Clinical trial NCT03421431
Conditions: Non-Alcoholic Steatohepatitis
Keywords: NASH Non-Alcoholic Steatohepatitis (NASH)
Sponsor: Enanta Pharmaceuticals, Inc
Start date: 2018-04-25; Completion date: 2019-07-10
Enrollment: 134 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized, double-blind study to assess the safety, tolerability, PK and efficacy of EDP-305 in subjects with Non-Alcoholic Steatohepatitis

Detailed description:

Arms: arm 1: Subjects will take 2 tablets once a day orally for 12 weeks arm 2: Subjects will take 2 tablets once a day orally for 12 weeks arm 3: Subjects will take 2 tablets once a day orally for 12 weeks
Interventions: intervention 1: EDP-305 Dose 1 intervention 2: EDP-305 Dose 2 intervention 3: Placebo
Intervention descriptions: intervention 1: Two tablets daily for 12 weeks intervention 2: Two tablets daily for 12 weeks intervention 3: Two tablets daily for 12 weeks

Protocol documents:
Prot_000.pdf: 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A PHASE 2 DOSE RANGING, RANDOMIZED, DOUBLE BLIND, AND 
PLACEBO-CONTROLLED STUDY EVALUATING THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS AND 
EFFICACY OF EDP-305 IN SUBJECTS WITH NON-
ALCOHOLIC STEATOHEPATITIS (NASH) 
Protocol Number:  EDP 305-101 
EudraCT Number: 2017-004365-27 
 
Protocol Version: 
3.0 (Amendment 2.0) 
Date: 
Amendment 2.0: 21 Feb 2018 
Amendment 1.0: 14 Dec 2017 
 
Original Protocol: 27 Oct 2017 
 
 
Study Sponsor: 
Enanta Pharmaceuticals, Inc. 
500 Arsenal St. 
Watertown, MA  02472 
 
 
Sponsor Medical Monitor: 
 
Enanta Pharmaceuticals, Inc. 
500 Arsenal St. 
Watertown, MA  02472 
Phone: 
 
 
 
CONFIDENTIAL 
Information and data in this protocol contain trade secrets and privileged or confidential information, which is the 
property of Enanta Pharmaceuticals, Inc.  No person is authorized to make it public without the written permission 
of Enanta Pharmaceuticals, Inc. 




Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 3 of 86 
 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
Principal Investigator:   
 
Signed: 
 
Date: 
 
 
 
 
 


Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
 
Page 4 of 86 
 
TABLE OF CONTENTS 
CONTACT INFORMATION ...................................................................................................... 2 
1. 
INTRODUCTION ..........................................................................................................21 
1.1. 
OVERVIEW .......................................................................................................................... 21 
1.2. 
BACKGROUND ..................................................................................................................... 21 
1.2.1. 
NASH and Farnesoid X Receptor (FXR) ................................................................... 21 
1.2.2. 
Rationale for Development of EDP-305 for NASH ..................................................... 21 
1.3. 
NONCLINICAL STUDIES ......................................................................................................... 22 
1.3.1. 
Mechanism of Action and Pharmacology .................................................................. 22 
1.3.2. 
Safety Pharmacology .............................................................................................. 24 
1.3.3. 
Pharmacokinetics ................................................................................................... 24 
1.3.4. 
Toxicology ............................................................................................................. 25 
1.4. 
CLINICAL STUDIES ............................................................................................................... 29 
1.4.1. 
Study EDP 305-001 ................................................................................................ 30 
1.4.2. 
Ongoing Phase 1 Studies ......................................................................................... 31 
1.5. 
POTENTIAL RISKS AND BENEFITS ........................................................................................... 37 
2. 
OBJECTIVES AND ENDPOINTS ..................................................................................39 
2.1. 
OBJECTIVES ......................................................................................................................... 39 
2.1.1. 
Primary Objective .................................................................................................. 39 
2.1.2. 
Secondary Objectives .............................................................................................. 39 
2.2. 
ENDPOINTS .......................................................................................................................... 39 
2.2.1. 
Primary Endpoints .................................................................................................. 39 
2.2.2. 
Secondary Endpoints .............................................................................................. 39 
3. 
SELECTION OF SUBJECTS .........................................................................................41 
3.1. 
SUBJECT INCLUSION CRITERIA............................................................................................... 41 
3.2. 
SUBJECT EXCLUSION CRITERIA.............................................................................................. 42 
4. 
STUDY DESIGN ............................................................................................................45 
4.1. 
DOSE AND TREATMENT SCHEDULE ........................................................................................ 45 
4.2. 
RATIONALE FOR STUDY DESIGN ............................................................................................ 45 
4.2.1. 
Justification of Design and Control Group ................................................................ 46 
4.2.2. 
Justification of EDP-305 Dose ................................................................................. 46 
5. 
STUDY DRUG AND TREATMENT OF SUBJECTS ......................................................49 
5.1. 
DESCRIPTION OF STUDY DRUG .............................................................................................. 49 
5.2. 
PACKAGING AND LABELING .................................................................................................. 49 
5.3. 
STORAGE ............................................................................................................................. 49 
5.4. 
ACCOUNTABILITY ................................................................................................................ 49 
5.5. 
HANDLING AND DISPOSAL .................................................................................................... 50 
5.6. 
TREATMENT ASSIGNMENT/ RANDOMIZATION .......................................................................... 50 
5.7. 
STUDY DRUG DOSE AND ADMINISTRATION ............................................................................. 50 
5.7.1. 
Dispensing of Study Drug ........................................................................................ 51 
5.7.2. 
Treatment Compliance ............................................................................................ 51 


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EDP 305-101 v 3.0 (Amendment 2.0) 
 
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5.8. 
CONCOMITANT MEDICATIONS ............................................................................................... 51 
5.8.1 
 51 
5.9. 
PROHIBITED MEDICATIONS ................................................................................................... 51 
5.10. 
OTHER RESTRICTIONS........................................................................................................... 52 
6. 
BLINDING ....................................................................................................................54 
6.1. 
BLINDING OF STUDY SAMPLES .............................................................................................. 54 
6.1.1. 
Blinding of NASH Biomarkers, Fibrosis and Inflammatory Markers, MRI/MRE, 
and Laboratory Liver Test Results ............................................................................ 54 
6.1.2. 
Blinding of Pharmacokinetic Samples ...................................................................... 55 
6.2. 
UNBLINDING ........................................................................................................................ 55 
7. 
STUDY CONDUCT AND VISIT SCHEDULE ................................................................56 
7.1. 
STUDY VISITS ...................................................................................................................... 56 
7.1.1. 
Screening ............................................................................................................... 56 
7.1.2. 
Rescreening ........................................................................................................... 56 
7.1.3. 
Baseline (Day 1) ..................................................................................................... 56 
7.1.4. 
Treatment Period Visits (Day 3, Weeks 2, 4, 8, and 12/EOT) ...................................... 57 
7.1.5. 
Safety Follow-up Period (End of Study Visit) ............................................................ 57 
7.2. 
SUBJECT WITHDRAWAL / EARLY TERMINATION ...................................................................... 57 
7.2.1. 
Withdrawal Criteria ................................................................................................ 58 
7.2.2. 
Documentation of Withdrawal of Subjects................................................................. 58 
7.3. 
SITE OR STUDY DISCONTINUATION ........................................................................................ 59 
7.3.1. 
Study Discontinuation ............................................................................................. 59 
7.3.2. 
Site Termination ..................................................................................................... 59 
7.3.3. 
Study Termination Procedures ................................................................................. 59 
8. 
STUDY PROCEDURES/EVALUATIONS ......................................................................60 
8.1. 
TIMING OF ASSESSMENTS ...................................................................................................... 60 
8.2. 
DEMOGRAPHICS AND MEDICAL HISTORY ................................................................................ 60 
8.3. 
CLINICAL EVALUATIONS ....................................................................................................... 60 
8.3.1. 
Vital Sign Measurements and Electrocardiograms .................................................... 60 
8.3.2. 
Physical Examination ............................................................................................. 60 
8.3.3. 
Weight, Body Mass Index, and Waist to Hip Ratio ..................................................... 61 
8.3.4. 
Adverse Events ....................................................................................................... 61 
8.4. 
CLINICAL LABORATORY AND DIAGNOSTIC PROCEDURES ......................................................... 61 
8.4.1. 
Safety Laboratory Assessments ................................................................................ 62 
8.4.2. 
Noninvasive Evaluations of Fibrosis ........................................................................ 62 
8.4.3. 
Pharmacokinetic Samples ........................................................................................ 65 
8.4.4. 
Pregnancy and Menopausal LaboratoryTesting ........................................................ 66 
8.4.5. 
Liver Magnetic Resonance Imaging ......................................................................... 66 
8.4.6. 
PD biomarkers for FXR activity ............................................................................... 66 
8.4.7. 
Exploratory Research Samples ................................................................................ 67 
9. 
SAFETY MONITORING AND REPORTING ................................................................68 
9.1. 
DEFINITIONS ........................................................................................................................ 68 
9.1.1. 
Pretreatment Events ................................................................................................ 68 
9.1.2. 
Adverse Events ....................................................................................................... 68 


Clinical Study Protocol 
 
 
   
 
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EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
 
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9.1.3. 
Serious Adverse Events (SAEs) ................................................................................ 68 
9.2. 
DOCUMENTING AND REPORTING OF ADVERSE EVENTS (INCLUDING SERIOUS ADVERSE 
EVENTS) .............................................................................................................................. 69 
9.2.1. 
Documenting and Reporting Adverse Events ............................................................. 69 
9.2.2. 
Assigning Attribution of Adverse Events ................................................................... 70 
9.2.3. 
Classifying Action Taken with Study Drug ................................................................ 71 
9.2.4. 
Classifying Adverse Event Outcome ......................................................................... 71 
9.2.5. 
Documenting and Reporting Serious Pretreatment Events and Serious Adverse 
Events .................................................................................................................... 72 
9.2.6. 
Documenting and Reporting of Pregnancy ................................................................ 72 
9.3. 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .......................................... 73 
9.4. 
SPONSOR’S REVIEW OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................... 73 
9.5. 
DATA SAFETY MONITORING BOARD ...................................................................................... 73 
10. 
SUBJECT SAFETY MANAGEMENT ............................................................................74 
10.1. 
INDIVIDUAL SUBJECT STOPPING RULES .................................................................................. 74 
10.2. 
MANAGEMENT OF LIVER ENZYME ELEVATIONS ...................................................................... 74 
11. 
STATISTICAL CONSIDERATIONS .............................................................................76 
11.1. 
GENERAL CONSIDERATIONS .................................................................................................. 76 
11.2. 
SAMPLE SIZE CONSIDERATIONS ............................................................................................. 76 
11.3. 
ANALYSIS POPULATIONS ....................................................................................................... 76 
11.4. 
SUBJECT DISPOSITION AND DEMOGRAPHIC DATA .................................................................... 76 
11.5. 
EFFICACY ENDPOINTS ........................................................................................................... 77 
11.6. 
PRIMARY EFFICACY ENDPOINTS ............................................................................................ 77 
11.6.1. Secondary Efficacy Endpoints .................................................................................. 77 
11.7. 
SAFETY ENDPOINTS .............................................................................................................. 78 
11.7.1. Adverse Events ....................................................................................................... 78 
11.7.2. Clinical Laboratory Data ........................................................................................ 78 
11.7.3. Electrocardiogram Data ......................................................................................... 78 
11.7.4. Vital Signs.............................................................................................................. 78 
11.7.5. Concomitant Medications ........................................................................................ 79 
11.7.6. Physical Examinations ............................................................................................ 79 
11.8. 
PHARMACOKINETIC ENDPOINTS ............................................................................................. 79 
11.9. 
 79 
12. 
STUDY ADMINISTRATION .........................................................................................80 
12.1. 
ETHICAL CONSIDERATIONS ................................................................................................... 80 
12.1.1. Ethical Conduct of the Study .................................................................................... 80 
12.1.2. Ethical Review ....................................................................................................... 80 
12.1.3. Written Informed Consent ....................................................................................... 80 
12.1.4. Investigator Compliance ......................................................................................... 80 
12.2. 
DATA COLLECTION .............................................................................................................. 81 
12.3. 
STUDY MONITORING ............................................................................................................ 81 
12.4. 
QUALITY ASSURANCE .......................................................................................................... 81 
12.5. 
RETENTION OF RECORDS ....................................................................................................... 82 
12.6. 
INFORMATION DISCLOSURE ................................................................................................... 82 
12.6.1. Confidentiality ........................................................................................................ 82 


Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
 
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12.6.2. Publication Policy .................................................................................................. 82 
13. 
REFERENCES ..............................................................................................................84 
14. 
APPENDICES ...............................................................................................................85 


Clinical Study Protocol 
 
 
   
 
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EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 8 of 86 
 
 
LIST OF FIGURES 
Figure 1. 
Study Design ...................................................................................................... 45 
 
