Conditions: NASH - Nonalcoholic Steatohepatitis Fibrosis, Liver NAFLD - Nonalcoholic Fatty Liver Disease
Keywords: Anti-fibrotic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 47
Healthy volunteers: no

Brief summary:
This is a randomized, single-blind, placebo-controlled, once daily (QD) dose study of CRV431 in presumed NASH F2/F3 subjects.

Detailed description:
This is a randomized, single-blind, placebo-controlled, once daily (QD) dose study of CRV431 in presumed NASH F2/F3 subjects. Study will evaluate the safety and tolerability of a once daily 75mg dose and 225mg of CRV431 compared to placebo over 28 days of dosing. Pharmacokinetic parameters of CRV431 and its major metabolites and fraction unbound will also be evaluated. Non-invasive antifibrotic bio-markers will be collected and quantified from presumed NASH F2/F3 subjects dosed with 75mg CRV431 or placebo.

Arms:
arm 1: CRV431, softgel capsule, 75mg, QD, 28 days, fasted conditions arm 2: Placebo, softgel capsule, QD, 28 days, fasted conditions arm 3: CRV431, softgel capsule, 225mg, QD, 28 days, fasted conditions arm 4: CRV431, 3 softgel capsules, 225mg, QD, 28 days, fasted conditions

Interventions: intervention 1: CRV431 75mg intervention 2: Placebo (1 softgel) intervention 3: CRV431 225mg intervention 4: Placebo (3 softgels)
Intervention descriptions: intervention 1: 1 x 75mg softgel capsule intervention 2: 1 x placebo softgel capsule intervention 3: 3 x 75mg softgel capsule intervention 4: 3 x placebo softgel capsule

Protocol document:
Prot_SAP_001.pdf: 
NCT04480710


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for CRV431.  I have read the attached 
protocol for study HEPA-CRV431-201 and agree to conduct the study as outlined.  I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol. 
I will provide copies of the protocol and of the pre-clinical and clinical information on the Study 
Drug, which was furnished to me by the Sponsor, to all members of the study team responsible 
to me who participate in the study.  I will discuss this material with them to assure that they are 
fully informed regarding the test article and the conduct of the study. 
Once the protocol has been approved by the Investigational Review Board (IRB) or Independent 
Ethics Committee (IEC), I will not modify this protocol without obtaining the prior approval of 
the Sponsor and of the IRB/IEC.  I will submit all protocol modifications and/or any informed 
consent modifications to the Sponsor and the IRB/IEC, and approval will be obtained before any 
modifications are implemented.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 




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2. 
SYNOPSIS 
Name of Sponsor/Company: Hepion Pharmaceuticals, Inc. 
Name of Investigational Product: CRV431 
Name of Active Ingredient: Cyclo[L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-
methyl-L-valyl-(3R,4R)-10-acetylamino-3-hydroxy-N,4-dimethyl-L-2-aminodecanoyl-L-2-
aminobutanoyl-N-methyl-D-alanyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl] 
Title of Study: 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 
Study Acronym: AMBITION 
Study center(s): approximately 10 U.S. sites 
Studied period (years): Estimated Q2 2020 to Q2 2021 
Phase of development: 2A 


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Objectives:  
Primary: 
• 
To evaluate the safety and tolerability of once daily (QD) 75 mg and 225 mg doses of 
CRV431 in presumed nonalcoholic steatohepatitis (NASH) fibrosis stage 2 (F2)/fibrosis 
stage 3 (F3) subjects compared to placebo control over 28 days of dosing;  
• 
To evaluate the pharmacokinetics (PK) of a QD dose of CRV431, its major metabolites 
and fraction unbound in presumed NASH F2/F3 subjects over 28 days of dosing. 
Secondary: 
• 
To evaluate non-invasively the antifibrotic activity of a QD dose of CRV431, as 
measured by quantification of selected biomarkers of fibrosis, in presumed NASH F2/F3 
subjects over 28 days of dosing. 
Exploratory Objectives: 
• 
To generate exploratory data regarding the antifibrotic activity of a QD dose of CRV431 
over 28 days of dosing by performing hepatic evaluations via laboratory assessments of 
biomarkers such: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
− 
Pharmacokinetic/pharmacodynamic (PK/PD) analyses to assess concentration effect 
relationship on all biomarkers; 
− Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) decrease 
from baseline. 
Number of subjects (planned): Thirty-six (36) adult male or female subjects will be enrolled. 
• 
Cohort A:  Twelve (12) presumed NASH F2/F3 subjects on CRV431 75 mg QD; 
• 
Cohort B: Six (6) presumed NASH F2/F3 subjects on matching placebo for Cohort A. 
• 
Cohort C:  Twelve (12) presumed NASH F2/F3 subjects on CRV431 225 mg QD; 
• 
Cohort D: Six (6) presumed NASH F2/F3 subjects on matching placebo for Cohort C. 


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Methodology:  
This is a randomized, single-blind, placebo-controlled, multi-center study to evaluate the safety and 
PK of CRV431 in subjects with presumed NASH F2/F3 fibrosis. Antifibrotic biomarker activity will 
be evaluated on an exploratory basis. 
 
Cohort* 
Fibrosis 
Stage 
N 
Day 1 – 28, fasted oral 
dosing 
Day 29 - 42 
A 
F2/F3 
12 
CRV431 75 mg 
Observation/Follow up 
B 
6 
Placeboa 
C 
12 
CRV431 225 mg 
D 
6 
Placebob 
*Randomized assignment; 2:1 – CRV431:Placebo 
a Matching Placebo for Cohort A - 75 mg dose. 
b Matching Placebo for Cohort C - 225 mg dose. 
 
This study consists of 3 phases: (i) Screening and Randomization; (ii) treatment; and (iii) follow up. 
During Screening, each subject will provide informed consent prior to starting any study specific 
procedures. The randomization of subjects in each cohort will be performed in a 2:1 ratio (12 
CRV431 subjects and 6 placebo subjects). During the treatment period, randomized subjects will be 
provided the treatment and assessments according to Schedule of Events, Table 3. In the follow up 
phase, investigational product (IP) will be discontinued followed by 14 Days of safety follow-up. 
Subjects randomized into either Cohort A or Cohort B will receive a 75 mg QD dose of CRV431 or 
matching placebo in a fasted state, respectively. Subjects randomized into either Cohort C or Cohort 
D will receive a 225 mg QD dose of CRV431 or matching placebo in a fasted state, respectively.  
 
Safety and available PK data will be reviewed by a DSMB prior to proceeding with the next higher 
dose cohort.  The DSMB will also conduct a safety review if stopping criteria are met.  
 
Subjects who do not complete the study may be replaced within the dosing cohort, unless a stopping 
rule (see Section 7.5) precludes replacement.  
 
Subjects who miss more than 2 consecutive QD doses of CRV431 may be replaced, unless a stopping 
rule (Section 7.5) precludes replacement. 


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Inclusion and Exclusion Criteria: 
Inclusion Criteria 
Subjects must fulfill all the following inclusion criteria to be eligible for participation in the study.   
1.  Capable of giving written informed consent and able to effectively communicate with the 
investigator and study personnel.  A signed informed consent form (ICF) must be on file prior 
to initiating the Screening procedures; 
2. Willing and able to complete all study requirements, restrictions, visits and procedures; 
3. AST ≥ 20 IU/L and FibroScan ≥ 8.5 kPa values. Historical value of FibroScan obtained 
within 3 months prior to Screening can be accepted. If historical value is not available, a 
FibroScan must be obtained as part of Screening. If a potential subject does not meet the 
inclusion AST and/or FibroScan requirements, a historical biopsy obtained within 6 months 
confirming NASH F2 fibrosis stage or a historical biopsy obtained within 12 months 
confirming NASH F3 fibrosis stage can be accepted to supersede the AST and/or FibroScan 
results; 
4. 
 
5. Male or female between 18 and 75 years of age (inclusive); 
6. Females of reproductive potential, defined as women who have not been postmenopausal for 
at least 24 consecutive months (i.e., who have had menses within the preceding 24 months), 
or women who have not undergone surgical sterilization, specifically, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy, hysteroscopic sterilization, and/or tubal ligation, must 
have a negative pregnancy test at Screening and within the 24-hour period prior to Day 1; 
7. All participants must agree not to participate in a conception process (i.e., active attempt to 
become pregnant or to impregnate, sperm or egg donation, in vitro fertilization).  If 
participating in sexual activity that could lead to pregnancy, the participant must agree to use 
2 reliable methods of contraception simultaneously while receiving study treatment and for 3 
months after subject has stopped taking study drug.  A combination of TWO of the following 
methods MUST be used appropriately: 
a. Condoms (male or female) with or without a spermicidal agent; 
b. Diaphragm or cervical cap with spermicide; 
c. Intrauterine device (IUD); 
d. Hormonal-based contraception. 
Note:  Participants who are not of reproductive potential (women who have been 
postmenopausal for at least 24 consecutive months or have undergone hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy, hysteroscopic sterilization, and/or tubal ligation, or 
men who have documented azoospermia) are eligible without requiring the use of 
contraceptives.  Acceptable documentation of sterilization, menopause or male partner’s 
azoospermia must be provided; serum follicle stimulating hormone (FSH) measurement can 
be used to document menopausal status. 
 
 
 


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Exclusion Criteria 
Subjects who meet any of the following criteria prior to the first dose of study drug are not eligible for 
randomization.   
1. Pregnant or breastfeeding or planning to become pregnant during the study period; 
2. Known allergy to CRV431, cyclosporine, or any of their inactive ingredients; 
3. Positive test for hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCVAb) 
or human immunodeficiency virus antibodies (HIVAb). If HCVAb test is positive, then an 
HCV-RNA test will be performed. If the HCV-RNA test is negative, the subject is allowed to 
participate in the study, as long as the subject meets all other inclusion criteria and has never 
been treated for HCV or was treated >2years ago and achieved a sustained virologic response 
at that time; 
4. History of or any current medical condition which could compromise the safety of the 
participant in the study, as determined by the investigator; 
5. Subjects with a systolic pressure >150 or a diastolic pressure >90. At the discretion of the 
investigator, the blood pressure may be re-measured after 10 minutes to ensure the blood 
pressure is in fact out of range. Out of range blood pressure after the second measurement 
will exclude a subject. If a subject has a blood pressure within the desired range due to anti-
hypertension medication, that subject can be included at the discretion of the investigator, 
provided the anti-hypertension medication is not a contraindicated medication. Please refer to 
Appendix A for a list of drugs considered contraindicated;  
6. Clinically significant gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, 
renal, hepatic, respiratory, inflammatory, or infectious disease, as determined by the 
investigator; 
7. Subjects with a history of clinically significant acute cardiac events within 6 months prior to 
Screening such as stroke, transient ischemic attack, or coronary heart disease (angina pectoris 
requiring therapy, myocardial infarction, revascularization procedures with left ventricular 
ejection fraction [LVEF] <50% as determined by previous echocardiography or multiple 
gated acquisition [MUGA] scan); 
8. Subjects with uncontrolled or unstable cardiac arrhythmias: 
a. Severe conduction disturbance (e.g., second-degree or third-degree AV block); 
b. QTc-interval >450 msec (males) or >470 msec (females); 
c. History of congenital long QT syndrome, congenital short QT syndrome, Torsades de 
Pointes, or Wolff Parkinson White syndrome; 
9. Subjects with transaminases >5 x upper limit of normal (ULN) and with alkaline phosphatase 
(ALP) >2 x ULN; 
10. Subjects with total serum bilirubin >1.5 x ULN, unless the subject has Gilbert’s Syndrome, in 
which case the subject can be enrolled provided the direct bilirubin is within 30% of the total 
bilirubin (TBL); 
11. Subjects with a platelet count <150,000/m3; 


