance protein 
BMI 
body mass index 
CLcr 
creatinine clearance 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COVID-19 
Coronavirus Disease 2019 
CsA 
cyclosporine A 
CSPM 
Clinical Sample Processing Manual 
CV% 
coefficient of variation 
CYP450 
cytochrome P450 
Cyp A 
cyclophilin A 
Cyp B 
cyclophilin B 
Cyp D 
cyclophilin D 
DDI 
drug-drug interaction 
DMP 
data management plan 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
GCP 
good clinical practice 
GLP 
good laboratory practice 
HBsAg 
hepatitis B surface antigen 
HCC 
Hepatocellular carcinoma 
HCV Ab 
hepatitis C virus antibody 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IMP 
investigational medicinal product 


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ISF 
Investigator Site File 
MAD 
multiple ascending dose 
MATE 
Multidrug and toxin extrusion protein 
MHRA 
Medicines and Healthcare products Regulatory 
Agency 
NAFLD 
Non-alcoholic fatty liver disease 
NASH 
Non-alcoholic Steatohepatitis 
NMT 
not more than 
NOAEL 
no-observed-adverse-effect-level 
OAT 
(human) organic ion transporter 
PgP 
P-glycoprotein 
PIS 
Participant Information Sheet 
PK 
pharmacokinetic(s) 
QA 
quality assurance 
QD 
once daily 
QTcF 
Corrected QT interval by Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
SAD 
single ascending dose 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SMEDDS 
self-microemulsifying drug delivery system 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TDF 
tenofovir disoproxil fumarate 
TK 
toxicokinetic 
TR 
total radioactivity 
TV 
tidal volume 
 
The mass balance and pharmacokinetic definitions used in this study are presented in 
Section 15.3.1 and Section 15.3.2.


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5 Background Information 
5.1 
Introduction  
Rencofilstat, previously known as CRV431, is a non-immunosuppressive cyclosporine A 
(CsA) analogue being developed by Hepion Pharmaceuticals, Inc. for the treatment of 
fibrotic diseases, including Non-alcoholic Steatohepatitis (NASH) and Hepatocellular 
Carcinoma (HCC).  
The molecular action of CRV431 is binding and inhibition of cellular enzymes called 
cyclophilins. Cyclophilins are peptidyl prolyl isomerases that catalyse changes in the 
isomeric conformation (cis and trans) of peptide bonds between prolines and adjacent 
amino acids. Cyclophilins are involved in diverse cellular process, including intracellular 
signalling and inflammation (Cyclophilin A [Cyp A]), protein folding and secretion 
(Cyclophilin B [Cyp B]), and regulation of mitochondrial permeability transition pores 
(Cyclophilin D [Cyp D]), which protect cells in response to injury. 
Cyclophilins were first characterized through the discovery that cyclosporine A (CsA), a 
drug used for prevention of organ graft rejection, exerts its immunosuppressive activity 
by a two-step mechanism involving inhibition of Cyp A and calcineurin [1],[2],[3],[4]. 
Researchers have chemically modified CsA to diminish its calcineurin binding and 
thereby reduce its immunosuppressive properties while retaining its binding and 
inhibition of cyclophilins. This class of compounds is known as “non-immunosuppressive 
CsA analogues,” and includes rencofilstat. The safety and efficacy of this class of drug 
has been demonstrated by the partial clinical development of alisporivir wherein the 
compound was administered to over 2000 subjects [5],[6],[7]. 
Rencofilstat displays the basic functional characteristics of the family – high potency 
cyclophilin inhibition but low immunosuppressive activity – but it also possesses distinct 
properties that distinguish it from other compounds in the class such as increased 
solubility and less interaction with membrane transporters. The functional distinctiveness 
of rencofilstat derives in part from its unique modifications at amino acids 1 and 3, in 
comparison to most other non-immunosuppressive CsA analogues which are modified 
at amino acid positions 3 and 4. 
Non-alcoholic fatty liver disease (NAFLD) and its more severe form, NASH are significant 
health burdens with prevalence increasing throughout the world. NAFLD is characterized 
by fat accumulation in the liver and often is associated with obesity, insulin resistance, 
dyslipidaemia and other aspects of metabolic syndrome. NASH shares these 
characteristics but additionally is characterized by liver inflammation and fibrosis. 
Extensive fibrosis in the absence of compensatory fibrolysis leads to scarring and 
cirrhosis and an increased likelihood of developing complications such as HCC, with an 
annual incidence of 0.5% to 2.6% [8]. HCC represents more than 80% of the primary 
liver cancers. 
Worldwide NAFLD prevalence is 25% with the highest rates in the Middle East and South 
America. NASH affects between 1.5% and 6.5% of the global population. In the US, 
NAFLD prevalence is projected to increase from 83 million people in 2015 to 101 million 
people in 2030, with 33% of the population over the age of 15 impacted. The incidence 
of NASH and HCC are expected to similarly increase resulting in an excess 800,000 liver 
deaths during this period [9]. There are currently no US Food and Drug Administration 
(FDA) or UK Regulatory authority approved drugs for NASH, and metabolism-regulating 
drugs are largely not efficacious. Most drugs currently under development target 
metabolic disease rather than fibrosis. Multiple cyclophilin isoforms potentially contribute 


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to NASH pathophysiology, including Cyp A, Cyp B, and Cyp D, by participating in energy 
and lipid metabolic activities, regulation of hepatocyte death, inflammation, and fibrosis 
[10]. 
Reduction of liver steatosis, hepatocyte death, inflammation, and especially fibrosis are 
the primary outcomes being sought in NASH clinical trials. Achieving these endpoints is 
expected to alleviate the risks of advancing to compensated cirrhosis, decompensated 
cirrhosis, HCC, and liver failure [10]. 
5.2 
Investigational Medicinal Product 
The investigational medicinal product (IMP) that will be used in this clinical study is 
presented in Table 1. 
Table 1 
Investigational Medicinal Product 
IMP Name 
Dose 
Route of Administration 
[14C]CRV431 SMEDDS Concentrate 
for Oral Emulsion, 225 mg 
(NMT 6.4 MBq) 
225 mg 
Oral administration, Fasted 
14C: carbon-14, MBq: megabecquerel, NMT: not more than, SMEDDS: self-microemulsifying drug delivery 
system 
The 
carbon-14 
([14C])-rencofilstat 
(also 
referred 
to 
as 
[14C]CRV431) 
self-microemulsifying drug delivery system (SMEDDs) oral emulsion is an un-licensed 
medicinal product for use only in the proposed clinical trial.  
Only subjects enrolled in the study may receive study treatment and only authorised site 
staff may supply or administer study treatment. All study treatments will be stored in a 
secure, environmentally-controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff. 
[14C]-rencofilstat will be manufactured in accordance with Good Manufacturing Practice 
(GMP) by Quotient Sciences. Where Quotient Sciences (hereafter referred to as 
Quotient) is manufacturing the final [14C]-rencofilstat SMEDDs oral emulsion, suitability 
of the manufacturing process will be documented in a Pharmaceutical Development and 
Control Strategy Report. 
IMP will be reconciled and destroyed in accordance with the study-specific quality 
agreement and technical addendum. 
5.3 
Previous Study Findings 
Full details of previous study findings can be found in the Investigator’s Brochure (IB) 
[11]. A summary of the non-clinical and clinical findings is provided below. 


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5.3.1 Non-clinical Findings 
Non-clinical Pharmacology 
Rencofilstat has been shown to bind specifically and with high potency to several human 
cyclophilin isoforms including Cyp A, Cyp B, Cyp D, and cyclophilin G. Across different 
species, organ types, and experimental systems, rencofilstat treatment resulted in 
therapeutic effects. Notably, rencofilstat decreased markers of inflammation and fibrosis 
in vitro, such as collagen and fibronectin secretion, and decreased liver fibrosis by 37% 
to 82% in disease models.  
Anti-neoplastic properties of rencofilstat were examined both in vitro and in vivo. 
Rencofilstat alone or in combination with other anti-cancer agents decreased growth of 
tumours and reduced tumour burden in mouse models.  
Rencofilstat demonstrated no indication of cytotoxicity, mitochondrial toxicity, 
immunosuppression, or off-target safety findings, consistent with long-term toxicology 
studies in rat and monkey that showed no rencofilstat-induced toxicity. 
Non-clinical Pharmacokinetics and Metabolism 
The PK characteristics of rencofilstat including drug absorption, distribution, and 
metabolism were determined in vitro and in rat and monkey. Seven-day, 30-day, 
26-week, and 39-week TK studies were conducted in rat and monkey.  
Whole blood is the preferred matrix as rencofilstat partitions primarily in red blood cells 
at concentrations ≤ 2 μM, and predominantly in the plasma fraction at 10 μM. Rencofilstat 
exhibited >96% plasma protein binding and is stable in rat, monkey and human whole 
blood and plasma for at least 8 h.  
Rencofilstat was predominantly metabolized by cytochrome P450 (CYP450) 3A4 into at 
least 12 distinct metabolites which is consistent with the reported metabolism of other 
cyclosporine analogues. Rencofilstat was not a significant inhibitor of any CYP450s and 
was not found to be an enzyme inducer.  
The pharmacokinetics (PK) of rencofilstat in rats and monkeys showed an increase in 
exposure with dose but appeared to reach a saturation point at the higher doses with a 
Tmax ranging from 1 to 8 h. 
Non-clinical Toxicology 
In both acute (30-day) and chronic (6- and 9-month) toxicology studies in rats and 
monkeys, rencofilstat was well tolerated and did not result in notable changes in weight, 
appetence, or clinical signs and symptoms.  
In rat, multiples of human exposure were up to 4.9-fold at the clinical dose of 75 mg and 
up to 3.4-fold relative to the 225 mg dose. In the monkey, multiples of human exposure 
were up to 5.4-fold at the clinical dose of 75 mg and 3.7-fold relative to the 225 mg dose.  
Genotoxicity studies included in vitro bacterial reverse mutation assay and mammalian 
chromosomal aberration test, and in vivo mammalian erythrocyte micronucleus test 
(conducted as part of the 30-day rat toxicity study). No genotoxicity findings were 
observed. 


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In single- and repeat-dose toxicity studies in rats and monkeys, no mortality, clinical 
signs, changes in body weight, or genotoxicity were observed throughout the studies. 
The NOAEL for both rat and monkey was considered to be the highest dose level tested 
or the highest dose before plateau of exposure. 
5.3.2 Clinical Findings 
Rencofilstat PK parameters, safety, and efficacy in humans was investigated in three 
Phase 1 clinical studies and one Phase 2 clinical study. To date there have been no 
deaths or serious adverse events (SAEs). Most TEAEs were mild or moderate in severity 
and occurred at comparable rates between placebo and rencofilstat. There are two 
ongoing clinical studies in NASH subjects. 
Brief Safety Summary of Completed Clinical Studies 
During the first in human study of rencofilstat  in healthy volunteers (CRV431-101) there 
was no trend observed for adverse event (AE) reporting in relation to the rencofilstat 
dose. There were also no remarkable observations in the remaining safety assessments 
for vital signs, 12-lead ECGs, or safety laboratory measurements in this study. 
The result of CRV431-103 study in healthy volunteers indicated that rencofilstat does not 
alter the PK of midazolam or its metabolite, 1-hydroxymethyl midazolam. Midazolam and 
ketoconazole did alter the PK of rencofilstat, resulting in approximately 2-fold and 4-fold 
higher exposures, respectively. One subject was discontinued from study participation 
due to an AE of elevated alanine aminotransferase (ALT)/AST who was later determined 
to have infection with Coronavirus Disease 2019 (COVID-19). 
Administration of rencofilstat with a high fat meal in study CRV431-104 led to increases 
in Cmax, AUC(0-24), and AUC(0-inf) fed to fasted geometric mean ratios of 102.2%, 
114.5% and 132.9%, respectively. The upper bounds of the 90% confidence intervals 
extended beyond the 80-125% range for AUC(0-last) and AUC(0-inf), All AUC geometric 
mean ratios were outside of the 80–125% range, suggesting a high fat meal can increase 
the extent of rencofilstat exposure. Tmax increased from 1.5 to 1.8 h in the fasted and 
high fat groups, respectively, suggesting slightly delayed absorption. Mean half-life was 
approximately 22 h longer for subjects administered rencofilstat with food compared to 
subjects administered rencofilstat under fasted conditions, although inter-subject 
variability was considerably higher for the fed cohort. 
During CRV431-201 study, a multiple dose study in patients with NASH, two subjects 
discontinued the study treatment due to an AE; one subject experienced palpitations 
leading to discontinuation on study day 3 and another withdrew due to myalgia, migraine, 
and pyrexia on study day 7. A total of 21 (44.7%) subjects experienced 36 AEs, with 
most (69.4%) being unrelated to study treatment. A majority (97.2%) were mild to 
moderate in severity. One AE, constipation, was reported as severe (Grade 3), and there 
were no deaths or SAEs reported in the study. There were no AEs related to change in 
laboratory values, including liver biochemical markers, reported except for one subject 
with hypercholesterolaemia and one subject with a urinary tract infection. 
Overall, rencofilstat was deemed safe and well tolerated at all combinations tested to 
date in both healthy and NASH subjects. 


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Summary of Completed and Ongoing Clinical Studies to Date 
Study ID 
Phase 
Population 
Study Title 
Study design 
Dosing regimen 
Completed Clinical Studies 
CRV431-
101 
 
Phase 1 
Healthy 
Subjects 
A Randomized, Partially 
Blinded, Placebo-controlled, 
Ascending Sequential Dose 
Groups, Single Dose Study of 
the Safety, Tolerability and 
Pharmacokinetics of CRV431, 
Alone and in Combination with 
Tenofovir Disoproxil Fumarate 
and in Multiple Ascending 
Sequentially Dosed Healthy 
Subjects 
Randomised, 
subject-
blinded, 
placebo 
controlled 
ascending 
SAD and MAD 
Part 1 (SAD): 
75, 225, 375, or 
525 mg PO 
Part 2 (DDI): 
375 mg rencofilstat PO, 
300 mg TDF PO, or 
combination  
Part 3 (MAD): 
75, 150, 225, 300 or 
375 mg PO QD, 
28 days 
CRV431-
103  
 
Phase 1 
Healthy 
Subjects 
A Single Center, Open-Label, 
Phase 1 DDI Study to 
Evaluate the Pharmacokinetics 
of CRV431 in Normal Healthy 
Volunteer Subjects 
Randomised, 
open label, 
Phase 1, 
single-centre 
DDI study 
75 mg rencofilstat PO 
alone or in combination 
with 400 mg 
ketoconazole PO or 2 
mg midazolam IV 
CRV431-
104 
 
Phase 1 
Healthy 
Subjects 
A Single Center, Open-Label, 
Phase 1 Study to Evaluate the 
Pharmacokinetics of CRV431 
Under Fasted and Fed States 
in Normal Healthy Volunteer 
Subjects 
Open label, 
single dose 
225 mg PO 
CRV431-
201 
 
Phase 2a 
Presumed 
F2/F3 NASH 
Subjects 
AMBITION: A Phase 2a, Multi-
Center, Single-Blind, Placebo-
Controlled Study to Evaluate 
the Safety and Tolerability of 
CRV431 Dosed Once Daily in 
NASH Induced F2 and F3 
Subjects 
Multi-centre, 
single blind, 
placebo 
controlled 
75 mg or 225 mg PO 
QD,  
28 days 
Ongoing Clinical Studies 
CRV431-
207 
 
Phase 2b 
NASH 
Subjects 
ASCEND-NASH: A Phase 2B, 
Randomized, Multi-center, 
Double-blind, Placebo-
controlled Study to Evaluate 
the Efficacy and Safety of 
Rencofilstat in Adult Subjects 
with Nonalcoholic 
Steatohepatitis and Advanced 
Liver Fibrosis 
Multi-centre, 
double blind, 
placebo 
controlled 
75 mg, 150 mg and 
225 mg plus placebo, 
QD for 365 days PO  
 
CRV431-
210 
 
Phase 2 
NASH 
Subjects 
ALTITUDE-NASH: A Phase 2, 
Randomized, Multi-center, 
Open-label Study to Evaluate 
the Safety and Efficacy of 
Rencofilstat in Adult Subjects 
with Nonalcoholic 
Steatohepatitis Stage 3 
Fibrosis 
Multi-centre, 
open label 
75 mg, 150 mg and 
225 mg QD for 
120 days PO 
DDI: drug-drug interaction, MAD: Multiple Ascending Dose, SAD: Single Ascending Dose, TDF: tenofovir 
disoproxil fumarate 
Pharmacokinetics Summary of Single Ascending Doses in Healthy Volunteers 
PK analyses have been performed in all of the completed clinical trials to date. 
Rencofilstat PK have been consistent and repeatable in both healthy volunteer subjects 


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and presumed F2/F3 NASH subjects. As the current study is a single dose study, only 
single ascending dose (SAD) PK parameters are summarised here. 
In the CRV431-101 SAD part of the study, healthy volunteers received single doses of 
rencofilstat at 75, 225, 375, and 525 mg, or vehicle (liquid formulation), and PK was 
assessed for 6 days post-dose. Results demonstrated a plateauing of the apparent rate 
(Cmax) and extent (AUC) of rencofilstat exposure at dose levels above 225 mg. This 
was consistent with PK observations in rat and monkey that showed a plateau between 
middle and high dosing levels. 
Single dose PK of rencofilstat approximated first-order behaviour from 75 mg to 225 mg 
with decreasing exposure after 375 mg. Dose proportionality was initially greater than 
1:1 but decreased with the plateauing of exposure (Table 2).  
Table 2 
Summary of Whole Blood Rencofilstat Pharmacokinetic Parameters 
Following Single Oral Doses (SAD, PK Population) 
PK 
Parameters 
Rencofilstat 
75 mg (N=6) 
Rencofilstat 
225 mg (N=6) 
Rencofilstat  
375 mg (N=6) 
Rencofilstat  
525 mg (N=6) 
AUC(0-24) 
(ng.hr/mL) 
6048 ± 24.9 
17720 ± 27.8 
15670 ± 29.3 
18170 ± 18.2 
AUC(0-last) 
(ng.hr/mL) 
16620 ± 18.7 
53530 ± 32.4 
50640 ± 34.9 
62340 ± 24.2 
AUC(0-inf) 
(ng.hr/mL) 
20550 ± 18.1 
80030 ± 36.2 
79980 ± 50.2 
92870 ± 32.1 
Cmax  
(ng/mL) 
320.5 (32.0) 
1354 (15.5) 
1204 (58.3) 
1640 (15.0) 
Tmax 
(hr) 
2.99 
(2.00, 10.00) 
1.00 
(1.00, 2.00) 
1.00 
(1.00, 4.00) 
1.00 
(1.00, 100) 
T1/2 (hr) 
73.6 ± 15.2 
98.14 ± 17.96 
111.27 ± 37.25 
94.05 ± 17.87 
CL/F 
(L/hr) 
3.7 ± 0.7 
3.0 ± 0.9 
5.2 ± 2.7 
5.9 ± 1.6 
Vz/F (L) 
392.6 ± 115.50 
412.7 ± 144.0 
753.7 ± 244.7 
765.7 ± 136.9 
Cmax presented as geometric mean (geometric CV%). Tmax presented as median (minimum, maximum). 
Other parameters are presented as arithmetic mean ± SD. 
Safety Summary of Single Ascending Doses in Healthy Volunteers 
In the CRV431-101 SAD part of the study there were no deaths, SAEs, or subject 
discontinuations due to AEs in Part 1 of the study. Overall, a total of 20 AEs were 
experienced by 14 (47%) subjects following active treatment, with 3 (50%) subjects 
reporting 3 events following rencofilstat 75 mg, 1 (17%) subject reporting 5 events 
following rencofilstat 225 mg, 3 (50%) subjects reporting 3 events following rencofilstat 
375 mg, 3 (50%) subjects reporting 5 events following rencofilstat 525 mg, 4 (67%) 
subjects reporting 4 events following rencofilstat 375 mg ingested immediately following 
dilution, and 6 (60%) subjects reported 15 events following placebo.  
Mild constipation was the most commonly reported event, reported a total of 3 times by 
3 (10%) active-treatment subjects in Part 1 of the study, with 1 subject each reporting 
1 event following rencofilstat 375 mg, rencofilstat 525 mg, and rencofilstat 375 mg 
ingested immediately following dilution. The investigator considered all events to be 
possibly related to the study treatment. Each of the remaining AE terms were reported 
in ≤ 2 subjects (≤ 7%). 


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6 Rationale 
6.1 
Study Rationale 
This study aims to understand the absorption, distribution, metabolism and elimination 
(ADME) of rencofilstat in humans further through the assessment of the mass balance 
recovery after a single oral dose of [14C]-rencofilstat. The routes and rates of elimination 
of [14C]-rencofilstat will be determined and whole blood, urine and faecal samples will be 
used for metabolic profiling and structural identification. 
This is a single dose mass balance study of a single formulation, the study will be 
open-label and no randomisation is required. 
6.2 
Dose Rationale 
The Phase I clinical study found that rencofilstat was safe and well tolerated at single 
doses from 75 mg to 525 mg and at multiple doses of 75 mg to 375 mg, administered 
daily for 28 days.  
Systemic exposure of rencofilstat as measured by Cmax and AUC are approximately 
10 to 100-fold above the drug’s IC50 for inhibition of cyclophilins. Thus, the doses tested 
from the 75 mg dose upwards achieve systemic concentrations necessary to adequately 
engage the drug receptors at the site of action. Doses of 75 mg and 225 mg per day for 
28 days were studied in the Phase 2 study in patients with NASH. A dose of 225 mg has 
been chosen for this study as in previous clinical studies, rencofilstat systemic exposure 
has been found to plateau at doses equal to and higher than 225 mg. It is expected that 
225 mg will be the most efficacious dose and is currently the highest dose being 
evaluated in the Phase II clinical trials. 
The dose of radioactivity has been determined following review of human dosimetry 
calculations provided by UK Health Security Agency. The associated radiation exposure 
will fall within International Commission on Radiological Protection (ICRP) (1992) 
Guidelines for Category IIb studies (1 to 10 mSv). The dose of radioactivity will be no 
more than 6.4 MBq. 
To ensure that the [14C] drug product does not exceed the limit for radioactive dose 
approved by the Administration of Radioactive Substances Advisory Committee 
(ARSAC), the target specific activity of the drug substance will be set at 90% of 90% of 
the threshold radioactive dosing limit. This will allow for tolerances in the manufacturing 
processes for both drug substance and drug product thereby providing continued 
assurance for compliance with the ARSAC-approved limit for drug product radioactivity 
dose. 
6.3 
Population Rationale 
As this is a Phase I study assessing the ADME, PK and safety of rencofilstat, the most 
relevant population is healthy volunteers. Subjects who are non-smokers without a 
history of alcohol or drug abuse or regular co-medication are proposed to avoid 
interaction on drug metabolism and to avoid non-compliance.  
Data is not currently available from fertility and teratology studies with rencofilstat and 
subjects will be exposed to radiation; therefore, female subjects will not be enrolled in 
this study. 


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We acknowledge the ARSAC Notes for Guidance recommend that wherever possible, 
healthy subjects selected for research projects should be aged over 50 years [12]. 
However, the current study is designed to generate data for supporting the investigation 
of the human ADME of a drug, as well as generating samples for metabolite profiling and 
structural identification. 
There are two main reasons for generating these data within a clinical development 
programme. The first is to provide human metabolite data that can be used to interpret 
the metabolism profiles seen in the preclinical species employed in the longer-term 
toxicity studies, to ensure that there is adequate toxicology coverage for the safe 
development of the drug in patients. The second is to provide data to understand how 
the drug is processed in physiologically normal subjects, because understanding the 
routes of metabolism and elimination in a healthy population generates the appropriate 
data to guide the clinical pharmacology package required to fulfil the regulatory 
requirements of a New Drug Application.  
In order to address these two main aims of an ADME study, investigation of the drug 
under development is required in a population with normal physiological function, as it is 
recognised that certain physiological processes eg renal function, deteriorate with age 
and therefore it is preferable to use as healthy a population as possible, to mitigate 
against factors which may make interpretation of the data difficult. Also, healthy subjects 
as a trial population are ideal since they have a relatively stable physiological, 
biochemical and hormonal status, which removes any disease-related variations and 
variations due to concomitant medications. Therefore, given the aims of this ADME study 
our target age range for this study will be 30 to 65 years. 
In addition, the initial target indication of this drug is NASH and, therefore, the target age 
range for the indication is included in the proposed age range for the study.  
6.4 
Risks and Benefits 
6.4.1 Risks Associated with Rencofilstat Administration 
Rencofilstat, previously known as CRV431, has been studied in three Phase I studies in 
healthy volunteers (CRV431-101, CRV431-103, and CRV431-104) as well as in a 
Phase 2a study in NASH patients (CRV431-201). CRV431-101 was a first in human 
study of rencofilstat comprised of 1) a SAD study; 2) a DDI study between rencofilstat 
and TDF; and 3) a 28-day MAD study. There were no deaths or SAEs in any parts of the 
study.  
In Part 1, 20 AEs were experienced by 14 (47%) subjects following active treatment. The 
investigator assessed 18 events to be Grade 1, and 2 events to be Grade 2 in severity; 
9 events were possibly related to study treatment, and 11 events were assessed as 
unrelated to the study treatment. Mild constipation was the most commonly reported AE, 
by 3 (10%) active treatment subjects, with 1 subject each in the 375 mg, 525 mg, and 
375 mg (SMEDD ingested immediately following dilution) cohorts reporting 1 event each 
and was considered by the PI to be possibly related to the study. 
In Part 2 headache was the most reported AE, reported 11 times by 8 subjects (44%). 
Fatigue and oropharyngeal pain were reported 3 times by 3 subjects (17%); dyspepsia, 
myalgia, nausea, and dizziness were reported 2 times by 2 subjects (11%). Events were 
generally distributed across treatment conditions, with a moderate increase seen in AEs 
in the combination rencofilstat plus TDF treatment (12/18 subjects [67%]) than in 
rencofilstat (8/18 [44%]) or TDF (7/18 [39%]) alone. 


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In Part 3, 2 subjects were discontinued due to AEs (1 due to urinary tract and yeast 
infections and 1 due to headache and lower abdominal pain). Only 3 AEs occurred in 
≥ 3 subjects: headache in 4 subjects (12%); fatigue, and diarrhoea in 3 subjects (9%). 
All events were Grade 1 or 2 in severity. There was no apparent relationship between 
rencofilstat dose level and AE frequency. 
Overall, there was no trend observed for AE reporting in relation to rencofilstat dose. 
There were no remarkable observations in the remaining safety assessments for vital 
signs, 12-lead ECGs, or safety laboratory measurements in this study.  
In study CRV431-103, there were no SAEs or deaths reported following treatment with 
75 mg rencofilstat alone or in combination with 400 mg ketoconazole or 2 mg midazolam. 
One patient discontinued study participation due to a TEAE of elevated ALT/AST and 
subsequent COVID-19 infection. Twenty-eight AEs were recorded for 12 subjects. 
Investigators assessed 21 AEs as Grade 1, 6 AEs as Grade 2, and 1 AE as Grade 3. 
The grade 3 AE, elevated ALT, was considered unrelated to study drug and instead 
related to COVID-19 infection. TEAEs reported in 2 or more subjects were nausea 
(4 subjects [14.8%], diarrhoea, dizziness, headache, alanine aminotransferase 
increased, and aspartate aminotransferase increased (2 subjects [7.4%]). There were 
no findings or changes from baseline observed in any of the laboratory parameters 
(haematology, coagulation, blood chemistry, urinalysis), vital signs, pulse oximetry or 
ECG that were deemed to be clinically significant by the investigator. 
In study CRV431-104, there was 1 AE related to clinically significant out-of-range vital 
signs (blood pressure increased) reported by 1 subject in the fed cohort. The AE was 
Grade 1 (mild) and judged by the Investigator as not related to study treatment. 
Overall, rencofilstat was safe and well tolerated at all combinations tested to date in 
healthy subjects. There are no important identified risks or potential identified risks from 
the rencofilstat development program.  
Non-clinical genotoxicity studies were all negative. These data presented a favourable 
safety profile for rencofilstat with acceptable safety margins that support the proposed 
clinical development program. No reproductive or developmental toxicity studies of 
rencofilstat have been performed as of the IB cut-off date of 01 Oct 2022. However, no 
females will take part in this study, and the male volunteers must agree to adhere to the 
contraception requirements defined in Section 9.4. No phototoxicity studies have been 
conducted on rencofilstat as of the IB cut-off date of 01 Oct 2022. Owing to the 
unavailability of phototoxicity data, subjects will be advised to minimise exposure to 
sunlight following dosing until discharge from the study (see Section 9.6). 
All formulation excipients are United States Pharmacopeia (USP) grade or National 
Formulary (NF) grade and therefore have a Generally Recognised As Safe (GRAS) 
designation. Consequently, it is deemed safe to use in this study.  
Given the current safety results, the benefit-risk is anticipated to be favourable at all dose 
levels tested. 