LIST OF TABLES 
Table 1: 
Safety Pharmacology Studies ................................................................................ 24 
Table 2: 
Mouse 91-Day Repeat Dose GLP Toxicology Study ................................................ 26 
Table 3: 
Monkey 91-Day Repeat Dose GLP Toxicology Study .............................................. 27 
Table 4: 
Embryo-Fetal Development Studies ....................................................................... 28 
Table 5: 
Clinical Studies with EDP-305 .............................................................................. 29 
Table 6:  
Ongoing Phase 1 Studies ...................................................................................... 32 
Table 7: 
Statistical Analysis (ANOVA) of Primary Pharmacokinetic Parameters ..................... 33 
Table 8: 
EDP 305-004 Activity and Treatment Schedule ...................................................... 33 
Table 9: 
 PK 
Parameters .......................................................................................................... 34 
Table 10: 
EDP 305-005 Part 1 Activity and Treatment Schema ............................................... 35 
Table 11: 
EDP 305-005 Part 2 Activity and Treatment Schema ............................................... 35 
Table 12: 
Summary of Key EDP-305 PK Parameters by Study Part ......................................... 36 
Table 13: 
Statistical Analysis of EDP-305 Relative Bioavailability .......................................... 37 
Table 14: 
Protocol Restrictions ............................................................................................ 52 
Table 15: 
Laboratory Evaluations ........................................................................................ 64 
Table 16: 
Options for Action Taken with Study Drug ............................................................. 71 
Table 17:  
Classification and Definition of AE Outcomes ........................................................ 71 
Table 18: 
PK Parameters .................................................................................................... 79 
Table 19: 
Schedule of Assessments ...................................................................................... 85 
 
 
 


Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 9 of 86 
 
 
LIST OF ABBREVIATIONS 
AE, AR 
adverse event(s), adverse reaction(s) 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance  
ANCOVA 
analysis of covariance 
apo 
apolipoproteins  
APRI 
AST to Platelet Ratio Index 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BA 
bile acid 
BCRP 
breast cancer resistance protein 
BMI 
body mass index 
BSEP 
bile salt export pump 
C4 
complement component 4 
CK18 
cytokeratin 18 
Cmax 
maximum concentration 
CRO 
contract research organization 
CV 
cardiovascular 
CYP 
cytochrome P450 
CYP7A1 
cholesterol 7α-hydroxylase 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EFD 
embryo-fetal development 
ELF 
enhanced liver fibrosis 
EOS 
end-of-study 
EOT 
End-of-treatment 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor  
FIH 
first-in-human 
FE 
food effect 
FIB-4 
Fibrosis-4 
FSH 
follicle stimulating hormone 
FXR 
farnesoid X receptor 
GCP 
good clinical practice 
GLP 
good laboratory practice 
GLP-1 
glucagon-like peptide-1 
HbA1c 
glycated hemoglobin 
HDL-C 
high density lipoprotein cholesterol 


Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
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HEK293 
human embryonic kidney 293 cells 
HOMA 
homeostasis model assessment 
HV 
healthy volunteers 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IL 
interleukin 
INR 
international normalized ratio 
IRB 
institutional review board 
IWRS 
interactive web response system 
LDL-C 
low density lipoprotein cholesterol 
MAD 
multiple ascending dose 
MRE 
magnetic resonance elastography 
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging - proton density fat fraction 
mRNA 
messenger ribonucleic acid 
NAFLD 
non-alcoholic fatty liver disease 
NASH 
non-alcoholic steatohepatitis 
NCI CTCAE 
National Cancer Institute, Common Terminology Criteria for Adverse Events 
NFS 
NAFLD fibrosis score 
NOAEL/NOEL 
no observed adverse effect level / no observed effect level 
OCA 
obeticholic acid 
PBC 
primary biliary cholangitis 
PBO 
placebo 
PD 
pharmacodynamics 
P-gp 
P-glycoprotein 
PI 
Principal Investigator 
PIIINP 
procollagen III amino terminal peptide 
PK 
pharmacokinetics 
PN 
presumptive NAFLD; defined as obese with or without prediabetes or type 2 
diabetes mellitus 
PR 
electrocardiographic interval occurring between the onset of the P wave and 
the QRS complex, representing time for atrial and ventricular depolarization, 
respectively 
PRO C3 
type 3 procollagen 
PSC 
primary sclerosing cholangitis 
QD 
once daily 
QRS 
electrocardiographic deflection between the beginning of the Q wave and 
termination of the S wave, representing the time for ventricular depolarization 
QT 
electrocardiographic interval between the beginning of the Q wave and 
termination of the T wave, representing the time for both ventricular 
depolarization and repolarization to occur 


Clinical Study Protocol 
 
 
   
 
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EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
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QTcF 
QT interval corrected by Fridericia's formula 
RR 
interval between successive heart beats using the R-wave peaks 
SAD 
single ascending dose 
SAD/FE 
single ascending dose / food effect 
SAE 
serious adverse event(s) 
SAP 
statistical analysis plan 
SHP 
small heterodimer partner 
SoA 
Schedule of Assessments 
T2DM 
type 2 diabetes mellitus 
TC 
total cholesterol 
TEAE 
treatment emergent adverse event 
TG 
triglyceride(s) 
TIMP-1 
tissue inhibitor of metalloproteinase 1 
TNF 
tumor necrosis factor 
TGR5 
Takeda G-protein-coupled receptor 5/ also known as M-BAR 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WTH 
waist to hip ratio 
 
 


Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
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PROTOCOL SYNOPSIS  
Name of Sponsor/Company: Enanta Pharmaceuticals, Inc. 
Name of Investigational Product: EDP-305 
Study Title: A Phase 2 Dose Ranging, Randomized, Double Blind, and Placebo-Controlled 
Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in 
Subjects with Non-Alcoholic Steatohepatitis (NASH) 
Protocol Number:  EDP 305-101 
Phase of Development: 2 
Study Center: The study will be conducted at approximately 65 US and ex-US sites  
Number of Subjects Planned: Approximately 125 subjects will be enrolled 
Investigational Product, Dosage, and Mode of Administration: EDP-305 will be supplied as 
1mg and 2.5mg tablets for oral administration; doses administered will be 1mg, 2.5mg or 
placebo taken once daily (QD) for 12 weeks.  
Duration of Treatment: 12 weeks  
Study Objectives: 
Primary Objectives:  
• To evaluate change in alanine aminotransferase (ALT) levels 
• To evaluate the safety and tolerability of EDP-305   
Secondary Objectives: 
• To evaluate the effect of EDP-305 on liver fat  
• To evaluate the effect of EDP-305 on fibrosis (liver stiffness) 
• To evaluate the effect of EDP-305 on noninvasive liver fibrosis markers 
• To evaluate the effects of EDP-305 on lipids  
• To evaluate the effects of EDP-305 on glucose metabolism 
• To evaluate the effects of EDP-305 on inflammatory markers 
• To evaluate the pharmacokinetics (PK) of EDP-305 and its metabolites in plasma 
• To evaluate the effect of EDP-305 on body weight 
• To evaluate the effect of EDP-305 on waist to hip (WTH) ratio 
• To evaluate the pharmacodynamics of EDP-305 


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EDP 305-101 v 3.0 (Amendment 2.0) 
 
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Criteria for Evaluation:  
Primary Endpoint: 
• Change from baseline in ALT levels at Week 12 
• Frequency of adverse events (AEs), serious adverse events (SAEs), and AEs leading to 
discontinuation through Week 12  
Secondary Endpoints: 
• Change from Baseline in percentage of fat in the liver as assessed by magnetic resonance 
imaging-estimated proton density fat fraction (MRI-PDFF) at Week 12 
• Change from Baseline in liver stiffness as assessed by magnetic resonance elastography 
(MRE) at Week 12 
• Change from Baseline of noninvasive liver fibrosis markers (Enhanced Liver Fibrosis 
[ELF] panel) and PRO C3 at Week 12  
• Change from Baseline in non-alcoholic fatty liver disease (NAFLD) Fibrosis Score 
(NFS), AST to Platelet Ratio Index (APRI), and fibrosis 4 (FIB-4) at Week 12 
• Change form Baseline in triglycerides (TG), total cholesterol (TC), high density 
lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), 
adiponectin and apolipoproteins (Apo)A1, B, C3 at Week 12 
• Change from Baseline in fasting glucose and insulin, homeostasis model assessment 
(HOMA) index (in nondiabetic subjects) and glycated hemoglobin (HbA1c) in subjects 
with Type 2 diabetes mellitus (T2DM) at Week 12 
• Change from Baseline in fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β , alpha2 
macroglobulin and haptoglobin levels at Week 12 
• Pharmacokinetic  parameters of EDP-305 (and metabolites): Cmax, tmax, and AUClast  
• Change from Baseline in body weight at Week 12  
• Change in WTH ratio at Week 12 
• Pharmacodynamic  parameters of EDP-305: FGF19, C4, and bile acid (BA) at Week 12 
 
Study Design: 
This is a Phase 2 dose-ranging, randomized, double blind, and placebo-controlled study 
evaluating the safety, tolerability, PK and efficacy of EDP-305 in subjects with NASH.  
The duration of the study will be approximately 20 weeks. The study will consist of a Screening 
Period, Treatment Period, and a Safety Follow-up Period. 
 
 
 




Clinical Study Protocol 
 
 
   
 
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EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
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Study Design 
 
Abbreviations: D=Day; W=Week 
Eligibility Criteria:  
Inclusion Criteria  
A subject must meet all of the following criteria in order to participate in the study. 
1. An informed consent document must be signed and dated by the subject 
2. Male and female subjects of any ethnic origin between the ages of 18 and 75 years, 
inclusive 
3. Male or female with presence of NASH by: 
• Histologic evidence on a  historical liver biopsy within 24 months of Screening 
consistent with NASH with fibrosis (no cirrhosis), and elevated ALT at Screening 
NOTE: Vitamin E should not have been initiated after the date the biopsy was performed 
and subjects should have a stable weight since the liver biopsy was performed defined by no 
more than a 5% change of initial body weight 
OR 
• Phenotypic diagnosis of NASH based on elevated ALT and diagnosis of T2DM or 
pre-diabetes 
NOTE: Elevated ALT must be ≥50 IU/L and ≤200 IU/L; Known T2DM or pre-diabetes with 
one of the following criteria: : random plasma glucose concentration >200 mg/dL 
(11.1 mmol/L) OR fasting plasma glucose >126 mg/dL (7.0 mmol/L) OR 2-hour post-load 
glucose >200 mg/dL (11.1 mmol/L) during a 75 g oral glucose tolerance test (OGTT) OR 
HbA1c of at least 6% with or without concomitant treatment with metformin 
AND 
• Screening MRI-PDFF with >8% steatosis  


Clinical Study Protocol 
 
 
   
 
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  CONFIDENTIAL 
 
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4. Body mass index (BMI) >25 kg/m2. NOTE: for Asian-Americans, BMI >23 kg/m2  
5. Subjects must have Screening laboratory values for Hepatitis B surface antigen (HBsAg), 
anti-HCV antibodies and HCV RNA, and Human Immunodeficiency Virus (HIV) 1 and 
2 antibodies (Ab) as seronegative. Note: subjects previously infected by chronic hepatitis 
C and treated with direct acting antivirals (DAAs) with sustained virologic response 
(SVR) for at least 3 years will be allowed. 
6. Female subjects of childbearing potential must agree to use two effective methods of 
contraception from the date of Screening until 90 days after the last dose of EDP-305.  
Effective methods of contraception are defined as: 
• a condom for the male partner and at least one of the following for the female 
participant: 
o Intrauterine device 
o Oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive 
Note: The above does not apply to female subjects of nonchildbearing potential (ie, 
physiologically incapable of becoming pregnant) defined as: 
- has had a complete hysterectomy greater than or equal to 3 months prior to  dosing 
or 
- has had a bilateral oophorectomy (ovariectomy) or 
- has had a bilateral tubal ligation or fallopian tube inserts or 
- is post-menopausal (a demonstration of a total cessation of menses for ≥1 year 
with a follicle stimulating hormone (FSH) level of >35 mIU/mL).   
7. All male participants who have not had a vasectomy must use effective contraception 
from Day −1 to 90 days after their last dose of study drug. Effective contraception is 
defined as a condom and spermicide for the male, or condom and at least one of the 
following for a female partner: 
• 
Intrauterine device 
• 
Oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive 
• 
Be of non-childbearing potential 
8. Male subjects must agree to refrain from sperm donation from the date of Screening until 
90 days after their last dose of study drug 
9. Subject must be willing and able to adhere to the assessments, visit schedules, 
prohibitions and restrictions, as described in this protocol 
Exclusion Criteria  
Subjects will not be eligible to participate in the study if they meet any of the following criteria: 
1. Laboratory Screening Results: 
• Total bilirubin >ULN (normal range 0.2–1.2 mg/dL)  
NOTE: Patients with Gilbert’s syndrome will be allowed if they have a known history of 


Clinical Study Protocol 
 
 
   
 
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  CONFIDENTIAL 
 
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Gilbert’s syndrome with a normal direct bilirubin value and normal reticulocyte count, 
and upon review by the medical monitor 
• Total white blood cells (WBC) <3,000 cells/mm3 
• Absolute neutrophil count (ANC) <1,500 cells/mm3 
• Platelet count <140,000/mm3 
• Prothrombin time (international normalized ratio, INR)>1.2 
• Creatine kinase above the upper limit of normal (ULN) except when in relation with 
intense exercise 
• Serum creatinine >2 mg/dL or clearance creatinine <60 ml/min (based on 
Cockroft-Gault method) 
2. Known history of alpha-1-antitrypsin deficiency 
3. Use of an experimental treatment for NASH within the past 6 months 
4. Prior use and/or concurrent treatment with obeticholic acid (OCA) 
5. Use of immunosuppressant (eg, corticosteroids) for more than 2 weeks in duration within 
1 year prior to Screening and during the course of the study 
6. Use of experimental or unapproved drugs within a year of Screening 
7. Any other condition(s) (including cardiovascular diseases) that would compromise the 
safety of the subject or compromise the quality of the clinical study, as judged by the 
Principal Investigator (PI) 
8. Pregnant or nursing females 
9. Recipients of liver or other organ transplantation or anticipated need for orthotropic organ 
transplantation in one year as determined by a Model for End-Stage Liver Disease 
(MELD) Score ≥15 
10. Clinical suspicion of advanced liver disease or cirrhosis 
11. Coexisting liver or biliary diseases, such as primary sclerosing cholangitis (PSC), 
choledocholithiasis, acute or chronic hepatitis, autoimmune hepatitis, alcoholic liver 
disease, acute infection of bile duct system or gall bladder, history of gastrointestinal 
bleeding (secondary to portal hypertension), cirrhosis 
12. Suspicion of cancer (eg, liver cancer) with the exception of basal cell carcinoma that has 
been resected 
13. Cirrhosis with or without  complications, including history or presence of: spontaneous 
bacterial peritonitis, hepatocellular carcinoma, bilirubin >2 × ULN 
14. Hepatorenal syndrome (type I or II) or Screening serum creatinine > 2 mg/dL 
(178 μmol/L) 
15. Prior variceal hemorrhage, uncontrolled encephalopathy, Child-Pugh Class A, B, and  C, 
esophageal varices, or refractory ascites within the previous 6 months of Screening 
(defined as date informed consent signed) 