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12. Systemic immunosuppression within 6 months prior to the first dose of study drug apart from 
short-term treatment for asthma, COPD or other respiratory conditions; 
13. Current clinically significant diarrhea or gastric stasis that, in the investigator’s opinion, could 
influence drug absorption or bioavailability; 
14. Subject with any history or presence of decompensated cirrhosis; 
15. Other well documented causes of chronic liver disease according to standard diagnostic 
procedures including, but not restricted to: 
a. Suspicion of drug-induced liver disease; 
b. Alcoholic liver disease; 
c. Autoimmune hepatitis;  
d. Wilson’s disease; 
e. Primary biliary cholangitis, primary sclerosing cholangitis;  
f. Genetic hemochromatosis (Homozygosity for C282Y or C282Y/H63D compound 
heterozygote);  
g. Known or suspected hepatocellular carcinoma (HCC); 
h. History or planned liver transplant, or current Model for End-Stage Liver Disease 
(MELD) score >15; 
16. History of, or current evidence of, gallstones, gall bladder disease, cholestasis that has not 
been treated with cholecystectomy, or pancreatitis; 
17. Subjects with hemoglobin A1c (HbA1c) >9.5%. For subjects with an HbA1c >9.5% at the 
Screening Visit, a repeat test may be performed. A repeat HbA1c result >9.5% will lead to 
exclusion; 
18. At Screening, an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (calculated 
by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] method) and/or a 
Kidney Disease Improving Global Outcomes (KDIGO) category of >G2; 
19. Safety laboratory abnormalities at Screening which are clinically significant as determined by 
the investigator; 
20. Weight loss of more than 5% within 3 months prior to randomization; 
21.  Current abuse of alcohol or illicit drugs, or history of alcohol or illicit drug abuse within the 
preceding 2 years, as determined by the investigator. History of excess alcohol intake as 
defined by ≥21 units of alcohol per week in males and ≥14 units of alcohol per week in 
females for 2 years prior to enrollment where a “unit” of alcohol is equivalent to 12-ounce 
beer, 4-ounce of wine, or 1-ounce shot of hard liquor; 
22. A positive urine drug screen for drugs with a high potential for abuse (amphetamines, 
cannabinoids, opiates, cocaine, benzodiazepine) or alcohol test at Screening or Day -1. For 
benzodiazepine’s only: positive results will be accepted if due to an approved prescription. 
For cannabinoids, opiates and amphetamines: On a case by case basis, positive results will be 
evaluated by the Sponsor and Medical Monitor in order to determine the subject’s eligibility 
to safely be included in the study; 
23. Significant medical or psychiatric illness that would interfere with compliance and ability to 
tolerate treatment as outlined in the protocol;  


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24. Subjects who cannot be contacted in case of emergency; 
25. Judgement by the investigator that the subject should not participate in the study if the subject 
is unlikely to comply with all study procedures and treatment; 
26. Received an investigational drug or investigational vaccine or used an investigational medical 
device within 30 days prior to first dose of study drug; 
27. Subjects who have used any drugs or substances known to be strong inhibitors or inducers of 
cytochrome P4503A4/5 (CYP3A4/5) and drugs whose major elimination pathway is the bile 
salt export pump (BSEP) or organic anion transporter 3 (OAT3), and drugs that are major 
substrates of the hepatic uptake transporters, organic anion transporting polypeptide1B1 
(OATP1B1) and OATP1B3 within 30 days prior to the first dose of study drug.  (NOTE: 
Please refer to Appendix A for a list of drugs considered contraindicated. If there are 
questions, please contact the sponsor);  
28. Subjects with a history of organ transplantation. Corneal transplantation will be allowed. 
Abnormal electrocardiogram (ECG) or laboratory parameters may be repeated once, if in the opinion 
of the investigator, the results are due to technical factors or are inconsistent with the potential 
subject’s medical evaluation. 
Potential study subjects who met all inclusion and none of the exclusion criteria for this study but 
who, for personal or administrative reasons, were not included in a study cohort may be re-screened if 
more than 30 days have passed since their previous Screening. For these subjects, use of ELF or Pro-
C3 results previously obtained for this study will be extended for an additional 30 days up to a total of 
60 days. There are no restrictions on the number of re-screens permitted for these subjects. 
 
 
Investigational product, dosage and mode of administration: 
• 
CRV431, 75 mg, softgel capsule, orally QD, in fasted condition 
• 
Placebo, softgel capsule orally QD, in fasted condition 
Duration of treatment: Full treatment duration will be defined as 28 days of treatment with CRV431 
or placebo. 






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3. 
TABLE OF CONTENTS AND LIST OF TABLES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ........................................................................................................... 1 
INVESTIGATOR’S AGREEMENT ........................................................................................... 2 
PROCEDURES IN CASE OF EMERGENCY ............................................................................ 3 
2. 
SYNOPSIS ............................................................................................................... 4 
3. 
TABLE OF CONTENTS AND LIST OF TABLES ................................................ 13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS ............................................... 18 
5. 
INTRODUCTION .................................................................................................. 19 
5.1. 
Background ............................................................................................................ 19 
5.2. 
Rationale ................................................................................................................ 19 
5.3. 
Rationale for this Study Design and Dose Selection ................................................ 20 
5.4. 
Risks and/or Benefits to Subjects ............................................................................ 21 
6. 
STUDY OBJECTIVES........................................................................................... 23 
6.1. 
Primary Objectives ................................................................................................. 23 
6.2. 
Secondary Objective ............................................................................................... 23 
6.3. 
Exploratory Objectives ........................................................................................... 23 
6.4. 
Study Endpoints ..................................................................................................... 23 
6.4.1. 
Safety Endpoints ..................................................................................................... 23 
6.4.2. 
Pharmacokinetic Endpoints ..................................................................................... 23 
6.4.3. 
Exploratory Endpoints ............................................................................................ 24 
7. 
INVESTIGATIONAL PLAN ................................................................................. 25 
7.1. 
Overall Study Design .............................................................................................. 25 
7.1.1. 
Screening and Randomization Period ...................................................................... 25 
7.1.2. 
Treatment Period .................................................................................................... 26 
7.1.3. 
Follow Up Period ................................................................................................... 26 
7.2. 
Number of Subjects ................................................................................................ 30 
7.3. 
Treatment ............................................................................................................... 30 
7.3.1. 
Treatment Administration ....................................................................................... 30 
7.3.2. 
Treatment Compliance ............................................................................................ 30 
7.3.3. 
Randomization and Blinding................................................................................... 30 
7.4. 
Study Restriction .................................................................................................... 31 


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7.4.1. 
Prohibited and Concomitant Medication ................................................................. 31 
7.4.2. 
Meals ...................................................................................................................... 31 
7.5. 
COVID-19 Vaccine ................................................................................................ 31 
7.6. 
Data Safety Monitoring Board ................................................................................ 32 
7.7. 
Safety Criteria for Adjustment or Stopping Doses ................................................... 32 
7.7.1. 
Individual Subject Criteria ...................................................................................... 32 
7.7.2. 
Study Criteria ......................................................................................................... 33 
7.7.2.1. 
Study Stopping Criteria .......................................................................................... 34 
7.7.3. 
Pharmacokinetic Criteria for Dose Adjustment ....................................................... 34 
7.8. 
Close Observation .................................................................................................. 34 
7.9. 
Criteria for Study Termination ................................................................................ 35 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................ 36 
8.1. 
Subject Inclusion Criteria ....................................................................................... 36 
8.2. 
Subject Exclusion Criteria ...................................................................................... 37 
8.3. 
Subject Withdrawal Criteria .................................................................................... 39 
8.3.1. 
Early Termination of Subjects from the Study......................................................... 39 
8.4. 
Subject Replacement .............................................................................................. 40 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ......................................... 41 
9.1 
  Investigational Product ......................................................................................... 41 
9.2          
 Placebo .................................................................................................................. 41 
9.3          
 Study Drug Packaging and Labeling ...................................................................... 41 
9.4          
 Study Drug Storage ............................................................................................... 41 
9.5         
 Study Dug Preparation ........................................................................................... 41 
9.6        
 Study Drug Accountability .................................................................................... 41 
9.7         
 Study Drug Handling and Disposal ........................................................................ 42 
10. 
PHARMACOKINETIC ASSESSMENTS .............................................................. 43 
10.1. 
Blood Sample Collection ........................................................................................ 43 
10.2. 
Sample Handling and Shipment .............................................................................. 43 
10.3. 
Sample Analysis ..................................................................................................... 43 
10.4. 
Whole Blood Pharmacokinetic Parameters.............................................................. 43 
11. 
ASSESSMENT OF SAFETY ................................................................................. 46 
11.1. 
Safety Parameters ................................................................................................... 46 
11.1.1. 
Demographic .......................................................................................................... 46 


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11.1.2. 
Vital Signs .............................................................................................................. 46 
11.1.3. 
Weight and Height .................................................................................................. 46 
11.1.4. 
Physical Examination and Medical History ............................................................. 46 
11.1.5. 
Electrocardiogram .................................................................................................. 46 
11.1.6. 
Laboratory Assessments ......................................................................................... 46 
11.1.6.1. 
Hematology and Coagulation .................................................................................. 47 
11.1.6.2. 
Blood Chemistry ..................................................................................................... 47 
11.1.6.3. 
Urinalysis ............................................................................................................... 48 
11.1.6.4. 
Drug Screen ............................................................................................................ 48 
11.1.6.5. 
Pregnancy Screen ................................................................................................... 48 
11.2. 
Adverse and Serious Adverse Events ...................................................................... 48 
11.2.1. 
Adverse Events ....................................................................................................... 48 
11.2.2. 
Serious Adverse Events .......................................................................................... 49 
11.2.3. 
Other Adverse Events ............................................................................................. 49 
11.3. 
Relationship to Study Drug ..................................................................................... 49 
11.4. 
Recording Adverse Events ...................................................................................... 50 
11.5. 
Reporting Adverse Events ...................................................................................... 50 
12. 
STATISTICS .......................................................................................................... 52 
12.1. 
Sample Size Determination ..................................................................................... 52 
12.2. 
Population for Analyses .......................................................................................... 52 
12.2.1. 
Pharmacokinetic Population.................................................................................... 52 
12.2.2. 
Safety Population.................................................................................................... 52 
12.3. 
Statistical Analyses ................................................................................................. 52 
12.3.1. 
Interim Safety Review ............................................................................................ 53 
12.3.2. 
Analysis of Covariance ........................................................................................... 53 
12.3.3. 
Ratios and Confidence Intervals.............................................................................. 53 
12.3.4. 
Pharmacokinetics Analyses ..................................................................................... 54 
12.3.5. 
Safety Analyses ...................................................................................................... 54 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................................... 55 
13.1. 
Study Monitoring.................................................................................................... 55 
13.2. 
Audits and Inspections ............................................................................................ 55 
13.3. 
Institutional Review Board ..................................................................................... 56 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 57 


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15. 
ETHICS.................................................................................................................. 58 
15.1. 
Ethics Review ......................................................................................................... 58 
15.2. 
Ethical Conduct of the Study .................................................................................. 58 
15.3. 
Written Informed Consent ...................................................................................... 58 
16. 
DATA HANDLING AND RECORDKEEPING ..................................................... 59 
16.1. 
Inspection of Records ............................................................................................. 59 
16.2. 
Retention of Records .............................................................................................. 59 
17. 
LIST OF REFERENCES ........................................................................................ 60 
18. 
APPENDICES ........................................................................................................ 62 
APPENDIX A. CONTRAINDICATED DRUGS ................................................................... 63 
 
 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ............................................................................... 3 
Table 2: 
Study Design .......................................................................................................... 25 
Table 3: 
Schedule of Events ................................................................................................. 27 
Table 4 
Investigational Product ........................................................................................... 41 
Table 5: 
Pharmacokinetic Parameters ................................................................................... 43 
Table 6: 
Pharmacokinetic Sampling Schedule ...................................................................... 45 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviations/Acronyms 
Definition 
AE(s) 
Adverse event(s) 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration time curve  
AUC0-24 
Area under the concentration time curve from time 0 
to the 24-hour time point 
AUC0-48 
Area under the concentration time curve from time 0 
to the 48-hour time point 
AUC0-last 
Area under the concentration time curve calculated 
from 0 to the last observed concentration 
AUC0-inf 
Area under the concentration time curve from 0 to 
infinity  
AUC0-t 
Area under the concentration time curve from time 
zero to time t 
%AUCtexpol 
Percentage of AUC0-inf extrapolated beyond Tlast 
CL/F 
Apparent total oral clearance (parent compound only) 
Cmax 
Maximum observed whole blood concentration 
Cmin 
Minimum observed whole blood concentration 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
NAFLD 
Nonalcoholic fatty liver disease 
fu 
Fraction Unbound 
PK 
Pharmacokinetics  
PK/PD 
Pharmacokinetics/Pharmacodynamics 
QD 
Once daily 
QTcF 
Friderica’s QT Correction Formula 
SAE(s) 
Serious adverse event(s) 
Vz/F 
Apparent volume of distribution during the terminal 
elimination phase  