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6.4.2 Risks Associated with Administration of Radioactivity 
The dosage form will contain a radionuclide, not more than (NMT) 6.4 MBq 14C, so 
subjects will be exposed to ionising radiation. The effective dose that each subject will 
receive from 1 administration of 6.4 MBq 14C will not exceed 2.0 mSv. This is 
approximately 9 months of the average radiation exposure received in the UK each year 
(2.7 mSv; data obtained from UK Health Security Agency Ionising Radiation Exposure 
of the UK Population: 2010 Review [13]) and is slightly more (1.1 times) than the radiation 
dose that would result from 4 abdominal X-rays (0.47 mSv each). It is believed that any 
increase in the amount of radiation that is received above natural radiation carries a risk 
of later developing serious and possibly fatal conditions. The risk associated with the 
maximum possible dose of radiation in this study is very small indeed and is considered 
to be acceptable. 
Extrapolation of data from epidemiological studies of cancers induced by radiation 
exposure indicates that the risk factor for an adult UK population of both sexes (age 
range 18 to 64) is 5 × 10-2 per Sv [14]. From this it can be estimated that the lifetime risk 
of inducing a fatal cancer in a healthy individual from the total exposure of 2.0 mSv is 
approximately 1 in 10,000. The lifetime risk for being diagnosed with cancer in the UK is 
around 1 in 2 [15], indicating that this additional risk from this amount of radiation 
exposure is minimal. 
6.4.3 COVID-19 Related Risks and Risk Mitigation Measures 
The following risks and risk mitigating measures apply to the time in which the study is 
conducted during the COVID-19 pandemic.  
6.4.3.1 IMP Related Risk 
Against the background of the COVID-19 pandemic, the potential risk of a subject 
developing COVID-19 has been considered in terms of the risk-benefit evaluation. The 
mode of action of the IMP – as a cyclophilin inhibitor – has been considered alongside 
available pre-clinical and clinical data (including class effects) and it is considered that a 
subject would not be at increased risk of either becoming infected with severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2; the virus that causes COVID-19) or 
experiencing a more severe illness. That is, the IMP has no known immunomodulatory 
effect that would confer an increased risk to healthy subjects enrolled in the study. 
6.4.3.2 General COVID-19 Related Risk Mitigation Measures 
General risk mitigation against COVID-19 will be implemented in accordance with 
Quotient’s monitoring and prevention control measures. 
COVID-19 testing may be performed based on current infection rates and availability of 
tests. If required, it is planned that testing will comprise an antigen test performed on 
Day -1 prior to admission to the clinical unit and at return visits. Testing time points may 
be changed, and additional time points may be added throughout the study as required. 
The decision on COVID-19 testing and the definition of the testing time points are subject 
to change based on the current risk mitigation in place and will be agreed by the study 
team and documented in the Investigator Site File (ISF) via the Clinical Kick-Off Meeting 
minutes. 
The risk mitigation measures, where applicable, will be amended based on emerging 
government guidance. 


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6.4.3.3 COVID-19 Vaccine-Related Risk 
Approved (including health authority conditional marketing authorisation) COVID-19 
vaccines eg killed, inactivated, peptide, DNA and RNA vaccines may be permitted 
according to the investigator’s discretion and as per local guidance.  
Based on the mechanism of action of the IMP, as an inhibitor of cyclophilin, there is no 
perceived impact on the safety of the study subjects or on the study objectives for 
subjects who may receive these vaccines. It is also very unlikely that administration of 
the IMP would interfere with COVID19 vaccination response; however, no specific 
preclinical or clinical investigations have been conducted at this point with rencofilstat.  
6.4.4 General Risks and Overall Risk-Benefit Assessment  
Collecting a blood sample from a vein may cause pain, swelling, bruising, 
light-headedness, fainting, and very rarely, clot formation, nerve damage and/or infection 
at the site of the needle stick. 
During cannulation, more than one attempt may be needed to insert the cannula in a 
vein of a subject and it is possible that bruising and/or inflammation may be experienced 
at the site of cannulation.  
ECG stickers on the subjects' chests and limbs may cause some local irritation and may 
be uncomfortable to remove but subjects will be closely monitored to ensure any local 
irritation does not persist. 
There is no benefit to the subjects from taking part in this study. The development of a 
product to treat NASH and viral hepatitis-induced liver disease may be of benefit to the 
patients with these diseases. 
The overall risk benefit balance is therefore considered to be acceptable. 
 
 


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7 Objectives and Endpoints 
Objectives 
Endpoints 
Primary  
 
To determine the mass balance recovery after a 
single oral dose of [14C]-rencofilstat 
 
Mass balance recovery of total radioactivity (TR) in 
all excreta (urine and faeces): CumAe and 
Cum%Ae 
To determine % parent drug unchanged versus 
metabolites 
Parent to total radioactivity ratio for whole blood 
based on AUC 
To perform metabolite profiling and structural 
identification from whole blood, urine and faecal 
samplesa 
Collection of whole blood, urine and faeces 
samples 
for 
metabolite 
profiling, 
structural 
identification, and quantification analysis 
Secondary 
To determine the routes and rates of elimination of 
[14C]-rencofilstat 
 
Mass balance recovery of TR in urine and faeces 
separately: Ae, %Ae, CumAe and Cum%Ae by 
interval 
To identify the chemical structure of each metabolite 
accounting for more than 10% of circulating TR or 
accounting for 10% or more of the dose in excreta 
Identification of the chemical structure of each 
metabolite accounting for more than 10% by AUC 
of circulating TR or accounting for 10% or more of 
the dose in excreta 
To evaluate the extent of distribution of TR into 
blood cells 
Evaluation of whole blood:plasma concentration 
ratios for TR 
To provide additional safety and tolerability 
information for rencofilstat 
To provide additional safety and tolerability 
information for rencofilstat by assessing: incidence 
of AEs, physical examinations and change from 
baseline for vital signs, ECGs, and laboratory safety 
tests 
To further explore the oral PK of rencofilstat 
PK parameters for rencofilstat in whole blood and 
TR in plasma and whole blood following a single 
oral dose, including but not limited to: Tlag, Tmax, 
Cmax, 
AUC(0-last), 
AUC(0-inf), 
AUC(0-24), 
Lambda-z, T1/2, CL/F, Vz/F, MRT(0-last) and 
MRT(0-inf) as applicable 
a Metabolite profiling and identification will be reported separately from the clinical study report as a 
standalone document. 
8 Study Design 
8.1 
Study Plan 
This is a single centre, open-label, non-randomised, single period, single dose study in 
healthy male subjects designed to assess the mass balance recovery, PK, metabolite 
profile and metabolite identification of rencofilstat. It is planned to enrol a single cohort 
of 6 subjects.  
All subjects will receive a single 225 mg oral dose of [14C]-rencofilstat, as a SMEDDS 
oral emulsion, containing NMT 6.4 MBq, in the fasted state.  
Subjects will undergo preliminary screening procedures for the study at the screening 
visit (Day -28 to Day -2). Subjects will be admitted in the evening on the day before 
dosing (Day -1). 
Whole blood, plasma, urine and faeces samples will be collected at regular intervals for 
PK analysis, TR analysis, metabolite profiling, mass balance and safety as applicable, 
from pre-dose to discharge from the clinical unit. Urine and faeces samples may be 
collected at return visits or home visits if mass balance criteria has not been met by a 
subject. 


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Subjects will be dosed on the morning of Day 1 following an overnight fast (minimum 8 h) 
and will remain resident in the clinical unit until up to 504 h after dosing (up to Day 22).  
It is planned that subjects will be released as a group when all subjects have achieved a 
mass balance cumulative recovery of >90% or if <1% of the dose administered has been 
collected in urine and faeces within two separate, consecutive 24 h periods. This may 
result in the subjects being discharged as a group prior to completion of the planned 
residency period.  
If the mass balance criteria are achieved during the planned residency period, collection 
of all samples (blood, urine and faeces) will be stopped once the current 24 h collection 
period is complete, and subjects will undergo discharge assessments. 
If the mass balance criteria have not been met by all subjects on the morning of 
Day 22, the residency period for the subjects not achieving the mass balance criteria 
may be extended up to a maximum of 96 h (Day 26; 600 h post-dose). Only urine and/or 
faecal samples will be collected during the extended residency period. 
If the mass balance criteria have not been met by all subjects on the morning of 
Day 26, subjects not achieving the release criteria may be required to make up to 
2 return visits (each of 24 h duration) at (nominally) Day 28 (+2 days) and 
Day 35 (±2 days) for additional collection of excreta samples (urine and/or faecal 
samples). 
If the mass balance criteria have not been met following the return visits, then home 
collections of urine and/or faeces may be requested at the discretion of the investigator 
for individual subjects. 
A subject will be considered evaluable if they have provided mass balance and PK 
samples for up to 21 days after drug administration or have demonstrated >90% mass 
balance recovery or have <1% of the administered dose eliminated in excreta for two 
consecutive days, whichever is sooner. 


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Figure 1 
Study Sequence 
Screening 
Day -28 to Day -2 
 
Admission 
Day -1 
 
Dose 
Day 1 
 
Discharge 
Day 22  
 
Or, if mass balance criteria are 
not met by Day 22a: 
Extended Residency Discharge 
Day 23, 24, 25 or 26 
 
And, if mass balance criteria 
are not met by Day 26b: 
Return Visit 
Day 28 (+2 days) 
 
And, if mass balance criteria 
are not met by Day 28b: 
Return Visit 
Day 35 (±2 days) 
a If all subjects have not achieved a mass balance cumulative recovery of >90% or if a total of <1% of the 
dose administered has not been collected in urine and faeces within 2 separate, consecutive 24 h periods 
on the morning of Day 22, the residency period for the subjects not achieving the mass balance criteria may 
be extended up to a maximum of 96 h (Day 26). Only urine and/or faecal samples will be collected during 
the extended residency period.  
b If the mass balance criteria have not been met by all subjects on the morning of Day 26, subjects not 
achieving the release criteria may be required to make up to 2 return visits (each of 24 h duration) at 
(nominally) Day 28 (+2 days) and Day 35 (±2 days) for additional collection of excreta samples (urine and/or 
faecal samples). If the mass balance criteria have not met following the return visits, then home collections 
of urine and/or faeces may be requested at the discretion of the investigator for individual subjects. 
8.2 
Criteria for In-Study Decisions 
Not applicable for this study. 
8.3 
Subject Withdrawal 
If a subject wishes to leave the study at any time, they will be permitted to do so. Every 
reasonable effort will be made by Quotient to complete a final assessment/discharge 
procedures. Quotient will advise the sponsor of the withdrawal of any subject from the 
study. 
Early withdrawal is defined as the date of the decision to withdraw the subject from the 
study. Subject completion is defined as the date of the last procedure conducted or last 
contact (eg unscheduled phone call or visit) for that subject. 


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Note that if a subject requests to leave the clinical unit earlier than the planned discharge 
time, eg due to unforeseen personal circumstances, they may be withdrawn from the 
study and may not be able to return to the clinical unit to complete the study. 
This is a single dose study, therefore, after an individual subject has received a dose of 
IMP, withdrawal of that subject from further dosing is not possible. Subjects will be 
monitored for the following criteria which may require their withdrawal from some or all 
study procedures if continuation is not in their best interests, except when the withdrawal 
is a result of withdrawal of consent:  
• 
Experiencing a serious or severe AE including but not limited to: 
− corrected QT interval by Fridericia’s formula (QTcF) of >500 msec or 
increase in QTcF interval of >60 msec from baseline (confirmed following 
a repeat ECG)  
− ALT concentration >3 × the upper limit of the reference range (confirmed 
following a repeat ALT blood test) 
• 
Termination of the study 
• 
Upon the subject’s request (withdrawal of consent) 
• 
Significant deviation from the protocol 
• 
Concurrent illness that would adversely affect subject safety or data integrity or 
requirement for prohibited medication 
• 
At the discretion of the investigator 
For the purpose of withdrawal criteria, baseline will be considered as the last available 
assessment prior to IMP dose. 
For a subject who withdraws because of an IMP-related AE, every effort will be made to 
ensure the subject completes follow-up procedures.  
Early withdrawal of consent by the subject to participate in any further activities will be 
distinguished from withdrawal for any of the other above reasons. 
8.4 
Subject Replacement 
No replacement subjects are planned for this study. 
8.5 
Stopping Criteria 
The study will be halted, and the risk to other subjects evaluated if any of the following 
criteria are met:  
• 
A serious adverse reaction (ie a SAE considered at least possibly related to the IMP 
administration) in one subject. 
• 
Severe non-serious adverse reactions (ie severe non-serious AE considered as, at 
least possibly related to the IMP administration) in two subjects in the same cohort, 
independent of within or not within the same system organ class. 
Relatedness to IMP will be determined by the investigator.  


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If the study is halted, a temporary halt will be submitted to the Medicines and Healthcare 
products Regulatory Agency (MHRA) and ethics committee (EC) in the form of a 
substantial amendment. The study may be resumed or terminated; however, it will not 
be resumed until a further substantial amendment to resume the study is submitted and 
approved by MHRA and EC. 
The ARSAC Practitioner will also be informed of the temporary halt. 
8.6 
Study Termination 
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the sponsor and investigator without consultation with the MHRA, 
EC, ARSAC practitioner or ARSAC. The ARSAC practitioner and ARSAC (if ARSAC 
research application has been submitted or approved) must be notified promptly, that the 
study will no longer be taking place. Notification of early termination should also be 
provided to the EC and MHRA within 15 days, clearly explaining the reasons for the 
termination. 
If the study is abandoned prior to commencement of any protocol activities, the 
investigator or sponsor must notify the EC, MHRA, ARSAC practitioner and ARSAC (if 
ARSAC research application has been submitted or approved) outlining the reasons for 
abandonment of the trial. 
New information regarding the safety of the IMP that indicates a change in the risk/benefit 
profile for the compound, such that the risk/benefit is no longer acceptable for subjects 
participating in the study may also mean termination of the study prior to dosing.  
Once exposure to dosing has begun, the study will be completed as planned unless the 
following criteria are satisfied that require a temporary halt or early termination of the 
study.  
• 
The occurrence of serious or severe AE(s), as defined in Section 8.5, if considered 
to be related to the IMP, as defined in Section 14.2, on the dosing day. 
• 
Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises subject safety. 
If any of the above occurs, the study will be terminated if careful review of the overall 
risk/benefit analysis described in Section 6.4 demonstrates that the assumptions have 
changed and that the overall balance is no longer acceptable. In these circumstances, 
termination can only take place with the agreement of the investigator and sponsor. The 
MHRA, EC, ARSAC practitioner and ARSAC will be informed of study termination. 
If it becomes necessary to consider termination of the study on the dosing day, dosing 
may be suspended pending discussion between the investigator, sponsor and ARSAC 
practitioner (where discussion is related to administration of radiation). Dosing will be 
stopped immediately on safety grounds. 
The study may be terminated or suspended at the request of the MHRA or EC. 
8.7 
Lost to Follow-up 
A subject will be considered lost to follow-up if they fail to return for scheduled visits and 
cannot be contacted by the clinical unit.  


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If a subject fails to return to the clinical unit for a required study visit: 
• 
The clinical unit must attempt to contact the subject and reschedule the missed visit 
as soon as possible. 
• 
Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (eg three telephone calls on three 
separate occasions and, if necessary, an email or letter to the participant’s last known 
email/postal address). These contact attempts should be documented in the 
subject’s source. 
• 
If the subject cannot be contacted, they will be considered lost to follow-up.  
8.8 
Treatment Assignment 
This is an open-label, non-randomised study, therefore a randomisation schedule will not 
be produced. Instructions to dispense and dose will be produced prior to dosing with 
IMP, which will dictate the order in which the treatments should be administered to each 
subject. The instructions to dispense and dose will be retained in the ISF. 
8.8.1 Subject Numbers 
Subject numbers will be allocated on the morning of dosing according to the code 001 to 
006 using the lowest number available.  
8.8.2 Blinding  
This is an open-label, non-randomised study and therefore blinding is not required. 
9 Selection of Subjects 
Subjects will be recruited from the Quotient panel or by direct advertising to the public. 
Before subjects are admitted to the clinical unit, The Over Volunteering Prevention 
System (TOPS) will be checked to ensure that each subject has not been dosed in a 
study within 90 days of the planned dosing date of this study.  
9.1 
Informed Consent 
Subjects will be provided with a written explanation of the study at least the day before 
the screening visit. Additionally, subjects may be provided with an information video 
before the screening visit that introduces them to the study. In the video and/or during 
the screening visit, a physician or nurse will explain to each subject the nature of the 
study, its purpose, expected duration and the benefits and risks involved in study 
participation. Subjects will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that carry out 
clinical studies nationally. Subjects will then be given the opportunity to ask questions 
and will be informed of their right to withdraw from the study without prejudice. After this 
explanation and before entering the study, the subject will voluntarily sign an informed 
consent form (ICF). Until written consent has been obtained from the subject no study 
specific procedure or investigation will be performed. If an amendment is made to the 
participant information sheet (PIS), participants will be re-consented to the most current 
version of the ICF(s) where appropriate. 
9.2 
Inclusion Criteria 
 Healthy males 
 Aged 30 to 65 years inclusive at the time of signing informed consent  


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 Body mass index (BMI) of 18.0 to 35.0 kg/m2 as measured at screening  
 Must be willing and able to communicate and participate in the whole study 
 Must have regular bowel movements (ie average stool production of ≥1 and 
≤3 stools per day) 
 Must provide written informed consent 
 Must agree to adhere to the contraception requirements defined in Section 9.4 
Inclusion criteria 1, 4, 5 and 7 from the list above will be re-assessed at admission or 
pre-dose. 
9.3 
Exclusion Criteria 
 Subjects who have received any IMP in a clinical research study within the 
90 days prior to Day 1, or less than 5 elimination half-lives prior to Day 1, 
whichever is longer 
 Subjects who are, or are immediate family members of, a study site or sponsor 
employee 
 Evidence or history of current SARS-CoV-2 infection within 4 weeks prior to IMP 
administration  
 History of any drug or alcohol abuse in the past 2 years prior to screening 
 Regular alcohol consumption in males >21 units per week (1 unit = ½ pint beer, 
or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on 
type) 
 A confirmed positive alcohol breath test at screening or admission 
 Current smokers and those who have smoked within the last 12 months prior to 
screening 
 A confirmed breath carbon monoxide reading of greater than 10 ppm at screening 
or admission 
 Current users of e-cigarettes and nicotine replacement products and those who 
have used these products within the last 12 months prior to screening 
 Radiation exposure, including that from the present study, excluding background 
radiation but including diagnostic x-rays and other medical exposures, exceeding 
5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally 
exposed worker, as defined in the Ionising Radiation Regulations 2017 [16], shall 
participate in the study 
 Subjects who do not have suitable veins for multiple venepunctures/cannulation 
as assessed by the investigator or delegate at screening 
 Clinically significant abnormal clinical chemistry, haematology or urinalysis as 
judged by the investigator (laboratory parameters are listed in Appendix 1). 
Subjects known to have Gilbert’s syndrome are excluded 
 Confirmed positive drugs of abuse test result (drugs of abuse tests are listed in 
Appendix 1) 
 Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) 
or human immunodeficiency virus (HIV) antibody results 
 Evidence of renal impairment at screening, as indicated by an estimated eGFR of 
<60 mL/min/1.73m2 using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI; 2009) equation 
 History of clinically significant cardiovascular, renal, hepatic, dermatological, 
chronic respiratory or gastrointestinal disease, malabsorptive, neurological or 
psychiatric disorder, as judged by the investigator 
 Serious adverse reaction or serious hypersensitivity to any drug or the formulation 
excipients  


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 Presence or history of clinically significant allergy requiring treatment, as judged 
by the investigator. Hay fever is allowed unless it is active 
 Donation of blood or plasma within the previous 3 months or loss of greater than 
400 mL of blood 
 Subjects who have taken known strong or moderate CYP3A4 inducers in the 
30 days before IMP administration 
 Subjects who are taking, or have taken, any prescribed or over-the-counter drug 
or herbal remedies (other than up to 4 g of paracetamol per day) in the 14 days 
before IMP administration (see Section 11.4). Exceptions may apply, as 
determined by the investigator, if each of the following criteria are met: medication 
with a short half-life if the washout is such that no pharmacodynamic activity is 
expected by the time of dosing with IMP; and if the use of medication does not 
jeopardize the safety of the trial subject; and if the use of medication is not 
considered to interfere with the objectives of the study 
 Subjects who have had a COVID-19 vaccine 7 days before dosing 
 Failure to satisfy the investigator of fitness to participate for any other reason 
Exclusion criteria 3, 6, 8, 9, 13, 18, 20, 21 and 22 from the list above will be re-assessed 
at admission/pre-dose.  
Healthy subjects who do not meet the inclusion/exclusion criteria for the study will not be 
enrolled. 
9.4 
Contraception and Restrictions 
Male Subjects with Partners of Childbearing Potential 
Male subjects who are sexually active with a partner of childbearing potential must use, 
with their partner, a condom plus an approved method of highly effective contraception 
from the time of informed consent until 111 days after IMP administration. This has been 
calculated based on 90 days (one cycle of spermatogenesis) plus 5 half-lives of the IMP. 
5 half-lives have been calculated as 21 days based on the mean half-life of 98.138 h 
observed in healthy volunteers at a single dose of 225 mg. 
The following methods are acceptable: 
• 
Partner’s use of combined (oestrogen and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation:  
− oral  
− intravaginal  
− transdermal  
• 
Partner’s use of progestogen-only hormonal contraception associated with inhibition 
of ovulation:  
− oral  
− injectable/implantable 
− intrauterine hormone-releasing system  
• 
Partner’s use of intrauterine device  
• 
Vasectomised 
• 
Partner’s bilateral tubal occlusion 
These contraception requirements are considered to be more conservative than the 
guidance issued by the Heads of Medicines Agency: Clinical Trials Facilitation Group 
[17]. 


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Males with Partners of Non-childbearing Potential 
There is a significant risk of drug exposure through the ejaculate (which also applies to 
vasectomised males) that might be harmful to sexual partners. Therefore, even if a male 
is sexually active with a partner of non-childbearing potential they will be required to use 
a condom from IMP administration until discharge from the study.  
All Subjects  
Alternatively, sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
subject. 
9.4.1 Sperm Donation 
Male subjects should not donate sperm for the duration of the study and for 111 days 
after IMP administration. 
9.5 
Pregnancy 
Subjects will be instructed that if their partner becomes pregnant during the study this 
should be reported to the investigator. The investigator should also be notified of 
pregnancy occurring during the study but confirmed after completion of the study. In the 
event that a subject’s partner is subsequently found to be pregnant after the subject is 
included in the study, then consent will be sought from the partner and, if granted, any 
pregnancy will be followed and the status of mother and/or child(ren) will be reported to 
the sponsor after delivery.  
A pregnancy notification form and follow-up will be completed. 
9.6 
Additional Study Restrictions 
The following additional restrictions will be in place for the duration of the study: 
1. Subjects must abstain from alcohol during the 24 h prior to screening and the 24 h 
prior to admission until discharge from the clinical unit 
2. Subjects must not drink liquids or eat food containing grapefruit, cranberry, 
caffeine or other xanthines from 24 h prior to admission until discharge from the 
clinical unit 
3. Subjects should refrain from eating food containing poppy seeds for 48 h prior to 
screening and for 48 h prior to admission until discharge from the clinical unit 
4. Subjects must not take part in any unaccustomed strenuous exercise from the 
72 h before the screening visit and then from 72 h prior to admission until 
discharge from the study  
5. Must not donate blood or plasma (outside of this study), from screening, 
throughout the study duration, and for at least 90 days following dose of IMP 
6. Due to the unavailability of phototoxic data for rencofilstat, subjects will be advised 
to minimise exposure to sunlight by spending a reduced amount of time 
outdoors/remaining inside the clinical unit during the residential periods of the 
study, wearing sunglasses and clothing that minimises exposure to sunlight and 
using sun cream on exposed areas when going outdoors. They will also be 
advised not to use sunbeds. This restriction will be advised from dosing until 
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7. Subjects will not be permitted to shower for 24 h post-dose (to ensure the 
collection of all samples) 
The additional restrictions above are not exclusion criteria; if non-compliance occurs, a 
protocol deviation will be completed.  
10 Study Procedures 
Study procedures will be performed as detailed in the study schedule of assessments in 
Appendix 2, and in accordance with Quotient’s standard operating procedures (SOP)s 
unless otherwise stated in this protocol. 
10.1 Screening 
Within the 28 days preceding dosing, all subjects will be required to undergo a screening 
visit. Screening procedures will be carried out in accordance with the schedule of 
assessments in Appendix 2. 
If the start of the study is delayed for any reason so that the interval between screening 
and dosing exceeds 28 days, all or part of the screening procedures will be repeated at 
the discretion of the investigator. 
Screening safety procedures such as safety bloods, ECGs, vital signs, carbon monoxide 
breath tests, alcohol breath tests and urinalysis can be repeated as clinically indicated 
under the discretion of the investigator or sub-investigator if there is a concern regarding 
a subject’s safety or eligibility to participate in the trial. 
10.1.1 Subject Re-Screening 
This study permits the re-screening of a subject who has discontinued the study as a 
pre-treatment failure (ie subject has not been treated); the reason for failure must be 
temporary and expected to resolve. If re-screened, the subject must be re-consented. 
10.2 Admission and Pre-dose Procedures 
The identity of the subjects will be confirmed at admission and pre-dose.  
In addition, the ongoing eligibility of subjects will be re-assessed at admission/pre-dose, 
as described in Sections 9.2 and 9.3.  
Admission/pre-dose safety procedures such as safety bloods, ECGs, vital signs, 
urinalysis and drugs of abuse tests can be repeated as clinically indicated under the 
discretion of investigator or sub-investigator if there is a concern regarding a subject’s 
safety or eligibility to participate in the clinical trial. 
If dosing is delayed, subjects who have completed admission procedures do not need 
admission procedures to be repeated if dosing is within 2 days and the subjects have 
remained resident in the clinical unit. 
The subjects will be admitted to the clinical unit on the evening before dosing (Day -1).  
In addition, subjects may be required to visit the clinical unit on Day -1 prior to admission 
to the clinical unit for SARS-CoV-2 antigen tests (if required; see Sections 6.4.3.2 and 
14.5.7). Test results must be available prior to dosing. 


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The admission and pre-dose procedures are presented in Appendix 2. 
10.3 Study Day Procedures 
10.3.1 Blood Volume 
The total blood volume for each subject will not exceed 550 mL in a 4-week period.  
The first 0.5 mL of blood withdrawn via cannula will be discarded. 
10.3.2 Timing of Procedures 
There are times where the protocol requires more than one procedure to be completed 
at the same time point. In these instances, the following will apply to post-dose time 
points: 
• 
PK samples should take priority over other procedures scheduled at the same time 
point  
• 
ECGs should be taken prior to vital signs when both measurements are scheduled 
at the same time point  
• 
Other assessments, eg physical examinations, will be performed within the required 
time windows 
As guidance, the preferred order of assessments is: 
 
 
 
 
Nominal 
time 
 
 
ECGs 
 
Vitals 
 
PK blood 
sampling 
 
Other assessments 
eg physical 
examinations 
ECGs should be taken 
prior to vital signs when 
both measurements are 
scheduled at the same 
time point 
 
PK samples should take priority over 
other procedures scheduled at the 
same time point 
Other assessments will 
be performed within the 
required time windows 
 
All safety assessments will be timed and performed relative to the start of dosing. 
10.3.3 Discharge from the Clinical Unit 
A subject will be allowed to leave the premises without additional investigator or 
sub-investigator review, following completion of study-specific procedures providing that: 
• 
No AEs have been reported during the study visit  
• 
The subject responds in the affirmative when asked if they are feeling well 
Refer to Section 8.1 for further details of subject discharge.  
If any of these conditions are not met, then the subject will only be allowed to leave the 
clinical unit with the authorisation of the investigator or sub-investigator. 
There will be no continued provision of the study intervention or treatment for subjects 
as this study involves healthy volunteers only. 


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10.3.4 Return Visits 
If the mass balance criteria have not been met by the morning of Day 26, subjects not 
achieving the release criteria may be required to return to the clinical unit for up to 2 
return visits on Day 28 (+2 days; 648 h post-dose) and (if mass balance criteria are still 
not met by Day 28) Day 35 (±2 days; 816 h post-dose) for 24-h faeces and/or urine 
collections as described in Appendix 2. 
Refer to Section 8.1 for further details. 
10.3.5 Medical Supervision 
A physician will be responsible for the clinical aspects of the study and will be available 
at all times during the study. In accordance with the current Association of the British 
Pharmaceutical Industry guidelines [18], each subject will receive a card stating the 
telephone number of the investigator and the 24/7 contact details of the Quotient’s on-call 
physician. 
11 Dosing of Subjects 
11.1 Food and Fluid Intake 
Subjects will be allowed water up to 1 h before the scheduled dosing time and will be 
provided with 240 mL of water at 1 h post-dose (to ensure adequate hydration), and 
thereafter water will be allowed ad libitum after 1 h post-dose. Decaffeinated fluids will 
be allowed ad libitum from lunch time on the day of dosing. 
If, for technical reasons, dosing is delayed for more than 2 h beyond the expected dosing 
time, subjects will receive 200 mL of an electrolyte drink (eg Lucozade Sport) at the 
originally scheduled dosing time, or earlier if possible. 
The calorie/fat content of meals are not required to be controlled. Subjects will be 
provided with a standardised menu.  
Subjects will be provided with a light snack and then fast from all food and drink (except 
water) for a minimum of 8 h on the day prior to dosing until approximately 4 h post-dose 
at which time lunch will be provided. An evening meal will be provided at approximately 
10 h post-dose and an evening snack at approximately 14 h post-dose. On subsequent 
days, meals will be provided at appropriate times. 
If an individual subject has not experienced a bowel movement in any 36 h period 
post-dose, fluid intake should be increased and administration of a mild laxative (eg 
prune juice or a mild stool softener) should be implemented. 
11.2 Administration of Test Preparations 
Specific details of the IMP and doses to be administered are provided in Section 5.2 and 
Section 8.1, respectively. Subjects will be dosed on the morning of Day 1.  
The exact time of dosing will be decided based on logistics and will be documented in 
the source.  
Subjects will receive 1 single administration on a single occasion. 