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16. Any condition possibly affecting drug absorption (eg, gastrectomy <3 years prior to 
Screening) 
17. History of regular alcohol consumption exceeding 14 drinks/week for females and 
21 drinks/week for males within 6 months of Screening. One drink is defined as 5 ounces 
(150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor 
18. Subject has received an investigational agent or vaccine within 30 days, or a biological 
product within 3 months or 5 elimination half-lives (whichever is longer) prior to the 
planned intake of study drug.  NOTE: Flu vaccine will be allowed upon Medical 
Monitor’s approval 
19. Clinically significant electrocardiogram (ECG) abnormalities or QTcF greater than 
450 ms for males and 470 ms for females at either Screening or Baseline, or any prior 
history of QT abnormality 
20. Use of cytochrome P450 (CYP)3A4 and P-glycoprotein (P-gp) inducers and inhibitors 
within 14 days prior to the first dose of study medication and throughout study duration 
21. Use of a new statin regimen from Screening and throughout study duration.            
NOTE: Subjects on a stable dose of statins for at least three months prior to Screening are 
allowed. No dose modification during the study will be allowed.  
22. Current use of fibrates.  NOTE: Subjects who discontinued fibrates for at least 3 months 
before Screening can participate 
23. Clinically significant history of drug sensitivity or allergy, as determined by the PI 
24. Uncontrolled diabetes mellitus (ie, HbA1c ≥9% or higher) 60 days prior to Day 1 
25. Use of a new antidiabetic regimen from Screening and throughout study duration, 
including metformin, GLP-1 agonists, sodium-glucose cotransporter-2 (SGLT2) 
inhibitors, sulfonylureas, or dipeptidyl peptidase-4 (DPP4) inhibitors, insulin or 
peroxisome proliferator-activated receptor (PPAR)γ agonists (pioglitazone or 
rosiglitazone). For pre-existing antidiabetic treatment, subjects should be on a stable 
dose of antidiabetic drugs: (1) for at least 2 months (for metformin and/or sulfonylureas), 
(2) 3 months (for SGLT2 or DPP4 inhibitors), or (3) 6 months (for GLP-1 receptor 
agonists and thiazolidinediones) prior to Screening. NOTE: Sulfonylureas and insulin are 
only permitted if glycemia is self-monitored by the subject; subjects treated with insulin 
are eligible if clinically stable on insulin treatment (ie, no recurrent acute hypo- or 
hyperglycemic episodes diagnosed clinically with serum glucose levels of <50 mg/dL or 
>200 mg/dL) for at least two months prior to Screening. 
26. Subjects with contraindications to MRI imaging, or not being able to have the MRI 
performed  
Subject Withdrawal: 
Subjects may choose to discontinue from the study at any time. Subjects may also be 
discontinued from the study at any time if the subject, Investigator or Sponsor determines that it 
is not in the best interest of the subject to continue participation. Subjects who prematurely 
withdraw from the study for any reason after having been randomized will not be replaced. 
Subjects who prematurely discontinue treatment early and received at least one dose of study 


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drug should return to the clinic as soon as possible to complete the EOT Visit and for the Safety 
Follow up Visit 4 weeks after their last dose. 
Individual subjects who meet the following Stopping Rules will be discontinued from further 
dosing and thorough evaluation (eg, close monitoring, additional PK samples, and follow-up) 
will be performed:  
• If ALT or aspartate aminotransferase (AST) increases to >5 × Baseline. 
• If ALT or AST increase >2 × Baseline AND the increase is accompanied by a 
concomitant total bilirubin increase >2 × Baseline OR the INR concomitantly increases 
by >0.2 
• If elevations of ALT/AST are accompanied by signs or symptoms of right upper quadrant 
abdominal pain, anorexia, nausea, vomiting fever, eosinophilia, and/or rash.  
Statistical Methods: 
Detailed statistical analysis will be outlined in the statistical analysis plan (SAP).   
Analyses Population 
• Safety Population: All subjects who receive at least one dose of study medication. 
Subjects will be included in the treatment group that corresponds to the study 
medication received during the study. 
• Efficacy Population: All subjects who receive at least one dose of study medication. 
Subjects will be included in the randomized treatment group. 
• Pharmacokinetic Population: All subjects receiving active study medication and 
having any measurable plasma concentration of study medication at any timepoint. 
Safety Analyses: Statistical methods for the safety analyses will be primarily descriptive in 
nature. No formal statistical comparisons of EDP-305 dose levels will be made. Safety data, 
including AEs, vital signs, ECGs, concomitant medications, and laboratory values will be 
summarized separately for each treatment group. Change from baseline will be included in 
summary tables for vital signs, ECG parameters, and laboratory parameters. Shift tables will also 
be generated for each safety laboratory parameter. All laboratory data will be included in the data 
listings and all test values outside the normal range will be flagged. Adverse events will be 
summarized by the Medical Dictionary for Regulatory Activities (MedDRA) system organ class 
and preferred term by treatment group.  
Efficacy Analyses: Change in ALT levels at Week 12 from pretreatment value will be calculated.  
All subjects in the efficacy population will be included. Comparisons of treatment arms will be 
performed using an analysis of covariance (ANCOVA) model with treatment and baseline values 
included in the model where appropriate. 
Pharmacokinetic Analyses: Plasma PK parameters for each dose level will be calculated from the 
concentrations of EDP-305 and its major metabolites measured in predose and postdose plasma 
samples. For each EDP-305 dose level, descriptive statistics (sample size, arithmetic means, 
geometric means, standard deviation (SD), % coefficient of variation, minimum, median, and 
maximum) will be presented. Figures will be created to display mean and individual subject 
EDP-305 concentration time curves in plasma on both a linear and logarithmic scale. The PK 


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parameters AUC0-t, Cmax, and Tmax will be calculated as indicated for plasma EDP-305 and its 
major metabolites.  
Sample Size Consideration:  Group sample sizes of 44 (in each dose group) and 22 placebo 
subjects achieves 80.438% power to reject the null hypothesis of equal means when the 
population mean difference in ALT is (−40.0)–(−10.0) =−30.0 with a standard deviation for both 
groups of 40.0 and with a significance level (alpha) of 0.050 using a two-sided two-sample 
equal-variance t-test. To account for a 20% discontinuation rate, 15 additional subjects will be 
enrolled to attempt to have at least 110 subjects who complete treatment bringing the total 
number of subjects enrolled to 125. 
 
 


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1. 
INTRODUCTION 
1.1. 
Overview 
EDP-305 
 is a farnesoid X receptor (FXR) 
agonist being investigated as a potential treatment for Nonalcoholic Steatohepatitis (NASH) with 
liver fibrosis. This study, EDP 305-101, is a randomized, double-blind, placebo-controlled, 
Phase 2 study designed to assess the safety, tolerability, and effectiveness of EDP-305 in subjects 
with NASH.  
1.2. 
Background  
1.2.1. 
NASH and Farnesoid X Receptor (FXR) 
Non-alcoholic fatty liver disease (NAFLD) is defined by excess accumulation of lipids in the 
liver which develops in the absence of other causes for secondary hepatic fat accumulation. 
Historically, NAFLD encompasses a wide spectrum of conditions from nonalcoholic fatty liver 
(NAFL) characterized by simple steatosis with minimal or no inflammation to NASH which is 
characterized by hepatic steatosis and inflammation with hepatocyte damage (ballooning) and 
with or without fibrosis (Bertot & Adams, 2016; Chalasani et al., 2012). 
Bile acids (BA) play a key role in regulating liver and metabolic homeostasis including 
regulation of lipid and glucose metabolism mediated through two receptor pathways, FXR and 
TGR5. FXR is a member of the nuclear hormone receptor superfamily and is considered a master 
regulator of many BA activities including feedback regulation of BA synthesis, gluconeogenesis 
and glycogenolysis in the liver, and peripheral insulin sensitivity in adipose tissue (McMahan et 
al., 2013). Given the critical role BAs play in liver homeostasis and the role of FXR in regulating 
BA biosynthesis, FXR has become a target for therapeutic intervention in NASH. 
1.2.2. 
Rationale for Development of EDP-305 for NASH 
NASH is considered a serious disease with unmet medical need and if not treated, it can progress 
to life-threatening conditions such as cirrhosis and hepatocellular carcinoma. Recently, NASH 
has been associated with an approximate 10-fold increase in liver-related mortality when 
compared to an identical age and sex-matched population (Ratziu, 2013). Over the past decade 
the frequency of NASH as the primary indication for liver transplant has increased dramatically, 
and is continuing to rise (Agopian et al., 2012). Based on the United Network for Organ Sharing 
and Organ Procurement and Transplantation Network (UNOS/OPTN) registry, from 2004 to 
2013, the number of registrants diagnosed with NASH demonstrated the greatest change, 
increasing 170% (from 804 to >2000 registrants) to become the second leading etiology of 
chronic liver disease among new waitlist registrants in 2013 (Wong et al., 2015). Data showed 
that patients with NASH were less likely to undergo liver transplantation and less likely to 
survive for 90 days on the waitlist than patients with hepatitis C virus (HCV) infection, alcoholic 
liver disease (ALD), or combination of HCV and ALD. In addition, by 2012 NASH had become 
the second leading etiology of hepatocellular carcinoma (HCC) leading to liver transplantation in 
the United States (US) (Wong et al., 2015). 


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Farnesoid X receptors are nuclear hormone receptors expressed in high amounts in body tissues 
that participate in BA metabolism including the liver, intestines, and kidneys. Bile acids (BAs) 
are the natural ligands of the FXRs. Farnesoid X receptors regulate the expression of the gene 
encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. 
Additionally, FXRs play a critical role in carbohydrate and lipid metabolism and in the 
regulation of insulin sensitivity. These receptors also modulate liver growth and regeneration 
during liver injury.  
Data has shown that hepatic expression of FXR is decreased in NAFLD patients, which is 
associated with hepatic triglyceride (TG) accumulation and hepatic steatosis. Effects observed in 
FXR deficiency animal models include hepatic steatosis, hyperlipidaemia, hyperglycemia, BA 
overload, inflammation and fibrosis (Xu, Li, Zhang, & Ji, 2014). Moreover, studies have shown 
that these metabolic dysfunctions can be improved by FXR activation, indicating that FXR 
agonism may represent a new modality for NASH treatment.  
In line with these findings, and to address the unmet medical need of NASH, Enanta 
Pharmaceuticals is developing EDP-305 as a FXR agonist that selectively activates FXRs. 
Nonclinical studies have shown that EDP-305 can decrease the expression of genes that encode 
lipogenic enzymes, as well as inflammation and fibrosis-related genes. In models of NASH and 
dyslipidemia, EDP-305 has demonstrated the potential for reduction in NASH and improvement 
in insulin sensitivity. Due to its promising early nonclinical safety and pharmacological profile, 
In a First-in-Human (FIH) clinical study in a limited number of subjects, EDP-305 appeared to 
positively affect levels of biomarkers associated with FXR activity. Thus, due to its promising 
nonclinical safety and pharmacological profile, and early clinical safety results, the Sponsor 
plans to continue investigation of EDP-305 as a potential treatment for NASH. 
 
 
1.3. 
Nonclinical Studies 
1.3.1. 
Mechanism of Action and Pharmacology 
A summary of pharmacology studies is presented below. Additional details for each study as 
well as details on additional studies can be found in the Investigator’s Brochure (IB). As noted 
for each study, the natural agonist of FXR, chenodeoxycholic acid (CDCA) and/or its close 
synthetic analog obeticholic acid (OCA), were used as controls. Obeticholic acid has recently 
been approved for the treatment of primary biliary cholangitis (PBC) and is being evaluated for 
the treatment of NASH. 
1.3.1.1. 
Mechanism of Action 
EDP-305 is an FXR agonist which, as discussed above, plays an essential role in the feedback 
regulation of BA biosynthesis. The efficacy and potency of EDP-305 was demonstrated in 
several in vitro assays.   
• In FXR Chinese Hamster Ovary (CHO) cell reporter assays and full-length FXR 
Human Embryonic Kidney 293 (HEK 293) cell reporter assays, EDP-305 and its 
major metabolites were potent stimulators of FXR activity. 