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5. 
INTRODUCTION 
5.1. 
Background 
Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis 
(NASH) are significant health burdens and are on the rise across the globe. Nonalcoholic fatty 
liver disease is characterized by fat accumulation in the liver and often is associated with obesity, 
insulin resistance, diabetes mellitus, dyslipidemia, hypertension, and other aspects of metabolic 
syndrome. Nonalcoholic steatohepatitis shares these characteristics but additionally is 
characterized by liver inflammation, hepatocyte necrosis and potentially fibrosis, which places 
patients at increased risk of developing cirrhosis and liver cancer.  
The prevalence of NAFLD, NASH and HCC are on the rise throughout the world. In a recent 
study published by Estes et al. (Estes, 2018), NAFLD cases in the USA are projected to increase 
from 83.1 million in 2015 to 100.9 million in 2030. This equates to a 33.5% prevalence among 
adults over the age of 15. Nonalcoholic steatohepatitis cases in the USA are projected to rise 
from 16.5 million in 2015 to 27 million in 2030.  In addition, the incidence of HCC is projected 
to increase by 137% from 2015 to 2030 leading to an increase in liver related deaths.  From 2015 
to 2030, the estimate of nearly 800,000 excess liver deaths are expected.  From a global 
perspective, NAFLD prevalence is 25.4% with the highest rates in the Middle East and South 
America.  This correlates with a 40.76% rate of NASH and/or fibrosis progression.  The HCC 
incidence was 0.44 per 1,000 person years in NAFLD patients.  Liver associated mortality had a 
higher risk ratio 1.94 compared to overall mortality 1.05 in a NAFLD patient population 
(Siddiqui, 2018).  When looking at the USA, it is reported the NAFLD rates to be between 10 
and 30%.  These rates also apply to Europe and Asia (Younossi, 2016).  
There are currently no USA Food and Drug Administration (FDA) approved medications 
specifically for NAFLD or NASH, but many drug candidates are in development. 
Many pathological processes contribute to NASH, including the toxic effects of fat 
accumulation, oxidative stress, cell injury and cell death, leukocyte recruitment and activation of 
infiltrating cells and resident macrophages, profibrogenic activation of hepatic stellate cells, 
fibrosis, and carcinogenic transformation of liver cells.  Effective therapies for NASH likely will 
require targeting multiple pathogenic mechanisms.  Targeting late-disease processes, especially 
those related to fibrosis, is especially important.  Most patients with NAFLD and early NASH 
are asymptomatic and therefore it is expected that they will already have moderately advanced 
NASH by the time that they are diagnosed.  Also, fibrosis is the strongest predictor of adverse 
clinical outcomes associated with NASH such as progression to cirrhosis and HCC.  Whereas 
therapies targeting dyslipidemia, inflammation, and other triggers of NASH will be important for 
halting disease progression, it is vitally important to develop treatments that more directly inhibit 
fibrogenesis, stimulate fibrolysis, promote restoration of liver function, reduce the risks of 
carcinogenesis, and restrict tumor progression.  CRV431 is a drug candidate that is proposed to 
directly target many of these pathological events. 
5.2. 
Rationale 
CRV431 is a chemically modified analog of the immunosuppressive drug, cyclosporine A (CsA). 
Cyclosporine A exerts its immunosuppression by a two-step process. Cyclosporine A first binds 


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to cyclophilin A (Cyp A), a peptidylprolyl isomerase that regulates target protein structure and 
function by influencing the cis-trans conformation of proline peptide bonds.  Then the CsA-Cyp 
A duplex binds to and inhibits the activity of the phosphatase, calcineurin, in lymphocytes.  
CRV431 is chemically and functionally different from CsA in that it retains binding to Cyp A, 
but the CRV431-cyclophilin duplex does not strongly bind to calcineurin and therefore does not 
have significant immunosuppressive potential.  
CRV431 binding and inhibition of Cyp A is 13-times more potent than that of CsA with an 
inhibitor constant, Ki = 1 nM, and it is this high-affinity, cyclophilin inhibition that is proposed 
to mediate therapeutic effects of CRV431. Moreover, CRV431 inhibits not only Cyp A but also 
other cyclophilin isoforms, notably cyclophilin B (Cyp B) and cyclophilin D (Cyp D), which 
contribute to a variety of pathological processes (Nigro et al., 2013; Naoumov, 2014; Bukrinsky, 
2015; Dawar et al., 2017a, b; Briston et al., 2018; Wang et al., 2018; Xue et al., 2018). For 
example, Cyp A is an abundant cytosolic cyclophilin that influences many intracellular signaling 
pathways.  It is released from injured cells and stimulates inflammation by binding to CD147 and 
contributes to cancer cell adaptation to hypoxia and is recruited into the life cycles of many 
viruses, including hepatitis B virus (HBV) and hepatitis C virus (HCV).  Cyclophilin B is located 
in the endoplasmic reticulum where it participates in protein folding and secretion of proteins. 
Notably, Cyp B regulates procollagen hydroxylation, formation of procollagen triple-helices, and 
rates of secretion of procollagen from cells.  Impairment of Cyp B-regulated procollagen 
production is hypothesized to be the major mechanism by which CRV431 decreases liver 
fibrosis.  Cyp D is located in the mitochondrial matrix and is the primary regulator of 
mitochondrial permeability transition pores (mPTP).  These mitochondrial pores open in 
response to common types of cellular injury, such as oxidative stress and calcium overload, 
leading to mitochondrial destruction and cell necrosis.  Inhibition of Cyp D protects cells from a 
variety of insults and may be important for reducing cell loss and ensuing pathological cascades 
in NASH livers. Cyclophilin D also is implicated in liver steatosis and in oncogenic events 
related to the tumor suppressor, p53, to which Cyp D binds. In summary, several cyclophilin-
dependent pathological processes in NASH livers are likely to be attenuated by CRV431.  For 
information on mechanism of action and additional preclinical data, please refer to the CRV431 
Investigational Brochure.   
5.3. 
Rationale for this Study Design and Dose Selection 
CRV431 has consistently demonstrated the ability to prevent the progression of liver fibrosis in a 
variety of animal models and in precision-cut human liver slices.  The primary mechanism of 
action to prevent collagen synthesis is via Cyp B inhibition although additional mechanisms may 
involve Cyp A and Cyp D.  The half maximal inhibitory concentration (IC50) for cyclophilin 
inhibition ranges from 3.2 to 9.5 ng/mL.  Human whole blood concentrations after a single dose 
75 mg of CRV431 achieved a maximum observed whole blood concentration (Cmax) of 334 ± 
106 ng/mL.  Steady state concentrations for 75 mg QD dosed for 28 days achieved a Cmax of 
1397.5 ± 97.8 ng/mL with a mean trough level of 889.5 ± 70.4 ng/mL demonstrating that whole 
blood concentrations are above the cellular IC50 range for the entire dosing period which ensures 
target engagement. In order to evaluate the potential dose response of CRV431 on safety and 
NASH biomarkers, a second dose of 225 mg QD demonstrating a steady-state Cmax of 1844 ± 
321.9 ng/mL will be explored.    








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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, single-blind, placebo-controlled, QD dose study of CRV431 in presumed 
NASH F2/F3 subjects. This study will consist of 3 phases: (i) Screening and Randomization; (ii) 
treatment; and (iii) follow up.  
7.1.1. 
Screening and Randomization Period 
Screening visits will be conducted within 30 days prior to study Day 1. During the Screening 
Phase, each potential subject will provide informed consent prior to starting any study-specific 
procedures.  
Due to the logistics and time needed for the retest of the 
, for those subjects 
that an investigator requests a retest of these samples, as described in Section 8.2, the screening 
period may be extended an additional 30 days for a screening period of up to 60 days total in 
order to allow subjects who are waiting the retest results the opportunity to meet all study entry 
criteria. 
Once a subject is considered eligible, prior to Day 1, a concomitant medication form will be 
completed by the site and sent to the sponsor for approval. See Section 7.4.1 for prohibited 
medications. 
Subjects who are eligible will be randomized as described in Section 7.3.3 and as shown in Table 2.   
Table 2: 
Study Design  
Cohort* 
Fibrosis 
Stage 
N 
Day 1 – 28, fasted oral 
dosing 
Day 29 - 42 
A 
F2/F3 
12 
CRV431 75 mg 
Observation/Follow up 
B 
6 
Placeboa 
C 
12 
CRV431 225 mg 
D 
6 
Placebob 
*Randomized assignment; 2:1 – CRV431:Placebo 
a Matching Placebo for Cohort A - 75 mg dose. 
b Matching Placebo for Cohort C - 225 mg dose. 
Potential study subjects who meet all inclusion and exclusion criteria for this study, but who, for 
personal or administrative reasons, are not included in the study may be re-screened if more than 
30 days has passed since their previous screening. For these subjects, use of 
 results 
previously obtained for this study will be extended for an additional 30 days up to a total of 60 
days. There are no restrictions on the number of re-screens permitted. 
Potential study subjects who previously screened and failed only 
 but met all 
other inclusion criteria and met none of the exclusion criteria for this study may be re-screened. 


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7.1.2. 
Treatment Period 
Subjects will receive treatment with CRV431 or matching placebo from Day 1 to Day 28. Study 
visit days that include treatment administration occur on Days 1, 2, 7, 14, and 28. Visit windows 
will be allowed and are as follows: Day 7 and Day 14, the visit window is ± 1 day and Day 28 the 
visit window is + 2 days.  If the study visit for Day 28 is extended, the subject must continue taking 
study drug until the visit is completed. 
Whole blood samples will be collected pre-dose and through Day 42 or early termination for 
safety and PK assessments as shown in Table 3 and Table 6, respectively. AEs will be collected 
as described in Section 11.4. 
7.1.3. 
Follow Up Period 
After completion of the treatment period, the subjects will be monitored for additional 14 days. 
A visit window of ±2 days will be allowed for the Day42/EOS visit. 
Subjects who do not complete the study may be replaced within a dosing cohort, unless a 
stopping rule precludes replacement. Safety criteria for dose adjustments or stopping rules are 
provided in Section 7.5. 
The overall study design of all scheduled procedures is shown in Table 3. 


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Table 3: 
Schedule of Events 
Procedure 
Screening 
(Day -30 to -2) 
Day -1 
Day 1 
Day 2 
Day 7 
(±1) 
Day 14 
(±1) 
Day 28 
(+2) 
EOS/ 
Day 42 
(±2) 
ETa 
Informed Consentb 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
HIV, HBV, HCV tests 
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Pregnancy testc 
X 
X 
 
 
 
 
 
X 
X 
FSH 
X 
 
 
 
 
 
 
 
 
Drugs of abuse and alcohol 
screen 
X 
X 
 
 
 
 
 
 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECGe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistryf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PKg 
 
 
X 
 
 
X 
X 
 
Xh 
Fraction Unboundg 
 
 
X 
 
 
 
X 
 
 
ELF Score 
X 
 
 
 
 
 
X 
 
 


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Procedure 
Screening 
(Day -30 to -2) 
Day -1 
Day 1 
Day 2 
Day 7 
(±1) 
Day 14 
(±1) 
Day 28 
(+2) 
EOS/ 
Day 42 
(±2) 
ETa 
  
Xi 
 
X 
 
 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administrationk 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
X 
Concomitant medications 
 
 
 
 
 
 
 
 
X 
Abbreviations: ECG, electrocardiogram; EOS, End of Study; ET, Early Termination; FSH, follicle stimulating hormone; HBV, hepatitis B virus; HCV, hepatitis 
C virus; HIV, human immunodeficiency virus; PK, pharmacokinetic(s). 
a If an Early Termination visit and a scheduled visit coincide, procedures for both visits should be completed without duplication. 
b Subjects must provide written informed consent prior to initiating any study procedures. To participate in this study, subjects must consent to all procedures 
outlined in Table 3, 
 
c All females of childbearing potential will have a serum beta human chorionic gonadotropin pregnancy test or urine dipstick pregnancy test at Screening, and 
urine dipstick pregnancy tests at all other indicated visits. 
d Blood pressure will be measured with a standard mercury sphygmomanometer or an automated oscillometric blood pressure monitor after the subject has been 
resting in a supine position for at least 5 minutes.  Heart rate will be measured by an automated vital signs machine.  Respiratory rate will be measured only if 
medically indicated. 
e Twelve-lead ECGs should be performed after the subject has been supine for 5 minutes and should be scheduled 1½ to 3 hours after the morning dose. On Day 
1 and Day 28, ECGs will be performed prior to the 2 hr. PK draw. ECGs performed on non-dosing Days should be completed within the same time window as 
the ECGs that were done 1½ to 3 hours after the time the morning doses were administered.  The timing of the ECG may be adjusted to Cmax as new data 
becomes available. 
f HbA1c will be checked at Screening, D28, EOS and ET only. 
g Subjects in all cohorts will have blood PK and fraction unbound samples collected at the time points indicated in Table 6. 
h PK not performed if ET visit occurs after Day 28. 
i At Screening, only Pro-C3 will be analyzed. At all other time points all collagen biomarker listed in Section 6.3 will be analyzed. 
j Obtained within 3 months prior to Screening or during Screening Period.  