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Immediately after administration of the oral emulsion, the dosing vessel will be rinsed 
with water and subjects will consume the rinse solution. Subjects will then consume 
further water to a total volume of 240 mL (including the dosing volume and volume used 
to rinse the dosing vessel). 
11.3 Dosing Compliance 
During all clinical phases of the study, subjects will be observed by study staff to assure 
compliance to all study procedures, including dose administration.  
Mouth checks will be conducted after dosing to ensure the emulsion has been 
swallowed.  
The date and time that each subject is dosed will be recorded in the subject’s source 
data. Any violation of compliance will require evaluation by the investigator and sponsor 
to determine if the subject can continue in the study. 
11.4 Prior and Concomitant Medications 
No prescribed, over-the-counter medication or herbal remedies will be permitted from 
14 days before IMP administration until discharge from the study except up to 4 g of 
paracetamol per day and those deemed necessary by the investigator to treat AEs (see 
also Section 9.3).  
In addition, no strong or moderate CYP3A4 inducers will be permitted from 30 days 
before IMP administration until discharge from the study. 
Any medications used will be recorded in the source. 
Subjects are not permitted to receive the COVID-19 vaccine within 7 days prior to 
administration of IMP, so that by the time of dosing any effects of the vaccine (eg, 
pyrexia, fatigue, pain/stiffness at site of injection) are likely to have abated. Subjects will 
be permitted to have the vaccination when discharged from the clinical unit. 
Emergency equipment and drugs will be available within the clinical unit as per current 
standard procedures. In the unlikely event that they are required, their use will be 
documented. 
12 Assessment of Efficacy 
Not applicable for this Phase I study.  
13 Assessment of Mass Balance, Pharmacokinetics, Metabolite 
Profiling and Identification, and Pharmacodynamics 
13.1 Assessment of Mass Balance, Pharmacokinetic, and Metabolite Profiling and 
Identification 
Mass balance, PK, and metabolite profiling and identification assessments will be 
performed as detailed in the study schedule of assessments in Appendix 2. 


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13.1.1 Pharmacokinetic and Metabolite Profiling and Identification Blood 
Sampling 
Venous blood samples will be collected from the subjects by a trained member of the 
clinical team. Consent will be collected from the subjects for use of these samples for the 
purposes of the proposed study. Samples will be processed to isolate plasma and PK 
analysis will be carried out on plasma (TR) and whole blood (rencofilstat, TR, metabolite 
profiling and identification) samples. 
Plasma and whole blood samples will be sent for laboratory testing in linked anonymised 
form (subject number only). This information is able to be linked directly to the volunteer 
by the Quotient research team and study monitor, however not by the laboratory staff or 
sponsor. 
Venous blood samples will be withdrawn via an indwelling cannula or by venepuncture 
according to the time schedule presented in Appendix 2. 
All PK and metabolite profiling and identification windows will be timed relative to the 
start of dosing. 
The acceptable deviations from the nominal blood sampling times are as follows: 
• 
The pre-dose samples will be taken ≤1 h before dosing 
• 
0 to 1 h post-dose samples will be taken within ± 2 min of the nominal post-dose 
sampling time  
• 
1.5 h to 12 h post-dose samples will be taken within ± 10 min of the nominal 
post-dose sampling time 
• 
16 h to 504 h post-dose samples (or up to 600 h post-dose if the residency period is 
extended) will be taken within ± 30 min of the nominal post-dose sampling time  
Samples will be collected into appropriate tubes as specified by the bioanalytical 
laboratory. Details of sample tubes and processing will be contained in the 
Clinical Sample Processing Manual (CSPM). 
Samples will be shipped to Pharmaron UK for the analysis of rencofilstat, metabolite 
profiling and TR. 
13.1.2 Mass Balance and Metabolite Profiling and Identification Urine Sampling 
Urine samples will be collected according to the time schedule presented in Appendix 2. 
A single urine sample will be taken at pre-dose (or the first void of the day). Where a 
sample is not provided, this will not be considered a deviation. All individual urine voids 
will be collected and shipped to the metabolism laboratory for analysis, according to 
Quotient’s SOPs, unless indicated otherwise by the sponsor. 
Consent will be collected from the subjects for use of these samples for the purposes of 
the proposed study. Samples will be collected into appropriate containers as specified 
by the bioanalytical laboratory. Details of sample containers and processing will be 
contained in the CSPM. 
Urine samples will be sent for laboratory testing in linked anonymised form (subject 
number). This information is able to be linked directly to the volunteer by the Quotient 
research team and study monitor; however, not by the laboratory staff or sponsor. 


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Samples will be shipped to Pharmaron for the analysis of metabolite profiling and TR. 
13.1.3 Mass Balance and Metabolite Profiling and Identification Faecal Sampling 
Faecal samples will be collected according to the time schedule presented in Appendix 2. 
The pre-dose faecal sample will be taken between admission and pre-dose. If a pre-dose 
faecal sample cannot be obtained, the subject will still be dosed. Where a sample is not 
provided, this will not be considered a deviation. 
Consent will be collected from the subjects for use of these samples for the purposes of 
the proposed study. Samples and toilet paper will be collected into appropriate 
pots/containers as specified by the metabolism laboratory. Details of sample containers 
and processing will be contained in the CSPM. 
Faecal samples will be sent for laboratory testing in linked anonymised form (subject 
number). This information is able to be linked directly to the volunteer by the Quotient 
research team and study monitor; however, not by the laboratory staff or sponsor. 
Samples will be shipped to Pharmaron for the analysis of TR and for metabolite profiling. 
13.1.4 Unexpected Sources of Elimination  
During the study, other accidental sources of elimination will be collected as voided (eg 
emesis). 
Samples will be shipped to the Pharmaron for the analysis of TR. 
13.2 Assessment of Pharmacodynamics 
Not applicable for this Phase I study. 
14 Assessment of Safety 
14.1 Definition and Classification of Adverse Events 
An AE is any untoward medical occurrence in a subject that occurs either before dosing 
(referred to as a pre-dose AE) or once a medicinal product has been administered, 
including occurrences which are not necessarily caused by or related to that product.  
An adverse drug reaction is any AE where a causal relationship with the IMP is at least 
a reasonable possibility (possibly related or related).  
AEs will be monitored from the time the subject signs the ICF until discharge from the 
study. The severity of AEs should be assessed as follows: 
Mild 
An AE that is easily tolerated by the subject, causes minimal discomfort and 
does not interfere with everyday activities 
Moderate An AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed 
Severe 
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed 


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14.2 Assessment of Causality 
Every effort should be made by the investigator to try to explain each AE and assess its 
relationship, if any, to the IMP. The temporal relationship of the event to IMP 
administration should be considered in the causality assessment (ie if the event starts 
soon after IMP administration and resolves when the IMP is stopped). 
Causality should be assessed using the following categories:  
Unrelated: 
Clinical event with an incompatible time relationship to IMP 
administration, and that could be explained by underlying 
disease or other drugs or chemicals or is incontrovertibly not 
related to the IMP 
Possibly related: 
Clinical event with a reasonable time relationship to IMP 
administration, and that is unlikely to be attributed to concurrent 
disease or other drugs or chemicals 
Related: 
Clinical event with plausible time relationship to IMP 
administration and that cannot be explained by concurrent 
disease or other drugs or chemicals 
The degree of certainty with which an AE is attributed to IMP administration (or 
alternative causes, eg natural history of the underlying disease, concomitant therapy) will 
be determined by how well the experience can be understood in terms of one or more of 
the following: 
• 
Known pharmacology of the IMP 
• 
Reactions of a similar nature have been previously observed with the IMP or this 
class of drug 
• 
The experience being related by time to IMP administration 
• 
Alternative cause 
14.3 Recording Adverse Events 
AEs (including SAEs) will be recorded from the time of providing written informed consent 
until discharge from the study. During each study visit the subject will be questioned 
directly regarding the occurrence of any adverse medical event according to the 
schedule in the source. All AEs, whether ascribed to study procedures or not, will be 
documented immediately in the subject’s source. This will include the date and time of 
onset, a description of the AE, severity, seriousness, duration, actions taken, outcome 
and an investigator’s current opinion on the relationship between the study drug and the 
event. A diagnosis and final opinion on the relationship between the study drug and the 
event will be provided at the end of the study by the investigator.  
Any subject who withdraws from the study due to an AE will be followed up until the 
outcome is determined and written reports are provided by the investigator. 
14.4 Serious Adverse Events 
14.4.1 Definition of Serious Adverse Events 
A SAE is defined as any untoward medical occurrence that at any dose:  
• 
Results in death 


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• 
Is life-threatening 
• 
Requires hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Consists of a congenital anomaly or birth defect 
• 
An important medical event as recognised by the investigator 
14.4.2 Definition of Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are believed 
to be related to an IMP and are both unexpected (ie the nature or severity is not expected 
from the information provided in the IB) and serious. SUSARs are subject to expedited 
reporting to the MHRA and EC and ARSAC practitioner (when related to radiation 
exposure) (see Section 16.3.2 for details on reporting SUSARs). 
14.5 Laboratory Measurements 
Venous blood and urine samples will be collected from the subjects by a trained member 
of the clinical team. Consent will be collected from the subjects for use of these samples 
for the purposes of the proposed study. 
Blood and urine samples are sent for laboratory testing in linked anonymised form 
(subject number, gender and date of birth for analytical reasons). This information is able 
to be linked directly to the volunteer by the Quotient research team and study monitor; 
however, not by the laboratory staff or sponsor. 
Safety laboratory tests and virology will be carried out on blood samples, and drugs of 
abuse tests and urinalysis will be carried out on urine samples. The research will not 
involve analysis or use of human DNA. 
Blood and urine samples results will be reviewed by a physician and acted upon before 
the subject is dosed or receives their next dose, or is released from the study, as is 
appropriate. A list of the laboratory parameters measured is presented in Appendix 1. 
14.5.1 Haematology and Clinical Chemistry 
Laboratory tests will be performed by The Doctors Laboratory according to the time 
schedule presented in Appendix 2. Blood samples will be collected and processed as 
detailed in the CSPM. Scheduled blood samples will be taken following a fast of at least 
8 h. 
The acceptable deviations from the nominal blood sampling time points for laboratory 
assessments are: 
• 
The pre-dose blood sample will be taken ≤2 h before dosing 
• 
Post-dose blood samples will be taken ± 1 h from the nominal blood sampling time 
eGFR will be calculated at screening by The Doctors Laboratory using CKD-EPI equation 
[19] for eligibility purposes. 
14.5.2 Virology 
HBsAg, HCV Ab and HIV 1 and 2 tests will be performed from the clinical chemistry 
sample (see Section 14.5.1 for sample collection and processing information). 


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14.5.3 Urinalysis 
Urinalysis will be performed on-site using a dipstick according to the time schedule 
presented in Appendix 2. Urine samples will be collected and processed as detailed in 
the CSPM. If microscopy is required, a urine sample (approximately 20 mL) will be taken 
from the urine collection for TR and metabolite profiling and identification and sent to The 
Doctors Laboratory, after the void has been weighed. 
The acceptable deviations from the nominal urine sampling time points for urinalysis are: 
• 
The pre-dose urine sample will be the first void of the day or a sample collected ≤3 h 
before dosing  
• 
Post-dose urine samples will be taken ± 2 h from the nominal urine sampling time 
14.5.4 Drug Screen 
A urine drug screen will be performed on-site using a point of care testing method 
(eg Alere Drug Screen Test Cup) according to the time schedule presented in 
Appendix 2. The sample will be collected and processed as detailed in the CSPM. 
Subjects will be screened for the drugs of abuse listed in Appendix 1.  
14.5.5 Alcohol Breath Test 
An alcohol breath test will be performed according to the time schedule presented in 
Appendix 2. A positive result will exclude the subject from dosing during that admission. 
14.5.6 Carbon Monoxide Breath Test 
A carbon monoxide breath test will be performed according to the time schedule 
presented in Appendix 2. A result of greater than 10 ppm will exclude the subject from 
the study. 
14.5.7 SARS-CoV-2 Tests (If Required) 
Testing for the SARS-CoV-2 virus may be performed based on current infection rates 
and availability of tests. Tests will be performed according to the time schedule presented 
in Appendix 2. The samples will be collected and processed as detailed in the CSPM. 
Testing time points may be changed and additional time points may be added throughout 
the study as required. The decision on COVID-19 testing and the definition of the testing 
time points are subject to change based on the current risk mitigation in place and will 
be agreed by the study team and documented in the ISF via the Clinical Kick-Off Meeting 
minutes. 
14.5.8 Abnormal Laboratory Findings 
In cases where laboratory findings are outside the normal range and the investigator 
believes that the results may be of clinical significance, repeat sampling may be 
requested as clinically indicated. If the abnormal finding is clinically significant, 
appropriate actions will be taken eg the subject will not be entered into the study or the 
subject may be withdrawn from the study. The subject will be referred to their general 
practitioner or other appropriate provider for further care if necessary. The same will 
apply if the results of the HBsAg, HCV Ab or HIV test are positive and in addition the 
investigator will ensure that adequate counselling is available if requested. 


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Abnormal results at follow-up assessments will also require repeat testing if the 
investigator believes the results may be of clinical significance. 
Any clinically significant abnormality, including changes from baseline, must be reported 
as an AE. 
Additional blood and/or urine samples may be taken for safety tests. Furthermore, 
additional assays outside those specified in the protocol may be performed for safety 
reasons as requested by the investigator or sub-investigator. 
14.6 Vital Signs Measurements 
Blood pressure and heart rate will be measured by an automated recorder after the 
subject has been in a supine position for a minimum of 5 min and oral temperature will 
be measured according to the time schedule presented in Appendix 2. The acceptable 
deviations from the nominal vital signs measurement time points are: 
• 
The pre-dose vital signs measurements will be taken ≤2 h before dosing 
• 
Post-dose vital signs measurements will be taken ± 15 min from the nominal 
post-dose time points 
• 
Discharge vital signs measurements will be taken ± 1 h from the nominal time point 
• 
For return visits vital signs measurements will be taken ± 2 h from the nominal return 
visit time point 
If a subject shows an abnormal assessment at any stage, repeat measurements may be 
made and the abnormality followed to resolution if required. Additional measurements 
may be taken as deemed necessary by the investigator or sub-investigator. 
Any clinically significant abnormality, including changes from baseline, must be reported 
as an AE. 
14.7 ECG Measurements 
Single 12-lead ECGs will be measured after the subject has been in the supine position 
for a minimum of 5 min according to the time schedule presented in Appendix 2. The 
acceptable deviations from the nominal ECG measurement time points are: 
• 
The pre-dose ECG measurements will be taken ≤2 h before dosing 
• 
Post-dose ECG measurements will be taken ± 15 min from the nominal post-dose 
time point  
• 
Discharge ECG measurements will be taken ± 1 h from the nominal time point 
If a subject shows an abnormal assessment at any stage, repeat measurements may be 
made and the abnormality followed to resolution if required. Additional measurements 
may be taken as deemed necessary by the investigator or sub-investigator. 
Any clinically significant abnormality, including changes from baseline, will be reported 
as an AE. 
14.8 Body Weight, Height and BMI 
The subject’s body weight and height will be measured and their BMI will be calculated 
according to the time schedule presented in Appendix 2. 


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14.9 Physical Examination 
Subjects will undergo a physical examination according to the time schedule presented 
in Appendix 2. 
In the targeted (symptom driven) physical examination, a physician will assess the 
subject; if the subject reports feeling unwell or has ongoing AEs, then the physician will 
examine the appropriate body system(s) if required. 
14.10 Additional Safety Procedures 
Additional non-invasive procedures that are already specified in the protocol may be 
performed, if it is believed that an important effect of the IMP(s) is occurring or may occur 
at a time when no measurements are scheduled, or if extra procedures are needed in 
the interests of safety. 
Additional blood samples for safety assessments may be taken if required by the 
investigator or sub-investigator at any point. 
15 Statistics and Data Analysis 
15.1 Sample Size Justification 
The study is exploratory and no formal sample size calculation has been made. Based 
on experience from previous studies of a similar design, a total of 6 subjects are to be 
enrolled and a minimum of 4 evaluable subjects are considered sufficient. 
15.2 Data Management 
Data management will be performed by Quotient. 
Study data will be managed using a validated electronic case report form (eCRF) 
database system and subjected to data consistency and validation checks. Data queries 
will be raised within the study eCRF database by data management staff and resolved 
with the assistance of clinical staff. 
AEs, medical histories and medications will be coded using the Medical Dictionary for 
Regulatory Activities (version to be specified in the Data Management Plan [DMP]) and 
the World Health Organization (WHO) Drug Dictionary Global Drug Reference (version 
to be specified in the DMP), respectively. An independent coding review will also be 
performed within the Data Sciences department. 
Clinical chemistry and haematology data (and other safety laboratory data) will be 
collected by a central laboratory (The Doctors Laboratory) and stored electronically in 
their clinical pathology system. The data will be transferred electronically to Quotient and 
all demographic details and sample dates will be cross-referenced with the 
corresponding data on the study database. All queries will be resolved with the 
assistance of laboratory staff, or if necessary, clinical staff.  
The database will be closed after all queries have been resolved. The database will be 
locked when all criteria listed in the DMP are met.  
Further details are addressed in the DMP. 


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15.3 Mass Balance, Pharmacokinetic, and Metabolite Profiling and Identification 
Data Analysis 
15.3.1 Mass Balance Data Analysis  
The mass balance parameters presented in Table 3 will be calculated by Quotient using 
the concentration data for TR in urine and faeces (and emesis, if applicable) provided by 
Pharmaron.  
Table 3 
Mass Balance Parameters  
Parameter 
Definition 
Ae(urine) 
amount of TR excreted in urine 
%Ae(urine) 
amount of TR excreted in urine expressed as a percentage of the radioactive 
dose administered 
CumAe(urine) 
cumulative amount of TR excreted in urine 
Cum%Ae(urine) 
cumulative amount of TR excreted in urine expressed as a percentage of the 
radioactive dose administered 
Ae(faeces) 
amount of TR eliminated in faeces 
%Ae(faeces) 
amount of TR eliminated in faeces expressed as a percentage of the 
radioactive dose administered 
CumAe(faeces) 
cumulative amount of TR eliminated in faeces 
Cum%Ae(faeces) 
cumulative amount of TR eliminated in faeces expressed as a percentage of 
the radioactive dose administered 
Ae(total) 
amount of TR excreted in urine and faeces combined 
%Ae(total) 
amount of TR excreted in urine and faeces combined expressed as a 
percentage of the radioactive dose administered 
CumAe(total) 
cumulative amount of TR excreted in urine and faeces combined 
Cum%Ae(total) 
cumulative amount of TR excreted in urine and faeces combined expressed as 
a percentage of the radioactive dose administered 
Further analysis details will be included in the Reporting and Analysis Plan (RAP). 
15.3.2 Pharmacokinetic and Total Radioactivity Data Analysis 
The whole blood concentration data for rencofilstat and plasma and whole blood TR 
concentration data provided by Pharmaron will be analysed by Quotient, using 
Phoenix WinNonlin v8.3 or a more recent version (Certara USA, Inc., USA). 
Calculated rencofilstat concentrations may be corrected for specific activity of the 
administered radiolabelled oral dose by the Data Sciences department at Quotient. 
PK analysis of the whole blood concentration-time data obtained will be performed using 
appropriate non-compartmental techniques to obtain estimates of the PK parameters 
presented in Table 4 and where possible and appropriate. 
Table 4 
Whole Blood Pharmacokinetic Parameters 
Parameter 
Definition 
Tlag 
Time prior to the first measurable concentration 
Tmax 
Time of maximum observed concentration 
Cmax 
Maximum observed concentration 
AUC(0-24) 
Area under the curve from time 0 to 24 h post-dose 
AUC(0-last) 
Area under the curve from time 0 to the time of last measurable concentration 
AUC(0-inf) 
Area under the curve from time 0 extrapolated to infinity 


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Parameter 
Definition 
AUCextrap 
Area under the curve from time of the last measurable concentration to infinity as a 
percentage of the area under the curve extrapolated to infinity 
AUC ratio 
Parent to total radioactivity ratio for whole blood based on AUC 
T1/2  
Terminal elimination half-life 
Lambda-z 
First order rate constant associated with the terminal (log-linear) portion of the curve 
CL/F 
Total body clearance calculated after a single extravascular administration where F 
(fraction of dose bioavailable) is unknown 
Vz/F 
Apparent volume of distribution based on the terminal phase calculated using AUC(0-
inf) after a single extravascular administration where F (fraction of dose bioavailable) 
is unknown 
MRT(0-last) 
Mean residence time from time 0 to time of the last measurable concentration  
MRT(0-inf) 
Mean residence time from time 0 extrapolated to infinity  
In addition, whole blood-to-plasma TR concentration ratios will be calculated. 
Further details of the PK data analysis will be included in the RAP. 
15.3.3 Metabolite Profiling and Identification  
Metabolite profiling of whole blood, urine and faeces will be performed using liquid 
chromatography-radio-detection with subsequent mass spectrometry where appropriate.  
Identification of the chemical structure of each metabolite accounting for greater than 
10% of circulating radioactivity in whole blood (“AUC pool”) and accounting for greater 
than 10% of the dose in the urine and faeces (from urine pools and faeces homogenate 
pools) will be performed.  
These aspects will be reported separately from the clinical study report as a standalone 
document. 
15.4 Statistical Data Analysis  
Production of summary tables, figures and listings for this study will be performed by 
Quotient using the statistical package SAS (v9.4 or more recent version).  
All safety, mass balance recovery and PK data will be listed. 
No formal statistical analysis will be performed for this study. Descriptive statistics 
(eg mean, median, standard deviation, minimum, maximum and number of subjects with 
an observation [n]) are considered adequate for a study of this type. Additional statistics 
will be provided for PK-related data, including coefficient of variation (CV%), geometric 
mean and geometric CV%.  
Populations and analysis sets will be determined for safety, PK and mass balance data 
after database lock when the relevant data are available, using the criteria defined in the 
RAP; the RAP will be signed off prior to database lock. 
Further details relating to the statistical analysis will be included in the RAP including the 
following: 
• 
Criteria to be used to define each of the population and analysis sets 
• 
Additional detail covering the analyses and/or description of primary and secondary 
analyses and safety data 


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• 
Handling of missing data, unused or spurious data 
• 
Handling of data from withdrawn subjects 
15.5 Interim Analysis 
No formal interim analyses are planned for this study. 
16 Safety Reporting to Regulatory Authorities and Ethics 
Committees 
16.1 Events Requiring Expedited Reporting 
SUSARs (Section 14.4.2) are subject to expedited reporting to the appropriate regulatory 
authority and EC and the ARSAC practitioner when related to radioactive exposure. 
In addition to SUSARs, other safety issues may qualify for expedited reporting where 
they might materially alter the current benefit-risk assessment of an IMP or that would 
be sufficient to consider changes in the IMPs’ administration or in the overall conduct of 
the study, for instance: 
• 
An increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important 
• 
SAEs that occur after the subject has completed the clinical study where the sponsor 
considers them to be a SUSAR 
• 
New events related to the conduct of the study or the development of the IMPs and 
likely to affect the safety of the subjects, such as: 
− An SAE which could be associated with the study procedures and which 
could modify the conduct of the study 
− A major safety finding from a newly completed animal study (such as 
carcinogenicity) 
− Any anticipated end or temporary halt of a study for safety reasons and 
conducted with the same IMPs in another country by the same sponsor 
16.2 Urgent Safety Measures 
If Quotient or any of its staff or contractors becomes aware of an actual or potential 
urgent safety issue, then the sponsor must be immediately contacted so that appropriate 
urgent safety measures can be agreed. An urgent safety issue is defined as:  
• 
An immediate hazard to the health or safety of subjects participating in a clinical study 
• 
A serious risk to human health or potentially a serious risk to human health 
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, inter-current illness (including pandemic infections), concomitant 
medications, concurrent medical conditions or any other issues related to the safe 
conduct of the study or that pose a risk to study subjects. 
In exceptional circumstances of imminent hazard and in order to safeguard the health or 
safety of individuals, Quotient may take urgent safety measures before informing the 
sponsor, but the sponsor must be informed immediately after the hazard has resolved.  
The sponsor is responsible for informing the appropriate regulatory authorities, and the 
EC; the task of reporting urgent safety measures will be delegated to Quotient. 


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16.3 Reporting 
16.3.1 Reporting Serious Adverse Events 
The investigator must notify the study sponsor and pharmacovigilance provider of any 
SAE or serious adverse reaction immediately, and in all cases within 24 h of becoming 
aware of the event or reaction. A copy of the written report of the event should promptly 
be sent to the study sponsor for information purposes, in accordance with International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) guidelines for GCP [20]. 
16.3.2 Reporting of Suspected Unexpected Serious Adverse Reactions 
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible. 
16.3.3 Expedited Reporting of Events 
It is the responsibility of the sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible. 
Where expedited reporting is required, the following procedures should be followed. 
Fatal or life-threatening SUSARs 
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
MHRA as soon as possible, but no later than 7 calendar days after they first became 
aware of the reaction. Any additional relevant information should be sent within 8 days 
of the report. The task of reporting fatal or life-threatening SUSARs may be delegated to 
the pharmacovigilance provider.  
The sponsor is required to notify the EC of any fatal or life-threatening SUSAR as soon 
as possible, but no later than 7 calendar days after they first became aware of the 
reaction. Any additional relevant information should be sent within 8 days of the report. 
The task of reporting fatal or life-threatening SUSARs may be delegated to the 
investigator. 
The ARSAC Practitioner will be notified of any fatal or life-threatening SUSAR that is 
considered related to the exposure to radioactivity. 
Other SUSARs 
It is the responsibility of the sponsor to report other SUSARs to the MHRA as soon as 
possible, but no later than 15 calendar days after they first became aware of the reaction. 
The task of reporting other SUSARs may be delegated to the pharmacovigilance 
provider. 
The sponsor is required to notify the EC of other SUSARs as soon as possible, but no 
later than 15 calendar days after they first became aware of the reaction. The task of 
reporting other SUSARs may be delegated to the investigator. 
The ARSAC Practitioner will be notified of any SUSAR that is considered related to the 
exposure to radioactivity. 


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16.3.4 Reporting of Urgent Safety Measures 
Quotient is required to notify the MHRA and the EC of an urgent safety measure 
immediately by telephone and follow-up in writing within 3 calendar days from the date 
the measures are taken. 
16.3.5 Reporting of COVID-19 Vaccine-Related Adverse Events 
AEs considered by the investigator to be related to COVID-19 vaccines will be reported 
to the MHRA via the Yellow Card system. 
16.4 Serious Breaches 
It is the responsibility of the sponsor to notify the MHRA of any serious breach, which is 
likely to affect, to a significant degree, the safety or mental integrity of the subjects of the 
study or the scientific value of the study.  
All serious breaches will be notified to the MHRA within 7 days. The reporting will be 
performed by the party who suspects the serious breach. 
17 Protocol Amendments and Deviations 
17.1 Amendments 
After the protocol has been submitted to the MHRA and EC, any amendment must be 
agreed by the investigator after discussion with the sponsor and will be formally 
documented. 
All substantial amendments will be submitted to the MHRA and/or EC for approval and/or 
an opinion, respectively, as required by current regulations. Any amendments relating to 
the administration of radioactive substances will be reviewed by the ARSAC practitioner 
prior to submission to ARSAC as required by the current ARSAC Notes for Guidance 
[12]. The ARSAC practitioner will also be notified of any substantial amendments to the 
PIS and ICF and/or protocol. 
If the PIS and ICF are updated as a result of the substantial amendment, the new 
approved versions will be used to re-consent currently enrolled subjects and must be 
provided to newly enrolled subjects prior to their entry into the study. 
17.2 Protocol Deviations 
The study must be conducted in accordance with the Clinical Protocol. Should a protocol 
deviation occur, it must be promptly assessed in order to decide whether any of these 
non-compliances should be reported to the MHRA as a serious breach of GCP and the 
Clinical Protocol. 
Protocol waivers are not acceptable. 
Deviations from the protocol will be recorded in the source as noted by the clinical staff. 
If necessary, the sponsor will be informed of the deviation. 
Any protocol deviations assessed as major will be discussed with the sponsor in order 
to determine if the withdrawal criteria stated in Section 8.3 have been met. 


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18 Regulatory 
18.1 Compliance 
This study will be conducted in accordance with the protocol and with the following 
legislation: 
• 
ICH GCP Guidelines approved by the Committee for Medicinal Products for Human 
Use (CHMP) on 17 Jul 1996, which came into force on 17 Jan 1997, updated Jul 
2002, Integrated Addendum E6 (R2) dated 09 Nov 2016 [20] 
• 
The Medicines for Human Use (Clinical Trials) Regulations. Statutory Instruments 
2004 No. 1031 [21] 
• 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2006 No. 1928 [22] 
• 
The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984 [23] 
• 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2008 No. 941 [24] 
• 
The Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations. 
Statutory Instruments 2019 No. 744 [25] 
• 
Health and Safety. The Ionising Radiations Regulations 2017. Statutory Instrument 
2017 No. 1075 [14]  
• 
Health and Safety. Ionising Radiation (Medical Exposure) Regulations 2017. 
Statutory Instrument 2017 No. 1322 [16]  
In addition, the study will be performed according to the ethical principles outlined in the 
World Medical Association Declaration of Helsinki and its amendments [15]. 
18.2 MHRA and Ethical Approval 
Prior to the initiation of the study, the clinical trial of an investigational medicinal product 
(CTIMP) application, the protocol and associated documentation must be approved by 
the MHRA and given a favourable opinion by an EC. A copy of this written approval and 
any correspondence with the MHRA and EC will be available at the clinical site and will 
be provided to the sponsor.  
18.3 Administration of Radiation 
Dr Stuart Mair will be the ARSAC practitioner for this study, which includes the 
administration of radiation at Quotient. Administration will be conducted in accordance 
with Dr Mair’s current ARSAC practitioner licence and Quotient’s current ARSAC 
Employer licence. Additionally, a research application will be submitted to ARSAC to 
obtain approval for the conduct of the study before dosing. 
Before submitting to the ARSAC, a summary of available non-clinical tissue distribution 
and excretion information on [14C]-rencofilstat will be submitted to the Radiation 
Protection Division of UK Health Security Agency for human dosimetry calculations in 
order to facilitate the selection of the dose of radioactivity to be administered. The final 
report from the UK Health Security Agency will be included in the application to the 
ARSAC. 
The protocol will be reviewed and the final version will be approved by the ARSAC 
practitioner, Dr Stuart Mair. 