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• In human Huh7.5 hepatocyte cells, EDP-305 affected a dose-dependent increase in 
small heterodimer partner (SHP) gene expression and decrease in cytochrome P450 
(CYP)7A1 messenger ribonucleic acid (mRNA) expression. 
• In reporter gene assays measuring activation of 25 different nuclear receptors, only 
FXR was activated following incubation with EDP-305. 
1.3.1.2. 
In Vitro Pharmacology 
The ability of EDP-305 to regulate over 30 key genes involved in BA and lipid metabolism, 
inflammation, fibrosis, and glucose metabolism was evaluated using in vitro systems. 
Obeticholic acid was used as a comparator/control in all cases. The results, which are described 
in the IB, demonstrated that EDP-305 affected the expression of 38 genes important in BA 
(5 genes) and lipid (9 genes) metabolism, inflammation (10 genes), fibrosis (8 genes) and 
glucose metabolism (6 genes).   
1.3.1.3. 
In Vivo Pharmacology 
The efficacy of EDP-305 was demonstrated in animal models of disease: 
• The regulation of FXR downstream genes critical for BA metabolism was assessed in 
C57BL/6 mice treated with EDP-305 or OCA orally for 5 days. EDP-305 induced a 
dose-dependent increase in fibroblast growth factor (FGF)-15 and SHP gene 
expression in the ileum, and dose-dependent increases in SHP and bile salt export 
pump (BSEP) mRNA and decreases in CYP7A1 mRNA in the liver. In all cases, 
EDP-305 was more active than OCA. 
• STAM mice develop NASH, fibrosis and ultimately hepatocellular carcinoma, in a 
manner replicating the pathological progression seen in the human disease. Treatment 
of STAM mice with EDP-305 for 4 weeks resulted in a significant reduction in 
nonfasted blood glucose levels, significant improvement in the NAFLD activity score 
(NAS), and significant reductions in key genes associated with fibrosis (ie, smooth 
muscle actin), and lipogenesis (sterol regulatory element binding protein 1c). In all 
cases, EDP-305 was more active than OCA. 
• The effects of preventative and therapeutic treatment with EDP-305 and OCA on 
hepatic lipids were assessed in a hamster model of dyslipidemia. In this study, 
treatment began concurrently with the start of a 4-week high fat/high cholesterol diet 
(preventative model) or two weeks later (therapeutic model). EDP-305 and OCA 
stimulated significant reductions in hepatic lipid levels in both the therapeutic and 
preventative treatment protocols. Additionally, both EDP-305 and OCA showed a 
moderate reduction in homeostasis model assessment – insulin resistance 
(HOMA-IR) and plasma insulin levels in the therapeutic model, suggesting the 
potential for improvement in insulin sensitivity. 
• Mdr2-/- mice develop progressive biliary-type (periportal) fibrosis resembling that 
observed in primary sclerosing cholangitis (PSC), PBC, cystic fibrosis liver disease 
(CFLD) and congenital biliary cirrhosis (Ikenaga et al., 2015). In Mdr2-/- mice with 
pre-established fibrosis, administration of EDP-305 (10 or 30 mg) resulted in 
significant decreases in serum alanine aminotransferase (ALT) and aspartate 
































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2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is as follows:  
• To evaluate change in ALT levels 
• To evaluate the safety and tolerability of EDP-305 
2.1.2. 
Secondary Objectives 
The secondary objectives of the study are as follows: 
• To evaluate the effect of EDP-305 on liver fat  
• To evaluate the effect of EDP-305 on fibrosis (liver stiffness) 
• To evaluate the effect of EDP-305 on non-invasive liver fibrosis markers 
• To evaluate the effects of EDP-305 on lipids  
• To evaluate the effects of EDP-305 on glucose metabolism 
• To evaluate the effects of EDP-305 on inflammatory markers 
• To evaluate the PK of EDP-305 and its metabolites in plasma 
• To evaluate the effect of EDP-305 on body weight 
• To evaluate the effect of EDP-305 on waist to hip (WTH) ratio 
• To evaluate the pharmacodynamics of EDP-305 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoints of the study are: 
• Change from Baseline in ALT levels at Week 12 
• Frequency of AEs, SAEs, and AEs leading to discontinuation through Week 12  
2.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are as follows: 
• Change from Baseline in percentage of fat in the liver as assessed by magnetic 
resonance imaging-estimated proton density fat fraction (MRI-PDFF) at Week 12 
• Change from Baseline in liver stiffness as assessed by magnetic resonance 
elastography (MRE) at Week 12 


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• Change from Baseline of noninvasive liver fibrosis markers (Enhanced Liver Fibrosis 
[ELF] panel) and PRO C3 at Week 12  
• Change from Baseline in NAFLD Fibrosis Score (NFS), AST to Platelet Ratio Index 
(APRI), and fibrosis 4 (FIB-4) at Week 12 
• Change form baseline in TG, total cholesterol (TC), high density lipoprotein 
cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), adiponectin and 
apolipoproteins (Apo)A1, B, C3 at Week 12 
• Change from Baseline in fasting glucose and insulin, HOMA index (in nondiabetic 
subjects) and glycated hemoglobin (HbA1c) in subjects with Type 2 diabetes mellitus 
(T2DM) at Week 12 
• Change from Baseline in fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β, alpha2 
macroglobulin, and haptoglobin levels at Week 12 
• Pharmacokinetic parameters of EDP-305 (and metabolites): Cmax, tmax, and AUClast  
• Change from Baseline in body weight at Week 12  
• Change in WTH ratio at Week 12 
• Pharmacodynamic parameters of EDP-305: FGF19, C4, and bile acid (BA) at 
Week 12 
 


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3. 
SELECTION OF SUBJECTS 
A total of approximately 125 subjects with a diagnosis of NASH are planned for enrollment into 
this study.   
3.1. 
Subject Inclusion Criteria  
Each subject must meet all of the following criteria to be enrolled into this study: 
1. An informed consent document must be signed and dated by the subject 
2. Male and female subjects of any ethnic origin between the ages of 18 and 75 years, 
inclusive 
3. Male or female with presence of NASH by: 
• Histologic evidence on a historical liver biopsy within 24 months of Screening 
consistent with NASH with fibrosis (no cirrhosis), and elevated ALT at Screening 
NOTE: Vitamin E should not have been initiated after the date the biopsy was performed 
and subjects should have a stable weight since the liver biopsy was performed defined by 
no more than a 5% change of initial body weight 
 OR 
• Phenotypic diagnosis of NASH based on elevated ALT and diagnosis of T2DM or 
pre-diabetes 
NOTE: Elevated ALT must be ≥ 50 IU/L and ≤ 200 IU/L; Known T2DM or pre-diabetes 
with one of the following criteria: random plasma glucose concentration >200 mg/dL 
(11.1 mmol/L) OR fasting plasma glucose >126 mg/dL (7.0 mmol/L) OR 2-hour post-
load glucose >200 mg/dL (11.1 mmol/L) during a 75 g oral glucose tolerance test 
(OGTT) OR HbA1c of at least 6% with or without concomitant treatment with 
Metformin 
AND 
• Screening MRI-PDFF with >8% steatosis  
4. Body mass index (BMI) >25 kg/m2. NOTE: for Asian-Americans, BMI >23 kg/m2  
5. Subjects must have Screening laboratory values for Hepatitis B surface antigen (HBsAg) 
anti-HCV antibodies and HCV RNA and Human Immunodeficiency Virus (HIV) 1 and 2 
antibodies (Ab) as seronegative. Note: subjects previously infected by chronic hepatitis C 
and treated with direct acting antivirals (DAAs) with sustained virologic response (SVR) 
for at least 3 years will be allowed 
6. Female subjects of childbearing potential must agree to use two effective methods of 
contraception from the date of Screening until 90 days after the last dose of EDP-305. 
Effective methods of contraception are defined as: 
• A condom for the male partner and at least one of the following for the female 
participant: 
o Intrauterine device 
o Oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive 
Note: The above does not apply to female subjects of nonchildbearing potential (ie, 
physiologically incapable of becoming pregnant) defined as: 


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- 
Has had a complete hysterectomy greater than or equal to 3 months prior to dosing or 
- 
Has had a bilateral oophorectomy (ovariectomy) or 
- 
Has had a bilateral tubal ligation or fallopian tube inserts or 
- 
Is post-menopausal (a demonstration of a total cessation of menses for ≥1 year with a 
follicle stimulating hormone (FSH) level of >35 mIU/mL) 
7. All male participants who have not had a vasectomy must use effective contraception 
from Day −1 to 90 days after their last dose of study drug. Effective contraception is 
defined as a condom and spermicide for the male, or condom and at least one of the 
following for a female partner: 
• Intrauterine device 
• Oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive 
• Be of non-childbearing potential 
8. Male subjects must agree to refrain from sperm donation from the date of Screening until 
90 days after their last dose of study drug 
9. Subject must be willing and able to adhere to the assessments, visit schedules, 
prohibitions and restrictions, as described in this protocol 
3.2. 
Subject Exclusion Criteria 
Subjects will not be eligible to participate in the study if they meet any of the following criteria: 
1. Laboratory Screening Results: 
• Total bilirubin >ULN (normal range 0.2–1.2 mg/dL)  
NOTE: Patients with Gilbert’s syndrome will be allowed if they have a known 
history of Gilbert’s syndrome with a normal direct bilirubin value and normal 
reticulocyte count, and upon review by the medical monitor. 
• Total white blood cells (WBC) <3,000 cells/mm3 
• Absolute neutrophil count (ANC) <1,500 cells/mm3 
• Platelet count <140,000/mm3 
• Prothrombin time (international normalized ratio, INR) >1.2 
• Creatine kinase above the upper limit of normal (ULN) except when in relation 
with intense exercise 
• Serum creatinine >2 mg/dL or clearance creatinine <60 mL/min (based on 
Cockroft-Gault method) 
2. Known history of alpha-1-Antitrypsin deficiency 
3. Use of an experimental treatment for NASH within the past 6 months 
4. Prior use and/or concurrent treatment with obeticholic acid (OCA) 
5. Use of immunosuppressant (eg, corticosteroids) for more than 2 weeks in duration within 
1 year prior to Screening and during the course of the study 
6. Use of experimental or unapproved drugs within a year of Screening 
7. Any other condition(s) (including cardiovascular diseases) that would compromise the 
safety of the subject or compromise the quality of the clinical study, as judged by the 
Principal Investigator (PI) 


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8. Pregnant or nursing females 
9. Recipients of liver or other organ transplantation or anticipated need for orthotropic organ 
transplantation in one year as determined by a Model for End-Stage Liver Disease 
(MELD) Score ≥15 
10. Clinical suspicion of advanced liver disease or cirrhosis 
11. Coexisting liver or biliary diseases, such as PSC, choledocholithiasis, acute or chronic 
hepatitis, autoimmune hepatitis, alcoholic liver disease, acute infection of bile duct 
system or gall bladder, history of gastrointestinal bleeding (secondary to portal 
hypertension), cirrhosis 
12. Suspicion of cancer (eg, liver cancer) with the exception of basal cell carcinoma that has 
been resected 
13. Cirrhosis with or without  complications, including history or presence of: spontaneous 
bacterial peritonitis, hepatocellular carcinoma, bilirubin >2 × ULN 
14. Hepatorenal syndrome (type I or II) or Screening serum creatinine >2 mg/dL 
(178 μmol/L) 
15. Prior variceal hemorrhage, uncontrolled encephalopathy, Child-Pugh Class A, B, and C, 
esophageal varices, or refractory ascites within the previous 6 months of Screening 
(defined as date informed consent signed) 
16. Any condition possibly affecting drug absorption (eg, gastrectomy <3 years prior to 
Screening) 
17. History of regular alcohol consumption exceeding 14 drinks/week for females and 
21 drinks/week for males within 6 months of Screening. One drink is defined as 5 ounces 
(150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor 
18. Subject has received an investigational agent or vaccine within 30 days, or a biological 
product within 3 months or 5 elimination half-lives (whichever is longer) prior to the 
planned intake of study drug. NOTE: Flu vaccine will be allowed upon Medical 
Monitor’s approval 
19. Clinically significant electrocardiogram (ECG) abnormalities or QTcF greater than 
450 ms for males and 470 ms for females at either Screening or Baseline, or any prior 
history of QT abnormality 
20. Use cytochrome P450 (CYP)3A4 and P-glycoprotein (P-gp) inducers and inhibitors 
within 14 days prior to the first dose of study medication and throughout study duration 
21. Use of a new statin regimen from Screening and throughout study duration.            
NOTE: Subjects on a stable dose of statins for at least three months prior to Screening are 
allowed. No dose modification during the study will be allowed.  
22. Current use of fibrates. NOTE: Subjects who discontinued fibrates for at least 3 months 
before Screening can participate 
23. Clinically significant history of drug sensitivity or allergy, as determined by the PI. 
24. Uncontrolled diabetes mellitus (ie, HbA1c ≥9% or higher) 60 days prior to Day 1 
25. Use of a new antidiabetic regimen from Screening and throughout study duration, 
including metformin, GLP-1 agonists, sodium-glucose cotransporter-2 (SGLT2) 
inhibitors, sulfonylureas, or dipeptidyl peptidase-4 (DPP4) inhibitors, insulin or 
peroxisome proliferator-activated receptor (PPAR)γ agonists (pioglitazone or 
rosiglitazone). For pre-existing antidiabetic treatment, subjects should be on a stable 
dose of antidiabetic drugs: (1) for at least 2 months (for metformin and/or sulfonylureas), 
(2) 3 months (for SGLT2 or DPP4 inhibitors), or (3) 6 months (for GLP-1 receptor 


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agonists and thiazolidinediones) prior to Screening. NOTE: Sulfonylureas and insulin are 
only permitted if glycemia is self-monitored by the subject; subjects treated with insulin 
are eligible if clinically stable on insulin treatment (ie, no recurrent acute hypo- or 
hyperglycemic episodes diagnosed clinically with serum glucose levels of <50 mg/dL or 
>200 mg/dL) for at least two months prior to Screening. 
26. Subjects with contraindications to MRI imaging, or not being able to have the MRI 
performed 


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4. 
STUDY DESIGN  
This is a Phase 2 dose-ranging, randomized, double blind, and placebo-controlled study 
evaluating the safety, tolerability, PK and efficacy of EDP-305 in subjects with NASH.  
The study is composed of 3 phases or periods:  
• Screening period which includes the Screening Visit and may occur over a time period of 
28 days prior to the first dose of study drug   
• Treatment period which begins with the first dose of study drug on Day 1 and concludes 
with the End of Treatment (EOT) Visit on Day 84 (Week12) 
• Safety Follow-up period which includes the End of Study (EOS) Visit on Day 112 
4.1. 
Dose and Treatment Schedule 
Subjects will be randomized 2:2:1 to receive one of two doses of EDP-305 or placebo. Every 
subject will receive a single daily dose of blinded study drug for a total of 12 weeks. An 
overview of the study design is shown in Figure 1. Study visits and assessments are detailed in 
the Schedule of Assessments (SoA) (Table 19). 
Figure 1. 
Study Design 
 
 
 
 
Abbreviations: D=Day; W=Week 
 
4.2. 
Rationale for Study Design  
This proposed study will evaluate EDP-305 in patients with NASH who will be randomized to 
one of three treatment groups: (1) 1 mg EDP-305, (2) 2.5 mg EDP-305, or (3) placebo in a 2:2:1 
ratio. 