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k On Day 1 and Day 28, subjects will fast overnight for at least 8 hours, will take CRV431 or matching placebo and will fast for an additional 2 hours following 
receipt of study drug. On subsequent days subject will fast overnight for at least 8 hours, will take CRV431 or matching placebo and will fast for an additional 
30 minutes following receipt of study drug. 
 


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7.2. 
Number of Subjects 
A total of 36 adult male or female subjects with presumed NASH F2/F3 will be enrolled. Of the 
36 subjects, 12 subjects will be enrolled in Cohort A to receive 75mg of CRV431, 6 subjects will 
be enrolled in Cohort B to receive the matching placebo of Cohort A, 12 subjects will be enrolled 
in Cohort C to receive 225mg of CRV431 and 6 subjects will be enrolled in Cohort D to receive 
the matching placebo of Cohort C. 
7.3. 
Treatment 
Subjects in Cohort A will receive CRV431 75 mg (1 x 75 mg softgel capsule) QD and subjects in 
Cohort B will receive the matching placebo (1 x placebo softgel capsule) for Cohort A. 
Subjects in Cohort C will receive CRV431 225 mg (3 x 75 mg softgel capsules) QD and subjects 
in Cohort D will receive the matching placebo (3 x placebo softgel capsules) for Cohort C. 
7.3.1. 
Treatment Administration 
Subjects will take study drug on the morning of each dosing day, with approximately 240 mL of 
water. On Day 1 and Day 28, subjects will fast overnight for at least 8 hours, will take CRV431 
or matching placebo and will fast for an additional 2 hours after treatment administration. On 
subsequent days, subject will fast overnight for at least 8 hours, will take CRV431 or matching 
placebo and will fast for an additional 30 minutes after treatment administration.  On visit days, 
the exact time of dosing will be decided based on logistics and will be documented in the source 
documents. 
7.3.2. 
Treatment Compliance 
While in the Clinical Research Unit, study treatment will be administered under the supervision 
of site personnel. Compliance during the non-study visit days will be assessed by subject 
reporting and pill count. Study personnel should counsel subjects on study medication 
compliance during each study visit. A qualified designee will be responsible for monitoring the 
administration of the timed oral doses on study visit days. 
7.3.3. 
Randomization and Blinding 
Upon determination that a subject meets all eligibility criteria, the subject will be randomized on 
Study Day -1 to receive either CRV431 or matching placebo in a 2:1 subject ratio (12 CRV431 
75mg to 6 matching placebo and 12 CRV431 225mg to 6 matching placebo) in accordance with 
a computer-generated randomization schedule generated by a non-study statistician.  Using this 
randomization schedule, pharmacy staff or designee will assign treatment sequentially to each 
eligible subject within a given cohort.     
This is a single blind study where the investigator and sponsor are unblinded.  However, the 
subject is blinded and will not know if he or she will receive CRV431 or matching placebo.  


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7.4. 
Study Restriction 
7.4.1. 
Prohibited and Concomitant Medication 
Any prescription medication or over the counter medication taken from 30 days prior to the time 
of consent to the End of Study/Early Termination Visit will be recorded in the subject’s medical 
record (source document) and Case Report Form (CRF).  
Once a subject is considered eligible, prior to Day 1, a concomitant medication form will be 
completed by the site and reviewed by the sponsor for approval. 
Use of the following medication prior to and during the study is prohibited: 
• Any drugs or substances known to be strong inhibitors or inducers of CYP3A4/5 and 
drugs whose major elimination pathway is via the BSEP or OAT3 transporters, and 
drugs that are major substrates of the hepatic uptake transporters OATP1B1 and 
OATP1B3 received within 30 days prior to the first dose of study drug. (NOTE: 
Please refer to Appendix A and if there are questions, please contact the sponsor); 
• Systemic immunosuppressants, with the exception of short-term treatment for asthma, 
received within 6 months prior to the first dose of study drug and during the study; 
• Any investigational product or investigational device received within 30 days prior to 
the first dose of study drug and during the study. 
For questions regarding the use of medications, the investigator should contact the sponsor for 
further discussion.  In case of an acute medical emergency, discussion with the Sponsor is 
excluded and the subject should be treated according to the judgement of the PI. 
 
Consumption of foods and beverages containing the following substances will be prohibited as 
indicated: 
• Xanthines/caffeine:  24 hours prior to dosing and throughout the period of PK sample 
collection; 
• Alcohol:  48 hours prior to dosing and throughout the period of PK sample collection; 
• Grapefruit/Seville orange:  14 days prior to dosing and throughout the period of PK 
sample collection. 
7.4.2. 
Meals 
On Day 1 and Day 28, subjects will fast overnight for at least 8 hours, will take CRV431 or 
matching placebo and will fast for an additional 2 hours after administration of study drugs.  On 
subsequent days, subject will fast overnight for at least 8 hours, will take CRV431 or matching 
placebo and will fast for an additional 30 minutes after administration of study drugs. 
7.5. 
COVID-19 Vaccine 
Hepion in no way wishes to preclude subjects from receiving the COVID-19 vaccine. However, 
in order to minimize potential adverse events associated with the vaccine, if possible, the subject 
should try to receive their second dose of the vaccine seven days prior to the commencement of 
receiving study drug (Day 1) or receive their first dose of the vaccine 96 hours after their last 
dose on Day 28.  


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Enrolled study subjects who have an opportunity to be vaccinated against COVID-19 should do 
so. Study subjects will be permitted to continue on the study if they receive the COVID-19 
vaccine. 
The COVID-19 vaccine should be recorded in the subject’s Concomitant Medications CRF page 
if the subject receives the vaccine after consent and through Day 42/EOS.  
7.6. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will monitor the trial.  The DSMB will 
comprise of medical professionals with expertise in NASH and clinical trials and are external to 
the Sponsor.  The DSMB will meet periodically or as needed to review accumulating safety data 
and any available PK data collected throughout the trial.  
Safety and available PK data will be reviewed by the DSMB prior to proceeding with the next 
higher dose cohort. The DSMB will review safety data when at least six (6) subjects in Cohort A 
(CRV431 75 mg) and at least three (3) subjects in Cohort B (matching placebo) have reached 28 
days of dosing, as described in Section 12.3.1. The DSMB will also review the Day 28 safety 
data from the remaining subjects to confirm there are no changes to the prior safety assessment.  
The roles and responsibilities will be further defined in a Charter. 
7.7. 
Safety Criteria for Adjustment or Stopping Doses 
7.7.1. 
Individual Subject Criteria 
If any of the criteria below are met by an individual subject, then no further dosing will occur at 
any of the study sites until a review of all available safety information is performed by the 
DSMB, Medical Monitor, and Sponsor.  Appropriate Regulatory Agencies and Ethics 
Committees will be informed as applicable. If it is later determined that further dosing can be 
performed safely then an application for a substantial protocol amendment will be submitted to 
the appropriate Regulatory Agencies and Ethics Committees, if applicable. Stopping criteria for 
an individual subject includes: 
• Grade 3 or higher CTCAE AEs possibly or probably related to study drug as 
determined by the investigator and sponsor; 
• Grade 4 CTCAE AEs regardless of relation to study drug as determined by the 
investigator and sponsor; 
• Any SAEs thought to be related to the study drug as determined by the investigator 
and sponsor.  
For subjects experiencing any hepatic AEs or SAEs judged by the investigator or sponsor to be 
related to study drug, the investigator, DSMB, Medical Monitor and Sponsor will review all 
available safety data and make a determination to proceed with one of the following options: 
• If the event was a drug-induced liver injury (DILI), considered as increases in 
aminotransferases (AT) >3 x ULN or >3 x baseline where baseline is defined as the 
average values of Screening and Day -1, no additional subjects will be dosed until it 
is determined that it is safe to proceed and in addition the frequency of blood 
chemistries will increase to daily, if appropriate.  


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− Repeat testing of ALT, AST, ALP, TBL will be performed within 48-72 hours to 
confirm the abnormality.  
− If there are persistent elevations of AT  > 3 x ULN or a 2-fold increase above 
baseline values (for those subjects with elevated values prior to drug exposure) 
upon repeat testing then close observation visits should be implemented and/or 
discontinuation of drug should be considered. Close Observations are described in 
Section 7.8. 
• If the event was not a DILI, as defined above, one of the following actions will be 
taken: 
− Dose an entire additional cohort at the same or lower dose than the dose taken by 
the subject that experienced the event in question; 
− Continue to pause the study, until it is determined, that it is safe to proceed. 
A decision to discontinue or temporarily interrupt the study drug for a subject will be considered 
based on following criteria: 
• If ALT/AST baseline measurements (BLM) are <2 x ULN, discontinue if ALT or 
AST increases to >5 x BLM; 
• If ALT/AST BLM ≥2 x ULN but <5 x ULN, discontinue if ALT or AST increases to 
3 x BLM; 
• If ALT/AST BLM ≥5 x ULN, discontinue if ALT or AST increases to >2 x BLM 
AND the increase is accompanied by a concomitant increase in TBL to >2 x BLM 
OR the International Normalized Ratio (INR) concomitantly increases by >0.2; 
• Any subjects with signs and symptoms of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, and/or rash, accompanied by a >5% increase in 
eosinophils; 
• Subjects who miss more than 2 consecutive QD doses of study drug. Subjects may be 
replaced unless a stopping rule precludes replacement. 
7.7.2. 
Study Criteria  
Dosing of study drug within the study will be stopped and recruitment into the study will be 
paused until a review of all available safety information is performed by the DSMB, Medical 
Monitor, and Sponsor if any of the following occur: 
• ≥3 subjects in the study experience an SAE that is judged to be related to study drug 
by the investigator and sponsor; 
• ≥3 subjects in the study experience a Grade 3 or Grade 4 CTCAE AE in the same 
system organ class (SOC) that are judged to be related to study drug by the 
investigator and sponsor; 
• ≥3 subjects in the study experience a Grade 3 or Grade 4 CTCAE laboratory 
abnormality that are judged to be related to study drug by the investigator and 
sponsor. Asymptomatic elevations in cholesterol or triglycerides accepted;  
• ≥3 subjects in the study experience a confirmed: 
− Friderica’s QT Correction Formula (QTcF) interval ≥500 msec; 
OR 


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− QTcF interval change from baseline ≥60 msec that has an absolute value 
≥ 480 msec; 
 The value of an individual ECG time point is the average of the triplicate 
values  
 “confirmed” is defined as the abnormality duplicated, at least 1 hour after 
the abnormality is first noted, by the results of a set of 3 ECGs performed 
in triplicate, at least 5, but not more than 10 minutes between each 
assessment. 
• ≥1 subject with AT >3 x ULN or   >3 x subject baseline that is confirmed, not 
initially cholestatic, and judged to be adversely related to study drug (DILI) by the 
investigator and sponsor. 
7.7.2.1. 
Study Stopping Criteria 
Study will be stopped and a review of all available safety information is performed by the 
DSMB, Medical Monitor, and Sponsor if any of the below criteria is met:  
• ≥1 subject develops a Grade 5 CTCAE adverse event attributed to CRV431 
• ≥2 subjects develop a Grade 4 CTCAE adverse event attributed to CRV431 
• ≥3 subjects develop the same Grade 3 CTCAE adverse event attributed to CRV431 
 