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18.4 Source Data 
A study-specific source document identification list will be finalised with the sponsor prior 
to the start of the clinical phase of the study. The document will identify what data should 
be considered source data for this study.  
For this study, electronic data capture will be used where possible and data will be 
automatically recorded into an eCRF. In instances where paper source documents are 
used, data to be transcribed into the eCRF will be identified using a Source Document 
Identification List, as governed by Quotient’s SOPs. 
18.5 Declaration of the End of the Study 
The end of the study is defined as the last visit of the last subject (eg discharge from the 
study). Any changes to this definition will be notified as a substantial amendment (see 
Section 17.1). 
The EC and MHRA should be notified of the conclusion of the study within 90 days of 
the end of the study, or within 15 days if the study is terminated early, clearly explaining 
the reasons for the termination. 
The ARSAC Practitioner will also be notified of the end of trial or early termination of the 
trial within an appropriate timeframe. 
18.6 Document Storage and Archiving 
All documentation and correspondence pertaining to the study (source data, raw data, 
letters etc) will be kept in accordance with the ICH guidelines for GCP 1996, updated 
2002, Integrated Addendum E6 (R2) dated 09 Nov 2016 (ICH GCP Section 4.9.5) [20], 
The Medicines for Human Use (Clinical Trials) Regulations 2004 [21], The Medicines for 
Human Use (Clinical Trials) Amendment Regulations 2006 [22],[23] and The Medicines 
for Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations [25]. 
All study related documents will be retained for a minimum period of 15 years. After this 
time, the sponsor will be contacted to ascertain whether continued storage or destruction 
is required in accordance with current regulations. 
18.7 Protection of Personal Data and Confidentiality 
Personal data are securely stored to prevent unauthorised access, disclosure, 
dissemination, alteration or loss of information and unauthorised personal data 
processing. Access to personal information is restricted so that only personnel who are 
required to access personal data as part of their job role can do so. All personnel who 
access personal information are bound by a duty of confidentiality. 
Technical arrangements surrounding the electronic storage and use of data are as 
follows: 
• 
Computers storing electronic personal data are protected by antivirus software and 
the network on which computers are linked are protected by industry grade firewalls 
• 
Off-site personnel can only access networked computers through a virtual private 
network  
• 
Electronic access of data is limited according to user roles 
• 
All data are stored on password protected computers 


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Organisational arrangements are as follows: 
• 
All buildings are secured by key-card access 
• 
Manual files of personal data are stored within locked cabinets/restricted areas of the 
clinical unit that can only be accessed by authorised personnel 
• 
Data security and/or confidentiality provisions are utilised in agreements with third 
parties 
• 
Documented Back-up and disaster recovery procedures are in place 
• 
Internal audit and compliance functions provide regulatory oversight 
The personal data of volunteers will be pseudonymised in that they will only include 
health, initials, date of birth and demographics (gender and ethnicity) and cannot be 
linked back to the individual by the recipient. The sponsor shall be the data controller in 
respect of the personal data of the study subjects collected in connection with the study, 
and shall act in accordance with the relevant data protection laws in relation to the 
collection and processing of those personal data. The study subjects’ pseudonymised 
personal data shall be collected and processed for the purposes of the study and may 
also be added to research databases and used in the future by the sponsor and its 
affiliates for certain additional clinical research, for product regulation and safety 
reporting purposes and for ensuring compliance with legal requirements. The study 
subjects’ pseudonymised personal data may be processed for such purposes by other 
parties including: the sponsor’s affiliates and licensing partners, its business partners, 
regulatory agencies and other health authorities, and ECs. The study subjects’ 
authorisation for such use and disclosure shall be obtained by the study subjects signing 
the ICF for the study. 
Additionally, Quotient personnel are contractually bound by a duty of confidentiality and 
receive training on this matter. 
18.8 Data Security Breach 
Quotient has a comprehensive process in place for identifying, assessing, resolving and 
reporting any potential data security breach. All staff are trained in the identification of 
potential data security breaches. Potential breaches are managed by appropriately 
trained quality assurance (QA) personnel in accordance with Quotient’s SOPs. After 
robust assessment of data breaches, those deemed serious will be reported to the 
sponsor and Information Commissioner’s Office, as applicable. 
19 Quality Control and Quality Assurance 
Quality control of all data collected from this study will be performed in accordance with 
Quotient’s SOPs. This study (or elements thereof) may be subject to Quotient QA audit, 
in line with current internal auditing procedures. Similarly, the study (or elements thereof) 
may be subject to sponsor QA audit. 
19.1 Monitoring 
GCP requires that studies are adequately monitored. The sponsor should determine the 
appropriate extent and nature of monitoring. A study monitor, independent of Quotient, 
will be appointed to verify that the study is conducted in accordance with current GCP, 
regulatory requirements, the protocol and that the data are authentic, accurate and 
complete.  


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The investigator agrees to receive visits from a study monitor and provide assistance to 
verify protocol implementation, source completion and transcription of data into the 
eCRF, document storage and AE reporting. 
Quotient will extend the professional privilege of access to the subjects’ clinical source 
documents to the study monitor, EC, regulatory bodies or other authorised personnel (eg 
auditor) for the purposes of source data verification. 
Following completion of the study both study related documents and subject data may 
be sent to the sponsor at a location outside of the UK where data protection laws differ. 
In the interests of confidentiality, subjects will not be identified on any such documents 
or data, and specific subject consent for such a disposition will be obtained. 
20 Finance and Insurance 
The sponsor Hepion Pharmaceuticals, Inc has funded this study. A no-fault clinical trials 
insurance has been obtained by the sponsor. The sponsor insurance will compensate 
subjects in accordance with the Association of the British Pharmaceutical Industry 
Guidelines for Phase I Clinical Trials 2018 edition [18]. 
21 Publication 
Please refer to the Master Services Agreement for information on publication.  
Quotient shall have the right to publish the results of the research, subject to the 
sponsor’s prior written consent, which shall not be unreasonably withheld or delayed. 
Following the receipt of such consent, Quotient shall submit a copy of the proposed 
publication to the sponsor who shall have 30 days in which to request amendments 
thereto which, to the extent that such proposed amendments are reasonable, Quotient 
shall be obliged to incorporate prior to such publication. 
The sponsor undertakes that, prior to publication of any information, article, paper, report 
or other material concerning the research, it will submit a copy of such publication to 
Quotient who shall have 30 days in which to request amendments thereto which, to the 
extent that such proposed amendment are reasonable, the sponsor shall be obliged to 
incorporate prior to such publication. 
22 References 
[1] 
Handschumacher RE, Harding MW, Rice J, et al. Cyclophilin: a specific cytosolic 
binding protein for cyclosporin A. Science. 1984; 226(4674):544-547. 
[2] 
Swanson SK, Born T, Zydowsky LD et al. Cyclosporin mediated inhibition of 
bovine calcineurin by cyclophilins A and B. Proc Natl Acad Sci USA. 1992; 
89(9):3741-3745. 
[3] 
Liu J, Farmer JD Jr, Lane WS, et al. Calcineurin is a common target of 
cyclophilin-cyclosporin 
A 
and 
FKBP-FK506 
complexes. 
Cell. 
1991; 
66(4):807-815. 
[4] 
Clipstone NA and Crabtree GR. Identification of calcineurin as a key signalling 
enzyme in T-lymphocyte activation. Nature. 1992; 357(6380):695-697. 


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[5] 
Pawlotsky J-MM, Flisiak R, Sarin SK, et al. Alisporivir plus ribavirin, interferon 
free or in combination with pegylated interferon, for hepatitis C virus genotype 2 
or 3 infection. Hepatology. 2015; 62:1013–1023. 
[6] 
Zeuzem S, Flisiak R, Vierling JM, et al. Randomised clinical trial: Alisporivir 
combined with peginterferon and ribavirin in treatment-naïve patients with chronic 
HCV genotype 1 infection (ESSENTIAL II). Aliment Pharmacol Ther. 2015; 
42:829–844. 
[7] 
Buti M, Flisiak R, Kao JH, et al.  Alisporivir with peginterferon/ribavirin in patients 
with chronic hepatitis C genotype 1 infection who failed to respond to or relapsed 
after prior interferon-based therapy: FUNDAMENTAL, a Phase II trial. J Viral 
Hepat. 2015; 22:596–606. 
[8] 
Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related 
HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol 
Hepatol. 2021; 18(4):223-238. 
[9] 
Estes C, Razavi H, Loomba R, et al. Modeling the epidemic of nonalcoholic fatty 
liver disease demonstrates an exponential increase in burden of disease. 
Hepatology. 2018; 67(1): 123–133. 
[10] 
Ure DR, Trepanier DJ, Mayo PR, et al. Cyclophilin inhibition as a potential 
treatment for nonalcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 
2020; 29(2):163-178. 
[11] 
Hepion Pharmaceuticals, Inc. Investigational Brochure: Rencofilstat. Version 6.0. 
December 2022. 
[12] 
Notes for guidance on the clinical administration of radiopharmaceuticals and use 
of sealed radioactive sources. Administration of Radioactive Substances 
Advisory Committee. September 2021. 
[13] 
Ionising Radiation Exposure of the UK population: 2010 Review. Public Health 
England. April 2016. https://www.gov.uk/government/publications/ionising-
radiation-exposure-of-the-uk-population-2010-review. 
[14] 
Health and Safety. The Ionising Radiations Regulations 2017. Statutory 
Instrument 2017 No. 1075. 
[15] 
World Medical Association, Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects (and all subsequent amendments). 
[16] 
Health and Safety. Ionising Radiation (Medical Exposure) Regulations 2017. 
Statutory Instrument 2017 No. 1322. 
[17] 
Heads of Medicines Agency: Clinical Trials Facilitation Group. Recommendations 
related to contraception and pregnancy testing in clinical trials. 21 Sep 2020. 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_gui
dance_Version_1.1_updated.pdf. 


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[18] 
Guidelines for Phase I Clinical Trials. Association of the British Pharmaceutical 
Industry Guidelines. London, UK; 2018 Edition (publication date 29 May 2018). 
[19] 
Levy AS, Stevens LA, Schmit CH et al A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009; 150(9): 604-612. 
[20] 
International Council for Harmonisation Good Clinical Practice (GCP) Guidelines 
approved by the Committee for Medicinal Products for Human Use (CHMP) on 
17 Jul 1996, which came into force on 17 Jan 1997, updated Jul 2002, Integrated 
Addendum E6 (R2) dated 09 Nov 2016. 
[21] 
The Medicines for Human Use (Clinical Trials) Regulations. Statutory 
Instruments 2004 No. 1031. 
[22] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2006 No. 1928. 
[23] 
The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984. 
[24] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2008 No. 941. 
[25] 
The Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) 
Regulations. Statutory Instruments 2019 No. 744. 


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Appendix 1 Clinical Laboratory Parameters  
Haematology 
Clinical Chemistry 
Virology 
Urinalysis 
Drugs of Abuse 
Basophils 
Eosinophils 
Haematocrit  
(Packed Cell Volume- PCV) 
Haemoglobin 
Lymphocytes 
Mean Cell Haemoglobin (MCH) 
Mean Cell Haemoglobin 
Concentration (MCHC) 
Mean Cell Volume (MCV) 
Monocytes 
Neutrophils 
Platelet Count 
Red Blood Cell (RBC) Count  
White Blood Cell (WBC) Count 
 
Alanine Aminotransferase 
(ALT) 
Albumin 
Alkaline Phosphatase 
Aspartate Aminotransferase 
(AST) 
Bicarbonate 
Bilirubin (Total) 
Bilirubin (Direct; only if Total is 
elevated) 
Calcium 
Chloride 
Creatine Kinase (CK) 
Creatinine 
eGFR will be calculated at 
screening using CKD-EPI 
2009  
Gamma Glutamyl Transferase 
(GGT) 
Glucose 
Glucose (Fasting) 
Potassium 
Phosphate (Inorganic) 
Protein (Total) 
Sodium 
Urea  
Serum Cholesterol (fasted) 
High-Density Lipoprotein 
(HDL) 
Low-Density Lipoprotein (LDL) 
Triglycerides (TRI) 
Amylase 
Lipase 
Hepatitis B Surface Antigen 
Hepatitis C Virus Antibody 
HIV Antibody 
 
If Required: 
SARS-CoV-2 Antigen 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocytes 
Nitrites 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
At discretion of 
investigator based on 
urinalysis results 
Microbiology  
Urine Microscopy 
 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cocaine 
Marijuana/Cannabis 
Methadone 
Methamphetamine/ 
Ecstasy 
Morphine/Opiates 
Phencyclidine 
Tricyclic Antidepressants 
 


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Appendix 2 
Schedule of Assessments 
Study day 
-28 to 
-2 
-1 
 
1 
2 
3 
4 
5 
6 
7 
8 
 
Times after dosing (h) 
 
S 
Aa  Pa  
0 
0.5 
1 
1.5 
2 
3 
4 
6 
8 
12 16 
24 
48 
72 
96 
120 144 168 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, Height and BMI 
X 
Xc  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon Monoxide Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Antigend 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted (symptom driven) Physical 
Examinatione 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Blood Samplesf  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
eGFRg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Single 12-Lead ECGs 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Vital Signsh 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Adverse Events 
---------------------------------------------------------------------X---------------------------------------------------------------------→ 
Prior and Concomitant Medication  
---------------------------------------------------------------------X---------------------------------------------------------------------→ 
Mass Balance, PK and Met Prof and ID Assessments 
Whole Blood Samples for Rencofilstat 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma Samples for TR 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole Blood Samples for TR 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole Blood Samples for Met Prof and ID 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
Urine Samples for TR and Met Prof and IDi 
 
 
---------------------------------------------------------------X------------------------------------------------------------------→ 
Faecal Samples for TR and Met Prof and IDj 
 
------------------------------------------------------------------X------------------------------------------------------------------→ 


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Appendix 2 
Schedule of Assessments (continued) 
Study day 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
28 (+2 
days) 
35 (±2 
days) 
Home 
Collectionsn 
Times after dosing (h) 
 
192 216 240 264 288 312 336 360 384 408 432 456 480 504k 
528l 
552l 
576l 
600l 
Return Visitsm 
General Assessments 
SARS-CoV-2 Antigend  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Safety Assessments 
Targeted (symptom driven) Physical 
Examinatione  
 
 
 
 
 
 
 
 
 
 
 
 
 
Xko 
 
 
 
 
 
 
 
Safety Labsf  
 
 
 
 
 
 
 
 
 
 
 
 
 
Xko 
 
 
 
 
 
 
 
Urinalysis  
 
 
 
 
 
 
 
 
 
 
 
 
 
Xko 
 
 
 
 
 
 
 
Single 12-Lead ECGs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xko 
 
 
 
 
 
 
 
Vital Signsh  
 
 
 
 
 
 
 
 
 
 
 
 
 
Xko 
 
 
 
 
X 
X 
 
Adverse Events 
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→ 
Prior and Concomitant Medication  
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→ 
Mass Balance, PK and Met Prof and ID Assessments 
Whole Blood Samples for 
Rencofilstat 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xp 
 
 
 
 
 
 
 
Plasma Samples for TR 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xp 
 
 
 
 
 
 
 
Whole Blood Samples for TR 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xp 
 
 
 
 
 
 
 
Whole Blood Samples for Met Prof 
and ID 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Urine Samples for TR and Met Prof 
and IDi 
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→ 
Faecal Samples for TR and Met Prof 
and IDj 
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→ 
A: admission; BMI: body mass index; ID: identification; Met Prof: Metabolite Profiling; P: pre-dose; PK: pharmacokinetic(s); S: screening; TR: total radioactivity 
a Eligibility will be re-assessed at admission/pre-dose 
b Update only 
c Weight only  
d Testing for SARS-CoV-2 may be performed based on current infection rates and availability of tests. If required, it is planned that testing will comprise an antigen test 
performed on Day -1 prior to admission to the clinical unit and at return visits. The decision on COVID-19 testing and the definition of the testing time points are subject to 
change based on the current risk mitigation in place and will be agreed by the study team and documented in the ISF via the Clinical Kick-Off Meeting minutes 
e Targeted (symptom driven) physical examination of the relevant body system(s) as clinically indicated, as per the investigator’s judgement 
f Haematology and clinical chemistry at each time point including virology at screening 
g eGFR will be calculated at screening using the CKD-EPI equation for eligibility purposes 


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h Blood pressure and heart rate will be measured at every time point; oral temperature will be checked at screening, pre-dose and at first return residential visit (Day 28 
+2 days) only 
i Urine will be collected for the following intervals: A single urine sample will be collected at pre-dose (or the first void of the day), then at: 0-12 h, 12-24 h and then for 24 h 
intervals until mass balance criteria have been met (see Section 8.1 for details of mass balance criteria) 
j Faeces will be collected at pre-dose (sample will be taken between admission and pre-dose), then at 24 h intervals until mass balance criteria have been met (see 
Section 8.1 for details of mass balance criteria) 
k Discharge from clinical unit. Discharge assessments will be performed at the time of actual discharge. It is planned that subjects will remain resident in the clinical unit 
until 504 h post-dose (Day 22). Subjects will be discharged from the clinical unit on Day 22 provided they have met the following mass balance discharge criteria: mass 
balance cumulative recovery of >90% OR <1% of the dose administered collected in urine and faeces within 2 separate, consecutive 24 h periods. It is also planned that 
subjects will be discharged from the clinical unit as a group if all subjects have achieved the mass balance discharge criteria 
l If mass balance discharge criteria have not been met by all subjects by Day 22, the residency period for the subjects not achieving the mass balance criteria may be 
extended up to a maximum of 96 h (Day 26). Urine and/or faeces will be collected during the additional residency period 
m If mass balance discharge criteria have not been met by all subjects by the end of the additional residency (Day 26), subjects not achieving the mass balance criteria 
may be required to make up to 2 return visits (each of 24 h duration) at (nominally) Day 28 (+2 days) and Day 35 (±2 days) for additional collection of excreta samples. 
Only urine and/or faeces will be collected during the return visits 
n If the mass balance criteria are not met following the return visits, then home collections of urine and/or faeces may be requested at the discretion of the investigator for 
individual subjects 
o In the event of early withdrawal, all safety discharge assessments should be completed 
p If the residency period for subjects not achieving the mass balance criteria is extended, a further sample will be taken at actual discharge 
 


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Protocol HEPA-CRV431-105 (QSC204643) Version 3.0 
22 Mar 2023 
Page 62 of 64 
 
Appendix 3 
Protocol Amendment Summary of Changes 
Protocol Version 3.0 
In Protocol Version 2.0 (dated 10 Mar 2023), it was noted that there was a urinalysis 
sample taken at 4 h post-dose. This sample is not required clinically and would require 
an aliquot of urine to be removed from the mass balance urine collections at a key time 
point. The 24 h post-dose urinalysis sample is deemed adequate and clinically 
appropriate. Therefore, the 4 h post-dose urinalysis sample has been removed from the 
protocol. 
All relevant sections of the protocol have been updated, including: 
Document History Page; Appendix 2 Schedule of Assessments. 
As these changes do not significantly affect the scientific value of the trial, the safety or 
physical or mental integrity of the subjects of the trial, or the quality of the IMP, the 
amendment to the protocol is considered to be non-substantial. 
Protocol Version 2.0 
The 11 timepoints for the whole blood metabolite ID collections have been rearranged to 
occur over a longer duration of time to ensure that the study objectives will be met. 
Pharmaron provided adjustments to the timings of sample collection. The timings but not 
the number of samples or blood volumes have been updated.  
In Protocol Version 1.0 (dated 21 Dec 2022), the time points for whole blood metabolite 
ID collection were scheduled to be taken at pre-dose, 2, 4, 8, 12, 24, 48, 72, 96 120 and 
168 h post-dose. The protocol has been updated to remove samples taken at 4, 12, 72, 
96 and 168 h post dose and add samples at 192, 264, 312, 408 and 456 h post-dose. 
Therefore, the updated metabolite ID time points are as follows: pre-dose, 2, 8, 24, 48, 
120,192, 264, 312, 408 and 456 h post-dose. 
Additionally, it was noted that in the footnotes of Table 1 and the table ‘Investigational 
Medicinal Product, Dose and Mode of Administration’ in the synopsis, the IMP was 
incorrectly stated as a salt form. These footnotes have been removed. 
Furthermore, minor typographical corrections have been made. 
All relevant sections of the protocol have been updated, including: 
Document History Page; Synopsis; 5.1 Introduction; 5.2 Investigational Medicinal 
Product; Appendix 2 Schedule of Assessments. 
As these changes do not significantly affect the scientific value of the trial, the safety or 
physical or mental integrity of the subjects of the trial, or the quality of the IMP, the 
amendment to the protocol is considered to be non-substantial. 


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22 Mar 2023 
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Signatures for Quotient Sciences 
CONFIDENTIALITY AND GCP COMPLIANCE STATEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
and any other product information provided by the sponsor. I agree to conduct this study 
in accordance with the requirements of this protocol and also protect the rights, safety, 
privacy, and well-being of study subjects in accordance with the following: 
•
The ethical principles that have their origin in the Declaration of Helsinki.
•
International 
Council 
for 
Harmonisation 
of 
Technical 
Requirements 
for
Pharmaceuticals for Human Use E6 (R2) Good Clinical Practice: Consolidated
Guideline.
•
All applicable laws and regulations, including, without limitation, data privacy laws
and regulations.
•
Regulatory requirements for reporting serious adverse events defined in Section 16.3
of this protocol.
Information taken from the study protocol may not be disseminated or discussed with a 
third party without the express consent of the sponsor.  
Litza McKenzie MBChB, BScMedSci (Hons) 
See electronic signature at the end of 
the document 
Principal Investigator 
Signature 
Senior Clinical Research Physician 
Date 


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Page 64 of 64 
Signatures for Sponsor 
Jill A Greytok 
Senior Director, Clinical Development 
Signature 
Hepion Pharmaceuticals, Inc. 
 
Date 
Patrick R Mayo BSc(Pharm), PhD, MTS 
SVP Clinical Pharmacology & Analytics 
Signature 
Hepion Pharmaceuticals, Inc. 
Date 
Todd Hobbs, MD 
Hepion Pharmaceuticals, Inc. 
Signature 
 
Date 
Daniel Trepanier, PhD  
Sr. Vice President, Drug Development 
Signature 
Hepion Pharmaceuticals, Inc. 
Date 
3/22/2023
3/22/2023
3/22/2023
3/22/2023


Document Approvals
Approved Date: 22 Mar 2023
Document Author(s):  Molly Boughey-Moore 
Approval Task
Verdict:  Approve
Litza McKenzie, Senior Clinical Research Physician
(Litza.McKenzie@quotientsciences.com)
Approval
22-Mar-2023 17:32:22 GMT+0000

SAP_001.pdf: 
Sponsor/Quotient Sciences Confidential 
 
 
Clinical Study Report HEPA-CRV431-105 (QSC204643) Version 1.0 
 
 
16.1.9 
Documentation of Statistical Methods 
Reporting and Analysis Plan Version 1.0 (dated 10 Feb 2023) 


Quotient Confidential 
Doc No: DOC-126103 
 
Version: 0.8 
Status: Ready for Approval 
Doc Name: QSC204643 (HEPA-CRV431-105) RAP 
Project Number: 204643 
Governing SOP: DOC-03176 
REPORTING AND ANALYSIS PLAN 
An Open Label, Single-Dose, Single-Period Study Designed to 
Assess the Mass Balance Recovery, Metabolite Profile and 
Metabolite Identification of [14C]-Rencofilstat in Healthy Male 
Subjects  
Quotient Study Number: 
QSC204643 
Sponsor Study Number: 
HEPA-CRV431-105 
Sponsor: 
Hepion Pharmaceuticals, Inc 
399 Thornall Street, First Floor 
Edison 
New Jersey 
08837 
Date of RAP: 
10 Feb 2023 
Status of RAP: 
Final v1.0 
Document Version History 
Version 
Number 
Reason for Update 
Updated By: 
Date 
v1.0 
Initial version 
Claire Wilson 
10 Feb 2023 
SPONSOR/QUOTIENT SCIENCES CONFIDENTIAL 
This Reporting and Analysis Plan may not be reproduced or communicated to a third 
party without the written permission of Hepion Pharmaceuticals, Inc. 


See electronic signature at end of document
See electronic signature at end of document
See electronic signature at end of document
See electronic signature at end of document
See electronic signature at end of document
17 Feb 2023
17 Feb 2023
2/16/2023
17 Feb 2023
20 Feb 2023
17 Feb 2023


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1 
Table of Contents 
1 
Table of Contents ................................................................................ 3 
2 
List of Abbreviations ............................................................................ 6 
3 
Introduction ......................................................................................... 9 
3.1 
Responsibilities ................................................................................... 9 
3.2 
Definitions ........................................................................................... 9 
3.2.1 
Subject Definitions .............................................................................. 9 
3.2.2 
Definition of Treatments ...................................................................... 9 
3.2.3 
Definition of Visits ............................................................................. 10 
4 
Objectives and Endpoints ................................................................. 10 
5 
Study Design ..................................................................................... 11 
5.1 
Brief Description ................................................................................ 11 
5.2 
Criteria for In-Study Decisions .......................................................... 12 
5.3 
Study Sample Size ............................................................................ 12 
5.4 
Randomisation (including Replacement Subjects) ........................... 12 
5.5 
Blinding Issues .................................................................................. 13 
6 
Populations and Analysis Sets .......................................................... 13 
6.1 
Safety Population and Safety Analysis Set ....................................... 13 
6.2 
Mass Balance Population and Analysis Set(s) ................................. 13 
6.3 
PK Population and Analysis Set(s) ................................................... 14 
7 
Subject Disposition, Demographics and Baseline Characteristics .... 14 
7.1 
Screening Failures ............................................................................ 14 
7.2 
Subject Disposition and Withdrawals ................................................ 15 
7.3 
Analysis Populations ......................................................................... 15 
7.4 
Analysis Sets and Subsets ............................................................... 15 
7.5 
Demographic Characteristics and Lifestyle Details ........................... 15 
7.6 
Medical History ................................................................................. 16 
7.7 
Prior and Concomitant Medication .................................................... 16 
7.8 
Other Baseline Characteristics ......................................................... 16 
8 
Efficacy ............................................................................................. 16 
9 
Mass Balance ................................................................................... 17 
9.1 
Mass Balance Parameter Estimation ................................................ 17 
9.1.1 
Definition of Mass Balance Parameters ............................................ 17 
9.1.2 
Rules for Mass Balance Parameter Estimation ................................ 18 


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9.2 
Mass Balance Summary Tables ....................................................... 20 
9.3 
Mass Balance Figures ...................................................................... 21 
9.4 
Mass Balance Listings ...................................................................... 21 
9.5 
Statistical Analysis of Mass Balance Parameters ............................. 21 
10 
Pharmacokinetics .............................................................................. 21 
10.1 
Plasma and Whole Blood PK Parameter Estimation ........................ 21 
10.1.1 
Definition of Plasma and Whole Blood PK Parameters .................... 21 
10.1.2 
Rules for Plasma and Whole Blood PK Parameter Estimation 
using WinNonlin ................................................................................ 23 
10.1.3 
Plasma and Whole Blood PK Parameter Reporting 
Specifications .................................................................................... 24 
10.2 
Concentration and PK Parameter Summary Tables ......................... 25 
10.3 
Concentration and PK Figures .......................................................... 25 
10.4 
Concentration and PK Listings .......................................................... 26 
10.5 
Statistical Analysis of PK Parameters ............................................... 26 
11 
Safety Assessments ......................................................................... 26 
11.1 
Extent of Exposure and Treatment Compliance ............................... 26 
11.2 
Adverse Events ................................................................................. 26 
11.2.1 
Summary Tables for Adverse Events ............................................... 27 
11.2.2 
Listings for Adverse Events .............................................................. 29 
11.3 
Laboratory Evaluations ..................................................................... 30 
11.3.1 
Summary Tables for Laboratory Evaluations .................................... 30 
11.3.2 
Listings for Laboratory Evaluations ................................................... 30 
11.4 
Vital Signs ......................................................................................... 31 
11.4.1 
Summary Tables for Vital Signs ........................................................ 31 
11.4.2 
Listings for Vital Signs ....................................................................... 31 
11.5 
ECGs ................................................................................................ 31 
11.5.1 
Summary Tables for ECGs ............................................................... 32 
11.5.2 
Listings for ECGs .............................................................................. 32 
11.6 
Body Weight ...................................................................................... 33 
11.7 
Physical Examination ........................................................................ 33 
12 
Interim Statistical Analyses ............................................................... 33 
13 
Changes in the Conduct of the Study or Planned Analysis .............. 33 
13.1 
Changes in the Conduct of the Study ............................................... 33 
13.2 
Changes to the Planned Analyses .................................................... 33 
13.3 
Any Other Relevant Changes ........................................................... 33 
14 
Overall Considerations ...................................................................... 33 
14.1 
Statistical Programming and Analysis ............................................... 33 


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14.2 
Quality Control of Summary Tables, Figures and Listings ................ 35 
14.2.1 
Quality Control - Summary Tables .................................................... 35 
14.2.2 
Quality Control - Figures ................................................................... 35 
14.2.3 
Quality Control - Data Listings .......................................................... 36 
15 
SAS Data Transfer ............................................................................ 36 
16 
Programming Conventions ............................................................... 36 
17 
Reference List ................................................................................... 36 
18 
Index of Tables ................................................................................. 37 
19 
Index of Figures ................................................................................ 41 
20 
Index of Listings ................................................................................ 44 
21 
Mock Tables...................................................................................... 48 
Appendix 1:  
Schedule of Assessments ................................................................. 70 


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2 
List of Abbreviations 
14C 
carbon-14 
ADaM 
analysis data model  
ADR 
adverse drug reaction 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
AUC 
area under the curve  
BLQ 
below the limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CHMP 
Committee for Medicinal Products for Human Use 
COVID-19 
Coronavirus disease 2019 
CSR 
clinical study report 
CV% 
coefficient of variation 
D 
‘substantial’ decrease from baseline for vital signs parameters 
DP 
decimal place 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
h 
hour 
H 
flag used for value that is above normal reference range 
HR 
heart rate 
I 
‘substantial’ increase from baseline for vital signs parameters / 
increase in QTcF interval from baseline 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
ISF 
Investigator Site File 


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L 
flag used for value that is below normal reference range 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
Max 
maximum 
MBq 
megabecquerel 
MedDRA 
Medical Dictionary for Regulatory Activities 
µCi 
microcurie 
Min 
minimum 
n 
number of subjects with an observation 
N 
number of subjects in the dataset 
NA 
not applicable 
NC 
not calculated 
NR 
not reportable/no result 
NS 
no sample 
PK 
pharmacokinetic 
PT 
preferred term 
QC 
quality control 
QTcF 
QT interval corrected for heart rate using Fridericia’s correction 
RAP 
reporting and analysis plan 
SAE 
serious adverse event 
SD 
standard deviation 
SDTM 
study data tabulation model 
SF 
significant figure 
SI 
SMEDDS 
substantial increase in QTcF interval from baseline 
self-microemulsifying drug delivery system 
SOC 
system organ class 
SOP 
standard operating procedure 


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TEAE 
Treatment -emergent adverse event 
TFL 
tables, figures and data listings 
WHO 
World Health Organisation  
Abbreviations used for mass balance and pharmacokinetic parameters and associated 
flags are defined in Section 9.1.1, Section 10.1.1, and Section 10.1.3  respectively. 