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A comprehensive list of CYP3A4 inducers and inhibitors can be found at: 
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.aspx 
Additionally, medications that inhibit or induce the transporter proteins P-gp are also prohibited 
during study participation. A list of these medications can be found at 
http://bts.ucsf.edu/fdatransportal/index/. 
Use of a new statin regimen is prohibited from Screening and throughout study duration. 
Subjects on a stable dose of statins  for at least three months prior to Screening are allowed. 
However, no dose modification during the study will be allowed. 
Use of a new antidiabetic regimen from Screening and throughout study duration, including 
metformin, GLP-1 agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, sulfonylureas, 
or dipeptidyl peptidase-4 (DPP4) inhibitors, insulin or peroxisome proliferator-activated receptor 
(PPAR)γ agonists (pioglitazone or rosiglitazone). For pre-existing antidiabetic treatment, 
subjects should be on a stable dose of antidiabetic drugs: (1) for at least 2 months (for metformin 
and/or sulfonylureas), (2) 3 months (for SGLT2 or DPP4 inhibitors), or (3) 6 months (for GLP-1 
receptor agonists and thiazolidinediones) prior to Screening. NOTE: Sulfonylureas and insulin 
are only permitted if glycemia is self-monitored by the subject; subjects treated with insulin are 
eligible if clinically stable on insulin treatment (ie, no recurrent acute hypo- or hyperglycemic 
episodes diagnosed clinically with serum glucose levels of <50 mg/dL or >200 mg/dL) for at 
least two months prior to Screening. 
5.10. 
Other Restrictions 
Table 14 outlines protocol restrictions other than prohibited medications outlined above and the 
timing of those restrictions.  
Table 14: 
Protocol Restrictions 
Restricted 
Medication/Food/Activity  
Timing of Restriction 
From (minimum) 
To 
Experimental treatment for NASH 
6 months prior to Screening 
End of Study Visit 
OCA 
Any prior or concurrent use 
End of Study Visit 
Immunosuppressants (eg, 
corticosteroids) for more than 
2 weeks 
1 year prior to Screening 
End of Study Visit 
New statin regimen 
3 months prior to Screening 
End of Study Visit 
Experimental or unapproved 
drugs  
Within 1 year of Screening 
End of Study Visit 
Investigational agent or vaccine* 
30 days prior to first dose of study 
drug 
End of Study Visit 
Biologic Product 
3 months ( or 5 elimination half-lives) 
prior to first dose of study drug 
End of Study Visit 
New antidiabetic regimen of 
metformin and/or 
sulfonylureas 
2 months prior to Screening 
End of Study Visit 
New antidiabetic regimen of 
insulin 
2 months prior to Screening 
End of Study Visit 


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Restricted 
Medication/Food/Activity  
Timing of Restriction 
From (minimum) 
To 
New antidiabetic regimen of 
SGLT2 inhibitors 
3 months prior to Screening 
End of Study Visit 
New antidiabetic regimen of 
DPP4 inhibitors 
3 months prior to Screening 
End of Study Visit 
New antidiabetic regimen of 
GLP-1 receptor agonists or 
thiazolidinediones 
6 months prior to Screening 
End of Study Visit 
*Flu vaccine will be allowed upon Medical Monitor’s approval 


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6. 
BLINDING  
The study will be double-blinded meaning the subjects, Investigators, and site staff will be 
blinded to treatment assignment until the completion of the study. 
All study personnel will be blinded to treatment assignment except for the following individuals:  
• Unblinded Enanta/Clinical Research Organization (CRO) statistician for purpose of 
generating and monitoring the randomization list 
• Unblinded Drug Supply Chain personnel for the purpose of monitoring drug supplies 
• Enanta/CRO Pharmacovigilance Group and Regulatory Affairs representatives when 
required to satisfy regulatory reporting requirements 
• Bioanalytical Laboratory for the purpose of measuring drug concentrations 
6.1. 
Blinding of Study Samples 
6.1.1. 
Blinding of NASH Biomarkers, Fibrosis and Inflammatory Markers, 
MRI/MRE, and Laboratory Liver Test Results 
Investigators, site personnel, and CRO/Sponsor will be blinded to the following laboratory tests 
postbaseline:  
• Biomarker laboratory data  
o FGF-19, total BAs  
o C4 [7α-OH-4-cholesten-3-one]  
o CK18  
o GLP-1 
• Fibrosis and inflammatory markers  
o ELF Panel (ie, hyaluronic acid [HA], procollagen III amino terminal peptide 
[PIIINP], and tissue inhibitor of metalloproteinase 1 [TIMP-1]) 
o PRO C3 
o Fibrinogen, CRP, alpha2 macroglobulin and Haptoglobin 
o Tumor necrosis factor alpha and beta (TNF-α and β) 
o Interleukin (IL)-6. IL1β 
o APRI 
o NFS 
o FIB-4 
• Liver Tests 
o ALT 


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o AST 
o GGT 
However, abnormal liver test results will be flagged if the lab results are ≥2 × baseline and these 
flagged results will be shared with the Investigator and the Medical Monitor (and/or designee) 
for safety monitoring purposes. 
MRI and MRE results postbaseline will be blinded to the Investigators, site personnel, and 
Sponsor. Additionally, the MRI facility and radiologist will be blinded to the subject’s study 
treatment and the MRI and MRE readings will be read centrally. 
6.1.2. 
Blinding of Pharmacokinetic Samples 
All PK sample concentration measurements will be blinded to the Investigators, site staff, and 
study subjects. The laboratory performing bioanalytical analysis, however, will be provided the 
randomization scheme.  
6.2. Unblinding  
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The unblinding method will use the IWRS process. 
Unblinding of individual subject treatment by the investigator should be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study treatment is 
necessary for clinical management. In such cases, the investigator must first attempt to contact 
the study medical monitor to discuss and agree to the need for unblinding. In situations in which 
investigator have attempted and failed to contact the medical monitor, and/or the urgency of the 
case required immediate action, investigators should use their best judgment, based on the nature 
and urgency of the clinical situation, and proceed with unblinding. 
• For unblinding, in the event the local 
 medical monitor cannot be reached, sites at all 
locations should call the following 24/7 global medical coverage hotline:  
 
Once a subject's treatment assignment has been unblinded for a medical emergency or urgent 
clinical situation, the medical monitor and study coordinator should be notified within 24 hours 
of unblinding of the treatment. Information relating to unblinding (eg, the reason, date) should be 
clearly recorded in the subject’s study file. In addition, the Investigator should consider whether 
the clinical event that prompted unblinding should be considered a serious adverse event (SAE), 
according to the regulatory definitions or criteria for SAEs, and if so, submit an SAE report as 
described in Section 9.2. 
The Safety and Risk Management group will also unblind any SAE reports in compliance with 
regulatory reporting requirements. In addition, Enanta may unblind individual subjects at any 
time for matters relating to safety concerns.  
NOTE: Investigative sites will be provided country-specific toll-free telephone numbers.  


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7. 
STUDY CONDUCT AND VISIT SCHEDULE 
7.1. 
Study Visits  
Details of assessments at each visit are presented in the SoA (Table 19).  
7.1.1. 
Screening  
Screening procedures will occur after the subject signs and dates an Institutional Review Board 
(IRB) or Ethics Committee (EC) approved informed consent form (ICF) and provides 
authorization to use protected health information (See Section 12.1.3). The ICF will be 
completed prior to conduct of any study-specific procedures.  
Screening procedures will be conducted as listed in the SoA (Table 19). Screening will occur 
over a period lasting no more than 28 days. For each subject, Screening can occur on one day or 
over multiple days. All Screening assessments must occur no earlier than 28 days before the first 
dose of study drug at the Day 1 visit. If any Screening assessment falls outside of that window, 
the Investigator should consult with the Sponsor’s Medical Monitor to determine if the 
assessment needs to be repeated.   
If a subject does not qualify for study entry due to an out-of-range lab value that is not consistent 
with the subject’s medical history or appears spurious, with the approval of the Medical Monitor, 
the subject may retest that lab parameter once if the Investigator believes that he/she would 
qualify upon retest. 
At the completion of Screening procedures/assessments, subjects who qualify for the study 
should be given detailed instructions on fasting requirements prior to the first dose and when to 
return to the clinic for the Day 1 visit. 
7.1.2. 
Rescreening 
Subjects who met all eligibility criteria that were current at the time of their Screening Visit may 
be rescreened under the following circumstances with the approval of the Medical Monitor: 
• Subjects within the Screening Period who met all eligibility criteria, but are not able 
to obtain required documentation within the allotted window for the Screening 
Period.  
• Subjects who are eligible, but transiently (for personal reasons) unable to commit to 
all study procedures. 
• Subjects who have abnormal laboratory results, which may potentially reflect 
erroneous results, based on Investigator judgement.  
7.1.3. 
Baseline (Day 1) 
Subjects who meet all inclusion criteria and none of the exclusion criteria will report to the clinic 
on the morning of Study Day 1 after fasting overnight for a minimum of 8 hours. After a review 
of applicable inclusion and exclusion criteria, subjects who continue to satisfy eligibility 




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If a subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. Enanta may retain and continue to use any data collected before such withdrawal of 
consent. 
For safety monitoring purposes, subjects who withdraw after receiving study drug should return 
to the clinic as soon as possible and undergo the EOT evaluations SoA (Table 19). Subjects 
should then return for the Safety Follow Up assessments 4 weeks after the last dose of study 
drug. Any subject who withdraws with ongoing AEs/SAEs should be followed until resolution of 
their AE(s) or until the Investigator has determined that the AE(s) has stabilized. 
Site personnel will attempt to contact any subject who does not return to the clinic for scheduled 
visit at least three times using the subject’s preferred method of communication, followed by a 
certified letter if the three attempts were unsuccessful. Any subject who still cannot be reached 
following those attempts will be considered Lost to Follow-up. These subjects will be included 
in the analysis as indicated in Section 11. 
7.2.1. 
Withdrawal Criteria 
Subjects may be discontinued from the study at any time if the subject, Investigator or Sponsor 
determines that it is not in the best interest of the subject to continue participation. Reasons for 
discontinuation include: 
• Adverse Event 
• Noncompliance with study drug dosing or study procedures 
• Lack of efficacy 
• Lost to follow-up 
• Withdrawal by subject 
• Protocol deviation  
• Pregnancy 
• Sponsor’s decision to terminate the study 
• Other 
Subject-specific stopping rules due to AEs and/or laboratory abnormalities are outlined in 
Section 10.1. 
Subjects who prematurely withdraw from the study for any reason after having been randomized 
will not be replaced. 
7.2.2. 
Documentation of Withdrawal of Subjects 
The reason for early withdrawal/termination/lost-to-follow-up of any subject from the study must 
be documented on the appropriate eCRF. If the reason for early withdrawal is an AE or an 
abnormal laboratory value, the specific event or test result, if available, should be recorded on 
the AE eCRF and the subject should be monitored until the event is resolved or deemed stable by 
the Investigator. 