The study may be restarted depending on the specific AE, relationship to the study drug and with 
the agreement of the DSMB, Medical Monitor and Sponsor.  
7.7.3. 
Pharmacokinetic Criteria for Dose Adjustment  
Dose adjustment is not available for subjects in Cohort A receiving 75 mg of CV431 QD. If a 
patient demonstrates adverse events that trigger the need for stopping, that patient will be 
stopped and an additional patient will be started on the same dose unless the study data indicates 
a problem with the dose level as recommended by the DSMB. Subjects in Cohort C, receiving 
225 mg of CRV431 QD, experiencing a drug exposure related Grade 3,4 or 5 CTCAE can have a 
dosage reduction to 150 mg of CRV431 once daily. 
7.8. 
Close Observation 
Upon detection and confirmation of early signs of possible DILI (see Section 7.7.1), close 
observation should be initiated immediately.   
Close observation will include the following:  
• Repeating liver enzyme and serum bilirubin tests 2 or 3-times weekly. The frequency 
of retesting can decrease to once a week or less if abnormalities stabilize or the trial 
drug has been discontinued and the subject is asymptomatic; 
• Obtaining a more detailed history of symptoms and prior or concurrent diseases; 
• Obtaining a history of concomitant drug use including non-prescription medications 
and herbal and dietary supplement preparations, alcohol use, recreational drug use, 
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• Ruling out acute viral hepatitis types A, B, C, D, and E, autoimmune or alcoholic 
hepatitis, hypoxic/ischemic hepatopathy, and biliary tract disease; 
• Obtaining a history of exposure to environmental chemical agents; 
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin); 
• Consider gastroenterology or hepatology consultations; 
• Consider liver biopsy. 
7.9. 
Criteria for Study Termination 
Conditions may arise during the study that could prompt the study to be halted.  Conditions that 
may prompt such considerations include, but are not limited to, the following: 
• The discovery of unexpected, serious, or unacceptable risk to subjects enrolled in the 
study; 
• A decision on the part of the sponsor or regulatory authority to suspend, discontinue, or 
shorten the study 
• Study conduct at a study site may warrant termination under conditions that include the 
following:  
− Failure of the site to enroll eligible subjects into the study; 
− Failure of the investigator to comply with FDA, country-specific, or local 
regulations;  
− Submission of false information from the research facility to the sponsor, the 
clinical Monitor, or a regulatory authority; 
− Insufficient adherence to protocol requirements; 
− A conflict of interest on the part of the investigator, his/her institution, or site 
personnel that would negatively impact the integrity of the clinical trial; 
− Institution, site, investigator, or IRB/ICE under investigation for cause by a 
regulatory agency. 




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8.2. 
Subject Exclusion Criteria 
Subjects who meet the following criteria prior to the first dose of study drug are not eligible for 
randomization.   
1. Pregnant or breastfeeding or planning to become pregnant during the study period; 
2. Known allergy to CRV431, cyclosporine, or any of their inactive ingredients; 
3. Positive test for HBsAg, HCVAb or HIVAb. If HCVAb test is positive, then an HCV-
RNA test will be performed. If the HCV-RNA test is negative, the subject is allowed to 
participate in the study, as long as the subject meets all other inclusion criteria and has 
never been treated for HCV or was treated >2years ago and achieved a sustained 
virologic response at that time; 
4. History of or any current medical condition which could compromise the safety of the 
participant in the study, as determined by the investigator; 
5. Subjects with a systolic pressure >150 or a diastolic pressure >90. At the discretion of the 
investigator, the blood pressure may be re-measured after 10 minutes to ensure the blood 
pressure is in fact out of range. Out of range blood pressure after the second measurement 
will exclude a subject. If a subject has a blood pressure within the desired range due to 
anti-hypertension medication, that subject can be included at the discretion of the 
investigator, provided the anti-hypertension medication is not a contraindicated 
medication. Please refer to Appendix A for a list of drugs considered contraindicated;  
6. Clinically significant gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, 
renal, hepatic, respiratory, inflammatory, or infectious disease, as determined by the 
investigator; 
7. Subjects with a history of clinically significant acute cardiac event within 6 months prior 
to Screening such as stroke, transient ischemic attack, or coronary heart disease (angina 
pectoris requiring therapy, myocardial infarction, revascularization procedures, with 
LVEF <50% as determined by previous echocardiography or MUGA scan); 
8. Subjects with uncontrolled or unstable cardiac arrhythmias: 
a. Severe conduction disturbance (e.g., second- or third-degree AV block); 
b. QTc interval >450 msec (males) or >470 msec (females); 
c. History of congenital long QT syndrome, congenital short QT syndrome, Torsades 
de Pointes, or Wolff Parkinson White syndrome; 
9. Subjects with transaminases >5 x ULN and with ALP >2 x ULN; 
10. Subjects with total serum bilirubin >1.5 x ULN, unless the subject has Gilbert’s 
Syndrome, in which case the subject can be enrolled provided the direct bilirubin is 
within 30% of the TBL; 
11. Subjects with a platelet count <150,000/m3; 
12. Systemic immunosuppression within 6 months prior to the first dose of study drug apart 
from short-term treatment for asthma, COPD or other respiratory conditions; 


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13. Current clinically significant diarrhea or gastric stasis that, in the investigator’s opinion, 
could influence drug absorption or bioavailability; 
14. Subject with any history or presence of decompensated cirrhosis; 
15. Other well documented causes of chronic liver disease according to standard diagnostic 
procedures including, but not restricted to: 
a. Suspicion of drug-induced liver disease; 
b. Alcoholic liver disease;  
c. Autoimmune hepatitis;  
d. Wilson’s disease; 
e. Primary biliary cholangitis, primary sclerosing cholangitis;  
f. Genetic hemochromatosis (Homozygosity for C282Y or C282Y/H63D compound 
heterozygote);  
g. Known or suspected HCC; 
h. History or planned liver transplant, or current MELD score >15; 
16. History of, or current evidence of, gallstones, gall bladder disease, cholestasis that has not 
been treated with cholecystectomy, or pancreatitis; 
17. Subjects with HbA1c >9.5%. For subjects with an HbA1c >9.5% at the Screening Visit, a 
repeat test may be performed. A repeat HbA1c result >9.5% will lead to exclusion; 
18. At Screening, an eGFR <60 mL/min/1.73 m2 (calculated by the CKD-EPI method) and/or 
a KDIGO category of >G2; 
19. Safety laboratory abnormalities at Screening which are clinically significant as 
determined by the investigator; 
20. Weight loss of more than 5% within 3 months prior to randomization; 
21. Current abuse of alcohol or illicit drugs, or history of alcohol or illicit drug abuse within 
the preceding 2 years, as determined by the investigator. History of excess alcohol intake 
as defined by ≥21 units of alcohol per week in males and ≥14 units of alcohol per week in 
females for 2 years prior to enrollment where a “unit” of alcohol is equivalent to 12-
ounce beer, 4-ounce of wine, or 1-ounce shot of hard liquor; 
22. A positive urine drug screen for drugs with a high potential for abuse (amphetamines, 
cannabinoids, opiates, cocaine, benzodiazepine) or alcohol test at Screening or Day -1. 
For benzodiazepine’s only: positive results will be accepted if due to an approved 
prescription. For cannabinoids, opiates and cocaine: On a case by case basis, positive 
results will be evaluated by the Sponsor and Medical Monitor in order to determine the 
subject’s eligibility to safely be included in the study; 
23. Significant medical or psychiatric illness that would interfere with compliance and ability 
to tolerate treatment as outlined in the protocol; 
24. Subjects who cannot be contacted in case of emergency; 
25. Judgement by the investigator that the subject should not participate in the study if the 
subject is unlikely to comply with all study procedures and treatment; 


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26. Received an investigational drug or investigational vaccine or used an investigational 
medical device within 30 days prior to first dose of study drug; 
27. Subjects who have used any drugs or substances known to be strong inhibitors or 
inducers of CYP3A4/5 and drugs whose major elimination pathway is the BSEP or 
OAT3, and drugs that are major substrates of the hepatic uptake transporters, OATP1B1 
and OATP1B3 within 30 days prior to the first dose of study drug.  (NOTE: Please refer 
to Appendix A for a list of drugs considered contraindicated. If there are questions, please 
contact the Sponsor); 
28. Subjects with a history of organ transplantation. Corneal transplantation will be allowed.  
Abnormal ECG or laboratory parameters may be repeated once, if in the opinion of the 
investigator, the results are due to technical factors or are inconsistent with the potential subject’s 
medical evaluation.  
Potential study subjects who met all inclusion and exclusion criteria for this study but who, for 
personal or administrative reasons, were not included in a study cohort may be re-screened if 
more than 30 days have passed since their previous screening. For these subjects, use of ELF or 
Pro-C3 results previously obtained for this study will be extended for an additional 30 days up to 
a total of 60 days. There are no restrictions on the number of re-screens permitted for these 
subjects. 
Potential study subjects who previously screened and failed only ELF or only Pro-C3 but met all 
other inclusion criteria and met none of the exclusion criteria for this study may be re-screened. 
8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Early Termination of Subjects from the Study  
Subjects who discontinue the study should complete all scheduled safety assessments at the 
Early Termination Visit. If an Early Termination Visit and a scheduled visit coincide, procedures 
for both visits should be completed, without duplication. Subjects must discontinue the study for 
the following reasons: 
• Subject withdraws consent; 
• Subject unwilling or unable to follow study procedures, per judgment of the 
investigator; 
• Investigator, sponsor, or Regulatory Authority judge that further dosing with study 
drug would be harmful to the subject; 
• Subject experiences an SAE that is judged, by the investigator and the sponsor, to be 
related to study drug; 
• Subject experiences a Grade 3 CTCAE AE judged, by the investigator and the 
sponsor, to be related to study drug;  
• Subject experiences a Grade 4 CTCAE AE judged, by the investigator and the 
sponsor, regardless of the relation to study drug;  
• Subject experiences a Grade 3 or Grade 4 CTCAE laboratory abnormality judged by 
the investigator and the sponsor, to be related to study drug except for asymptomatic 
elevations in cholesterol or triglycerides which are accepted;  


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• Subject with normal ALT and bilirubin at baseline who experiences confirmed, non-
cholestatic ALT >3 x ULN and bilirubin >2 x ULN OR subjects with elevated ALT at 
baseline who experiences confirmed, non-cholestatic ALT >10 x baseline value and 
bilirubin >2 x ULN; 
• Subject experiences a confirmed,  
− QTcF interval 500 msec;  
OR 
− QTcF interval change from baseline ≥60 msec that has an absolute value 
≥480 msec. The value of an individual ECG time point is the average of the 
triplicate values 
− “confirmed” is defined as the abnormality duplicated, at least 1 hour after the 
abnormality is first noted, by the results of a set of 3 ECGs performed in 
triplicate, at least 5, but not more than 10 minutes between each assessment; 
• Subject experiences any hepatic AE or SAE judged by the investigator or sponsor as 
DILI and to be related to study drug and not to the subject’s underlying NASH. 
Subjects who discontinue the study due to the safety stopping criteria will be replaced if the 
investigator and sponsor agree and the criteria outlined in Section 7.5 are not violated.  Subjects 
who discontinue the study for non-safety reasons may be replaced. 
If a subject is withdrawn from the study the reason(s) for withdrawal must be documented in the 
subject’s medical record and CRF.  An Early Termination Visit should be performed.  All 
subjects must be followed for safety until the time of the follow-up evaluation or until study drug 
related toxicities resolve, return to baseline or are deemed irreversible, whichever is longer. 
Subjects who cannot be reached after 3 documented attempts to be contacted to schedule a 
follow-up visit will be considered lost to follow up. 
8.4. 
Subject Replacement 
Subjects who do not complete the study may be replaced, at the sponsor’s discretion to ensure 
that the study is fully populated, unless a stopping rule precludes replacement. Replacement 
subjects will receive the same treatment assignment as the subject they are replacing. Each 
enrolled subject may only participate in this study once. The study is designed to have 12 
subjects on active treatment and 6 subjects on placebo to complete the study.  
 