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3 
Introduction 
This document details the following for Quotient Sciences (Quotient) Study QSC204643 
(HEPA-CRV431-105): 
• 
Criteria to be used for the definition of the populations and analysis sets relating to 
mass balance, pharmacokinetic (PK) and safety data 
• 
Handling of missing data 
• 
Proposed tables, figures and data listings (TFLs) for demographic, dosing, mass 
balance, PK and safety data  
• 
Methods for PK parameter estimation  
This document has been compiled according to the Quotient standard operating 
procedure (SOP) “Production of Reporting and Analysis Plans” and has been written 
based on information contained in the final study protocol (v1.0) dated 21 Dec 2022. 
3.1 
Responsibilities 
The Data Sciences Department at Quotient will be responsible for the production of the 
following items using Quotient SOPs: Clinical Data Interchange Standards Consortium 
(CDISC) study data tabulation model (SDTM) and analysis data model (ADaM) datasets, 
mass balance, PK and safety output; including all TFLs; and the clinical study report 
(CSR). 
Quotient will provide two sets of TFLs during the study: 
• 
Post database lock TFLs (draft) for Hepion Pharmaceuticals, Inc (Hepion) review 
• 
Post-review TFLs (final) for inclusion into the CSR 
Quotient will be responsible for the quality control (QC) of all deliverables prior to the 
client review (Section 14.2). 
Metabolite profiling and structural identification will be the responsibility of Pharmaron 
UK and will be the subject of a separate Analytical Work Plan. These aspects will be 
reported separately from the CSR as a standalone document. 
3.2 
Definitions 
3.2.1 
Subject Definitions 
During the clinical phase of the study, an evaluable subject is defined as a subject who 
has provided mass balance and PK samples for up to 21 days after drug administration 
or have demonstrated >90% mass balance recovery or have <1% of the administered 
dose eliminated in excreta for two consecutive days, whichever is sooner. This definition 
will not be used during the reporting phase including the identification of analysis 
populations and datasets which are defined in Section 6. No replacement subjects are 
planned for this study.  
An enrolled subject is defined as a subject who signed the informed consent, qualified 
per the inclusion/exclusion criteria and was allocated a subject number.  
3.2.2 
Definition of Treatments 
Throughout the reporting of the study, investigational medicinal product (IMP) will be 
reported as detailed in Table 1 below: 


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Table 1 
Study Treatments 
IMP Name 
Dose 
Route of Administration 
Label to be used for 
reporting 
[14C]CRV431 SMEDDS 
Concentrate for Oral 
Emulsion, 225 mg (NMT 
6.4 MBq) 
225 mg 
Oral administration, Fasted 
225 mg [14C]CRV431 
14C: carbon-14, MBq: megabecquerel, NMT: not more than, SMEDDS: self-microemulsifying drug delivery 
system 
3.2.3 
Definition of Visits 
For clinical data, visits will be referred to as Day throughout this document and will be 
referred to as screening, Day -1 (Admission), Day 1 through to discharge between 
Day 22 and Day 26, and return visits on Day 28, and Day 35 (if required). Time points 
within these days are detailed in the schedule of assessments in Appendix 1. 
Baseline is defined as nominally the last measurement recorded prior to the dose of IMP.  
4 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary  
 
To determine the mass balance recovery after a 
single oral dose of carbon-14 ([14C])-rencofilstat 
 
Mass balance recovery of total radioactivity (TR) 
in all excreta (urine and faeces): CumAe and 
Cum%Ae 
To determine % parent drug unchanged versus 
metabolites 
Evaluation of whole blood parent: whole blood 
TR ratios for AUC  
To perform metabolite profiling and structural 
identification from whole blood, urine and faecal 
samplesa 
Collection of whole blood, urine and faeces 
samples for metabolite profiling, structural 
identification, and quantification analysis 
Secondary 
To determine the routes and rates of elimination of 
[14C]-rencofilstat 
 
Mass balance recovery of TR in urine and faeces 
separately: Ae, %Ae, CumAe and Cum%Ae by 
interval 
To identify the chemical structure of each metabolite 
accounting for more than 10% of circulating TR or 
accounting for 10% or more of the dose in excreta 
Identification of the chemical structure of each 
metabolite accounting for more than 10% by 
AUC of circulating TR or accounting for 10% or 
more of the dose in excreta 
To evaluate the extent of distribution of TR into blood 
cells 
Evaluation of whole blood:plasma concentration 
ratios for TR 
To provide additional safety and tolerability 
information for rencofilstat 
To provide additional safety and tolerability 
information for rencofilstat by assessing: 
incidence of adverse events (AEs), physical 
examinations and change from baseline for vital 
signs, electrocardiograms (ECGs), and 
laboratory safety tests 
To further explore the oral pharmacokinetics (PK) of 
rencofilstat 
PK parameters for rencofilstat in whole blood and 
TR in plasma and whole blood following a single 
oral dose, including but not limited to: Tlag, 
Tmax, Cmax, AUC(0-last), AUC(0-inf), Lambda-
z, T1/2, CL/F, Vz/F, MRT(0-last) and MRT(0-inf) 
as applicable 
a Metabolite profiling and identification will be reported separately from the clinical study report as a 
standalone document. 


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5 
Study Design 
5.1 
Brief Description 
This is a single centre, open-label, non-randomised, single period, single dose study in 
healthy male subjects designed to assess the mass balance recovery, PK, metabolite 
profile and metabolite identification of rencofilstat. It is planned to enrol a single cohort 
of 6 subjects.  
All subjects will receive a single 225 mg oral dose of [14C]-rencofilstat, as a 
self-microemulsifying drug delivery system (SMEDDS) oral emulsion, containing NMT 
6.4 MBq, in the fasted state. 
Subjects will undergo preliminary screening procedures for the study at the screening 
visit (Day -28 to Day -2). Subjects will be admitted in the evening on the day before 
dosing (Day -1). 
Whole blood, plasma, urine and faeces samples will be collected at regular intervals for 
PK analysis, TR analysis, metabolite profiling, mass balance and safety as applicable, 
from pre-dose to discharge from the clinical unit. Urine and faeces samples may be 
collected at return visits or home visits if mass balance criteria has not been met by a 
subject.  
Subjects will be dosed on the morning of Day 1 following an overnight fast (minimum 
8 h) and will remain resident in the clinical unit until up to 504 h after dosing (up to 
Day 22) (Figure 1).  
It is planned that subjects will be released as a group when all subjects have achieved a 
mass balance cumulative recovery of >90% or if <1% of the dose administered has been 
collected in urine and faeces within two separate, consecutive 24 h periods. This may 
result in the subjects being discharged as a group prior to completion of the planned 
residency period.  
If the mass balance criteria are achieved during the planned residency period, collection 
of all samples (blood, urine and faeces) will be stopped once the current 24 h collection 
period is complete, and subjects will undergo discharge assessments. 
If the mass balance criteria have not been met by all subjects on the morning of 
Day 22, the residency period for the subjects not achieving the mass balance criteria 
may be extended up to a maximum of 96 h (Day 26; 600 h post-dose). Only urine and/or 
faecal samples will be collected during the extended residency period. 
If the mass balance criteria have not been met by all subjects on the morning of 
Day 26, subjects not achieving the release criteria may be required to make up to 
2 return visits (each of 24 h duration) at (nominally) Day 28 (+2 days) and 
Day 35 (±2 days) for additional collection of excreta samples (urine and/or faecal 
samples). 
If the mass balance criteria have not been met following the return visits, then home 
collections of urine and/or faeces may be requested at the discretion of the investigator 
for individual subjects. 


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Figure 1 
Study Sequence 
Screening 
Day -28 to Day -2 
 
Admission 
Day -1 
 
Dose 
Day 1 
 
Discharge 
Day 22  
 
Or, if mass balance criteria are 
not met by Day 22a: 
Extended Residency Discharge 
Day 23, 24, 25 or 26 
 
And, if mass balance criteria 
are not met by Day 26b: 
Return Visit 
Day 28 (+2 days) 
 
And, if mass balance criteria 
are not met by Day 28b: 
Return Visit 
Day 35 (±2 days) 
a If all subjects have not achieved a mass balance cumulative recovery of >90% or if a total of <1% of the 
dose administered has not been collected in urine and faeces within 2 separate, consecutive 24 h periods 
on the morning of Day 22, the residency period for the subjects not achieving the mass balance criteria may 
be extended up to a maximum of 96 h (Day 26). Only urine and/or faecal samples will be collected during 
the extended residency period.  
b If the mass balance criteria have not been met by all subjects on the morning of Day 26, subjects not 
achieving the release criteria may be required to make up to 2 return visits (each of 24 h duration) at 
(nominally) Day 28 (+2 days) and Day 35 (±2 days) for additional collection of excreta samples (urine and/or 
faecal samples). If the mass balance criteria have not met following the return visits, then home collections 
of urine and/or faeces may be requested at the discretion of the investigator for individual subjects. 
5.2 
Criteria for In-Study Decisions 
Not applicable for this study. 
5.3 
Study Sample Size 
The study is exploratory and no formal sample size calculation has been made. Based 
on experience from previous studies of a similar design, a total of 6 subjects are to be 
enrolled and a minimum of 4 evaluable subjects are considered sufficient.  
5.4 
Randomisation (including Replacement Subjects) 
This is an open-label, non-randomised study, therefore a randomisation schedule will not 
be produced. Instructions to dispense and dose will be produced prior to dosing with 
IMP, which will dictate the order in which the treatments should be administered to each 
subject. The instructions to dispense and dose will be retained in the investigator site file 
(ISF). Subject numbers will be allocated on the morning of dosing according to the code 


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001 to 006 using the lowest number available. No replacement subjects are planned for 
this study. 
5.5 
Blinding Issues 
This is an open-label, non-randomised study and therefore blinding is not required. 
6 
Populations and Analysis Sets 
6.1 
Safety Population and Safety Analysis Set 
The safety population will include all subjects who have received any amount of the IMP. 
The safety analysis set will include all safety data from the subjects included in the safety 
population. 
The safety population will be confirmed by Quotient with approval from Hepion after 
database lock and will be summarised for the populations table and to determine the 
subjects to be included in the safety analysis set. 
The safety analysis set will be confirmed by Quotient with approval from Hepion at the 
same time as the safety population and will be summarised for the analysis of 
demographic and baseline characteristics, and all safety data. 
6.2 
Mass Balance Population and Analysis Set(s) 
The mass balance population will include all subjects who have received one dose of 
IMP and who have evaluable total radioactivity concentration (urinary or faecal) data and 
who have no protocol deviations that affect the mass balance analysis. Such protocol 
deviations would include anything that affects the accurate measurement of the amount 
of urine/faeces collected or any AEs that may affect the mass balance analysis, for 
example: 
• 
Spillage of urine and/or faeces 
• 
Missing collections 
• 
AEs that may affect the mass balance analysis* 
*for example, if vomiting is observed, this will be assessed on a case-by-case basis to 
determine the potential impact on the mass balance recovery 
The mass balance population will be confirmed by Quotient with approval from Hepion 
once all urinary and faecal data have been received and will be used for the analysis of 
the mass balance concentration data and the provision of mass balance summary tables, 
figures and listings. 
If required, a mass balance analysis set and subset(s) will also be documented by 
Quotient, with approval from Hepion, at the same time as the mass balance population, 
if subjects are required to be excluded from the summary tables and figures (for example 
to exclude subjects who have incomplete collections for one matrix).  
All enrolled subjects will be used for the mass balance data listings. The mass balance 
population will be used for the populations table. The mass balance analysis set and/or 
the mass balance analysis subset(s), if defined, will be used for the provision of mass 
balance summary tables and figures. The mass balance analysis set or subset to be 


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used for the provision of mass balance summary tables and figures will be documented 
as the same time as the mass balance population. 
6.3 
PK Population and Analysis Set(s) 
The PK population will include all subjects who received IMP and who satisfy the 
following criteria for at least 1 profile: 
• 
No missing samples or invalid post-dose analytical results at critical time points 
eg around Cmax 
• 
No relevant protocol deviations which may impact the study objectives with 
respect to the PK endpoints 
• 
No relevant AEs such as vomiting which suggest that the whole dose was not 
available for absorption for a particular subject 
The PK analysis set will be defined on a per-treatment basis and will include all relevant 
data from the subjects included in the PK population who have received that treatment. 
Individual subject profiles (ie analyte/matrix) will be excluded from the PK analysis set 
where deemed appropriate such as if the subject’s data for the treatment affected did 
not meet the bullet point criteria above, or other study emergent point related to PK 
analysis or interpretation. 
The PK population and analysis set will be confirmed by Quotient with approval from 
Hepion following derivation of all PK parameter estimates. 
If required, a PK analysis subset(s) will also be documented by Quotient, with approval 
from Hepion, at the same time as the PK population and analysis set, if additional 
subjects are required to be excluded from the summary tables and figures.  
All enrolled subjects will be used for the PK data listings. The PK population will be used 
for the populations table. The PK analysis set and/or the PK analysis subset(s), if 
defined, will be used for the provision of PK summary tables and figures. The PK analysis 
set or subset to be used for the provision of PK summary tables and figures will be 
documented as the same time as the PK population. 
7 
Subject 
Disposition, 
Demographics 
and 
Baseline 
Characteristics 
No formal statistical testing will be performed on subject disposition, or on demographic 
or baseline data. Summaries of subject disposition and analyses populations will be 
based on all enrolled subjects and summaries of all other data described in this section 
will be based on the safety analysis set unless otherwise stated. 
7.1 
Screening Failures  
Data for participants who have failed screening will be databased but will not be cleaned 
and therefore will not be included in the SDTM or ADaM datasets or any of the TFLs or 
the CSR. 


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7.2 
Subject Disposition and Withdrawals 
The number and percentage of subjects enrolled, dosed, completed and discontinued 
will be presented overall. If any subjects discontinued from the study early then the 
number of subjects for each reason for discontinuation will be presented overall. 
However, if none of the subjects discontinued from the study early, then the reasons for 
discontinuation will not be populated in the summary table. A subject may be 
discontinued from the study early for 1 reason only. 
Subject disposition and withdrawal data will be listed including details of informed 
consent. 
Protocol deviations and any violations of the inclusion/exclusion criteria will also be listed. 
7.3 
Analysis Populations 
A summary table will be produced detailing the number and percentage of subjects in 
each population (i.e. safety, mass balance and PK) overall. The reasons for exclusion 
from each population will also be included in the summary table. However, if none of the 
subjects were excluded from a population, then the reasons for exclusion will not be 
populated in the summary table. A subject may be excluded from a population for more 
than 1 reason. The denominator for the percentage is the number of subjects enrolled. 
Details of subjects included and excluded in the different analysis populations will be 
listed. 
7.4 
Analysis Sets and Subsets 
A summary table will be produced detailing the number and percentage of subjects in 
each of the safety, mass balance and PK analysis sets and analysis subsets (if 
applicable). Separate tables will be presented for safety, mass balance and PK sets and 
each table will be based on the relevant population the analysis set is derived from. If 
analysis subsets are defined they will be included on the same table as the 
corresponding analysis set. The reasons for exclusion from each analysis set/subset will 
also be included in the summary. However, if none of the subjects were excluded from 
an analysis set, then the reasons for exclusion will not be populated in the summary 
table. A subject may be excluded from an analysis set for more than 1 reason. The 
denominator for the percentage is the number of subjects in the relevant population. 
Details of subjects included and excluded in the different analysis sets/subsets will be 
listed. 
7.5 
Demographic Characteristics and Lifestyle Details 
Demographic data (year of birth, age, ethnicity, race, sex, height [cm], weight [kg] and 
body mass index [BMI; kg/m2]) will be recorded at screening. 
Summary statistics (number of subjects with an observation [n], mean, standard 
deviation [SD], median, minimum and maximum) will be presented for age, height, weight 
and BMI at screening overall. The number and percentage of subjects will be presented 
for ethnicity, race and sex. The denominator for the percentage is all subjects in the 
safety analysis set. If any values are missing, a “missing” row will be presented on the 
table. 


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Lifestyle details (i.e., smoking history [does the subject smoke, use e-cigarettes or use 
nicotine replacement products?] and alcohol consumption) will be summarised by 
treatment as a categorical variable. 
Demographic and lifestyle data for all enrolled subjects will be listed. 
7.6 
Medical History 
Medical history will be recorded for each subject at the screening visit and updated at 
admission. Medical histories will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) v26.0 (or a more recent version) including Preferred Term (PT), and 
System Organ Class (SOC). All medical history data will be listed including coded terms. 
7.7 
Prior and Concomitant Medication 
Medications (product name) will be coded using the World Health Organization (WHO) 
Drug Dictionary Global Drug Reference: 2023 Mar version (or more recent version) using 
the following Anatomical Therapeutic Chemical (ATC) classification codes 
• 
Product name 
• 
Preferred name  
• 
Drug code 
• 
Therapeutic subgroup (ATC 2nd level code) 
• 
Chemical subgroup (ATC 4th level code) 
Prior medications are defined as medications that start and stop prior to the first dose of 
IMP. All other medications will be defined as concomitant medications including those 
that start prior to the first dose of IMP and continue thereafter. Any medications with an 
unknown start or stop date will be assumed to be concomitant medications unless a 
partial start or stop date indicates otherwise. 
All medications, including coded terms, and the underlying indication for which the 
medication was given, will be listed. One combined data listing of prior and concomitant 
medications will be provided. All prior medications as defined above will be flagged with 
a “#” symbol. Within this flagged group medications that started after screening and 
stopped before dosing of IMP will also be flagged using a “*” symbol. 
7.8 
Other Baseline Characteristics 
All other baseline characteristics, as listed below, at screening and on admission (unless 
otherwise stated) will be listed: 
• 
Carbon monoxide breath test 
• 
Urine drug screen 
• 
Alcohol breath test 
• 
SARS-CoV-2 Antigen test (if required – See detail in Appendix 1) 
• 
Virology (screening only) 
• 
eGFR (screening only) 
8 
Efficacy 
Not applicable.  


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9 
Mass Balance 
9.1 
Mass Balance Parameter Estimation 
Pharmaron will provide the following concentration and weight data on a per subject 
basis for each collection interval as specified in the clinical protocol: 
• 
Total radioactivity concentration for urine and faeces (mass unit equivalents/g) 
• 
Weight  of urine (g)  
• 
Faeces weight (g) i.e. not faecal homogenate weight 
Concentration values will be expressed in terms of mass unit equivalents of the free base 
form. Quotient Data Sciences will be responsible for the calculation of excretion and 
recovery of total radioactivity in urine, faeces and urine and faeces combined for 
inclusion into the clinical study report. For the purposes of this document “excretion” will 
be used when describing the amount of total radioactivity excreted and “recovery” will be 
used when describing the amount of total radioactivity expressed as a percentage of the 
radioactive dose administered. 
9.1.1 
Definition of Mass Balance Parameters 
A list of mass balance parameter definitions is provided in Table 2. 
Table 2 
Mass Balance Parameters and Reporting Specifications 
Parameter 
Definition 
Units 
DP or 
SF 
No. of 
DP/SF 
Ae(urine) 
amount of total radioactivity excreted in urine 
Mass unit 
equiv 
SF 
3 
%Ae(urine) 
amount of total radioactivity excreted in urine 
expressed as a percentage of the radioactive 
dose administered 
% 
DP 
2 
CumAe(urine) 
cumulative amount of total radioactivity 
excreted in urine 
Mass unit 
equiv 
SF 
3 
Cum%Ae(urine) 
cumulative amount of total radioactivity 
excreted in urine expressed as a percentage 
of the radioactive dose administered 
% 
DP 
2 
Ae(faeces) 
amount of total radioactivity eliminated in 
faeces 
Mass unit 
equiv 
SF 
3 
%Ae(faeces) 
amount of total radioactivity eliminated in 
faeces expressed as a percentage of the 
radioactive dose administered 
% 
DP 
2 
CumAe(faeces) 
cumulative amount of total radioactivity 
eliminated in faeces 
Mass unit 
equiv 
SF 
3 
Cum%Ae(faeces) 
cumulative amount of total radioactivity 
eliminated in faeces expressed as a 
percentage of the radioactive dose 
administered 
% 
DP 
2 
Ae(total) 
amount of total radioactivity excreted in urine 
and faeces combined 
Mass unit 
equiv 
SF 
3 
%Ae(total) 
amount of total radioactivity excreted in urine 
and faeces combined expressed as a 
percentage of the radioactive dose 
administered 
% 
DP 
2 


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Parameter 
Definition 
Units 
DP or 
SF 
No. of 
DP/SF 
CumAe(total) 
cumulative amount of total radioactivity 
excreted in urine and faeces combined 
Mass unit 
equiv 
SF 
3 
Cum%Ae(total) 
cumulative amount of total radioactivity 
excreted in urine and faeces combined 
expressed as a percentage of the radioactive 
dose administered 
% 
DP 
2 
 
Home collections of urine and/or faeces may be requested at the discretion of the 
investigator for individual subjects. For amount excreted and cumulative excretion this 
will be calculated for all time points including home collection, if applicable.  
Dose will be used in the calculation of mass balance parameters as per Table 3. 
Table 3 
Mass Balance Dose Specifications 
Radioactive dose level for mass 
balance analysis  
Actual 
Precision   
As provided by Pharmaron 
 
9.1.2 
Rules for Mass Balance Parameter Estimation  
The following will be calculated for total radioactivity in urine, faeces and urine and faeces 
combined by Quotient Data Sciences (note that the amount excreted in pre-dose 
samples will not be included in the calculation of the cumulative amount excreted or in 
the calculation of the cumulative percentage of the radioactive dose excreted): 
• 
The amount excreted in urine i.e. Ae(urine) and the amount excreted in faeces 
i.e. Ae(faeces) will be calculated for each collection interval the following formula 
(where matrix is either urine or faeces): using 
Ae(<matrix>) =  concentration * weight 
 
• 
Following Day 26, where urine/faecal collections are no longer continuous and return 
visits (i.e., Day 28 [±2 days] and Day 35 [±2 days]) are scheduled, additional 
interpolation of Ae will be calculated to estimate amount excreted on non-collection 
days (i.e., between Day 26 to Day 28, and Day 28 to Day 35 if required), as follows: 
Ae(interval) = ((Ae 24h [Day x + Day y) / 2 )* duration of interval (days) 
 
where Day x and Day y are the calculated amounts excreted for the preceding and 
proceeding days of the interval to be calculated. 
Interpolation may also be calculated to estimate the amount excreted between 
home collects if required. 
• 
The total amount excreted in urine and faeces combined, i.e. Ae(total), will be 
calculated for each collection interval using the following formula: 
Ae(total) = Ae(urine) + Ae (faeces) 
 


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• 
The cumulative amount excreted in urine i.e. CumAe(urine) and the cumulative 
amount excreted in faeces i.e. CumAe(faeces) will be calculated by the incremental 
summation of the Ae(<matrix>) across all collection intervals (where matrix is either 
urine or faeces). The amount excreted in the pre-dose sample should not be included 
in the calculation of the cumulative amount excreted. 
• 
The cumulative amount excreted in urine and faeces combined i.e. CumAe(total) will 
be calculated across all collection intervals using the following formula: 
CumAe(total) = CumAe(urine) + CumAe(faeces) 
• 
The % amount of the total radioactive dose excreted in urine i.e. %Ae(urine) and the 
% amount of the total radioactive dose excreted in faeces i.e. %Ae(faeces) will be 
calculated for each collection interval using the following formula (where matrix is 
either urine or faeces): 
%Ae(<matrix>) = 100 * Ae(<matrix>) / Total Radioactive Dose Administered 
• 
The % amount of the total radioactive dose excreted in urine and faeces combined 
will be calculated for each collection interval using the following formula: 
%Ae(total) = %Ae(urine) + %Ae(faeces) 
• 
The cumulative % amount of the total radioactive dose excreted in urine i.e. 
Cum%Ae(urine) and the cumulative % amount of the total radioactive dose 
excreted in faeces i.e. Cum%Ae(faeces) will be calculated by the incremental 
summation of the %Ae(<matrix>) across all collection intervals (where matrix is 
either urine or faeces). The % amount of the total radioactive dose excreted in 
the pre-dose sample should not be included in the calculation of the cumulative 
% of dose excreted. 
• 
The cumulative % amount of the total radioactive dose excreted in urine and faeces 
combined will be calculated for each collection interval using the following formula: 
Cum%Ae(total) = Cum%Ae(urine) + Cum%Ae(faeces) 
For urine and faeces, where a subject has failed to void over a particular collection 
interval the Amount Eliminated (Ae) will be set to zero. 
If part of a void over a particular collection interval is missing due to spillage or accidental 
discarding, the Ae will still be calculated providing other samples have be collected within 
the interval. Where no other samples are collected within the interval the data will be set 
to missing for the purposes of the calculation of Ae, CumAe and Cum%Ae. In both 
scenarios the data will be flagged to highlight a missing void. 
Imputation of non-numerical values reported in the urine and faecal data set (i.e. 
concentrations that are not detectable [ND] below the limit of quantification [BLQ]) will be 
entered as zero for calculation of parameters such as Ae. 
When converting urine collection weights to urine volume (if required), the following 
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1.02 g of urine = 1 mL of urine 
This will be calculated in SAS as follows: 
Urine weight (g) / 1.02 = Urine volume (mL) 
If total radioactivity concentrations in urine have been provided in mass unit/g units the 
following conversion (if required) will be performed using SAS: 
Concentration (mass units/g) * 1.02 = Concentration (mass units/mL) 
The radioactivity associated with toilet paper may be determined with the approval of 
Hepion. The results will be reported for each subject as a single value for the whole 
collection period and included in the calculation of total amount excreted and % of dose 
recovered. 
Accidental sources of elimination, e.g., vomiting, will be collected and sent for total 
radioactivity analysis. This will be reported on a case by case basis and details will be 
included in the documentation of the mass balance population. 
9.2 
Mass Balance Summary Tables 
Summary statistics (i.e. n, mean, SD, coefficient of variation [CV%], minimum, median 
and maximum) will be presented for amount excreted (Ae) and recovery (%Ae) by 
collection period for the following: 
• 
Urine [i.e. Ae(urine) and %Ae(urine)] for total radioactivity 
• 
Faeces [i.e. Ae(faeces) and %Ae(faeces)] for total radioactivity 
• 
Urine and faeces combined [i.e. Ae(total) and %Ae(total)] for total radioactivity 
In addition, summary statistics (i.e. n, mean, SD, CV%, minimum, median and maximum) 
will be presented for the cumulative excretion and cumulative recovery by collection 
period for each of the following:  
• 
Urine [i.e. CumAe(urine) and Cum%Ae(urine)] for total radioactivity 
• 
Faeces [i.e. CumAe(faeces) and Cum%Ae(faeces)] for total radioactivity 
• 
Urine and faeces combined [i.e. CumAe(total) and Cum%Ae(total)] for total 
radioactivity 
Finally, summary statistics (i.e. n, mean, SD, CV%, minimum, median and maximum) 
will be presented for the cumulative excretion and cumulative recovery for the study as 
a whole for each of the following: 
• 
Urine [i.e. CumAe(urine) and Cum%Ae(urine)] for total radioactivity 
• 
Faeces [i.e. CumAe(faeces) and Cum%Ae(faeces)] for total radioactivity 
• 
Urine and faeces combined [i.e. CumAe(total) and Cum%Ae(total)] for total 
radioactivity 
If any subject withdraws prior to the end of a study visit or if subjects have differing 
collection intervals [(e.g. Day 10 for some subjects and Day 14 for others)] then a last 
observation carried forward (LOCF) approach will be used whilst calculating cumulative 
Ae and %Ae (i.e. CumAe and Cum%Ae), where the last observed value will be carried 
forward to the subsequent time point. The number of subjects included at each collection 