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7.3. 
Site or Study Discontinuation 
7.3.1. 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects. 
• Subject enrollment is unsatisfactory. 
• A decision from the IRB/EC or regulatory authority to terminate the study. 
If the study is suspended or terminated for safety reasons, Enanta Pharmaceuticals, Inc. will 
promptly notify the Investigator and will also inform the regulatory authorities of the suspension 
or termination of the study and the reasons for the action. The Investigator is responsible for 
promptly informing the IRB/EC, and providing the reasons for the suspension or termination of 
the study. 
7.3.2. 
Site Termination 
A single site may warrant termination under the following conditions: 
• Failure of the site to enroll subjects into the study at an acceptable rate 
• Failure of the site to comply with pertinent governmental regulations as appropriate 
• Submission of knowingly false information from the research facility to the Sponsor, 
clinical monitor, or governmental authority 
• Failure to adhere to the protocol requirements 
• Data recording is inaccurate or incomplete. 
• Principal Investigator does not adhere to the protocol or applicable regulatory 
guidelines in conducting the study. 
7.3.3. 
Study Termination Procedures 
If the study is terminated by Enanta Pharmaceuticals, Inc. for one of the reasons listed above, or 
upon completion of the study, the following activities must be conducted by the study monitor 
and/or site personnel: 
• Return of all study data to Enanta Pharmaceuticals, Inc. or designee 
• Respond to and complete all requests for data clarifications 
• Accountability and final disposition of used and unused study drug 
• Review of site records for completeness 
• Shipment of all applicable biological samples (including PK samples) to the 
designated laboratory 


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8. 
STUDY PROCEDURES/EVALUATIONS  
8.1. 
Timing of Assessments 
The timing of assessments is shown in Table 19. 
8.2. 
Demographics and Medical History 
Demographics and baseline characteristics including date of birth, gender, race, ethnicity and 
medical history will be obtained from each subject and entered in the eCRF as reported. As a 
general rule, all medical events occurring within the last 6 months should be recorded. For events 
which occurred more than 6 months ago (and which are not ongoing), only significant or relevant 
events should be entered on the eCRF. Any items in the history that are still ongoing should be 
noted as such in the eCRF. All surgeries occurring in adulthood should be recorded in the eCRF 
while methods of contraception, if applicable, should only be documented in the source 
documents. If possible, the date of diagnosis of NASH should be recorded. 
8.3. 
Clinical Evaluations 
8.3.1. 
Vital Sign Measurements and Electrocardiograms 
Vital signs will include heart rate (HR), respiratory rate, blood pressure (BP) and oral 
temperature. Vital signs will be measured at times shown in the SoA after the subject has been 
supine for 5 minutes and before dosing. Oral temperature should be taken at the Screening, 
Day 1, and EOS visits. 
Resting 12-lead ECGs will be done locally and recorded at the times indicated in the SoA after 
the subject has been supine for 5 minutes and before dosing. A standard bedside 12-lead ECG 
machine that calculates heart rate and measures the PR, QRS, QT, RR, and QTc (QTcF) intervals 
will be utilized. If a blood draw and ECG are scheduled at the same time, then the ECG should 
be obtained first.  
The Investigator or designee should review the ECGs in real-time for gross abnormalities and 
interval measurements of concern (absolute readings and for postdose ECGs, change from 
baseline). The clinical interpretation by the PI or designee of the ECGs should be recorded on a 
hard copy of the ECGs (ie, clinically significant [CS] or nonclinically significant [NCS]).  
The Investigator or designee should repeat any ECG with a change from Baseline in QTcF 
>60 msec or a QTcF interval >500 msec. Also, ECGs may be repeated at the discretion of the 
Investigator to account for erroneous readings. 
Prior to dosing the Baseline ECG must be reviewed to confirm that no clinically significant 
cardiac abnormalities are present.  
8.3.2. 
Physical Examination 
The Investigator or designee will perform the physical examination. A full physical examination 
will be conducted at Screening and EOS as indicated in the SoA (Table 19) and will include a 
review of the following systems: head/neck/thyroid; eyes/ears/nose/throat (EENT); respiratory; 


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cardiovascular; chest, lymph nodes; abdomen; skin; musculoskeletal; and neurological. Breast, 
anorectal, and genital examinations will be performed when medically indicated. All subsequent 
physical examinations will be targeted to new signs and symptoms including specific 
assessments of any changes from previous status. Only clinically significant abnormalities 
should be recorded in the eCRF (eg, use of contact lenses does not need to be recorded). 
8.3.3. 
Weight, Body Mass Index, and Waist to Hip Ratio 
Height and body weight should be obtained with the subject in light clothes and no shoes. Body 
mass index should be calculated at Screening (to assess eligibility) according to the following 
equation: 
BMI=weight (kg)/height (m)2 
The waist to hip measurements should be obtained with the subject in light cloths or 
undergarments only. The waist circumference measurement should be obtained level with the 
belly button and upon exhale. The hip measurement should be obtained with the measuring tape 
across the largest part of the buttocks. The ratio is calculated by dividing the measurement of the 
waist circumference by the measurement of the hip circumference.  
These measurements will be obtained as specified in the SoA (Table 19). 
8.3.4. 
Adverse Events 
The Investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in Section 8.1 of this protocol. All AEs and SAEs 
must be recorded in the source documents and eCRF as described below (Section 9.2). At all 
visits, the Investigator or designee should inquire about the occurrence of AEs. The following are 
examples of open-ended questions that may be used to obtain this information: “How are you 
feeling?”; "Have you had any medical problems recently?"; "Have you taken any new medicines 
since your last visit/assessment?" 
It is the Investigator’s responsibility to ensure any necessary additional therapeutic measures and 
follow-up procedures are performed and documented in the subject source notes and eCRF. Any 
medication taken during the course of the study through the end of the study will be recorded 
with indication, dosage, route of administration, and start and stop dates of administration. All 
subjects will be questioned about concomitant medication at each clinic visit as indicated in the 
SoA (Table 19).  
8.4. 
Clinical Laboratory and Diagnostic Procedures 
All laboratory samples will be analyzed by a centralized laboratory (ie, Covance Laboratory). A 
laboratory reference manual will be provided to the site detailing kit contents, reordering 
supplies, sample collection (see below), handling, storage and shipment instructions. All 
unblinded laboratory values will be reviewed by the Investigator, documented, and the results 
maintained in the source documents. All out-of-range lab findings require an interpretation as to 
whether or not they are of clinically significance. Clinically significant laboratory findings in the 
opinion of the Investigator should be recorded as an AE (or SAE as appropriate) (Section 9.1).  


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At all visits blood samples should be collected before the first dose of the study drug. Additional 
clinical laboratory evaluations will be performed at other times if judged clinically appropriate 
by the Investigator, or if the safety review of the data suggests a more detailed assessment of 
clinical laboratory safety evaluations. Any changes to the scheduled times of the clinical 
laboratory determination will be agreed to by Enanta and the Investigator, and documented in the 
study trial master file (TMF). 
For selected biomarker analysis, fasting serum or plasma samples should be collected before the 
daily dose of study drug for analysis of FGF-19, BAs, and C4 at visits indicated in the SoA 
(Table 19).Samples should be collected after an overnight fast of a minimum of 8 hours. 
8.4.1. 
Safety Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected according to the 
SoA (Table 19). Subjects should be instructed to fast overnight for at least 8 hours prior to the 
blood draw for the laboratory testing for all visits. Samples will be collected and processed 
according to the procedures provided by the clinical laboratory in the Laboratory Manual. 
Laboratory parameters to be collected are outlined in Table 15. 
Creatinine clearance will be calculated by the central laboratory using the Cockcroft Gault 
equation and actual body weight: 
CLCr (mL/min) = {((l40−age [years])×weight)/(72×SCr)}×0.85 (if female).  
On line calculator can be found at: 
https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc. 
SCr =serum creatinine 
8.4.2. 
Noninvasive Evaluations of Fibrosis 
The ELF panel combines 3 biomarkers that have been shown to correlated with the level of liver 
fibrosis assessed by a liver biopsy. These biomarkers include HA, PIIINP, and TIMP-1. These 
parameters along with PRO-C3 will be assessed as outlined in Table 19.  
Fibrosis will be estimated using the APRI, the fibrosis 4 (FIB-4) formulae, and the NAFLD 
fibrosis score (NFS).  
The APRI will be calculated by the central laboratory using the following formula: 
([AST IU/L / AST ULN] / [Platelet count 109/L]) × 100 = APRI 
On line calculator can be found at:  http://www.hepatitisc.uw.edu/page/clinical-calculators/apri 
The FIB-4 score will be calculated using the following formula:  
(Age [years] × AST [IU/L]) / (Platelet count [109/L] × ( √ ALT [IU/L]) ) 
On line calculator can be found at: http://www.hepatitisc.uw.edu/page/clinical-calculators/fib-4 
The NFS will be calculated by the central laboratory using the following formula:  
-1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG/diabetes (yes = 1, no = 0) + 
0.99 × AST/ALT ratio – 0.013 × platelet (×109/L) – 0.66 × albumin (g/dl) 
On line calculator can be found at: 


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 https://www.mdcalc.com/nafld-non-alcoholic-fatty-liver-disease-fibrosis-score 
Refer to the SoA (Table 19) for the timing of these tests. 


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Table 15: 
Laboratory Evaluations 
CHEMISTRY PANEL 
Alanine Aminotransferase (ALT/SGPT) 
Albumin, Serum 
Albumin/Globulin (A/G) Ratio (calculation) 
Alkaline Phosphatase, Serum 
Amylase 
Aspartate Aminotransferase (AST/SGOT) 
Bilirubin, Total and Direct 
Blood urea nitrogen (BUN) 
BUN/Creatinine Ratio (calculation) 
Calcium, (Serum) 
Creatine Kinase  
Creatinine, Serum (and creatinine clearance 
[Cockroft Gault]) 
Uric Acid 
Electrolyte Panel (Na+, K+, Cl-, Bicarb.) 
Phosphorus 
Gamma Glutamyl Transferase (GGT) 
Globulin, Total 
Glucose, Serum 
Lactate Dehydrogenase (LDH) 
Lipase 
Protein, Total, Serum 
HbA1c 
HOMA indices 
Fasting Insulinemia 
Fasting Glucose 
Total Cholesterol (TC) 
Triglycerides (TG) 
HEMATOLOGY PANEL 
Hemoglobin 
Hematocrit 
Differential WBC Count (percentage and absolute): 
Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelets 
Red Blood Count (RBC) 
White Blood Cell (Count) (WBC) 
VIRAL DETECTION FOR ENTRY CRITERIA 
Human immunodeficiency virus (HIV)-1, HIV-2, 
Hepatitis B virus (HBV) (Hepatitis B surface antigen 
[HBsAg]), hepatitis C virus (HCV) 
MARKERS OF CV RISKS AND LIPIDS 
Triglycerides (TG) 
HDL and LDL-P (high and low-density lipoprotein 
particles using a lipoprotein subfractions test; e.g., 
LIPOPROFILE)  
lipoprotein (a) [Lp(a)] assay  
apoA-I, apoB, apoC3, apoB/A Ratio, apoE isoforms (E2, 
E3, E4)  
Total Cholesterol (TC) 
High Density Lipoprotein – Cholesterol (HDL-C) 
Low-Density-Lipoprotein – Cholesterol (LDL-C) 
Total/HDL Cholesterol (CT) Ratio 
Adiponectin 
hs-CRP 
URINALYSIS 
Routine urinalysis to include:  Color and appearance, 
pH, SG, Bilirubin, Glucose, Ketones, Leukocytes, 
Nitrite, Occult blood, Protein, Urobilinogen, 
Microscopic (including RBCs and WBCs) 
 
BIOMARKERS FOR NASH 
Cytokeratin (CK)18 
GLP-1 (glucagon-like peptide-1) 
 
PD Markers for FXR Activity: 
Fibroblast growth factor (FGF)19 (fasting plasma) 
Total bile acids (BAs) (fasting serum) 
C4 (7α-OH-4-cholesten-3-one) 
PREGNANCY  
Serum pregnancy test  
Follicle-Stimulating Hormone (FSH)  
 
FIBROSIS AND INFLAMMATORY MARKERS 
ENHANCED LIVER FIBROSIS (ELF) PANEL 
       -Hyaluronic acid (HA),  
  -Procollagen III amino terminal peptide (PIIINP)         
-Tissue inhibitor of metalloproteinase 1 (TIMP-1) 
PRO C3 
Fibrinogen, CRP, alpha2 macroglobulin and haptoglobin 
Tumor necrosis factor alpha and beta  (TNF-α, and β) 
IL-6. IL1β 
AST to Platelet Ratio Index (APRI) 
Fibrosis 4 (FIB-4) 
NAFLD fibrosis score (NFS score) 
COAGULATION TEST 
International Normalized Ratio (INR) 
Prothrombin Time (PT) 
Partial thromboplastin time (PTT) 
 








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9. 
SAFETY MONITORING AND REPORTING 
9.1. 
Definitions 
9.1.1. 
Pretreatment Events 
A pretreatment event is any event that meets the criteria for an AE/SAE and occurs after the 
subject signs the ICF but before receiving the first administration of study drug. 
9.1.2. 
Adverse Events 
An AE is any event, side effect, or untoward medical occurrence in a subject enrolled in a 
clinical study whether or not it is considered to have a causal relationship to the study drug. An 
AE can therefore be any unfavorable and unintended sign, symptom, laboratory finding outside 
of normal range with associated clinical symptoms or suspected latent clinical symptoms in the 
opinion of the Investigator, physical examination finding, or disease temporally associated with 
the use of the study drug, whether or not the event is considered related to the study drug.  
The occurrence of adverse events should be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination, laboratory test, or other 
assessments. 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the subject was enrolled in the study are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the study (eg, surgery was performed earlier than 
planned). 
9.1.3. 
Serious Adverse Events (SAEs) 
An SAE is any untoward medical occurrence at any dose that:  
• Results in death: This includes deaths that appear to be completely unrelated to study 
medication (eg, a car accident).  
• Is a life-threatening event: An event that places the subject at immediate risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe.  
• Requires inpatient hospitalization or prolonged hospitalization of an existing 
hospitalization, unless hospitalization is for: 
o routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition 
o elective or preplanned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since signing the ICF 
o treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission 