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Drug accountability should be completed for CRV431 and placebo during this study. 
9.7          
Study Drug Handling and Disposal 
During the treatment period of the study, CRV431or placebo will be supplied by a pharmacist or 
investigator designee responsible for study drug administration and accountability.  On study 
visit days, treatment may only be administered under the supervision of the investigator or site 
designee(s). 
Any used, expired, or non-usable study drug can be destroyed on-site as per the sites standard 
operating procedures with approval of the sponsor.  If study drug cannot be destroyed on-site, it 
must be returned to the sponsor or designee.  






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Table 6: 
Pharmacokinetic Sampling Schedule 
Day 
Day 1 
Day 14 
Day 28 
Time (h) 
Pre-dose 
2.0 
4.0 
8.0 
312 
(Pre-dose) 
Pre-dose 
2.0 
4.0 
8.0 
Whole blood (PK) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma (fu) 
X 
X 
 
 
 
X 
X 
 
 
Abbreviations: fu, fraction unbound; h, hour; PK, pharmacokinetic(s).


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11. 
ASSESSMENT OF SAFETY 
11.1. 
Safety Parameters 
11.1.1. 
Demographic 
Demographic details will be collected at Screening only. 
11.1.2. 
Vital Signs 
Vital sign assessments will comprise of blood pressure, heart rate, temperature, and respiratory 
rate measurements.  Blood pressure will be measured with a standard mercury 
sphygmomanometer or an automated oscillometric blood pressure monitor, after the subject has 
been resting in a supine position for at least 5 minutes.  Heart rate will be measured by an 
automated vital signs machine. Respiratory rate will be measured only if medically indicated.  
Vital signs will be performed for all subjects at the time points indicated in Table 3, or as 
applicable. 
11.1.3. 
Weight and Height 
Weight and height will be assessed at the Screening visit only. 
11.1.4. 
Physical Examination and Medical History 
Physical examinations will be performed at Screening. Additional examinations may be 
performed throughout the study, if considered medically necessary. The examinations will 
include the following body systems: general appearance; eyes, ears, nose, and throat; head and 
neck; chest and lungs; cardiovascular; abdomen; musculoskeletal; lymphatic; dermatologic; 
neurologic; psychiatric; and extremities.  
A detailed medical history will be collected at the Screening visit only. 
11.1.5. 
Electrocardiogram  
Twelve-lead ECGs will be performed after the subject has been supine for 5 minutes, and 1½ to 
3 hours after the morning dose.  On Day 1 and Day 28, ECGs will be performed prior to the 2 hr. 
PK draw.  Electrocardiograms performed on non-dosing Days should be completed within the 
same time window as the ECGs that were done 1½ to 3 hours after the time the morning doses 
were administered.  These ECG schedules will therefore be close to the time of day the previous 
post-dose ECGs were obtained.  The timing of the ECG may be adjusted to Cmax values as new 
data becomes available.  All ECGs should be interpreted by the investigator or qualified designee 
within 12 hours of the time the ECGs were performed.  Electrocardiograms will be performed for 
all subjects at the time points indicated in Table 3, or as applicable. 
11.1.6. 
Laboratory Assessments 
All samples should be collected and shipped as directed in the Laboratory Procedures Manual. 


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Routine clinical laboratory testing will be performed for all subjects at the time points indicated 
in Table 3, or as applicable.  Samples may be stored up to 20 years. 
If the investigator believes that access to laboratory data is medically indicated and that a delay 
in access to central laboratory safety results would pose a potential safety risk to the subject, the 
sample will be split; a portion will be sent to the local laboratory for appropriate laboratory tests, 
and the other portion will be sent to the central laboratory for routinely scheduled testing. 
Samples will be collected and stored for testing for additional safety or PK testing as necessary.   
11.1.6.1. Hematology and Coagulation 
Samples will be collected before study drug dosing and after at least an 8-hour fast; however, in 
case of an early termination or recheck, subject fasting is not required prior to sample collection.  
The following will be performed:   
• Total white blood cell 
(WBC) count 
differential (absolute 
values) 
• Hematocrit 
• Hemoglobin 
• Red blood cell (RBC) 
distribution width 
• Mean corpuscular hemoglobin concentration 
• Mean corpuscular hemoglobin 
• Mean corpuscular volume 
• Platelet count 
• Prothrombin time with INR 
• RBC count 
11.1.6.2. Blood Chemistry 
Samples will be collected before study drug dosing and after at least an 8-hour fast; however, in 
case of an early termination or recheck, subject fasting is not required prior to sample collection.  
The following tests will be performed: 
• ALT 
• Albumin 
• ALPa 
• Amylase, totala or 
pancreatic amylase 
• Anion gap 
• AST 
• Bicarbonate 
• Bilirubin (total, 
unconjugated, conjugated) 
• Blood urea nitrogen 
• Calcium 
• Chloride 
• Cholesterol (total, high-density lipoprotein [HDL], 
and low-density lipoprotein [LDL]) 
• Creatinine 
• Creatine kinaseb 
• eGFR, using CKD-EPI method 
• Glucose 
• HbA1cc 
• Lipase 
• Phosphorus  
• Potassium  
• Sodium  
• Triglycerides 
a Reflex fractionation, if greater than ULN 
b Reflex fractionation if greater than critical value  
c HbA1c will be collected at Screening, D28, EOS and ET 


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Subjects with normal ALT and bilirubin at baseline who have ALT >3 x ULN and bilirubin >2 x 
ULN OR subjects with elevated ALT at baseline who have ALT > 10 x baseline value and 
bilirubin >2 x ULN will also have serum gamma-glutamyltransferase (GGT) determined at the 
time these abnormalities are discovered.  For these subjects, GGT may be repeated, as clinically 
indicated. 
11.1.6.3. Urinalysis 
Samples will be collected before study drug dosing and after at least an 8-hour fast; however, in 
case of an early termination or recheck, subject fasting is not required prior to sample collection.  
The following will be performed: 
• Bilirubin 
• Blood 
• Color 
• Glucose 
• Ketones 
• Leukocyte esterase 
• Nitrites 
• pH 
• Protein 
• Specific gravity 
• Turbidity 
• Urobilinogen 
• Microscopic examinationa 
a  Microscopic examination will be performed if dipstick test is positive for protein, blood, leukocyte esterase, or 
nitrites. (Microscopic examination includes bacteria, casts, crystals, epithelial cells, RBCs, and WBCs). 
11.1.6.4. Drug Screen 
A standard screen for drugs of abuse which includes testing for amphetamine, cannabinoids, 
opiates and cocaine will be performed for all subjects at the time points indicated in Table 3, or 
as applicable. 
11.1.6.5. Pregnancy Screen 
Females of reproductive potential defined as women who have not been postmenopausal for at 
least 24 consecutive months (i.e., who have had menses within the preceding 24 months), or 
women who have not undergone surgical sterilization; specifically, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy, hysteroscopic sterilization, and/or tubal ligation, must 
have a negative pregnancy test at Screening, within the 24 hour period prior to Day 1 and at all 
other time points indicated in Table 3, or as applicable. At Screening a serum beta human 
chorionic gonadotropin or urine dipstick pregnancy test will be performed. A urine dipstick 
pregnancy test will be performed at all other time points. 
All post-menopausal females will have an FSH test at Screening. 
11.2. 
Adverse and Serious Adverse Events 
11.2.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical study subject associated with 
the use of a drug (investigational or non-investigational) in humans, whether or not considered 
drug related. An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory 


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finding), symptom, or disease temporally associated with the use of a drug, without any 
judgement on causality.  An AE can arise from any use of the drug (e.g., off-label use, use in 
combination with another drug) and from any route of administration, formulation, or dose, 
including overdose. 
All AEs that occur after any subject has been consented, before treatment, during treatment, or 
up to and including the End of Study or Early Termination Visit, whether or not they are related 
to the study, must be recorded on forms provided by Hepion. 
11.2.2. 
Serious Adverse Events  
An AE is considered serious if, in the view of either the investigator or sponsor, it fulfills at least 
one of the following: 
• Results in death; 
• It is immediately life-threatening; 
• It requires in-patient hospitalization or prolongation of existing hospitalization; 
• It results in persistent or significant disability or incapacity; 
• Results in a congenital abnormality or birth defect; 
• It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
All SAEs that occur after any subject has been consented, before treatment, during treatment, or 
up to and including the End of Study or Early Termination Visit, whether or not they are related 
to the study, must be recorded on forms provided by Hepion. 
11.2.3. 
Other Adverse Events  
Other AEs will be identified by the investigator and if applicable also by the medical monitor 
during the evaluation of safety data for the Clinical Study Report.  Adverse events of special 
interest, other than SAEs or AEs leading to discontinuation of the subject from the study, will be 
classified as other AEs.  For each of these other AEs, a narrative may be written and included in 
the Clinical Study Report. 
11.3. 
Relationship to Study Drug 
An investigator who is qualified in medicine must make the determination of relationship to the 
investigational product, when appropriate, for each AE (unrelated, possibly related or probably 
related).  The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product.  If no 
valid reason exists for suggesting a relationship, then the AE should be classified as “unrelated.”  
If there is any valid reason, even if undetermined, for suspecting a possible cause and effect 
relationship between the investigational product and the occurrence of the AE, then the AE 
should be considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” the event will be considered to be related to the investigational product 
for the purposes of expedited regulatory reporting. 


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11.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question from 
the study personnel or revealed by observation will be recorded during the study at the 
investigational site.  Clinically significant changes in laboratory values, blood pressure, and pulse 
requiring an intervention should be reported as AEs. The AE term should be reported in standard 
medical terminology when possible.  For each AE, the investigator will evaluate and report the 
onset (date and time), resolution (date and time), severity, causality, action taken, serious outcome 
(if applicable), and whether or not it caused the subject to discontinue the study.  
Adverse events should be collected and recorded in the source documents and on the eCRF 
beginning at the time of signing the informed consent. Adverse events and SAEs should be reported 
through End of Study Visit or Early Termination Visit.  Both AEs and SAEs should be followed until 
resolution/stabilization or until a time that is mutually agreed upon between the medical monitor 
and investigator.   
Subjects who experience any AE or SAE should receive appropriate treatment and medical 
supervision as clinically indicated. 
All AEs will be graded for severity according to the Common Terminology Criteria for Adverse 
Events table v5.0 (CTCAE, 2017). 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 11.2.2. An AE of severe intensity 
may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on Hepion’s pregnancy form.  
Pregnancy, in itself, is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages should 
also be reported and handled as SAEs.  Elective abortions without complications should not be 
handled as AEs. 
11.5. 
Reporting Adverse Events 
Serious adverse events must be reported to the Sponsor within 24 hours of the investigator 
becoming aware of the event along with an assessment of causality.  If at the time the 
investigator submits an initial SAE report and the SAE has not been resolved, the investigator 
must provide a follow-up report as soon as the event resolves (or upon receipt of significant 
information if the event is still ongoing).  Additional follow-up information, if required or 
available, should reported to the Sponsor within one business Day of receipt. This should be 
completed on a follow-up SAE form and placed with the original SAE information and kept with 
the appropriate section of the CRF and/or study file. 
All SAEs must be followed until resolution/stabilization or until a time that is mutually agreed 
upon between the Medical Monitor and the Investigator. 


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Hepion (or representative) is responsible for notifying the relevant regulatory authorities of 
certain events.  It is the Investigator’s responsibility to notify the IRB or IEC of all SAEs that 
occur at his or her site.  Investigators will also be notified of all unexpected, serious, drug-related 
events that occur during the clinical trial.  Each site is responsible for notifying its IRB or IEC of 
these additional SAEs. 