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interval will therefore remain the same regardless of subject withdrawals. The LOCF 
approach will be used for all summary tables detailed above. 
9.3 
Mass Balance Figures 
Mean balance figures will be presented for the mass balance population. 
Mean cumulative excretion (i.e. CumAe) and cumulative recovery (i.e. Cum%Ae) vs time 
curves will be produced on a linear/linear scale and will include ± SD bars. These plots 
will be produced for CumAe and Cum%Ae, respectively, with urine, faeces and total 
overlaid: 
• 
Urine [i.e. CumAe(urine) and Cum%Ae(urine)] for total radioactivity 
• 
Faeces [i.e. CumAe(faeces) and Cum%Ae (faeces)] for total radioactivity 
• 
Urine and faeces combined [i.e. CumAe(total) and Cum%Ae(total)] for total 
radioactivity 
A legend identifying each profile (i.e. urine, faeces and total) will be displayed on the 
mean plots. Figures will be produced using the LOCF imputation strategy (see 
Section 9.2) if summary tables are produced using this method (a footnote to indicate 
this will be added to figures as required). 
9.4 
Mass Balance Listings 
The sample collection data (e.g. collection intervals) for all urine and faecal samples will 
be listed. In addition all total radioactivity concentrations, urine and faecal weights and 
all mass balance parameters will be listed on a per subject basis. The LOCF approach 
will be used for all cumulative mass balance parameters. Where LOCF values appear in 
the listings they will be flagged. 
9.5 
Statistical Analysis of Mass Balance Parameters 
No formal statistical analysis will be performed for the mass balance data in this study. 
Descriptive statistics (i.e. n, mean, SD, median, CV%, minimum and maximum) are 
considered adequate for a study of this type. 
10 Pharmacokinetics 
10.1 
Plasma and Whole Blood PK Parameter Estimation  
The PK parameters for rencofilstat in whole blood and total radioactivity in plasma and 
whole blood will be estimated where possible and appropriate for each subject profile by 
non-compartmental analysis methods using Phoenix WinNonlin software (v8.3 or a more 
recent version, Certara USA, Inc., USA). Additional parameters may be calculated if 
required, depending on the data. 
10.1.1 
Definition of Plasma and Whole Blood PK Parameters 
Plasma and whole blood PK parameter definitions are provided in Table 4. 
Table 4 
Plasma and whole blood PK Parameter Definitions and Rounding 
Specifications 
Parameter 
Definition 
Unit 
DP or 
SF 
No. of 
DP/SF 
Tlag 
Time prior to the first measurable 
concentration 
h 
DP 
2 


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Parameter 
Definition 
Unit 
DP or 
SF 
No. of 
DP/SF 
Tmax 
Time of maximum observed 
concentration 
h 
DP 
2 
Cmax 
Maximum observed concentration 
mass unit/mL 
SF 
3 
AUC(0-24) 
Area under the curve from time 0 to 24 
h post-dose 
Mass unit.h/mL 
SF 
3 
AUC(0-last) 
Area under the curve from time 0 to the 
time of last measurable concentration 
mass unit.h/mL 
SF 
3 
AUC(0-inf) 
Area under the curve from time 0 
extrapolated to infinity  
mass unit.h/mL 
SF 
3 
AUCextrap 
Area under the curve (AUC) from time 
of the last measurable concentration to 
infinity as a percentage of the area 
under the curve extrapolated to infinity 
% 
DP 
2 
T1/2  
Terminal elimination half-life 
h 
DP 
2 
lambda-z 
First order rate constant associated 
with the terminal (log-linear) portion of 
the curve 
1/h 
DP 
4 
CL/F 
Total body clearance calculated after a 
single extravascular administration 
where F (fraction of dose bioavailable) 
is unknown.  
mL/min 
SF 
3 
Vz/F 
Apparent volume of distribution based 
on the terminal phase calculated using 
AUC(0-inf) after a single extravascular 
administration where F (fraction of 
dose bioavailable) is unknown 
L 
SF 
3 
MRT(0-last) 
Mean residence time from time 0 to 
time of the last measurable 
concentration  
h 
DP 
2 
MRT(0-inf) 
Mean residence time 0 extrapolated to 
infinity 
h 
DP 
2 
AUC Ratio 
Parent to total radioactivity ratio for 
whole blood based on AUC(0-inf) 
NA 
DP 
2 
lambda-z 
lower* 
Lower limit on time for values to be 
included in the calculation of lambda-z 
h 
DP 
2 
lambda-z 
upper* 
Upper limit on time for values to be 
included in the calculation of lambda-z 
h 
DP 
2 
DP=decimal places 
SF=significant figures 
*=these values should be listed but omitted from the descriptive statistics 
NA=not applicable 
Dose will be used in the calculation of relevant PK parameters as per Table 5. 
Table 5 
PK Parameter Dose Specifications 
Dose Route 
Nominal/Actual 
Precision 
Oral 
Nominal 
As per Protocol 
 
Total radioactivity blood to plasma concentration ratios will be determined using SAS 
by the Lead Statistical Programmer (or designee) at the time points defined in the 
protocol. If either the blood or plasma concentration values are BLQ (i.e., <lower limit of 
quantification [LLOQ]) at any given timepoint the ratio will not be calculated. 


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When converting blood collection weights to blood volume (if required) for the calculation 
of the whole blood:plasma ratio, the following conversion factor will be used: 
1.06 g of blood = 1 mL of blood 
This will be calculated in SAS as follows: 
Blood weight (g) / 1.06 = Blood volume (mL) 
Alternatively, where total radioactivity concentrations in blood have been provided in 
mass unit/g units the following conversion will be performed using SAS: 
Concentration (mass units/g) * 1.06 = Concentration (mass units/mL) 
In addition, the ratio of rencofilstat to total radioactivity in whole blood will be calculated 
based on AUC using AUC(0-inf): 
AUC ratio = {
AUC(reconfilstat )
AUC (total radioactivity )} 
If for any reason the AUC(0-inf) is not calculable then an alternative or additional AUC 
over a partial area may be used to calculate the AUC ratio for all subjects. 
10.1.2 
Rules for Plasma and Whole Blood PK Parameter Estimation using 
WinNonlin 
The imputation of non-numerical (e.g. below the limit of quantification [BLQ] or below the 
level of detection [LOD]) or negative values (e.g. pre-dose sampling times) reported in 
the input data set will be performed as follows for calculation of PK parameters: 
• 
Predose sample times will be entered as zero 
• 
Values that are BLQ* obtained prior to Cmax will be entered as zero and values 
that are BLQ* after Cmax will be treated as missing 
• 
Values that are BLQ* after Cmax may be imputed as zero for the calculation of 
partial AUCs, in cases where lambda-z cannot be determined 
• 
Values that are measurable after at least 2 consecutive BLQ* values after Cmax 
will be treated as missing for the calculation of PK parameters 
• 
Values that are reported as “No Result” or “Not Reportable” (NR), “Not 
Calculated” (NC) or “No Sample” (NS) etc. will generally be considered missing 
* values that are reported as below the LOD will be treated in the same way as samples 
reported as BLQ. 
Missing or unusual concentration values in the input data may be queried to ascertain 
any underlying cause. Exclusion of missing or unusual concentration values, or repeat 
bioanalysis of samples, will only be performed if a definitive root cause can be 
established and approval from Hepion has been obtained. Any exclusions of 
concentration values or repeat analysis of samples will be documented appropriately.  
Plasma and whole blood PK parameters will be estimated using standard Phoenix 
WinNonlin methods, details of which may be found in the documentation accompanying 
the WinNonlin software package. The rules specified in Table 6 will be applied: 


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Table 6 
PK Parameter Estimation Details 
Sampling times 
Actual 
Calculation method 
Linear trapezoidal linear interpolation  
Number of points used for lambda-z 
At least 3, not including Cmax 
Minimum requirements for AUC  
At least 3 consecutive measurable concentrations 
 
Prior to PK parameter estimation the bioanalytical data may be corrected to account for 
the proportion of administered 14C material not measured due to the use of a 12C 
LC-MS/MS analysis method. Data correction will only be performed if the 14C contribution 
exceeds 1 % of the dose administered. Bioanalytical data will be multiplied by the 
determined data correction factor in SAS by the lead statistical programmer (or 
designee). 
Where possible, the terminal elimination rate constant (lambda-z) will be calculated for 
all subject profiles. The value of lambda-z will be determined by the slope of the 
regression line of the natural log transformed concentrations vs time.  
The WinNonlin determined choice of data points for determination of lambda-z will be 
reviewed by the pharmacokineticist who may adjust the selection in order to provide a 
more appropriate fit. The choice of data points for determination of lambda-z for each 
profile will be confirmed following a documented peer review. 
10.1.3 
Plasma and Whole Blood PK Parameter Reporting Specifications 
The following parameters will be reported for each period as applicable, according to the 
rounding specifications provided in Table 4: 
Tlag, Tmax, Cmax, AUC(0-24), AUC(0-last), AUC(0-inf), AUCextrap, T1/2, lambda-z, 
CL/F (Rencofilstat only), Vz/F (Rencofilstat only), MRT(0-last), MRT(0-inf), AUC ratio 
(Rencofilstat only), lambda z lower and lambda z upper 
The flags/footnotes given in Table 7 will be applied to the PK parameters where relevant 
and will be shown in PK parameter listings. Additional flags may be applied based on 
emerging data. 
Table 7 
PK parameter Flags and Footnotes 
Flag 
Footnote 
a 
Adjusted rsq of regression (the goodness of fit statistic for the elimination phase) was <0.9  
b 
Period used for regression analysis was less than 2-fold the calculated half-life 
c 
Extrapolated portion of AUC(0-inf) >20% 
d 
Insufficient post-Cmax data points for estimation of lambda-z 
e 
Entire profile BLQ, no PK parameters could be calculated 
f 
Fewer than 3 consecutive measurable concentrations, AUCs not calculated 
In the event that the adjusted rsq of regression was <0.9 (“a” flag) then lambda-z and 
parameter estimates derived using lambda-z and AUC(0-inf) will be deemed unreliable 
and will be flagged and listed but excluded from the summary statistics. 


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In the event that the time period used for regression analysis was less than 2-fold the 
calculated half-life (“b” flag) lambda-z and parameter estimates derived using lambda-z 
will be flagged, listed, and included in summary statistics. 
In the event that the extrapolated portion of AUC(0-inf) >20% (“c” flag), then AUC(0-inf) 
and parameter estimates derived using AUC(0-inf) will be deemed unreliable and will be 
flagged and listed but excluded from the summary statistics. 
In the event that there are insufficient post-Cmax data points for estimation of lambda-z 
(“d” flag) then lambda-z and parameter estimates derived using lambda-z and AUC(0-inf) 
will be reported as ‘NC’. 
In the event that there are fewer than 3 consecutive measurable concentrations (“f” flag) 
then all AUC parameter estimates will be reported as ‘NC’. 
10.2 
Concentration and PK Parameter Summary Tables 
Summary statistics (i.e. n, mean, SD, CV%, median, minimum, maximum, geometric 
mean, geometric SD and geometric CV%) of concentration data will be calculated for the 
following analytes/matrices. The number of BLQ values (n) per time point will also be 
presented. Geometric statistics will not be calculated for pre-dose concentrations.  
• 
Whole blood concentrations of rencofilstat by time point  
• 
Plasma concentrations of total radioactivity by time point  
• 
Whole blood concentrations of total radioactivity by time point 
• 
Whole blood:plasma concentration ratios of total radioactivity by time point 
Summary statistics (i.e. n, mean, SD, CV%, median, minimum and maximum) of whole 
blood PK parameters will be calculated for rencofilstat and total radioactivity. Geometric 
mean, geometric SD and geometric CV% will be presented for all PK parameters except 
Tlag and Tmax.  
Non-measurable values reported in the concentration data (i.e., values that are BLQ), 
will be entered as zero for the determination of summary statistics with the exception of 
geometric means, geometric SD and geometric CV%, where BLQ values will be imputed 
as half the LLOQ value. This also applies to any concentrations that are defined as PK 
parameters (e.g., C24). Data recorded as NR, NS or NC will be handled as missing (i.e., 
no assumption will be made about the actual concentration). 
10.3 
Concentration and PK Figures 
Mean, spaghetti and individual whole blood and plasma concentration vs time plots will 
be produced on both the linear/linear scale and on log10/linear scale. For all plots on a 
linear/linear scale, post-dose concentration values reported as BLQ will be set to zero, 
up to the point at which all concentrations fall below BLQ, after which they will be 
presented as missing. For all plots on a log 10/linear scale, post-dose concentration 
values reported as BLQ will be set to half the BLQ value, up to the point at which all 
concentrations fall below BLQ, after which they will be presented as missing.  Where 
curves from multiple treatment regimens or subjects are overlaid on the same plot, 
symbols will be used to identify different subjects/ treatment regimens and a legend will 
be included on the plots to define the symbols used. 
Mean concentration vs time plots (using nominal times) will be produced for: 


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• 
Rencofilstat in whole blood and total radioactivity in plasma and whole blood, on the 
same plot (3 profiles per plot) 
• 
Rencofilstat in whole blood and total radioactivity in whole blood on the same plot (2 
profiles per plot) 
• 
Total radioactivity in plasma and whole blood on the same plot (2 profiles per plot) 
 
These will be produced as follows: 
• 
Linear/linear scale using arithmetic mean concentrations (error bars ± arithmetic SD) 
• 
Log10/linear scale using geometric mean concentrations (error bars x/÷ geometric 
SD) 
Separate spaghetti plots (using actual sampling time after dosing) will be produced for 
each matrix and analyte with each plot displaying 1 line per subject. 
Individual plots (using actual sampling times after dosing) will be produced separately 
for each individual subject with all analytes and matrices on the same plot. 
10.4 
Concentration and PK Listings 
The sample collection data (e.g. collection times) for PK samples will be listed. In 
addition, all concentration data and PK parameters will be listed on a per subject basis. 
Any flags used will be included as a footnote with the appropriate definition. 
10.5 
Statistical Analysis of PK Parameters 
No formal statistical analysis will be performed for the PK data in this study. Descriptive 
statistics (i.e. n, mean, SD, median, CV%, minimum and maximum) are considered 
adequate for a study of this type. 
11 Safety Assessments 
Safety data summaries will be presented overall and the safety analysis set will be used 
throughout. 
11.1 
Extent of Exposure and Treatment Compliance 
The total dose given (including the dose of radioactivity in microcurie [µCi] and 
megabequerel [MBq]) will be summarised (i.e., n, mean, SD, median, minimum and 
maximum) for rencofilstat. 
Dosing details (including the date and time of all IMP administrations and any comments) 
will be listed for all enrolled subjects. Any recorded deviations from the planned dosing 
regimen will be listed as protocol deviations.  
11.2 
Adverse Events 
Throughout the study, all AEs will be evaluated by the investigator and noted in the AE 
section of the eCRF study build specification. An AE is any untoward medical occurrence 
in a subject that occurs either before dosing (referred to as a pre-dose AE) or once a 
medicinal product has been administered, including occurrences which are not 
necessarily caused by or related to that product. 
AEs will be coded using MedDRA v26.0 (or more recent version), including PT and SOC.  


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AEs will be classified into the following categories: 
• 
Pre-dose AEs: AEs recorded at screening or with a start date and time prior to the 
first dose of IMP  
• 
Treatment -emergent AEs (TEAEs): AEs that commence during/after the first dose 
of IMP or commence before first dose of IMP (i.e., a pre-dose AE or existing medical 
condition) but worsen in intensity during exposure to IMP 
AEs will be classified as “mild,” “moderate” or “severe” when considering their severity. 
AEs will be classified as “unrelated”, “possibly related” or “related” when considering their 
relationship to IMP. TEAEs classified as “possibly related” and “related” will be defined 
as adverse drug reactions (ADRs). An ADR is any AE where a causal relationship with 
the IMP is at least a reasonable possibility i.e., “possibly related” and “related”. Pre-dose 
AEs will always have the classification of “unrelated”. 
If the severity or relationship to IMP of a TEAE is missing, the severity/relationship will 
be tabulated as “missing” in the summary tables.  
When summary presentation is made by maximum severity, “missing” will be handled as 
follows: 
• 
If there are other events (i.e. same SOC and PT code) with a maximum severity 
recorded as “moderate” or “severe” for that subject, then the maximum observed 
severity for that subject will be categorised and presented as “moderate” or “severe”, 
respectively 
• 
If there are other events (i.e. same SOP and PT code) with a maximum severity 
recorded as “mild” for that subject, then the maximum observed severity for that 
subject will be categorised and presented as “missing” 
When summaries are presented by relationship to IMP, “missing” will be handled as 
follows: 
• 
If there are other events (i.e. same SOC and PT code) with a most closely related 
association recorded as “possibly related” or “related” for that subject, then the 
maximum observed relationship for that subject will be categorised and presented as 
“possibly related” or “related”, respectively 
• 
If there are other events (i.e. same SOP and PT code) with a most closely related 
association recorded as “unrelated” for that subject, then the maximum observed 
relationship for that subject will be categorised and presented as “missing” 
Where the start date of an AE is missing and the stop date is on or after the day of first 
dose of IMP or both the start and stop dates are missing then a “worst-case” scenario 
will be assumed i.e., the AE is assumed to have occurred post-dose and is therefore 
considered treatment-emergent. If a partial start date/time is available then the event will 
be considered as treatment-emergent unless the partial information suggests otherwise. 
11.2.1 
Summary Tables for Adverse Events 
All pre-dose AEs (as defined in Section 11.2) will be excluded from the summary tables 
but will be listed for all enrolled subjects.  
Descriptive statistical methods will be used to summarise the TEAE data.  


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The number and percentage of subjects reporting each TEAE will be presented for both 
SOC and PT. For summaries by SOC and PT, with the exception of TEAEs by severity 
and relationship to IMP, the number of subjects and the number of events will be 
summarised. For summaries by severity and relationship only the number of subjects will 
be summarised. 
For counts of subjects experiencing events the following will apply: 
• 
A subject with a TEAE in more than one body system will be counted once in the 
total number of subjects with TEAEs 
• 
A subject with more than 1 TEAE in the same SOC counts only once at the SOC 
level 
• 
A subject with more than 1 TEAE in the same PT counts only once at the PT level 
For event counts, all events are included. 
When it is necessary to calculate percentages, the denominator will be the total number 
of subjects in the safety analysis set and the numerator will be the total number of 
subjects reporting a TEAE within the relevant category. 
Summaries presented for SOC and PT will be presented in descending order of 
frequency overall i.e., most frequently reported SOC in the study and then by most 
frequently reported PT in the study within each SOC. 
11.2.1.1 
Overall Summary of Adverse Events 
The following will be summarised for the safety analysis set: 
• 
Number and percentage of subjects reporting at least 1 TEAE 
• 
Number and percentage of subjects reporting severe TEAEs 
• 
Number and percentage of subjects reporting ADRs  
• 
Number and percentage of subjects reporting serious TEAEs 
• 
Number and percentage of subjects reporting TEAEs leading to subject withdrawal  
• 
Number and percentage of subjects reporting TEAEs leading to death  
 
• 
Total number of TEAEs 
• 
Total number of severe TEAEs 
• 
Total number of ADRs  
• 
Total number of serious TEAEs 
• 
Total number of TEAEs leading to subject withdrawal  
• 
Total number of TEAEs leading to death  
11.2.1.2 
Summary of Treatment-Emergent Adverse Events  
All subjects reporting TEAEs will be summarised. Counts will be given for number of 
subjects and number of events. Subjects experiencing more than 1 TEAE will be counted 
only once for number of subjects but will be counted more than once for number of 
events. 
Additionally, subjects reporting TEAEs will be summarised for SOC and PT. Counts will 
be given for number of subjects and number of events. Subjects experiencing more than 
1 episode of a TEAE will be counted only once within each SOC and PT. 


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11.2.1.3 
Summary of Treatment -Emergent Adverse Events by Severity 
All subjects reporting TEAEs will be summarised by severity (i.e., mild, moderate or 
severe). Counts will be given for number of subjects, not number of events. Counts will 
be given by maximum severity (i.e., subjects experiencing more than 1 TEAE will be 
counted only once using the most severe episode). 
Additionally, subjects reporting TEAEs will be summarised for SOC and PT by maximum 
severity (i.e., mild, moderate or severe). Counts will be given for total number of subjects, 
not for events. Counts by maximum severity will be given (i.e., subjects experiencing 
more than 1 TEAE will be counted only once within each SOC and PT using the most 
severe episode). 
11.2.1.4 
Summary of Treatment -Emergent Adverse Events by Relationship to 
IMP 
All subjects reporting TEAEs will be summarised by relationship to IMP (i.e., unrelated, 
possibly related or related). Counts will be given for number of subjects, not number of 
events. Counts will be given by the closest relationship to IMP (i.e., subjects experiencing 
more than 1 TEAE will be counted only once using the most closely related event). 
Additionally, subjects reporting TEAEs will be summarised for SOC and PT by closest 
relationship to IMP (i.e., unrelated, possibly related or related). Counts will be given for 
total number of subjects, not for events. Counts by closest relationship will be given (i.e., 
subjects experiencing more than 1 TEAE will be counted only once within each SOC and 
PT using the most closely related event). 
11.2.1.5 
Summary of Adverse Drug Reactions (ADRs) 
All subjects reporting ADRs will be summarised. Counts will be given for number of 
subjects and number of events. Subjects experiencing more than 1 ADR will be counted 
only once for number of subjects but will be counted more than once for number of 
events. 
Additionally, subjects reporting ADRs will be summarised for SOC and PT. Counts will 
be given for number of subjects and number of events. Subjects experiencing more than 
1 episode of an ADR will be counted only once within each SOC and PT. 
11.2.1.6 
Summary of Serious Adverse Events 
All subjects reporting treatment -emergent serious AEs (SAEs) will be summarised. 
Counts will be given for number of subjects and number of events. Subjects experiencing 
more than 1 SAE will be counted only once for number of subjects but will be counted 
more than once for number of events. 
Additionally, subjects reporting treatment -emergent SAEs will be summarised for SOC 
and PT. Counts will be given for number of subjects and number of events. Subjects 
experiencing more than 1 episode of a SAE will be counted only once within each SOC 
and PT. 
11.2.2 
Listings for Adverse Events 
All pre-dose AEs (as defined in Section 11.2) will be listed including SOC and PT. 
A separate data listing of all TEAEs will be provided including the SOC and PT. In 
addition, a listing of all SAEs will be provided. 


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11.3 
Laboratory Evaluations 
The details of sample collection for laboratory safety analysis are described in the study 
protocol. 
Where a value is provided by the safety laboratory as either above or below the limit of 
detection (LOD) this will be set to the respective LOD itself for descriptive summaries. 
No imputations will be made in the individual listings. 
11.3.1 
Summary Tables for Laboratory Evaluations 
Haematology and clinical chemistry data will be summarised (n, mean, SD, median, 
minimum and maximum) for each laboratory parameter at each time point, including 
changes from baseline (Day 1, Pre-dose) at each scheduled post-baseline time point. 
Shift tables from baseline to each scheduled post-baseline time point (with respect to the 
number and percentage of subjects with values below, within or above the reference 
range) will be presented. Percentages will be based on the number of subjects with 
measurements at baseline and the relevant post-baseline time point. 
For fasting-sensitive laboratory parameters (i.e. glucose and serum cholesterol) results 
taken in the non-fasted state (i.e. LBFAST=N) will not be included in summary statistics 
by time point or be used in derivations of changes from baseline. For tabulations (e.g. 
shift tables) both fasted and non-fasted results will be pooled and used in the tabulations, 
using the appropriate fasted or non-fasted reference range. All results (fasted or 
non-fasted) will be listed with non-fasted data flagged. 
Reference ranges for each laboratory parameter will be presented for the relevant 
parameter in each summary table. 
11.3.2 
Listings for Laboratory Evaluations 
The sample collection data (e.g., collection times) for laboratory analysis and urinalysis 
data will be listed. 
All individual subject data, for planned haematology, clinical chemistry and urinalysis 
data including derivations, such as change from baseline, will be listed. If applicable, 
data from unscheduled laboratory tests will also be listed and flagged with a “#” to 
indicate it will not be used in the summary statistics. In these listings, individual data will 
be flagged with an “H” or an “L” for values that are higher or lower than their reference 
ranges, respectively. 
Separate listings of all haematology, clinical chemistry and urinalysis values outside their 
reference ranges by subject will also be provided. Reference ranges will be supplied by 
the safety laboratory for haematology and clinical chemistry and per the eCRF for 
urinalysis (i.e., a positive or negative result) with the exception of the following reference 
ranges for urinalysis: 
• 
pH: 5.0 to 9.0 
• 
Specific gravity: 1.000 to 1.030 


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11.4 
Vital Signs 
The details relating to the measurement of supine vital signs (i.e. systolic and diastolic 
blood pressure [BP], and heart rate) and non-supine vital signs (oral body temperature, 
respiratory rate, clinical assessment and findings) are described in the study protocol. 
Vital signs parameters will be reported in the order given above, i.e. both summary tables 
and data listings. 
11.4.1 
Summary Tables for Vital Signs 
Vital signs data, including change from baseline (Day 1, Pre-dose) will be summarised 
(i.e., n, mean, SD, median, minimum and maximum) at each post-baseline time point. 
In addition, the number of subjects with ‘substantial’ increases or decreases or no 
substantial change from baseline in systolic BP (>±20 mmHg), diastolic BP 
(>±10 mmHg) and heart rate (>±15 bpm) will be summarised. 
11.4.2 
Listings for Vital Signs 
All individual vital signs data including derivations, such as change from baseline, will be 
listed. Individual data will be flagged with an “H” or an “L” for values that are higher or 
lower than their reference ranges, respectively, and subjects with ‘substantial’ increases 
or decreases from baseline (as defined in Section 11.4.1) in systolic BP, diastolic BP and 
heart rate will be flagged with an ‘I’ (increase) or ‘D’ (decrease), respectively. If 
applicable, data from unscheduled vital signs assessments will also be listed and flagged 
with a “#” to indicate it will not be used in the summary statistics. 
In addition, a separate listing of all vital signs data outside their reference ranges by 
subject will also be provided. 
The reference ranges (from Quotient SOP “The Interpretation of the Electrocardiogram, 
Vital Signs and Clinical Laboratory Data During Phase I / II Clinical Trials” defined in 
Table 8 will be used. 
Table 8 
Vital Signs Reference Ranges 
Parameter 
Split 
Lower limit 
Upper limit 
Systolic BP 
18--45 years 
90 mmHg 
140 mmHg 
Systolic BP 
>45 years 
90 mmHg 
160 mmHg 
Diastolic BP 
NA 
40 mmHg 
90 mmHg 
Heart rate 
NA 
45 bpm 
100 bpm 
Oral Body Temperature 
NA 
35.5ºC 
37.5ºC 
NA=Not applicable 
11.5 
ECGs 
The details of measurement of supine ECG parameters (i.e. ventricular rate, QT interval, 
Frederica’s correction [QTcF] interval, PR Interval, QRS duration, QRS axis, rhythm, 
interpretation and clinical significance and findings) are described in the study protocol. 
ECG parameters will be reported in the order given above, i.e. both summary tables and 
data listings.  


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11.5.1 
Summary Tables for ECGs 
ECG data, including change from baseline (Day 1, Pre-dose), will be summarised (i.e., 
n, mean, SD, median, minimum and maximum) at each post-baseline time point.  
The number and percentage of subjects with normal and prolonged QT intervals 
corrected for heart rate using QTcF and increases in QTcF intervals from baseline within 
the categories defined in Table 9 (based on the International Council on Harmonisation 
[ICH] E14 guideline [1]) will be summarised. Percentages will be based on the number 
of subjects with measurements at the relevant time point. 
Table 9 
ICH E14 Ranges for QTcF Intervals 
Parameter 
ICH E14 Range 
QTcF interval 
≤450 msec (normal) 
451--480 msec 
481--500 msec 
>500 msec 
Increase in QTcF interval from 
baseline 
≤30 msec 
31--60 msec 
>60 msec 
11.5.2 
Listings for ECGs 
All ECG measurements (i.e., single readings) including derivations, such as change from 
baseline, will be listed. 
All ECG measurements will be flagged with an “H” or an “L” for values that are higher or 
lower than their reference ranges, respectively. If applicable, data from unscheduled 
ECG assessments will also be listed and flagged with a “#” to indicate it will not be used 
in the summary statistics. 
In addition, measurements with increase in QTcF interval from baseline (30-60 msec) 
and with ‘substantial increases’ (>60 msec) will be flagged with ‘I’ and ‘SI’, respectively. 
A separate listing of all ECG parameters outside their reference range by subject will 
also be provided. 
The reference ranges (from the eCRF study build specification for all parameters, except 
QT Interval, which is from Quotient SOP “The Interpretation of the Electrocardiogram, 
Vital Signs and Clinical Laboratory Data During Phase I / II Clinical Trials”) and defined 
in Table 10 will be used. 