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o social reasons and respite care in the absence of any deterioration in the 
subject's general condition 
• Results in permanent or prolonged (at least 28 days in duration) disability or 
incapacity  
• Is a congenital anomaly or birth defect in the offspring of a study subject 
• Medically important event: An event that may not be immediately life-threatening, or 
result in death or hospitalization, or require intervention to prevent one of the 
outcomes listed above, but is considered medically significant for other reasons.  An 
opportunistic or otherwise unusual infection for the PI's practice, such as tuberculosis, 
will be considered medically significant.  
The term severe is used to describe the intensity of a specific event (as in mild, moderate, or 
severe); the event itself, however, may be of minor medical significance (such as severe 
headache). This is not the same as serious, which is based on outcome of the event, as described 
above. Seriousness, not intensity, serves as a guide for defining regulatory reporting obligations. 
9.2. 
Documenting and Reporting of Adverse Events (Including Serious 
Adverse Events) 
Adverse Events will be evaluated and documented using the grading scales contained in the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
(Version 4.03). 
9.2.1. 
Documenting and Reporting Adverse Events 
All AEs reported from the time of informed consent to the end-of-study for each subject will be 
recorded in the subject’s source documents. For subjects who do not receive study drug (ie, 
screen failures), AEs will only be recorded in the source documents. For subjects enrolled into 
the study (i.e., randomized), record all AEs in the subject’s AE eCRF and Clinical Trials SAE 
Form (if applicable). The AE eCRF will indicate if the event occurred prior to the first dose of 
study drug, during treatment, or during the post-dosing follow-up period. Record all AEs 
regardless of the intensity, seriousness, or relationship to study drug.   
Grade AEs (serious and non-serious) in accordance with the NCI/CTCAE scale (available at 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf) as 
presented below:  
• Mild (Grade 1) asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Moderate (Grade 2) minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• Severe (Grade 3) Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living 


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• Life-threatening (Grade 4) Life-threatening consequences; urgent intervention 
indicated  
• Death (Grade 5) Death related to the AE. 
Any recurrence of an AE with similar causality to study drug will be reported as recurrence or 
exacerbation of the initial event, and not as a new event. Whenever possible, report AEs as a 
specific diagnosis or syndrome (eg, flu syndrome) rather than as individual signs or symptoms. If 
no specific diagnosis or syndrome is identified, AEs should be reported as separate and 
individual events.  
An AE includes the following:  
• Progression or exacerbation of the subject’s underlying disease. Clinical sequelae that 
result from disease progression, such as pleural effusion or small bowel obstruction, 
are reportable as AEs.  
• Pre-existing event that increases in frequency or intensity  
• Condition detected or diagnosed during the study period, even though it may have 
been present, in retrospect, prior to the first dose of study drug 
• Laboratory abnormalities outside of normal limits and requiring therapeutic 
intervention 
• An overdose of the study drug without any signs or symptoms – a calculated dose that 
exceeds its correct dose by 10% or more and is administered to the subject will be 
considered an overdose and documented as an AE.  
The following events will not be identified as AEs in this study:  
• Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, etc); 
however, the condition (the “triggering event”) that leads to the procedure may be an 
AE.  
• Pre-existing conditions present or detected prior to the first dose of study drug that do 
not worsen. 
9.2.2. 
Assigning Attribution of Adverse Events 
The Investigator must attempt to determine the cause of each event. Every effort will be made by 
the Investigator to assess the relationship of each AE to study drug. To ensure consistency of 
AE/SAE causality assessments, Investigator(s) should apply the following guideline:  
Related: There is an association between the event and the administration of study drug, a 
plausible mechanism for the event to be related to the study drug and causes other than the study 
drug have been ruled out, and/or the event re-appeared on re-exposure to the study drug.  
Possibly Related: There is an association between the event and the administration of the study 
drug and there is a plausible mechanism for the event to be related to study drug, but there may 
also be alternative etiology, such as characteristics of the subject’s clinical status or underlying 
disease.  


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Unlikely Related: The event is unlikely to be related to the study drug and likely to be related to 
factors other than study drug.  
Not Related: The event is related to an etiology other than the study drug (the alternative 
etiology must be documented in the study subject’s medical record). 
9.2.3. 
Classifying Action Taken with Study Drug 
In the case of an AE, the actions that can be taken with study drug are defined below in Table 16. 
Table 16: 
Options for Action Taken with Study Drug 
Classification  
Definition  
Dose Not 
Changed  
Study drug dose not changed in response to the AE  
Dose Reduced  
Study drug dose reduced in response to an AE  
Drug Interrupted  
Study drug administration interrupted in response to an AE  
Drug Withdrawn  Study drug administration permanently discontinued in response to an AE  
Not Applicable  
Action taken regarding study drug administration does not apply.  “Not applicable” should be 
used in circumstances when no opportunity to decide whether to continue, interrupt or withdraw 
treatment was possible such as when the investigational treatment had been completed before 
the adverse event began.  
9.2.4. 
Classifying Adverse Event Outcome 
For every AE/SAE, the possible outcomes of the event and the definition of the outcome are 
shown below in Table 17. One outcome must be entered into the appropriate field on the AE and 
(if appropriate) SAE form for each event as discussed in the eCRF instructions. 
Table 17:  
Classification and Definition of AE Outcomes  
Classification  
Definition  
Recovered / Resolved  
Resolution of an AE with no residual signs or symptoms  
Recovered / Resolved with 
sequelae  
Resolution of an AE with residual signs or symptoms  
Is Recovering / Is Resolving 
Incomplete improvement to date but AE continues to improve/resolve and 
complete resolution is expected over time 
Not Recovered / Not Resolved  
Either incomplete improvement or no improvement of an AE, such that it 
remains ongoing  
Fatal  
Outcome of an AE is death. “Fatal” should be used when death is at least 
possibly related to the adverse event.  
Unknown  
Outcome of an AE is not known (e.g., a subject lost to follow up)  


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9.2.5. 
Documenting and Reporting Serious Pretreatment Events and Serious Adverse 
Events 
All SAEs that occur after obtaining informed consent through the EOS/Follow–up visit, 
regardless of causality, must be reported by the Investigator to 
 
 and Enanta Pharmaceuticals, Inc., within 24 hours of learning of its occurrence.  In 
addition, all SAEs that occur after the EOS Visit and that are considered related to study drug(s) 
and all deaths must also be reported within 24 hours of learning of its occurrence. Additional 
details are provided in the Safety Management Plan.  The eCRF should be completed for 
new/initial events as well as to report follow-up information on previously reported events in the 
same way as for AEs. Upon stating the seriousness, further details should be provided in the 
eCRF. Investigators are asked report follow up information as soon as it becomes available, to 
ensure timely reporting to Health Authorities.   
The SAE Form should be sent to the 
 group via fax or email in 
case the eCRF is not available:  
 
Email (back up): 
(US) 
Email (back up): 
 (non-US) 
Fax (back up): 
 
Fax (back up): 
 
SAEs will be recorded on the SAE Form using a recognized medical term or diagnosis that 
accurately reflects the event. SAEs will be assessed by the Investigator for severity, relationship 
to the investigational study drug(s) and possible etiologies. Relationship to study drug(s) will be 
recorded as related or not related on the SAE form. For the purposes of study analysis, if the 
event has not resolved at the end of the study reporting period, it will be documented as ongoing. 
For purposes of regulatory safety monitoring, the Investigator is required to follow the event to 
resolution and report the outcome of the event to the 
 using 
the SAE Form.   
The Investigator is responsible for notifying 
/the 
Sponsor within 24 hours of identifying an SAE, regardless of the presumed relationship to 
the investigational study drug. The SAE Form should be completed for new/initial events 
as well as to report follow-up information on previously reported events. The Investigator 
is asked to report follow-up information as it becomes available.  
Enanta Pharmaceuticals, Inc. or its designees, as study sponsor, is responsible for reporting 
suspected, unexpected, serious adverse reactions (SUSARs) involving the study drug(s) to all 
regulatory authorities, and participating PIs, in accordance with FDA, International Conference 
on Harmonization (ICH) Guidelines, and/or local regional or country regulatory requirements, as 
applicable. 
9.2.6. 
Documenting and Reporting of Pregnancy 
While females of childbearing potential are allowed in the study, they must agree to use two 
effective methods of contraception from Screening until 90 days after the last dose of study drug. 


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However, as a precaution, subjects will be counseled to inform the Investigator of any pregnancy 
that occurs during study treatment and for 90 days after the last dose of study drug/s. 
If a female subject or the female partner of a male subject becomes pregnant while participating 
in the study, study treatment must be permanently discontinued immediately. The Investigator 
must notify the Sponsor’s Medical Monitor and 
 within one 
business day of the sites’ knowledge of the subject’s (or partner’s) pregnancy, by utilizing the 
study-specified pregnancy report form. If confirmed to be on active drug, the subject or partner 
will be followed until end of pregnancy and the infant will be followed for one year after the 
birth, provided informed consent is obtained. A separate ICF will be provided to explain these 
follow-up activities. Pregnancy itself does not constitute an AE. 
9.3. 
Follow-up of Adverse Events and Serious Adverse Events 
Follow all AEs (serious and nonserious) until resolution or otherwise explained (see Table 17), 
the subject dies, the event stabilizes and is not expected to further resolve with the maximum 
time limit for stabilization defined as 30 days after the occurrence of the event, or when 
alternative therapy is instituted, whichever occurs first. If alternative therapy is instituted, it 
should be documented. Enanta Pharmaceuticals, Inc., may request that the Investigator perform 
or arrange for supplemental measurements or evaluations to further clarify the nature of the 
event. 
9.4. 
Sponsor’s Review of Adverse Events and Serious Adverse Events 
Enanta Pharmaceuticals, Inc., will maintain an ongoing review of all AEs and SAEs. 
9.5. 
Data Safety Monitoring Board 
Safety data from this study will be reviewed by a Data Safety Monitoring Board (DSMB) 
throughout the study. The DSMB will be headed by a DSMB Chair and will include physicians 
with expertise in diseases of the liver including NASH. Procedures for data review including 
timing and potential outcomes will be governed by the DSMB charter. 


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10. 
SUBJECT SAFETY MANAGEMENT 
In the event that two or more subjects experience a similar drug-related Grade 3 or 4 AE or SAE 
or Grade 3 or 4 laboratory abnormality, a DSMB meeting will be immediately convened by the 
Sponsor. Based on the data presented, a decision will be made as to whether or not enrollment 
should be halted, the study should be halted, or if dosing and enrollment into the study should 
continue.  
10.1. 
Individual Subject Stopping Rules 
Study drug will be discontinued in subjects with elevated ALT or AST (see below) and thorough 
evaluation and follow-up will be performed: 
• If ALT or AST increases to >5 × Baseline 
• If ALT or AST increase >2 × Baseline AND the increase is accompanied by a 
concomitant total bilirubin increase to >2 × Baseline OR the INR concomitantly 
increases by >0.2 
• If elevations of ALT/AST are accompanied by signs or symptoms of right upper 
quadrant abdominal pain, anorexia, nausea, vomiting, fever, eosinophilia, and/or rash  
For subjects who meet the discontinuation criteria and have evidence of liver injury, additional 
PK samples will be obtained at the same visits as safety labs.  
Please refer to Section 10.2 for the close monitoring for subjects who meet criteria for drug 
discontinuation due to elevated ALT/AST.   
10.2. 
Management of Liver Enzyme Elevations 
The FDA Guidance for Industry for Drug Induced Liver Injury (FDA, 2009) will provide 
guidance for the management of changes in liver transaminases (ALT/AST) and total bilirubin.  
The following close observation guidelines will apply to subjects for whom the repeat 
assessment shows persistent elevations of transaminases, but who do not meet drug 
discontinuation criteria, and for subjects who discontinue study drug due to ALT/AST 
elevations. 
The protocol also includes an algorithm to respond to changes in liver enzymes and functions as 
follow:  
• To establish a baseline utilizing at least 2 lab values at least several weeks apart 
• For subjects with elevated baseline liver chemistry that develop AST or ALT 
elevations 2 × baseline, subjects will be reassessed promptly (eg, 48–72 hours) with 
full liver biochemistry and physical exam and if the repeat assessment shows 
persistent elevations in transaminases, subjects should be followed according to the 
“close observation” guidelines: 
o Repeat liver enzyme and serum bilirubin tests two or three times weekly. 
Frequency of repeat testing can decrease to once a week or less if 


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abnormalities stabilize or the trial drug has been discontinued and the subject 
is asymptomatic. 
o Collect additional PK samples at the same visits as safety labs 
o Obtain a more detailed history of symptoms and prior or concurrent diseases. 
o Obtain a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets. 
o Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or 
alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract 
disease. 
o Obtain a history of exposure to environmental chemical agents. 
o Obtain additional tests to evaluate liver function, as appropriate (eg, INR, 
direct bilirubin). 
o Consider gastroenterology or hepatology consultations. 
o Consider liver biopsy for any patient with persistent evidence of liver injury. 
• For subjects with alkaline phosphatase (ALP) elevations of 2 × ULN, subjects will be 
reassessed promptly (eg, 48–72 hours) with full liver biochemistry and physical 
exam. Labs should be repeated until resolution. Above guidelines for close 
monitoring should also apply. 
• If a subject lives in a remote area, they can be tested locally with the results promptly 
communicated to the Investigator site 