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AUC0-inf and Cmax. These ratios will be expressed as a percentage relative to the F2/F3 presumed 
NASH placebo control group. 
Ninety percent (90%) confidence intervals (CIs) for the ratios will be derived by exponentiation 
of the CIs obtained for the difference between F2/F3 presumed NASH groups LSM resulting 
from the analyses on the ln-transformed AUC0-inf and Cmax. The CIs will be expressed as a 
percentage relative to the F2/F3 presumed NASH placebo control group. 
12.3.4. 
Pharmacokinetics Analyses 
Values will be calculated for the whole blood concentrations and the PK parameters listed in 
Section 10.4, using appropriate summary statistics to be fully outlined in the SAP.  Population 
PK/PD analysis will be used to explore PK dependent covariates and quantitative concentration-
effect relationships. 
12.3.5. 
Safety Analyses  
All safety data will be populated in the individual CRFs. All safety data will be listed by 
subjects.  
Adverse events will be coded using the most current version of Medical Dictionary for 
Regulatory Activities (MedDRA) summarized by treatment for the number of subjects reporting 
the treatment emergent adverse event (TEAE) and the number of TEAEs reported. A by-subject 
AE data listing including verbatim term, coded term, treatment, severity, and relationship to 
population will be provided.   
Safety data including ECGs, vital signs assessments and clinical laboratory results, will be 
summarized by population and point of time of collection.  
Descriptive statistics using appropriate summary statistics will be calculated for quantitative 
safety data as well as for the difference to baseline, when appropriate. In addition, a shift table 
describing out of normal range shifts will be provided for clinical laboratory results.   
Concomitant medications will be listed by subject and coded using the most current version of 
WHO drug dictionary. Medical history will be listed by subject. 


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Study Monitoring 
Before an investigator can enter a subject into the study, Hepion (or representative) may visit the 
investigational study site to: 
• Determine the adequacy of the facilities; 
• Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Hepion (or representative).  This 
will be documented in a Clinical Study Agreement between Hepion (or 
representative) and the investigator. 
During the study, a monitor from Hepion (or representative) will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the investigator(s); 
• Confirm that facilities remain acceptable; 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the CRF, and that investigational product accountability 
checks are being performed; 
• Perform source data verification. This includes a comparison of the data in the CRF 
with the subject’s medical records at the hospital or practice, and other records 
relevant to the study.  This will require direct access to all original records for each 
subject (e.g., clinic charts); 
• Record and report any protocol deviations not previously sent to Hepion (or 
representative); 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any 
SAEs have been forwarded to Hepion (or representative) and those SAEs that met 
criteria for reporting have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
13.2. 
Audits and Inspections 
Authorized Hepion employee (or representative), regulatory authority personal, or members of 
IEC or IRB may visit the site to perform audits or inspections including source data verification.  
The purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice, guidelines of the International Conference on Harmonization , and any applicable 
regulatory requirements.  The investigator should contact Hepion immediately if contacted by a 
regulatory agency about an inspection. 


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13.3. 
Institutional Review Board 
The investigator must obtain IRB approval for the investigation.  Initial IRB approval, and all 
materials approved by the IRB for this study including the subject consent form and recruitment 
materials must be maintained by the investigator and made available for inspection. 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, 
Hepion (or representative) may conduct a quality assurance audit.  Please see Section 13.2 for 
more details regarding the audit process. 


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15. 
ETHICS 
15.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved, or given a 
favorable opinion in writing by an IRB or IEC as appropriate.  The investigator must submit 
written approval to Hepion (or representative) before he or she can enroll any subject into the 
study. 
The investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB or IEC must approve all advertising 
used to recruit subjects for the study.  The protocol must be re-approved by the IRB or IEC upon 
receipt of amendments and annually, as local regulations require. 
The investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the investigational product.  Hepion 
(or representative) will provide this information to the investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
15.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonization 
/Good Clinical Practice, and applicable regulatory requirements. 
15.3. 
Written Informed Consent 
The investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The investigator(s) must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the subject. 


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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Inspection of Records 
Hepion (or representative) will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study.  The investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, subject charts 
and study source documents, and other records relative to study conduct. 
16.2. 
Retention of Records 
The investigator must maintain all documentation relating to the study for a period of 2 years 
after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation.  If it becomes necessary for Hepion (or 
representative) or the Regulatory Authority to review any documentation relating to the study, 
the investigator must permit access to such records. 


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17. 
LIST OF REFERENCES 
Amrit Singh, Casey P Shannon, Benoît Gautier, Florian Rohart, Michaël Vacher, Scott J Tebbutt, 
Kim-Anh Lê Cao. DIABLO: an integrative approach for identifying key molecular drivers from 
multi-omics assays. Bioinformatics [Internet]. 2019 [cited 2019 Sept 1]; 35(17): 3055–3062. 
Available from: https://doi.org/10.1093/bioinformatics/bty1054 
Briston, T., Selwood, D. L., Szabadkai, G., & Duchen, M. R. Mitochondrial Permeability 
Transition: A Molecular Lesion with Multiple Drug Targets. Trends in Pharmacological Sciences 
[Internet]. 2018; 40(1):50-70. Available from: https://doi.org/10.1016/j.tips.2018.11.004 
Bukrinsky, M. Extracellular cyclophilins in health and disease. Biochimica et Biophysica Acta - 
General Subjects [Internet]. 2015; 1850(10): 2087–2095. Available from: 
https://doi.org/10.1016/j.bbagen.2014.11.013 
Center for Biologics Evaluation and Research. Enrichment strategies for clinical trials to support 
determination of effectiveness of human drugs and biological products guidance for industry 
[Internet]. U.S. Department of Health and Human Services: Food and Drug Administration; 
2019. Available from: https://www.fda.gov/media/121320/download 
Center for Drug Evaluation and Research. Drug Development and Drug Interaction: Table of 
Substrates, Inhibitors and Inducers [Internet]. U.S. Food and Drug Administration; [updated 
2019 Dec 03]. Available from: www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers. 
Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and 
management of nonalcoholic fatty liver disease: practice guidance from the American 
Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328-57. 
Dawar, F. U., Tu, J., Khattak, M. N. K., Mei, J., & Lin, L. Cyclophilin A: A key factor in virus 
replication and potential target for anti-viral therapy. Current Issues in Molecular Biology 
[Internet]. 2017; 21: 1–20. Available from: https://doi.org/10.21775/cimb.021.001 
Dawar, F. U., Xiong, Y., Khattak, M. N. K., Li, J., Lin, L., & Mei, J. Potential role of cyclophilin 
A in regulating cytokine secretion. Journal of Leukocyte Biology [Internet]. 2017; 102(1):989-
992. Available from: https://doi.org/10.1189/jlb.3RU0317-090RR 
Estes, C., Razavi, H., Loomba, R., Younossi, Z., & Sanyal, A. J. Modeling the epidemic of 
nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. 
Hepatology [Internet]. 2018; 67(1): 123–133. Available from: https://doi.org/10.1002/hep.29466 
European Medicines Agency. Guideline on the Investigation of Drug Interactions. 2013. 
Le Cao KA, Costello ME, Lakis VA, Bartolo F, Chua XY, Brazeilles R, Rondeau P. MixMC: a 
multivariate statistical framework to gain insight into microbial communities. PloS one 
[Internet]. 2016; 11(8). Available from: https://doi.org/10.1371/journal.pone.0160169. 
Liu J, Xiao Y, Wu X, Jiang L, Yang S, Ding Z, et al. A circulating microRNA signature as 
noninvasive diagnostic and prognostic biomarkers for nonalcoholic steatohepatitis. BMC 
genomics. 2018;19(1):188. 


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Michelena J, Alonso C, Martínez-Arranz I, Altamirano J, Mayo R, Sancho-Bru P, et al. 
Metabolomics Discloses a New Non-invasive Method for the Diagnosis and Prognosis of 
Patients with Alcoholic Hepatitis. Annals of hepatology. 2019; 18(1):144-54. 
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 
5.0 [Internet].  U.S. Department of Health and Human Services: National Institutes of Health; 
2017 Nov 27. Available from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf   
Naoumov, N. V. Cyclophilin inhibition as potential therapy for liver diseases. Journal of 
Hepatology [Internet]. 2014; 61(5): 1166–1174. Available from: 
https://doi.org/10.1016/j.jhep.2014.07.008 
Nigro, P., Pompilio, G., & Capogrossi, M. C. Cyclophilin A: A key player for human disease. 
Cell Death and Disease [Internet]. 2013; 4(10): e888-10. Available from: 
https://doi.org/10.1038/cddis.2013.410 
Schuppan D, Surabattula R, Wang XY. Determinants of fibrosis progression and regression in 
NASH. Journal of hepatology. 2018;68(2):238-50. 
Siddiqui, M. S., Harrison, S. A., Abdelmalek, M. F., Anstee, Q. M., Bedossa, P., Castera, L., et 
al. Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic 
steatohepatitis through the lens of regulatory science. Hepatology [Internet]. 2018; 67(5): 2001–
2012. Available from: https://doi.org/10.1002/hep.29607 
Vanhove, Thomas, Pieter Annaert, and Dirk RJ Kuypers. Clinical determinants of calcineurin 
inhibitor disposition: a mechanistic review. Drug metabolism reviews. 2016; 48(1): 88-112. 
Wang, X., Du, H., Shao, S., Bo, T., Yu, C., Chen, W., et al. Cyclophilin D deficiency attenuates 
mitochondrial perturbation and ameliorates hepatic steatosis. Hepatology [Internet]. 2018; 68(1): 
62–77. Available from: https://doi.org/10.1002/hep.29788 
Xue, C., Sowden, M. P., & Berk, B. C. Extracellular and Intracellular Cyclophilin A, Native and 
Post-Translationally Modified, Show Diverse and Specific Pathological Roles in Diseases. 
Arteriosclerosis, Thrombosis, and Vascular Biology [Internet]. 2018; 38(5): 986–993. Available 
from: https://doi.org/10.1161/ATVBAHA.117.310661 
Younossi, Z. M., Koenig, A. B., Abdelatif, D., Fazel, Y., Henry, L., & Wymer, M. Global 
epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, 
incidence, and outcomes. Hepatology [Internet]. 2016; 64(1): 73–84. Available from: 
https://doi.org/10.1002/hep.28431 
Zhou, Shu-Feng, et al. Clinically important drug interactions potentially involving mechanism-
based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. 
Therapeutic drug monitoring. 2007; 29(6): 687-710. 
 


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18. 
APPENDICES 
 


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APPENDIX A. 
CONTRAINDICATED DRUGS 
 CYP3A4/5: Inhibitors 
Enzyme 
Strong 
inhibitors 
Moderate 
inhibitors 
Weak 
inhibitors 
CYP3A 
boceprevir, cobicistat, conivaptan, 
danoprevir and ritonavir, 
elvitegravir and ritonavir, 
grapefruit juice, indinavir and 
ritonavir, itraconazole, 
ketoconazole, lopinavir and 
ritonavir, paritaprevir and ritonavir 
and (ombitasvir and/or dasabuvir), 
posaconazole, ritonavir, saquinavir 
and ritonavir, telaprevir, tipranavir 
and ritonavir, troleandomycin, 
voriconazole 
clarithromycin, diltiazem, 
idelalisib, nefazodone, nelfinavir 
aprepitant, cimetidine, 
ciprofloxacin, clotrimazole, 
crizotinib, cyclosporine, 
dronedarone, erythromycin, 
fluconazole, fluvoxamine, imatinib, 
tofisopam, verapamil 
amiodarone, chlorzoxazone, 
cilostazol, fosaprepitant, 
istradefylline, ivacaftor, lomitapide, 
ranitidine, ranolazine, tacrolimus, 
ticagrelor 
 
 


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CYP3A4/5: Inducers 
Enzyme 
Strong Inducers 
Moderate Inducers 
Weak Inducers 
CYP3A 
carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, St. 
John’s wort 
bosentan, efavirenz, etravirine, 
modafinil 
armodafinil, rufinamide 
Transporter Inhibitors 
Transporter 
Gene 
Inhibitor 
OATP1B1, OATP1B3 
SLCO1B1, 
SLCO1B3 
atazanavir and ritonavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, 
lopinavir and ritonavir, rifampin (single dose), simeprevir 
OAT1, OAT3 
SLC22A6, 
SLC22A8 
p-aminohippuric acid (PAH), probenecid, teriflunomide 
 