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Table 10 
ECG Reference Ranges 
Parameter 
Lower limit 
Upper limit 
Ventricular Rate (HR) 
45 bpm 
100 bpm 
QT Interval 
NA 
500 msec 
QTcF Interval 
NA 
450 msec 
PR Interval 
120 msec 
220 msec 
QRS Duration 
NA 
120 msec 
QRS Axis 
-30º 
100º 
HR=heart rate 
NA=Not applicable 
11.6 
Body Weight 
All body weight data will be listed. 
11.7 
Physical Examination  
All physical examination details and comments on any physical examination findings will 
be listed by subject for all subjects. 
12 Interim Statistical Analyses 
No interim statistical analysis is planned for this study. 
13 Changes in the Conduct of the Study or Planned Analysis 
13.1 
Changes in the Conduct of the Study 
No changes in the conduct of the study had been reported at the time this document was 
written. 
13.2 
Changes to the Planned Analyses 
No changes to planned analysis. 
13.3 
Any Other Relevant Changes 
Not applicable. 
14 Overall Considerations 
14.1 
Statistical Programming and Analysis 
The Data Sciences Department at Quotient will perform the statistical programming and 
analysis to produce all analysis datasets and TFLs using the statistical SAS Software 
v9.4. 
In general terms, categorical data will be presented using counts and percentages, while 
continuous variables will be presented using n, mean, SD, median, minimum and 
maximum. For PK data additional statistics including CV%, geometric mean, geometric 
SD and geometric CV% will be presented, as appropriate. 
The geometric mean is obtained by applying a natural log transformation to the raw data, 
calculating the arithmetic mean of the transformed values and then back transforming 
the arithmetic mean. 


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The following formula will be used to calculate the geometric SD: 
geometric SD = exp{SD[log(raw data)]} 
ie, a natural log transformation is applied to the raw data, the arithmetic SD of the 
transformed values is calculated, and then the arithmetic SD of the transformed values 
is back transformed. 
The following formula will be used to calculate the geometric CV%: 
geometric CV% = 100 × (exp{SD[(log(raw data)]}2 -1)1/2 
ie, a natural log transformation is applied to the raw data, the arithmetic SD of the 
transformed values is calculated. This value is then squared. The square value is back 
transformed and a value of 1 is subtracted from the back transformed value. A square 
root is then applied and the resulting value is multiplied by 100. 
In general summary statistics will be presented as detailed in Table 11, unless otherwise 
stated: 
Table 11 Reporting Conventions for Summary Statistics 
Data Type 
Statistic 
Number of decimal places for reporting (i) 
Frequency 
Counts (n) 
None 
Percentages (%) 
1 decimal place 
Summary statistic 
n 
None 
Mean 
i + 1 decimal places 
Median 
i + 1 decimal places 
SD 
i + 1 decimal places 
Min 
i decimal places 
Max 
i decimal places 
CV% 
1 decimal place 
Geometric Mean 
i + 1 decimal places 
Geometric SD 
i + 1 decimal places 
Geometric CV% 
1 decimal place 
i refers to the number of decimal places reported in the eCRF study build specification or other appropriate 
source data for the original data. Where bioanalytical or PK data are received rounded in significant figures 
rather than decimal places, summary statistics will be supplied to the same precision. 
 
Details of how the individual PK parameters will be presented are detailed in 
Section 10.1.1. Where data requires rounding, values ending with 1 to 4 will be rounded 
down and values ending with 5 to 9 will be rounded up. 
All data listings will be based on all enrolled subjects (as defined in Section 3.2.1). Details 
of age and sex will be included on all data listings. 
If any baseline measurements are found to be missing then consideration will be given 
to imputation using the preceding time point (e.g., screening, admission, if applicable). 
Unscheduled assessment may be used if appropriate. Details of any such imputations 
will be documented as part of the safety analysis set. 


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There will be no other imputations for the safety data with regard to missing values or 
study discontinuation (i.e., subjects who do not complete the study). Imputation for mass 
balance parameter estimation using SAS Software is described in Section 9.1.2, and for 
PK parameter estimation using WinNonlin is described in Section 10.1.2, imputations for 
reporting mass balance data are described in Section 9.2 and for reporting PK data are 
described in Section 10.2. 
                                                                                                                                                                       
If partial dates are available for smoking history, prior medications or medical history, 
there will be no date imputations. The data listings will only show the date information for 
the date part that is available, e.g., if only the year part of the date is available then YYYY 
will be presented in the listing. If the full date information is missing, then this will be 
presented as missing on the data listing. 
If all or part of this study is conducted during the Coronavirus disease 2019 [COVID-19] 
pandemic and there is evidence that data relating to primary and/or key secondary 
endpoints may have been affected in a way that may bias results, then sensitivity 
analyses may be conducted. Requirements for any sensitivity analyses will be 
documented at the same time as the related population (i.e. safety, mass balance, PK 
population) and details of any sensitivity analyses which were carried out would be fully 
documented in the CSR. 
14.2 
Quality Control of Summary Tables, Figures and Listings 
Isolated data errors detected as a result of the QC checks that are deemed significant 
(i.e., errors that would impact the interpretation of the results in relation to the study 
objectives) will be corrected as per the data management plan. Systematic data errors 
will be investigated further. The data will be corrected if necessary, and the appropriate 
table, figure, and/or listing re-generated and then re-checked. 
In addition to QC checks, a documented peer review will be performed of all SAS 
Software-generated report standard TFLs, including a review of SAS Software code and 
program log files. 
14.2.1 
Quality Control - Summary Tables 
Manual QC methods (i.e., comparison of results in the table to results calculated by a 
calculator or spreadsheet) will be used for all summary tables. All summary tables will 
be QC’d as follows: 
• 
For tables presented by treatment only (i.e., no time points), all summary statistics 
will be QC’d 
• 
For tables presented by treatment and time point, at least 1 time point in each table 
will be QC’d – different combinations of time point will be selected across tables 
• 
Where tables are produced using a macro for multiple parameters, a minimum of 
3 tables, using treatment and time point as appropriate, will be QC’d 
• 
For AEs, the treatment details will be 100% QC’d against the treatment allocation list 
for all subjects 
• 
AE summary tables will be 100% checked using the relevant data listing 
14.2.2 
Quality Control - Figures 
All figures will be QC’d manually using the corresponding/appropriate summary table or 
data listing, as follows: 


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• 
All data points for treatment will be checked 
• 
Where figures are produced using a macro for individual subjects and/or multiple 
parameters, a minimum of 3 figures will be QC’d 
• 
Mean figures will be QC’d using the corresponding summary table 
14.2.3 
Quality Control - Data Listings 
All data listings will be subjected to a 100% manual check against the eCRF study build 
specifications or other appropriate source data for a minimum of 2 subjects. If 
appropriate, the subjects checked will include at least 1 subject who withdrew early from 
the study. 
15 SAS Data Transfer 
All SAS study data used for analysis and reporting, including safety, mass balance and 
PK data will be transferred to Hepion on issue of the final CSR. These will be performed 
in compliance with CDISC (SDTM IG v3.3, ADaM IG v1.2). Quotient will provide 
metadata files and data will be transferred as SAS Software transport files. No define 
.xml output will be included. 
16 Programming Conventions 
Quotient standards for layout of TFLs and programming conventions will be used as 
follows: 
• 
Courier new, font size 8 
• 
Landscape 
• 
A4 paper 
Tables and listings will be produced as MS Word 2016 (or more recent version) 
documents and figures will be produced as PDF files. Listings will be sorted by subject 
ID number. 
The mock tables (Section 21) presented are a representation of Quotient reporting 
standards. However, these are provided for illustrative purposes only. The numbering 
and titles, formatting, labelling, footnotes and cosmetic appearance of all output may be 
modified or additional labelling/footnotes may need to be added during analysis and 
reporting, for clarification purposes. Any such changes will not be regarded as changes 
to planned analyses. 
17 Reference List 
[1] 
International Council for Harmonisation (ICH) Topic E 14, The Clinical Evaluation 
of 
QT/QTc 
Interval 
Prolongation 
and 
Proarrhythmic 
Potential 
for 
Non-Antiarrhythmic Drugs Guidelines approved by the Committee for Medicinal 
Products for Human Use (CHMP) in May 2005 which came into force November 
 


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18 Index of Tables 
Table 
Number 
Table Title 
 
Subject Disposition, Populations and Datasets 
14.1.1 
Subject Disposition by Reason 
Summary Statistics: All Enrolled Subjects 
14.1.2.1 
Analysis Populations 
Summary Statistics: All Enrolled Subjects 
14.1.2.2 
Safety Analysis Set 
Summary Statistics: Safety Population 
14.1.2.3 
Mass Balance Analysis Set  
Summary Statistics: Mass Balance Population 
14.1.2.4 
PK Analysis Set  
Summary Statistics: PK Population 
 
Demographic and Baseline Characteristics 
14.1.3 
Demographic and Baseline Characteristics 
Summary Statistics: Safety Analysis Set 
14.1.4 
Lifestyle Details: Smoking History and Alcohol Consumption  
Summary Statistics: Safety Analysis Set 
 
Dosing Details 
14.1.5 
Extent of Exposure 
Summary Statistics: Safety Analysis Set 
 
Excretion and Recovery – Urine Concentrations 
14.2.1.1 
Excretion: Total Radioactivity 
Ae(Urine) by Collection Period <(units)> 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
14.2.1.2 
Excretion: Total Radioactivity 
Cumulative Ae(Urine) <(units)> 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
14.2.1.3 
Recovery: Total Radioactivity 
%Ae(Urine) by Collection Period (%) 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
14.2.1.4 
Recovery: Total Radioactivity 
Cumulative %Ae(Urine) (%) 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 


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Table 
Number 
Table Title 
 
Excretion and Recovery – Faecal Concentrations 
14.2.2.1 
Excretion: Total Radioactivity 
Ae(Faeces) by Collection Period <(units)> 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
14.2.2.2 
Excretion: Total Radioactivity 
Cumulative Ae(Faeces) <(units)> 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
14.2.2.3 
Recovery: Total Radioactivity  
%Ae(Faeces) by Collection Period (%) 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
14.2.2.4 
Recovery: Total Radioactivity 
Cumulative %Ae(Faeces) (%) 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
 
Excretion and Recovery – Urine and Faeces Combined 
14.2.3.1 
Excretion: Total Radioactivity 
Ae(Total) by Collection Period <(units)> 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
14.2.3.2 
Excretion: Total Radioactivity 
Cumulative Ae(Total) <(units)> 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
14.2.3.3 
Recovery: Total Radioactivity  
%Ae(Total) by Collection Period (%) 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
14.2.3.4 
Recovery: Total Radioactivity 
Cumulative %Ae(Total) (%) 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
 
Cumulative Excretion and Recovery Parameters 
14.2.4 
Excretion and Recovery: Total Radioactivity 
Cumulative Excretion and Recovery Parameters 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis 
Subset> 
 
Whole Blood and Plasma Pharmacokinetic Concentrations 
14.2.5.1 
Whole Blood Pharmacokinetic Concentrations: Rencofilstat <(units)> 
Summary Statistics: <PK Analysis Set / PK Analysis Subset> 


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Table 
Number 
Table Title 
14.2.5.2 
Whole Blood Pharmacokinetic Concentrations Total Radioactivity<(units)>: 
Summary Statistics: <PK Analysis Set / PK Analysis Subset> 
14.2.5.3 
Plasma Pharmacokinetic Concentrations: Total Radioactivity <(units)>: 
Summary Statistics: <PK Analysis Set / PK Analysis Subset> 
14.2.5.4 
Whole Blood:Plasma Concentration Ratio: Total Radioactivity <(units)> 
Summary Statistics: <PK Analysis Set / PK Analysis Subset> 
 
Whole Blood and Plasma Pharmacokinetic Parameters 
14.2.6.1 
Whole Blood Pharmacokinetic Parameters: Rencofilstat  
Summary Statistics: <PK Analysis Set / PK Analysis Subset> 
14.2.6.2 
Whole Blood Pharmacokinetic Parameters: Total Radioactivity  
Summary Statistics: <PK Analysis Set / PK Analysis Subset> 
14.2.6.3 
Plasma Pharmacokinetic Parameters: Total Radioactivity  
Summary Statistics: <PK Analysis Set / PK Analysis Subset> 
 
Adverse Events 
14.3.1 
Overall Summary of Treatment Emergent Adverse Events 
Summary Statistics: Safety Analysis Set 
14.3.2 
Treatment Emergent Adverse Events 
By MedDRA System Organ Class and Preferred Term 
Summary Statistics: Safety Analysis Set 
14.3.3 
Treatment Emergent Adverse Events 
By MedDRA System Organ Class, Preferred Term and Severity 
Summary Statistics: Safety Analysis Set 
14.3.4 
Treatment Emergent Adverse Events 
By MedDRA System Organ Class, Preferred Term and Relationship to IMP 
Summary Statistics: Safety Analysis Set 
14.3.5 
Adverse Drug Reactions 
By MedDRA System Organ Class and Preferred Term  
Summary Statistics: Safety Analysis Set 
14.3.6 
Serious Adverse Events 
By MedDRA System Organ Class and Preferred Term  
Summary Statistics: Safety Analysis Set 
 
Laboratory Results 
14.4.1 
Haematology 
Summary Statistics: Safety Analysis Set 
Parameter <units> 
14.4.2 
Haematology 
Shift Analysis: Safety Analysis Set 
Parameter <units> 
14.4.3 
Clinical Chemistry 
Summary Statistics: Safety Analysis Set 
Parameter <units> 


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Table 
Number 
Table Title 
14.4.4 
Clinical Chemistry 
Shift Analysis: Safety Analysis Set 
Parameter <units> 
 
Vital Signs and ECG Results 
14.5.1 
Vital Signs 
Summary Statistics: Safety Analysis Set 
Parameter <units> 
14.5.2.1 
ECGs  
Summary Statistics: Safety Analysis Set 
Parameter <units> 
14.5.2.2 
ECGs 
QTcF Categorical Data 
Summary Statistics: Safety Analysis Set 
 
 


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19 Index of Figures 
Figure 
Number 
Figure Title 
 
Cumulative Excretion and Recovery 
14.2.1.1 
Mean Cumulative Excretion of Total Radioactivity 
CumAe(Urine), CumAe(Faeces) and CumAe(Total) 
Linear/Linear Scale 
Mean (± Arithmetic SD) Values: <Mass Balance Analysis Set / Mass 
Balance Analysis Subset>  
14.2.1.2 
Mean Cumulative Recovery of Total Radioactivity 
Cum%Ae(Urine), Cum%Ae(Faeces) and Cum%Ae(Total) 
Linear/Linear Scale 
Mean (±Arithmetic SD) Values: <Mass Balance Analysis Set / Mass 
Balance Analysis Subset> 
 
Whole Blood and Plasma Pharmacokinetic Concentrations 
14.2.2.1 
Whole Blood and Plasma Pharmacokinetic Concentrations: Rencofilstat 
and Total Radioactivity (units) 
Linear/Linear Scale 
Arithmetic Mean (±Arithmetic SD) Values: <PK Analysis Set/PK Analysis 
Subset> 
 
(Programming note: Rencofilstat in whole blood and total radioactivity in 
plasma and whole blood - 3 profiles per plot) 
14.2.2.2 
Whole Blood and Plasma Pharmacokinetic Concentrations: Rencofilstat 
and Total Radioactivity (units) 
Log10/Linear Scale 
Geometric Mean (×/÷ Geometric SD) Values: <PK Analysis Set/PK 
Analysis Subset> 
(Programming note: Rencofilstat in whole blood and total radioactivity in 
plasma and whole blood - 3 profiles per plot) 
14.2.2.3 
Whole Blood Pharmacokinetic Concentrations: Rencofilstat and Total 
Radioactivity (units) 
Linear/Linear Scale 
Arithmetic Mean (±Arithmetic SD) Values: <PK Analysis Set/PK Analysis 
Subset> 
 
(Programming note: 2 profiles per plot) 
14.2.2.4 
Whole Blood Pharmacokinetic Concentrations: Rencofilstat and Total 
Radioactivity (units) 
Log10/Linear Scale 
Geometric Mean (×/÷ Geometric SD) Values: <PK Analysis Set/PK 
Analysis Subset> 
(Programming note: 2 profiles per plot) 


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Figure 
Number 
Figure Title 
14.2.2.5 
Whole Blood and Plasma Pharmacokinetic Concentrations: Total 
Radioactivity (units) 
Linear/Linear Scale 
Arithmetic Mean (±Arithmetic SD) Values: <PK Analysis Set/PK Analysis 
Subset> 
 
(Programming note: 2 profiles per plot) 
14.2.2.6 
Whole Blood and Plasma Pharmacokinetic Concentrations: Total 
Radioactivity (units) 
Log10/Linear Scale 
Geometric Mean (×/÷ Geometric SD) Values: <PK Analysis Set/PK 
Analysis Subset> 
(Programming note: 2 profiles per plot) 
14.2.2.7 
Whole Blood Pharmacokinetic Concentrations: Rencofilstat (units) 
Linear/Linear Scale 
Spaghetti Plots of All Individual Values: <PK Analysis Set/PK Analysis 
Subset> 
14.2.2.8 
Whole Blood Pharmacokinetic Concentrations: Rencofilstat (units) 
Log10/Linear Scale 
Spaghetti Plots of All Individual Values: <PK Analysis Set/PK Analysis 
Subset> 
14.2.2.9 
Whole Blood Pharmacokinetic Concentrations: Total Radioactivity 
(units) 
Linear/Linear Scale 
Spaghetti Plots of All Individual Values: <PK Analysis Set/PK Analysis 
Subset> 
14.2.2.10 
Whole Blood Pharmacokinetic Concentrations: Total Radioactivity 
(units) 
Log10/Linear Scale 
Spaghetti Plots of All Individual Values: <PK Analysis Set/PK Analysis 
Subset> 
14.2.2.11 
Plasma Pharmacokinetic Concentrations: Total Radioactivity (units) 
Linear/Linear Scale 
Spaghetti Plots of All Individual Values: <PK Analysis Set/PK Analysis 
Subset> 
14.2.2.12 
Plasma Pharmacokinetic Concentrations: Total Radioactivity (units) 
Log10/Linear Scale 
Spaghetti Plots of All Individual Values: <PK Analysis Set/PK Analysis 
Subset> 


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Figure 
Number 
Figure Title 
14.2.2.13 
Whole Blood and Plasma Pharmacokinetic Concentrations: Rencofilstat 
and Total Radioactivity (units) 
Linear/Linear Scale 
Individual Values for Subject <xxx>: <PK Analysis Set/PK Analysis 
Subset> 
 
Programming note: Rencofilstat in whole blood, and total radioactivity in 
whole blood and plasma all on the same plot (i.e., 3 profiles per subject) 
14.2.2.14 
Whole Blood and Plasma Pharmacokinetic Concentrations: Rencofilstat 
and Total Radioactivity (units) 
Log10/Linear Scale 
Individual Values for Subject <xxx>: <PK Analysis Set/PK Analysis 
Subset> 
 
Programming note: Rencofilstat in whole blood, and total radioactivity in 
whole blood and plasma all on the same plot (i.e., 3 profiles per subject) 
 
 


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20 Index of Listings 
Listing 
Number 
Listing Title 
 
Subject Informed Consent and Completion/Withdrawal 
16.2.1 
Subject Informed Consent and Completion/Withdrawal 
Individual Values: All Enrolled Subjects 
 
Protocol Deviations and Inclusion/Exclusion Criteria 
16.2.2.1 
Protocol Deviations  
Individual Values: All Enrolled Subjects 
16.2.2.2 
Inclusion/Exclusion Criteria  
Individual Values: All Enrolled Subjects 
 
Analysis Populations and Reasons for Exclusion 
16.2.3.1 
Analysis Populations and Reasons for Exclusion  
Individual Values: All Enrolled Subjects 
16.2.3.2 
Analysis Sets and Analysis Subsets and Reasons for Exclusion  
Individual Values: All Enrolled Subjects 
 
Demographic and Baseline Characteristics 
16.2.4.1 
Demographics and Baseline Characteristics 
Individual Values: All Enrolled Subjects 
16.2.4.2 
Lifestyle Details: Smoking History and Alcohol Consumption  
Individual Values: All Enrolled Subjects 
16.2.4.3 
Medical/Surgical History  
Individual Values: All Enrolled Subjects 
16.2.4.4 
Prior and Concomitant Medication 
Individual Values: All Enrolled Subjects 
16.2.4.5 
Carbon Monoxide Breath Test 
Individual Values: All Enrolled Subjects 
16.2.4.6 
Urine Drug Screen 
Individual Values: All Enrolled Subjects 
16.2.4.7 
Alcohol Breath Test 
Individual Values: All Enrolled Subjects 
16.2.4.8 
SARS-CoV-Antigen Test 
Individual Values: All Enrolled Population 
 
(Programming note: This listing will only be produced if COVID-19 
testing takes place in this study) 
16.2.4.9 
Virology  
Individual Values: All Enrolled Subjects 
16.2.4.10 
eGFR 
Individual Values: All Enrolled Subjects 


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Listing 
Number 
Listing Title 
 
Dosing Details and Meal Details 
16.2.5.1.1 
Dosing Details 
Individual Values: All Enrolled Subjects 
16.2.5.1.2 
Meal Details 
Individual Values: All Enrolled Subjects 
 
Urine and Faecal Concentration Data 
16.2.5.2.1 
Urine Collection and Weight Details 
Individual Values: All Enrolled Subjects 
16.2.5.2.2 
Urine Concentrations and Excretion: Total Radioactivity (units) 
Individual Values: All Enrolled Subjects 
16.2.5.2.3 
Faecal Collection and Weight Details 
Individual Values: All Enrolled Subjects 
16.2.5.2.4 
Faecal Concentrations and Excretion: Total Radioactivity (units) 
Individual Values: All Enrolled Subjects 
16.2.5.2.5 
Urine and Faecal Concentrations and Excretion Combined: Total 
Radioactivity (units) 
Individual Values: All Enrolled Subjects 
 
Whole Blood and Plasma Pharmacokinetic Concentration Data 
16.2.5.3.1 
Blood Sample Collection Details Pharmacokinetic Analysis 
Individual Values: All Enrolled Subjects 
16.2.5.3.2 
Whole Blood and Plasma Pharmacokinetic Concentrations: Total 
Radioactivity <(units)> 
Individual Values: All Enrolled Subjects 
16.2.5.3.3 
Plasma Pharmacokinetic Concentrations: rencofilstat 
Individual Values: All Enrolled Subjects 
 
Whole Blood and Plasma Pharmacokinetic Parameter Data 
16.2.6.1 
Whole Blood Pharmacokinetic Parameters: Total Radioactivity 
Individual Values: All Enrolled Subjects 
16.2.6.2 
Plasma Pharmacokinetic Parameters: Total Radioactivity 
Individual Values: All Enrolled Subjects 
16.2.6.3 
Plasma Pharmacokinetic Parameters: rencofilstat 
Individual Values: All Enrolled Subjects 
16.2.6.4 
Pharmacokinetic Parameter Flags 
 
(Programming note: Details of the PK parameter flags will be added to 
listings 16.2.6.1-3 as footnotes if length of these details allows – in which 
case do not produce this listing. Otherwise display PK parameter flags 
in this listing). 


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Listing 
Number 
Listing Title 
 
Adverse Events 
16.2.7.1 
Pre-dose Adverse Events 
Individual Values: All Enrolled Subjects 
16.2.7.2 
All Treatment -Emergent Adverse Events  
Individual Values: All Enrolled Subjects 
16.2.7.3 
Serious Adverse Events  
Individual Values: All Enrolled Subjects 
 
Laboratory Data 
16.2.8.1 
Blood Sample Collection Details for Laboratory Analysis 
Individual Values: All Enrolled Subjects 
16.2.8.2 
Haematology 
Individual Values: All Enrolled Subjects 
16.2.8.3 
Haematology 
Individual Values Outside the Reference Range: All Enrolled Subjects 
16.2.8.4 
Clinical Chemistry 
Individual Values: All Enrolled Subjects 
16.2.8.5 
Clinical Chemistry 
Individual Values Outside the Reference Range: All Enrolled Subjects 
16.2.8.6 
Urinalysis Sample Collection 
Individual Values: All Enrolled Subjects 
16.2.8.7 
Urinalysis 
Individual Values: All Enrolled Subjects 
16.2.8.8 
Urinalysis 
Individual Values Outside the Reference Range: All Enrolled Subjects 
 
Vital Signs and ECGs 
16.2.9.1.1 
Vital Signs  
Individual Values: All Enrolled Subjects 
 
(Programming note: The order of Vital Signs parameters is to be as per 
Section 11.4 ) 
16.2.9.1.2 
Vital Signs  
Individual Values Outside the Reference Range: All Enrolled Subjects 
16.2.9.2.1 
ECGs 
Individual Values: All Enrolled Subjects 
 
(Programming note: The order of ECG parameters is to be as per 
Section 11.5 ) 
16.2.9.2.2 
ECGs 
Individual Values Outside the Reference Range: All Enrolled Subjects 


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Listing 
Number 
Listing Title 
 
Other Data 
16.2.9.3 
Physical Examination Data 
Individual Values: All Enrolled Subjects 
16.2.9.4 
Body Weight Data  
Individual Values: All Enrolled Subjects 
 
 


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21 Mock Tables 


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Hepion Pharmaceuticals, Inc                                                                                                    Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.1.1 
Subject Disposition by Reason 
Summary Statistics: All Enrolled Subjects 
 
                                           225 mg [14C]CRV431  
                                                 (N=XX)        
                                                 n (%)         
 _____________________________________________________________ 
                                                               
 Subjects enrolled (1)                         xx (xx.x)       
 Subjects dosed                                xx (xx.x)       
 Subjects completed                            xx (xx.x)       
 Subjects discontinued                         xx (xx.x)       
                                                               
 Reason for discontinuation                                    
   REASON 1                                    xx (xx.x)       
   REASON 2                                    xx (xx.x)       
   REASON 3                                    xx (xx.x)       
   …                                               …           
   <All categories on source>                  xx (xx.x)       
                                                               
                                                               
                                                               
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      (1) An enrolled subject is defined as a subject who signed the informed consent, qualified per the                                                      
      inclusion/exclusion criteria and was allocated a subject number                                                                                         
      A subject may be discontinued for one reason only                                                                                                       
      Percentages are based on the number of subjects enrolled                                                                                                
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all reasons for discontinuation as recorded on the eCRF. If none of the subjects                           
                   discontinued from the study early then reasons for discontinuation will not be populated in the summary table                              


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Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.1.2.1 
Analysis Populations 
Summary Statistics: All Enrolled Subjects 
 
                                                               225 mg [14C]CRV431  
                                                                     n (%)         
 _________________________________________________________________________________ 
                                                                                   
 Subjects in Safety Population                                     xx (xx.x)       
   Reasons for exclusion from Safety Population                                    
   <All categories on source listing>                              xx (xx.x)       
                                                                       …           
                                                                                   
 Subjects in Mass Balance Population                               xx (xx.x)       
   Reasons for exclusion from Mass Balance Population                              
   <All categories on source listing>                              xx (xx.x)       
                                                                       …           
                                                                                   
 Subjects in PK Population                                         xx (xx.x)       
   Reasons for exclusion from PK Population                                        
   <All categories on source listing>                              xx (xx.x)       
                                                                       …           
                                                                                   
                                                                                   
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      A subject may be excluded for more than 1 reason                                                                                                        
      Percentages are based on the number of subjects enrolled                                                                                                
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all reasons for exclusion. If none of the subjects were excluded from a                                    
                   population, then reasons for exclusion will not be populated in the summary table                                                          


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Hepion Pharmaceuticals, Inc                                                                                                    Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.1.2.2 
Safety Analysis Set 
Summary Statistics: Safety Population 
 
                                                               225 mg [14C]CRV431  
                                                                     n (%)         
 _________________________________________________________________________________ 
                                                                                   
 Subjects in Safety Analysis Set                                   xx (xx.x)       
   Reasons for exclusion from Safety Analysis Set                                  
   <All categories from source>                                    xx (xx.x)       
                                                                       …           
                                                                                   
                                                                                   
                                                                                   
                                                                                   
                                                                                   
                                                                                   
                                                                                   
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      A subject may be excluded for more than 1 reason                                                                                                        
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all reasons for exclusion. If none of the subjects were excluded from the safety                           
                   analysis set, then reasons for exclusion will not be populated in the summary table. Similar tables will be produced for                   
                   • Mass Balance Analysis Set, ie Table [14.1.2.3] and                                                                                       
                   • PK Analysis Set, ie Table [14.1.2.4]                                                                                                     
                   Each analysis set will be a subset of their respective populations and percentages will be based on number of subjects                     
                   in each population)                                                                                                                        


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Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.1.3 
Demographic and Baseline Characteristics 
Summary Statistics: Safety Analysis Set 
 
                                                                   225 mg [14C]CRV431  
                                                                         (N=XX)        
______________________________________________________________________________________ 
                                                                                       
Age (years)              n                                                 xx          
                         Mean                                            xx.xx         
                         SD                                              xx.xx         
                         Median                                          xx.xx         
                         Min                                              xx.x         
                         Max                                              xx.x         
                                                                                       
Ethnicity n(%)           <All categories on source>                    xx (xx.x)       
                                                                                       
Race n(%)                <All categories on source>                    xx (xx.x)       
                                                                                       
Sex n(%)                 Male                                          xx (xx.x)       
                                                                                       
Height (cm)              …                                                 …           
                                                                                       
Weight (kg)              …                                                 …           
                                                                                       
BMI (kg/m^2)             …                                                 …           
                                                                                       
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will continue for all categories of ethnicity and race. Height, Weight and BMI will be summarised using the                      
                   same descriptive statistics as Age. If any values are missing, then a ‘missing’ row will be presented in the table                         


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Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.1.4 
Lifestyle Details: Smoking History and Alcohol Consumption 
Summary Statistics: Safety Analysis Set 
 
                                                           225 mg [14C]CRV431  
                                                                 n (%)         
______________________________________________________________________________ 
                                                                               
Does the subject smoke (1)      NO                             xx (xx.x)       
                                PREVIOUSLY                     xx (xx.x)       
                                                                               
                                                                               
Alcohol Consumption (2)         NONE                           xx (xx.x)       
                                YES: NOT EXCESSIVE             xx (xx.x)       
                                                                               
                                                                               
                                                                               
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      (1) Smoked or used e-cigarettes or nicotine replacement products in the last 12 months                                                                  
      (2) Regular alcohol consumption (>21 units/week in males)                                                                                               
      1 unit = 1/2 pint beer, 25 mL of 40% spirit, 1.5 to 2 units = 125 mL glass of wine depending on type                                                    
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    


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10 Feb 2023 
Page 54 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.1.5 
Extent of Exposure 
Summary Statistics: Safety Analysis Set 
 
                                   225 mg [14C]CRV431                
                                         (N=XX)                      
                     _______________________________________________ 
                           mg              MBq             µCi       
____________________________________________________________________ 
                                                                     
n                          xx              xx              xx        
Mean                      xx.xx           xx.xx           xx.xx      
SD                        xx.xx           xx.xx           xx.xx      
Median                    xx.xx           xx.xx           xx.xx      
Min                       xx.x            xx.x            xx.x       
Max                       xx.x            xx.x            xx.x       
                                                                     
                                                                     
                                                                     
                                                                     
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    


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10 Feb 2023 
Page 55 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.2.1.1 
Excretion: Total Radioactivity 
Ae(Urine) by Collection Period <(units)> 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis Subset> 
  
225 mg [14C]CRV431 
 
Collection Period               n     Mean      SD      CV%   Median    Min     Max   
_____________________________________________________________________________________ 
                                                                                      
PRE-DOSE                        xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME0 - TIME1                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME1 - TIME2                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME2 - TIME3                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
…                               …      …        …        …       …       …       …    
<All other time intervals>      xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
                                                                                      
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      Where a subject has failed to void or has a ND concentration over a particular collection interval, the amount                                          
      excreted (Ae) has been set to zero                                                                                                                      
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming Note: This table will be continued for all collection periods. Similar tables will be produced for                                                
                   • %Ae(Urine) (Recovery), ie Table [14.2.1.3]                                                                                               
                   • Ae(Faeces), ie Table [14.2.2.1]                                                                                                          
                   • %Ae(Faeces) (Recovery), ie Table [14.2.2.3]                                                                                              
                   • Combined (Ae[total]), ie Table [14.2.3.1] and                                                                                            
                   • Combined (%Ae[total]) (Recovery), ie Table [14.2.3.3])                                                                                   


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Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 56 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                    Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.2.1.2 
Excretion: Total Radioactivity 
Cumulative Ae(Urine) <(units)> 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis Subset> 
  
225 mg [14C]CRV431 
 
Collection Period               n     Mean      SD      CV%   Median    Min     Max   
_____________________________________________________________________________________ 
                                                                                      
TIME0 - TIME1                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME0 - TIME2                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME0 - TIME3                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
…                               …      …        …        …       …       …       …    
<All other time intervals>      xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
                                                                                      
                                                                                      
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all collection periods. If required, as a result of early withdrawal or varying                            
                   follow-up periods, this table will be produced using the LOCF approach. Similar tables will be produced for                                
                   • Cumulative %Ae(Urine) (Recovery), ie Table [14.2.1.4]                                                                                    
                   • Cumulative Ae(Faeces), ie Table [14.2.2.2]                                                                                               
                   • Cumulative %Ae(Faeces) (Recovery), ie Table [14.2.2.4]                                                                                   
                   • Combined Cumulative (Ae[total]), ie Table [14.2.3.2] and                                                                                 
                   • Combined Cumulative (%Ae[total]) (Recovery), ie Table [14.2.3.4]                                                                         


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10 Feb 2023 
Page 57 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.2.4 
Excretion and Recovery: Total Radioactivity 
Cumulative Excretion and Recovery Parameters 
Summary Statistics: <Mass Balance Analysis Set / Mass Balance Analysis Subset> 
  
225 mg [14C]CRV431 
 
                        Urine                Faeces                 Total         
                _____________________ _____________________ _____________________ 
                  CumAe      Cum%Ae     CumAe      Cum%Ae     CumAe      Cum%Ae   
                 (units)      (%)      (units)      (%)      (units)      (%)     
_________________________________________________________________________________ 
                                                                                  
n                   xx         xx         xx         xx         xx         xx     
Mean              xx.xx      xx.xx      xx.xx      xx.xx      xx.xx      xx.xx    
SD                xx.xx      xx.xx      xx.xx      xx.xx      xx.xx      xx.xx    
CV%                xx.x       xx.x       xx.x       xx.x       xx.x       xx.x    
Median            xx.xx      xx.xx      xx.xx      xx.xx      xx.xx      xx.xx    
Min                xx.x       xx.x       xx.x       xx.x       xx.x       xx.x    
Max                xx.x       xx.x       xx.x       xx.x       xx.x       xx.x    
                                                                                  
                                                                                  
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      CumAe represents the cumulative excretion. Cum%Ae represents the cumulative recovery as a percentage of the                                             
      radioactive dose administered                                                                                                                           
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    


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10 Feb 2023 
Page 58 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.2.5.1 
Whole Blood Pharmacokinetic Concentrations: Rencofilstat <(units)> 
Summary Statistics: <PK Analysis Set / PK Analysis Subset> 
  
225 mg [14C]CRV431 
 
                                              Arithmetic (1)                          Geometric (2)      
                          ______________________________________________________ _______________________ 
Time Point                 n    n#   Mean     SD      CV%   Median  Min    Max    Mean     SD      CV%   
________________________________________________________________________________________________________ 
                                                                                                         
PRE-DOSE                   xx   xx   xx.xx   xx.xx   xx.x   xx.xx   xx.x   xx.x    NC      NC      NC    
TIME POINT 1               xx   xx   xx.xx   xx.xx   xx.x   xx.xx   xx.x   xx.x   xx.xx   xx.xx   xx.x   
TIME POINT 2               xx   xx   xx.xx   xx.xx   xx.x   xx.xx   xx.x   xx.x   xx.xx   xx.xx   xx.x   
TIME POINT 3               xx   xx   xx.xx   xx.xx   xx.x   xx.xx   xx.x   xx.x   xx.xx   xx.xx   xx.x   
…                          …    …      …       …       …      …      …      …       …       …       …    
<All other time points>    xx   xx   xx.xx   xx.xx   xx.x   xx.xx   xx.x   xx.x   xx.xx   xx.xx   xx.x   
                                                                                                         
                                                                                                         
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      n# indicates the number of subjects with a BLQ value recorded at the time point indicated                                                               
      (1) For arithmetic summary statistics, concentration values reported as BLQ have been set to zero                                                     
      (2) For calculation of geometric summary statistics, values reported as BLQ have been set to ½ × LLOQ,                                          
      except for pre-dose values which will not be summarised. The LLOQ value was <value, units>                                                          
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all time points. Similar tables will be produced for                                                       
                   • Whole Blood Concentrations: Total Radioactivity, ie Table [14.2.5.2] and                                                                 
                   • Plasma Pharmacokinetic Concentrations: Total Radioactivity, ie Table [14.2.5.3]                                                          
                   • Whole Blood:Plasma Concentration Ratio: Total Radioactivity, ie Table [14.2.5.4]                                                         


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10 Feb 2023 
Page 59 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.2.6.1 
Whole Blood Pharmacokinetic Parameters: Rencofilstat 
Summary Statistics: <PK Analysis Set / PK Analysis Subset> 
  
225 mg [14C]CRV431 
 
                   Parameter 1  Parameter 2  Parameter 3          All Other PK Parameters  
Statistic            (units)      (units)      (units)    ......          (units)          
__________________________________________________________________________________________ 
                                                                                           
n                       xx           xx           xx        …               xx             
Mean                  xx.xx        xx.xx        xx.xx       …              xx.xx           
SD                    xx.xx        xx.xx        xx.xx       …              xx.xx           
CV%                    xx.x         xx.x         xx.x       …              xx.x            
Median                xx.xx        xx.xx        xx.xx       …              xx.xx           
Min                    xx.x         xx.x         xx.x       …              xx.x            
Max                    xx.x         xx.x         xx.x       …              xx.x            
Geometric Mean        xx.xx        xx.xx        xx.xx       …              xx.xx           
Geometric SD          xx.xx        xx.xx        xx.xx       …              xx.xx           
Geometric CV%          xx.x         xx.x         xx.x       …              xx.x            
                                                                                           
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      For concentration parameters, BLQ values have been set to zero for arithmetic statistics and to ½ ×  LLOQ                                        
      for geometric statistics. The LLOQ value was <value, units>                                                                                          
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: A similar table will be produced for                                                                                                        
                   • Whole Blood Pharmacokinetic Parameters: Total Radioactivity, ie Table [14.2.6.2] and                                                     
                   • Plasma Pharmacokinetic Parameters: Total Radioactivity, ie Table [14.2.6.3]                                                              


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Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 60 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.3.1 
Overall Summary of Treatment-Emergent Adverse Events 
Summary Statistics: Safety Analysis Set 
 
                                                      225 mg [14C]CRV431           
                                                            (N=XX)                 
                                             _____________________________________ 
                                                                   Total Number    
Event                                               n(%)            of Events      
__________________________________________________________________________________ 
                                                                                   
TEAEs                                            xx (xx.x)              xx         
                                                                                   
Severe TEAEs                                     xx (xx.x)              xx         
                                                                                   
ADRs (1)                                         xx (xx.x)              xx         
                                                                                   
Serious TEAEs                                    xx (xx.x)              xx         
                                                                                   
TEAEs leading to subject withdrawal              xx (xx.x)              xx         
                                                                                   
TEAEs leading to death                           xx (xx.x)              xx         
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      TEAEs are coded using MedDRA vXX.X                                                                                                                      
      (1) ADR is any AE where a causal relationship with the IMP is at least a reasonable possibility ie “possibly                                            
      related” or “related”. n is the number of subjects reporting at least one event                                                                         
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    


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10 Feb 2023 
Page 61 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.3.2 
Treatment-Emergent Adverse Events 
By MedDRA System Organ Class and Preferred Term 
Summary Statistics: Safety Analysis Set 
 
                                             225 mg [14C]CRV431           
                                                   (N=XX)                 
                                    _____________________________________ 
System Organ Class                                        Total Number    
   Preferred Term                          n(%)            of Events      
_________________________________________________________________________ 
                                                                          
TEAEs                                   xx (xx.x)              xx         
                                                                          
SYSTEM ORGAN CLASS 1                    xx (xx.x)              xx         
   PREFERRED TERM 1                     xx (xx.x)              xx         
   PREFERRED TERM 2                     xx (xx.x)              xx         
   etc                                      …                  …          
                                                                          
SYSTEM ORGAN CLASS 2                    xx (xx.x)              xx         
   PREFERRED TERM 1                     xx (xx.x)              xx         
   PREFERRED TERM 2                     xx (xx.x)              xx         
   etc                                      …                  …          
                                                                          
…                                           …                  …          
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      TEAEs are coded using MedDRA vXX.X and are presented in descending order of frequency                                                                   
      Subjects experiencing more than one TEAE are counted only once for number of subjects but are                                                           
      counted more than once for number of events. Subjects experiencing more than one TEAE are                                                               
      counted only once within each SOC and PT                                                                                                                
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all SOC and PT                                                                                             


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Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 62 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.3.3 
Treatment-Emergent Adverse Events 
By MedDRA System Organ Class, Preferred Term and Severity 
Summary Statistics: Safety Analysis Set 
 
                                             225 mg [14C]CRV431                
                                                   (N=XX)                      
                               _______________________________________________ 
System Organ Class                  Mild          Moderate         Severe      
   Preferred Term                   n(%)            n(%)            n(%)       
______________________________________________________________________________ 
                                                                               
TEAEs                             xx (xx.x)       xx (xx.x)       xx (xx.x)    
                                                                               
SYSTEM ORGAN CLASS 1              xx (xx.x)       xx (xx.x)       xx (xx.x)    
   PREFERRED TERM 1               xx (xx.x)       xx (xx.x)       xx (xx.x)    
   PREFERRED TERM 2               xx (xx.x)       xx (xx.x)       xx (xx.x)    
   etc                                …               …               …        
                                                                               
SYSTEM ORGAN CLASS 2              xx (xx.x)       xx (xx.x)       xx (xx.x)    
   PREFERRED TERM 1               xx (xx.x)       xx (xx.x)       xx (xx.x)    
   PREFERRED TERM 2               xx (xx.x)       xx (xx.x)       xx (xx.x)    
   etc                                …               …               …        
                                                                               
…                                     …               …               …        
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      TEAEs are coded using MedDRA vXX.X and are presented in descending order of frequency                                                                   
      Counts are given for total number of subjects, not for events                                                                                           
      Counts of number of subjects are by maximum severity, ie subjects experiencing more than one TEAE are                                                   
      counted only once within each SOC and PT using the most severe episode                                                                                  
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all SOC and PT                                                                                             


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Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 63 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.3.4 
Treatment-Emergent Adverse Events 
By MedDRA System Organ Class, Preferred Term and Relationship to IMP 
Summary Statistics: Safety Analysis Set 
 
                                                     225 mg [14C]CRV431                       
                                                           (N=XX)                             
                               ______________________________________________________________ 
System Organ Class                  Unrelated         Possibly Related         Related        
   Preferred Term                      n(%)                 n(%)                 n(%)         
_____________________________________________________________________________________________ 
                                                                                              
TEAEs                               xx (xx.x)            xx (xx.x)            xx (xx.x)       
                                                                                              
SYSTEM ORGAN CLASS 1                xx (xx.x)            xx (xx.x)            xx (xx.x)       
   PREFERRED TERM 1                 xx (xx.x)            xx (xx.x)            xx (xx.x)       
   PREFERRED TERM 2                 xx (xx.x)            xx (xx.x)            xx (xx.x)       
   etc                                  …                    …                    …           
                                                                                              
SYSTEM ORGAN CLASS 2                xx (xx.x)            xx (xx.x)            xx (xx.x)       
   PREFERRED TERM 1                 xx (xx.x)            xx (xx.x)            xx (xx.x)       
   PREFERRED TERM 2                 xx (xx.x)            xx (xx.x)            xx (xx.x)       
   etc                                  …                    …                    …           
                                                                                              
…                                       …                    …                    …           
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      TEAEs are coded using MedDRA vXX.X and are presented in descending order of frequency                                                                   
      Counts are given for total number of subjects, not for events                                                                                           
      Counts of number of subjects are by closest relationship, ie subjects experiencing more than one TEAE                                                   
      are counted only once within each SOC and PT using the most closely related event                                                                       
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all SOC and PT                                                                                             


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Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 64 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.3.5 
Adverse Drug Reactions 
By MedDRA System Organ Class and Preferred Term 
Summary Statistics: Safety Analysis Set 
 
                                        225 mg [14C]CRV431           
                                              (N=XX)                 
                               _____________________________________ 
System Organ Class                                   Total Number    
   Preferred Term                     n(%)            of Events      
____________________________________________________________________ 
                                                                     
ADRs (1)                           xx (xx.x)              xx         
                                                                     
SYSTEM ORGAN CLASS 1               xx (xx.x)              xx         
   PREFERRED TERM 1                xx (xx.x)              xx         
   PREFERRED TERM 2                xx (xx.x)              xx         
   etc                                 …                  …          
                                                                     
SYSTEM ORGAN CLASS 2               xx (xx.x)              xx         
   PREFERRED TERM 1                xx (xx.x)              xx         
   PREFERRED TERM 2                xx (xx.x)              xx         
   etc                                 …                  …          
                                                                     
…                                      …                  …          
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      (1) An ADR is any AE where a causal relationship with the IMP is at least a reasonable possibility ie “possibly                                         
      related” or “related”. TEAEs are coded using MedDRA vXX.X and are presented in descending order of frequency                                            
      Subjects experiencing more than one ADR are counted only once for number of subjects but are                                                            
      counted more than once for number of events. Subjects experiencing more than one ADR are counted                                                        
      only once within each SOC and PT                                                                                                                        
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: A similar table will be produced for                                                                                                        
                   • Serious Adverse Events, ie Table [14.3.6]                                                                                                


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Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 65 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.4.1 
Haematology 
Summary Statistics: Safety Analysis Set 
  
225 mg [14C]CRV431 
<Parameter> (<units>) [ref range xxx - xxx (male)] 
 
                                            Result                                 Change from Baseline              
                         _____________________________________________ _____________________________________________ 
Time Point                 n    Mean     SD    Median    Min     Max     n    Mean     SD    Median    Min     Max   
____________________________________________________________________________________________________________________ 
                                                                                                                     
BASELINE                  xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x                                                 
TIME POINT 1              xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
TIME POINT 2              xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
…                          …      …       …       …       …       …      …      …       …       …       …       …    
<All other time points>   xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      BASELINE is defined as Day 1, Pre-dose                                                                                                                  
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all haematology parameters and all time points                                                             
                   A similar table will be produced for                                                                                                       
                   • Clinical Chemistry, ie Table [14.4.3]                                                                                                    


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Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 66 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.4.2 
Haematology 
Shift Analysis: Safety Analysis Set 
  
225 mg [14C]CRV431 
<Parameter> (<units>) [ref range xxx - xxx (male)] 
 
                                                Baseline                   
                              ____________________________________________ 
Time Point                        Below          Within         Above      
   Assessment            N#        n(%)           n(%)           n(%)      
__________________________________________________________________________ 
                                                                           
TIME POINT 1             xx                                                
   Below                        xx (xx.x)      xx (xx.x)      xx (xx.x)    
   Within                       xx (xx.x)      xx (xx.x)      xx (xx.x)    
   Above                        xx (xx.x)      xx (xx.x)      xx (xx.x)    
                                                                           
TIME POINT 2             xx                                                
   Below                        xx (xx.x)      xx (xx.x)      xx (xx.x)    
   Within                       xx (xx.x)      xx (xx.x)      xx (xx.x)    
   Above                        xx (xx.x)      xx (xx.x)      xx (xx.x)    
                                                                           
<All other time points>   …                                                
                                    …              …              …        
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      BASELINE is defined as Day 1, Pre-dose                                                                                                                  
      N# is the total number of subjects that have a value at baseline and each given time-point and is used in the                                           
      denominator for calculating the percentages of subjects, n indicates the number of subjects with a baseline and                                         
      a post baseline assessment at the time point indicated. Below/within/above indicate the number (%) of subjects                                          
      with assessments below/within/above the normal reference range                                                                                          
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all haematology parameters and all time points                                                             
                   A similar table will be produced for                                                                                                       
                   • Clinical Chemistry, ie Table [14.4.4]                                                                                                    


Sponsor/Quotient Sciences Confidential 
 
Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 67 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.5.1 
Vital Signs 
Summary Statistics: Safety Analysis Set 
  
225 mg [14C]CRV431 
<Parameter> (<units>) [ref range xxx - xxx (age xx - xx), xxx - xxx (age > xx)] 
 
                                                                            Change from                Substantial   
                                        Result                               Baseline                    Change      
                         _____________________________________ _____________________________________ _______________ 
Time Point                n   Mean    SD   Median   Min   Max   n   Mean    SD   Median   Min   Max  DEC  NONE  INC  
____________________________________________________________________________________________________________________ 
                                                                                                                     
BASELINE                 xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x                                                        
TIME POINT 1             xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
TIME POINT 2             xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
TIME POINT 3             xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
…                         …    …      …       …      …     …    …    …      …       …      …     …    …     …    …   
<All other time points>  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      BASELINE is defined as Day 1, Pre-dose                                                                                                                  
      Substantial change is defined as:  ± 20 mmHg Systolic BP, > ± 10 mmHg Diastolic BP and > ± 15 bpm HR                                                    
      DEC: number of subjects with substantial decrease from baseline, NONE: number of subjects with no substantial change                                    
      from baseline, INC: number of subjects with substantial increase from baseline                                                                          
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all vital signs parameters, which will follow the order given in the RAP text                              


Sponsor/Quotient Sciences Confidential 
 
Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 68 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.5.2.1 
ECGs 
Summary Statistics: Safety Analysis Set 
  
225 mg [14C]CRV431 
<Parameter> (<units>) [ref range xxx - xxx (male)] 
 
                                            Result                                 Change from Baseline              
                         _____________________________________________ _____________________________________________ 
Time Point                 n    Mean     SD    Median    Min     Max     n    Mean     SD    Median    Min     Max   
____________________________________________________________________________________________________________________ 
                                                                                                                     
BASELINE                  xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x                                                 
TIME POINT 1              xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
TIME POINT 2              xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
TIME POINT 3              xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
…                          …      …       …       …       …       …      …      …       …       …       …       …    
<All other time points>   xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      BASELINE is defined as Day 1, Pre-dose                                                                                                                  
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    
                                                                                                                                                              
Programming note: This table will be continued for all ECG parameters, which will follow the order given in the RAP text                                      


Sponsor/Quotient Sciences Confidential 
 
Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 69 of 72  
 
 
 
Hepion Pharmaceuticals, Inc                                                                                                     Page x of y 
Protocol: HEPA-CRV431-105 
 
TABLE 14.5.2.2 
ECGs 
QTcF Categorical Data 
Summary Statistics: Safety Analysis Set 
  
225 mg [14C]CRV431 
 
                                                     QTcF                                    QTcF Interval             
                                                Interval (msec)                             Increase (msec)            
                              ___________________________________________________ ____________________________________ 
                                <=450       451-480        481-500        >500       <=30        31-60         >60     
Time Point                N#     n(%)         n(%)           n(%)         n(%)       n(%)         n(%)         n(%)    
______________________________________________________________________________________________________________________ 
                                                                                                                       
BASELINE                  xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)                                       
TIME POINT 1              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
TIME POINT 2              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
TIME POINT 3              xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
…                         …       …            …              …            …          …            …            …      
<All other time points>   xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      All subjects were planned to receive a single oral dose of 225 mg [14C]CRV431                                                                           
      BASELINE is defined as Day 1, Pre-dose                                                                                                                  
      Categories for QTcF interval and QTcF interval increases are based on ICH E14 guidelines                                                                
      N# is the total number of subjects at the relevant time point and is used in the denominator for calculating the                                        
      percentages of subjects, n indicates the number of subjects with observations at the given time point                                                   
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSCXXXXXX\~\TFLS\PRODUCTION\TAB-XX                                      DDMMMYYYY HH:MM                                                    


Sponsor/Quotient Sciences Confidential 
 
Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 70 of 72  
 
 
 
Appendix 1:  
Schedule of Assessments 
Study day 
-28 to 
-2 
-1 
 
1 
2 
3 
4 
5 
6 
7 
8 
 
Times after dosing (h) 
 
S 
Aa  Pa  
0 
0.5 
1 
1.5 
2 
3 
4 
6 
8 
12 16 
24 
48 
72 
96 
120 144 168 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, Height and BMI 
X 
Xc  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon Monoxide Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Antigend 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted (symptom driven) Physical 
Examinatione 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Blood Samplesf  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
eGFRg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Single 12-Lead ECGs 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Vital Signsh 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Adverse Events 
---------------------------------------------------------------------X---------------------------------------------------------------------→ 
Prior and Concomitant Medication  
---------------------------------------------------------------------X---------------------------------------------------------------------→ 
Mass Balance, PK and Met Prof and ID Assessments 
Whole Blood Samples for Rencofilstat 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma Samples for TR 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole Blood Samples for TR 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole Blood Samples for Met Prof and ID 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
Urine Samples for TR and Met Prof and IDi 
 
 
---------------------------------------------------------------X------------------------------------------------------------------→ 
Faecal Samples for TR and Met Prof and IDj 
 
------------------------------------------------------------------X------------------------------------------------------------------→ 


Sponsor/Quotient Sciences Confidential 
Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 71 of 72 
Appendix 1: 
Schedule of Assessments (continued)
Study day 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
28 (+2 
days) 
35 (±2 
days) 
Home 
Collectionsn 
Times after dosing (h) 
192 216 240 264 288 312 336 360 384 408 432 456 480 504k 
528l 
552l 
576l 
600l 
Return Visitsm 
General Assessments 
SARS-CoV-2 Antigend  
X 
X 
Safety Assessments 
Targeted (symptom driven) Physical 
Examinatione
Xko 
Safety Labsf
Xko 
Urinalysis 
Xko 
Single 12-Lead ECGs 
Xko 
Vital Signsh  
Xko 
X 
X 
Adverse Events 
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→
Prior and Concomitant Medication 
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→
Mass Balance, PK and Met Prof and ID Assessments 
Whole Blood Samples for Rencofilstat 
X 
X 
X 
X 
X 
X 
X 
Xp 
Plasma Samples for TR 
X 
X 
X 
X 
X 
X 
X 
Xp 
Whole Blood Samples for TR 
X 
X 
X 
X 
X 
X 
X 
Xp 
Urine Samples for TR and Met Prof and IDi 
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→
Faecal Samples for TR and Met Prof and IDj 
---------------------------------------------------------------------------------------X---------------------------------------------------------------------------→
A: admission; BMI: body mass index; ID: identification; Met Prof: Metabolite Profiling; P: pre-dose; PK: pharmacokinetic(s); S: screening; TR: total radioactivity 
a Eligibility will be re-assessed at admission/pre-dose 
b Update only 
c Weight only  
d Testing for SARS-CoV-2 may be performed based on current infection rates and availability of tests. If required, it is planned that testing will comprise an antigen test 
performed on Day -1 prior to admission to the clinical unit and at return visits. The decision on COVID-19 testing and the definition of the testing time points are subject to 
change based on the current risk mitigation in place and will be agreed by the study team and documented in the ISF via the Clinical Kick-Off Meeting minutes 
e Targeted (symptom driven) physical examination of the relevant body system(s) as clinically indicated, as per the investigator’s judgement 
f Haematology and clinical chemistry at each time point including virology at screening 
g eGFR will be calculated at screening using the CKD-EPI equation for eligibility purposes 
h Blood pressure and heart rate will be measured at every time point; oral temperature will be checked at screening, pre-dose and at first return residential visit (Day 28 
+2 days) only
i Urine will be collected for the following intervals: A single urine sample will be collected at pre-dose (or the first void of the day), then at: 0-12 h, 12-24 h and then for 24 h
intervals until mass balance criteria have been met (see Section 5.1for details of mass balance criteria)
j Faeces will be collected at pre-dose (sample will be taken between admission and pre-dose), then at 24 h intervals until mass balance criteria have been met (see
Section 5.1 for details of mass balance criteria)


Sponsor/Quotient Sciences Confidential 
Reporting and Analysis Plan HEPA-CRV431-105 (QSC204643) Final v1.0 
10 Feb 2023 
Page 72 of 72 
k Discharge from clinical unit. Discharge assessments will be performed at the time of actual discharge. It is planned that subjects will remain resident in the clinical unit 
until 504 h post-dose (Day 22). Subjects will be discharged from the clinical unit on Day 22 provided they have met the following mass balance discharge criteria: mass 
balance cumulative recovery of >90% OR <1% of the dose administered collected in urine and faeces within 2 separate, consecutive 24 h periods. It is also planned that 
subjects will be discharged from the clinical unit as a group if all subjects have achieved the mass balance discharge criteria 
l If mass balance discharge criteria have not been met by all subjects by Day 22, the residency period for the subjects not achieving the mass balance criteria may be
extended up to a maximum of 96 h (Day 26). Urine and/or faeces will be collected during the additional residency period
m If mass balance discharge criteria have not been met by all subjects by the end of the additional residency (Day 26), subjects not achieving the mass balance criteria
may be required to make up to 2 return visits (each of 24 h duration) at (nominally) Day 28 (+2 days) and Day 35 (±2 days) for additional collection of excreta samples.
Only urine and/or faeces will be collected during the return visits
n If the mass balance criteria are not met following the return visits, then home collections of urine and/or faeces may be requested at the discretion of the investigator for
individual subjects
o In the event of early withdrawal, all safety discharge assessments should be completed
p If the residency period for subjects not achieving the mass balance criteria is extended, a further sample will be taken at actual discharge


Document Approvals
Approved Date: 20 Feb 2023
Document Author(s):  Rory McMurray 
Approval Task
Verdict:  Approve
Claire Wilson, Senior Statistician
(Claire.Wilson@quotientsciences.com)
Approval
17-Feb-2023 09:08:40 GMT+0000
Approval Task
Verdict:  Approve
Carl Burdett, Statistical Programmer
(Carl.Burdett@quotientsciences.com)
Approval
17-Feb-2023 10:05:25 GMT+0000
Approval Task
Verdict:  Approve
Francesca Ware, Medical Writer
(Francesca.Ware@quotientsciences.com)
Approval
17-Feb-2023 13:11:41 GMT+0000
Approval Task
Verdict:  Approve
Litza McKenzie, Senior Clinical Research Physician
(Litza.McKenzie@quotientsciences.com)
Approval
17-Feb-2023 16:30:30 GMT+0000
Approval Task
Verdict:  Approve
Anna Hunter, Senior Pharmacokineticist
(anna.hunter@quotientsciences.com)
Approval
20-Feb-2023 09:51:18 GMT+0000