 
 
 
 
 


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 
STATISTICAL ANALYSIS PLAN 
Version 1.0 
Protocol Number: HEPA-CRV431-201 
Protocol Version: 5.0 
            Protocol Date: 01 March 2021 
NCT04480710




 
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Table of Contents 
LIST OF ABBREVIATIONS ..................................................................................................................................... 5 
1. 
INTRODUCTION .............................................................................................................................................. 6 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................................................... 6 
2.1 
OBJECTIVES .................................................................................................................................................. 6 
 
Primary Objective .................................................................................................................................... 6 
 
Secondary Objectives ............................................................................................................................... 6 
 
Exploratory Objectives ............................................................................................................................ 6 
2.2 
ENDPOINTS ................................................................................................................................................... 7 
 
Study Endpoints ....................................................................................................................................... 7 
 
Safety Endpoints ............................................................................................................................................. 7 
 
Pharmacokinetic Endpoints ............................................................................................................................. 7 
 
Exploratory Endpoints ............................................................................................................................. 7 
3. 
INVESTIGATIONAL PLAN............................................................................................................................. 7 
3.1 
STUDY DESIGN ............................................................................................................................................. 7 
 
Screening and Randomization Period ..................................................................................................... 8 
 
Treatment Period ..................................................................................................................................... 8 
 
Follow Up Period .................................................................................................................................... 8 
3.2 
TREATMENT .................................................................................................................................................. 8 
 
Treatment Administration ........................................................................................................................ 8 
 
Treatment Compliance ............................................................................................................................. 8 
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ........................................................................... 9 
4.1 
DATA QUALITY ASSURANCE ........................................................................................................................ 9 
4.2 
ANALYSIS SETS ............................................................................................................................................. 9 
 
Pharmacokinetic Set ................................................................................................................................ 9 
 
Safety Set ................................................................................................................................................ 10 
4.3 
ASSESSMENT WINDOWS ............................................................................................................................. 10 
4.4 
HANDLING OF DROPOUTS OR MISSING DATA ............................................................................................. 10 
4.5 
MULTIPLE COMPARISONS ........................................................................................................................... 10 
4.6 
DATA DERIVATIONS AND TRANSFORMATIONS ........................................................................................... 10 
5. 
STUDY SUBJECTS .......................................................................................................................................... 10 
5.1 
DISPOSITION OF SUBJECTS .......................................................................................................................... 10 
5.2 
PROTOCOL DEVIATIONS .............................................................................................................................. 10 
5.3 
DEMOGRAPHIC CHARACTERISTICS ............................................................................................................. 11 
5.4 
MEDICAL HISTORY ..................................................................................................................................... 11 
5.5 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................................................. 11 
5.6 
NON-DRUG THERAPIES ............................................................................................................................... 11 
6. 
EFFICACY ANALYSIS ................................................................................................................................... 11 
6.1 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS .......................................................................................... 11 
6.2 
PHARMACOKINETIC ENDPOINTS AND ANALYSIS ......................................................................................... 11 
6.3 
EXPLORATORY ENDPOINTS AND ANALYSIS ................................................................................................ 11 
7. 
SAFETY ANALYSIS........................................................................................................................................ 12 


 
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7.1 
EXTENT OF EXPOSURE ................................................................................................................................ 12 
7.2 
ADVERSE EVENTS ....................................................................................................................................... 12 
 
Treatment-emergent Adverse Events ..................................................................................................... 12 
 
Adverse Event Severity ........................................................................................................................... 12 
 
Adverse Event Relationship to Study Medication .................................................................................. 12 
 
Serious Adverse Events .......................................................................................................................... 13 
 
Adverse Event Summaries ...................................................................................................................... 13 
7.3 
CLINICAL LABORATORY ASSESSMENTS ...................................................................................................... 14 
7.4 
VITAL SIGNS ............................................................................................................................................... 14 
7.5 
ECG............................................................................................................................................................ 15 
7.6 
PHYSICAL EXAMINATION ............................................................................................................................ 15 
8. 
DATA SAFETY MONITORING BOARD ..................................................................................................... 15 
9. 
INTERIM ANALYSIS ..................................................................................................................................... 15 
10. 
SAMPLE SIZE AND POWER CALCULATIONS ................................................................................... 15 
11. 
REFERENCES ............................................................................................................................................. 15 
12. 
APPENDICE ................................................................................................................................................. 16 
12.1 
APPENDIX A: SCHEDULE OF EVENTS .......................................................................................................... 16 
12.2 
APPENDIX B: LIST OF PROPOSED TABLES ................................................................................................... 18 
 
 








 
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Screening and Randomization Period 
Screening visits will be conducted within 30 days prior to study Day 1.  
Upon determination that a subject meets all eligibility criteria, the subject will be randomized on 
Study Day -1 to receive either CRV431 or matching placebo in a 2:1 subject ratio (12 CRV431 
75mg to 6 matching placebo and 12 CRV431 225mg to 6 matching placebo). 
 
Table 1: Study Design 
Cohort*  
Fibrosis 
Stage 
N 
Day 1 – 28, fasted 
oral dosing 
 
Day 29 - 42  
 
A 
F2/F3 
12 
CRV431 75 mg  
Observation/Follow up 
B 
6 
Placeboa  
C 
12 
CRV431 225 mg 
D 
6 
Placebob 
*Randomized assignment; 2:1 – CRV431: Placebo  
a Matching Placebo for Cohort A - 75 mg dose. 
b Matching Placebo for Cohort C - 225 mg dose. 
 
 
Treatment Period 
Subjects will receive treatment with CRV431 or placebo from Day 1 to Day 28.  
 
Follow Up Period 
After completion of the treatment period, the subjects will be monitored for additional 14 days. 
3.2 
Treatment 
Subjects in Cohort A will receive CRV431 75 mg (1 x 75 mg softgel capsule) QD and subjects in 
Cohort B will receive the matching placebo (1 x placebo softgel capsule) for Cohort A. 
Subjects in Cohort C will receive CRV431 225 mg (3 x 75 mg softgel capsules) QD and subjects 
in Cohort D will receive the matching placebo (3 x placebo softgel capsules) for Cohort C. 
 
Treatment Administration 
Subjects will take study drug on the morning of each dosing day, with approximately 240 mL of 
water. On Day 1 and Day 28, subjects will fast overnight for at least 8 hours, will take CRV431 
or matching placebo and will fast for an additional 2 hours after treatment administration. On 
subsequent days, subject will fast overnight for at least 8 hours, will take CRV431 or matching 
placebo and will fast for an additional 30 minutes after treatment administration.  
 
Treatment Compliance 
While in the Clinical Research Unit, study treatment will be administered under the supervision 
of site personnel. Compliance during the non-study visit days will be assessed by subject report 










 
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investigational product, when appropriate, for each AE (unrelated, possibly related or probably 
related). The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If no 
valid reason exists for suggesting a relationship, then the AE should be classified as “unrelated.” 
If there is any valid reason, even if undetermined, for suspecting a possible cause and effect 
relationship between the investigational product and the occurrence of the AE, then the AE 
should be considered “related.” 
 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” the event will be considered to be related to the investigational product 
for the purposes of expedited regulatory reporting. 
 
Serious Adverse Events 
An AE is considered serious if, in the view of either the investigator or sponsor, it fulfills at least 
one of the following: 
• Results in death 
• It is immediately life-threatening 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
 
Adverse Event Summaries 
All AEs (serious and non-serious) occurring after completion of the informed consent process 
and before the end of study, regardless of relationship to study drug, will be included and 
classified by SOC and PT using the Medical Dictionary for Regulatory Activities (MedDRA).     
For treatment-emergent AEs (TEAEs), the following will be summarized and presented for the 
safety analysis set: 
i. 
An overall summary of TEAEs, which includes:   
a. the number and percentage of subjects experiencing a TEAE 
b. the number and percentage of subjects experiencing a TEAE by strongest 
relationship to study medication 
c. the number and percentage of subjects experiencing a TEAE by greatest severity 
d. the number and percentage of subjects experiencing a TEAE leading to study 
withdrawal 
e. the number and percentage of subjects experiencing a treatment emergent SAE 
(TESAE) 
ii. 
the number and percentage of subjects experiencing a TEAE by SOC and PT 


 
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iii. 
the number and percentage of subjects experiencing a TEAE by SOC, PT and the 
highest severity 
iv. 
the number and percentage of subjects experiencing a TEAE by SOC, PT and the 
strongest relationship to study medication 
v. 
the number and percentage of subjects experiencing a TESAE by SOC and PT 
vi. 
the number and percentage of subjects experiencing a TEAE leading to study 
withdrawal by SOC and PT 
In the overall summary of TEAEs table (i), besides tabulating the number and percentage of 
subjects, the total number of TEAE episodes will also be provided. If a subject has repeated 
episodes of a particular TEAE, all episodes will be counted in the summary table.   
In the remaining summary tables, the incidence of TEAEs will be calculated by dividing the 
number of subjects who have experienced the event by the total number of subjects in the safety 
set.  Thus, the incidence of TEAEs is shown in terms of the total number of subjects and not in 
terms of the total number of episodes.  If a subject has repeated episodes of a particular TEAE, 
only the most severe episode, or the episode with the strongest causal relationship to study drug, 
will be counted in the summary tables.  
A subject with more than one type of TEAE in a particular SOC will be counted only once in the 
total of subjects experiencing TEAEs in that particular SOC.  Since a subject could have more 
than one type of TEAE within a particular SOC, the sum of subjects experiencing different 
TEAEs within the SOC could appear larger than the total number of subjects experiencing 
TEAEs in that SOC.  Similarly, a subject who has experienced a TEAE in more than one SOC 
will be counted only once in the total number of subjects experiencing AEs in all SOCs. 
All occurrences of all AEs will be listed for each subject, grouped by cohort.  The listing will 
contain the following information: treatment group, verbatim term, SOC, PT, severity, 
relationship to study medication, date and day of onset, date and day of resolution, treatment 
given to treat the adverse event, the outcome, whether the event was an SAE, whether it led to 
withdrawal and whether it is a TEAE.  Listings will be sorted by subject identification number, 
onset date, SOC, and PT. If the onset date is completely missing, then these events will be 
presented first. If the onset date is missing a month or a day, then these events will be presented 
before any complete dates. 
7.3 
Clinical Laboratory Assessments 
Hematology, Coagulation, Blood Chemistry and Urinalysis data will be summarized by 
treatment group and visit.  All clinical laboratory data will be converted to International System 
of Units (SI). Both raw and change from baseline values will be summarized by presenting the 
descriptive statistics by treatment group and visit. 
Central and local drug and alcohol test results and pregnancy tests results will be listed.  
7.4 
Vital Signs 
Vital signs raw and change from baseline values will be summarized by presenting the 
descriptive statistics of blood pressure, heart rate, temperature, and respiratory rate measurements 
by treatment group and visit.  




 
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12.2 
Appendix B: List of Proposed Tables 
Summary of Subject Disposition – All Subjects 
Summary of Protocol Deviations – Safety Set 
Summary of Demographics – Safety Set 
Summary of Medical History by System Organ Class and Preferred Term – Safety Set 
Summary of Prior and Concomitant Medications – Safety Set 
Summary of Non-drug Therapies by System Organ Class and Preferred Term – Safety Set 
Summary of Biomarkers: Change from Baseline – Safety Set 
Summary of Biomarkers: Percent Change from Baseline – Safety Set 
Summary of Exposure – Safety Set 
Overall Summary of Treatment-emergent Adverse Events – Safety Set 
Treatment-emergent Adverse Events by System Organ Class and Preferred Term – Safety Set 
Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Highest 
Severity – Safety Set 
Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Strongest 
Relationship to Study Drug – Safety Set 
Treatment-emergent Serious Adverse Events by System Organ Class and Preferred Term – 
Safety Set 
Treatment-emergent Adverse Events Leading to Study Withdrawal by System Organ Class and 
Preferred Term – Safety Set 
Summary of Blood Chemistry Results – Safety Set 
Summary of Hematology Results – Safety Set 
Summary of Urinalysis Results – Safety Set 
Summary of Vital Signs – Safety Set 
Summary of ECG – Safety Set