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11. 
STATISTICAL CONSIDERATIONS 
11.1. 
General Considerations 
All data will be mapped into the appropriate Study Data Tabulation Model (SDTM) domains per 
version 3.2. All analysis datasets will be in the appropriate Analysis Data Model (ADaM) data 
structure. Pinnacle21 will be used to ensure compliance of the SDTM domains and ADaM 
datasets to Clinical Data Interchange Standards Consortium (CDISC) standards.   
All quantitative endpoints will be summarized using an 8-number summary (n, mean, standard 
deviation, median, 25th quartile, 75th quartile, minimum and maximum values). All qualitative 
endpoints will be summarized by the number of subjects meeting the endpoint and the 
percentage of subjects out of the appropriate population. The denominator will be displayed 
when needed.  
Statistical inference will be performed as appropriate. Only two-sided test with an α =0.05 will 
be used. 
11.2. 
Sample Size Considerations 
Group sample sizes of 44 (in each dose group) and 22 placebo subjects achieves 80.438% power 
to reject the null hypothesis of equal means when the population mean difference in ALT is 
(−40.0)–(−10.0) =−30.0 with a standard deviation for both groups of 40.0 and with a significance 
level (alpha) of 0.050 using a two-sided two-sample equal-variance t-test. To account for a 20% 
discontinuation rate, 15 additional subjects will be enrolled to attempt to have at least 110 
subjects who complete treatment bringing the total number of subjects enrolled to 125. 
11.3. 
Analysis Populations 
The following analysis populations are planned:  
• Safety Population: All subjects who receive at least one dose of study medication. 
Subjects will be included in the treatment group that corresponds to the study 
medication received during the study. 
• Efficacy Population: All subjects who receive at least one dose of study medication. 
Subjects will be included in the randomized treatment group. 
• Pharmacokinetic Population: All subjects receiving active study medication and 
having any measurable plasma concentration of study medication at any timepoint. 
11.4. 
Subject Disposition and Demographic Data 
The number of subjects screened, randomized, randomized and treated, randomized and not 
treated, in the safety population, in the efficacy population, and in the PK population will be 
summarized. The denominator for the calculation of percentages will be from the number of 
subjects randomized.   
The following categories will also be summarized for subject disposition: 
• Completed study drug per protocol 


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• Discontinued study drug early and the reason for discontinuation 
• Completed the study  
• Discontinued from the study early and the reason for discontinuation 
Subject demographics will be summarized by randomized treatment group for all subjects in the 
safety population. Appropriate baseline characteristics will be included in addition to 
demographic characteristics. No statistical testing will be performed. Additional details will be 
provided in the Statistical Analysis Plan (SAP). 
11.5. 
Efficacy Endpoints 
11.6. 
Primary Efficacy Endpoints 
The primary efficacy endpoint of the study is the change from baseline in ALT at Week 12. All 
subjects in the efficacy population will be included. Comparisons of treatment arms will be 
performed using an analysis of covariance (ANCOVA) model with treatment and baseline values 
included in the model where appropriate. Multiple Imputation (MI) will be used to impute 
missing data. Details will be provided in the SAP. 
11.6.1. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• Change from Baseline in percentage of fat in the liver as assessed by MRI-PDFF at 
Week 12 
• Change from Baseline in liver stiffness as assessed by magnetic resonance 
elastography (MRE) at Week 12 
• Change from Baseline of noninvasive liver fibrosis markers (ELF panel) and PRO C3 
at Week 12  
• Change from Baseline in NFS, APRI, and FIB-4 at Week 12 
• Change form Baseline in TG, TC, HDL-C, LDL-C, adiponectin, and ApoA1, B, C3 at 
Week 12 
• Change from Baseline in fasting glucose and insulin, HOMA index (in nondiabetic 
subjects) and HbA1c in subjects with T2DM at Week 12 
• Change from Baseline in fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β , alpha2 
macroglobulin and haptoglobin levels at Week 12 
• Change from Baseline in body weight at Week 12  
• Change in waist to hip WTH ratio at Week 12 
• Pharmacodynamic  parameters of EDP-305: FGF19, C4, and bile acid (BA) at Week 
12 


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Each endpoint will be summarized using an 8-number summary. Subjects in the efficacy 
population will be included. Comparisons of treatment arms will be performed using an 
ANCOVA model with treatment and baseline values included in the model where appropriate. 
11.7. 
Safety Endpoints 
11.7.1. 
Adverse Events 
The primary safety endpoint of the study is the frequency of AEs, SAEs, and AEs leading to 
discontinuation through Week 12. 
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term by treatment group. All subjects in the safety 
analysis set will be included in the summaries. No statistical testing will be performed.   
Summaries of AEs will include the following: 
• An overall summary of AEs with a line for each of the categories provided below: 
• Treatment-emergent AEs 
• Treatment-emergent treatment-related AEs 
• Treatment-emergent AEs leading to study drug discontinuation 
• SAEs 
• Treatment-related SAEs 
• AEs leading to death 
11.7.2. 
Clinical Laboratory Data 
Summaries of clinical laboratory results will be performed using an 8-number summary by visit 
and treatment. All subjects in the safety population will be included in these summaries.   
The number and percentage of subjects with treatment-emergent laboratory abnormalities will be 
summarized by treatment group. In addition, shift from baseline tables will be generated by visit 
and treatment group. 
11.7.3. 
Electrocardiogram Data 
Electrocardiogram data will be summarized using an 8-number summary by visit and treatment. 
In addition, the number and percentage of subjects with significant changes in ECG parameters 
will be summarized by treatment. No statistical testing will be performed. 
11.7.4. 
Vital Signs 
Vital signs data will be summarized using an 8-number summary by visit and treatment. In 
addition, the number and percentage of subjects with significant changes in vital signs will be 
summarized by treatment. No statistical testing will be performed. 




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12. 
STUDY ADMINISTRATION 
12.1. 
Ethical Considerations 
12.1.1. 
Ethical Conduct of the Study 
The study will be conducted in compliance with this protocol, principles of E6 Good Clinical 
Practice: Consolidated Guidance (ICH-GCP), Declaration of Helsinki, and all applicable local 
laws and regulations governing clinical trials. 
12.1.2. 
Ethical Review 
It is the PI’s responsibility to ensure that this protocol is reviewed and approved by an 
appropriate IRB/EC which conforms to the regulations set forth in 21Code of Federal 
Regulations (CFR), Part 56 and other national, country, and regional regulations as applicable. 
The Investigator must also submit the ICF, any other written documentation provided to the 
subject, and all advertisements that may be used for study-specific recruitment to the IRB/EC for 
review and approval before commencing study-specific activities. If it is necessary to amend the 
protocol during the study, then it is the responsibility of the Investigator to ensure that IRB/EC 
approval is obtained before implementation of the amended procedures. It is also the 
responsibility of the Investigator to provide the IRB/EC with any SAE or Investigational New 
Drug safety reports. A copy of the ICF approved by the IRB/EC must be forwarded to Enanta 
Pharmaceuticals, Inc. for regulatory purposes. 
12.1.3. 
Written Informed Consent 
The Investigator or designee must explain to each subject the purpose and nature of the study, 
the study procedures, the possible adverse effects, and all other elements of consent as defined in 
§21CFR Part 5, and other applicable national and local regulations governing informed consent. 
Each subject must provide a signed and dated ICF prior to enrollment into this study. Signed 
consent forms must remain in each subject’s study file and be available for verification by study 
monitors at any time. In accordance with individual local and national or country-specific subject 
privacy regulations, the Investigator or designee must explain to each subject prior to screening 
that for the evaluation of study results, the subject’s protected health information obtained during 
the study may be shared with Enanta Pharmaceuticals, Inc. and its designees, regulatory 
agencies, and IRBs/ECs. As the study sponsor, Enanta Pharmaceuticals, Inc. will not use the 
subject’s protected health information or disclose it to a third party without applicable subject 
authorization. It is the PI’s or designee’s responsibility to obtain written permission to use 
protected health information from each subject. If a subject withdraws permission to use 
protected health information, it is the PI’s responsibility to obtain the withdrawal request in 
writing from the subject and to ensure that no further data will be collected from the subject. Any 
data collected on the subject prior to withdrawal will be used in the analysis of study results.   
12.1.4. 
Investigator Compliance 
No modifications to the protocol should be made without the approval of both the investigator 
and Enanta. Changes that significantly affect the safety of the subjects, the scope of the 


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investigation, or the scientific quality of the study (ie, efficacy assessments) will require 
IRB/IEC notification prior to implementation, except where the modification is necessary to 
eliminate an apparent immediate hazard to human subjects.   
If circumstances require an immediate departure from protocol procedures, the investigator will 
contact Enanta to discuss the planned course of action. Contact should be made prior to the 
implementation of any changes when possible. Any departures from protocol must be fully 
documented in the source documentation and in a protocol deviation log.   
12.2. 
Data Collection 
Study data for each randomized subject will be entered into an eCRF by site personnel. It is the 
investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness of the 
data reported in the subject’s eCRF. Source documentation supporting the eCRF data should 
indicate the subject’s participation in the study and should document the dates and details of 
study procedures, adverse events, other observations, and subject status. The Investigator, or 
designated representative, should complete the eCRF as soon as possible after information is 
collected. An explanation should be provided for all missing data. 
After the subject has completed the study, the Investigator must review and sign the signature 
page of the eCRF indicating that he has reviewed the completed eCRF and pertinent clinical data 
for that subject and that, to the best of his knowledge, all data recorded in the eCRF accurately 
reflects the subject’s clinical performance in the study.   
Sites are responsible for abiding by the rules and regulations of their IRB/EC for recording and 
reporting protocol deviations. All deviations reported to the IRB/EC must be reported to Enanta 
Pharmaceuticals, Inc. and/or their designee and recorded as deviations as appropriate in the 
eCRF. 
12.3. 
Study Monitoring 
Representatives of Enanta Pharmaceuticals, Inc. or its designee will monitor this study until 
completion. Monitoring will be conducted through on-site visits with the Investigator and site 
staff as well as any appropriate communications by mail, fax, e-mail, or telephone. The purpose 
of monitoring is to ensure compliance with the protocol and the quality and integrity of the data. 
The study monitor will insure that the investigation is conducted according to protocol and 
regulatory requirements, and as described in the Study Monitoring Plan. 
Every effort will be made to maintain the anonymity and confidentiality of all subjects during 
this clinical study. However, because of the experimental nature of this treatment, the 
Investigator agrees to allow the IRB/EC, representatives of Enanta Pharmaceuticals, Inc., its 
designated agent, and authorized employees of the appropriate regulatory agencies to inspect the 
facilities used in this study and, for purposes of verification, allow direct access to the hospital or 
clinic records of all subjects enrolled into this study. A statement to this effect will be included in 
the ICF authorizing the use of protected health information. 
12.4. 
Quality Assurance 
At its discretion, Enanta Pharmaceuticals, Inc. or its designee may conduct a quality assurance 
audit of this study. If such an audit occurs, the Investigator will give the auditor direct access to 


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all relevant documents, and will allocate his time and the time of his staff to the auditor as 
required. In addition, regulatory agencies may conduct an inspection of this study. If such an 
inspection occurs, the Investigator will allow the inspector direct access to all source documents, 
CRFs, and other study documentation for source data check and/or on-site audit inspection.  
12.5. 
Retention of Records 
The site will retain a copy of all study records in a safe, secure and accessible location for a 
minimum of 2 years after notification by Enanta Pharmaceuticals, Inc. that the investigations of 
EDP-305 have been discontinued or for 2 years following marketing approval of the drug, after 
which time Enanta Pharmaceuticals, Inc. will be contacted for instructions on the disposition of 
study materials. Study records will contain all of the appropriate documents as detailed in 
Section 8.0 of the E6 Good Clinical Practice: Consolidated Guidance (ICH-GCP).  
12.6. 
Information Disclosure 
12.6.1. 
Confidentiality 
Subject names will remain confidential and will not be supplied to Enanta Pharmaceuticals, Inc. 
or its designee. Only subject number, subject initials, and birth date will be recorded on the 
eCRF. If the subject name appears on any other document collected (eg, unit discharge 
summary), it must be obliterated before the document is transmitted to Enanta Pharmaceuticals, 
Inc. or its designee. All study findings will be stored in electronic databases. As indicated in the 
ICF, subjects will give permission for representatives of the Sponsor, regulatory authorities, and 
the IRB/EC to inspect their medical records to verify the information collected. Subjects will be 
informed that all personal information made available for inspection will be handled in the 
strictest confidence and in accordance with local data protection/privacy laws. 
Individual subject medical information obtained during this study is confidential and its 
disclosure to third parties other than those mentioned in the preceding paragraph is prohibited. 
Medical information obtained during this study may be provided to the subject’s personal 
physician or other appropriate medical personnel when required in connection with the subject’s 
continued health and welfare and with the subject’s prior knowledge and permission. 
12.6.2. 
Publication Policy 
It is the intention of Enanta Pharmaceuticals, Inc. to publish the results of this study in their 
entirety within a reasonable period of time following conclusion of the study. The Sponsor will 
determine when and where data will be first disclosed.   
All information generated from this study is the proprietary property of Enanta Pharmaceuticals, 
Inc. Enanta Pharmaceuticals, Inc. reserves the right, among other things, to: 
• Modify or amend study material to ensure that no confidential or proprietary 
information is disclosed 
• Ensure that the reported data are factually correct 
• Utilize the information generated from or as a result of this study in any manner it 
deems appropriate, including but not limited to regulatory submissions, annual 
reports, and other scientific or business affairs of the company 


Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 83 of 86 
 
 
• Modify the publication or disclosure or delay it a sufficient time to allow Enanta 
Pharmaceuticals, Inc.to seek patent protection of any invention contained therein 


Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 84 of 86 
 
13. 
REFERENCES 
 
Agopian, V. G., Kaldas, F. M., Hong, J. C., Whittaker, M., Holt, C., Rana, A., . . . Busuttil, R. 
W. (2012). Liver transplantation for nonalcoholic steatohepatitis: the new epidemic. Ann 
Surg, 256(4), 624-633. doi:10.1097/SLA.0b013e31826b4b7e 
Bertot, L.C., Adams, L.A. (2016). The Natural Course of Non-Alcoholic Fatty Liver Disease. 
Int. J. Mol. Sci. 17 (5): 774  
Chalasani, N., Younossi, Z., Lavine, J. E., Diehl, A. M., Brunt, E. M., Cusi, K., . . . Sanyal, A. J. 
(2012). The diagnosis and management of non-alcoholic fatty liver disease: practice 
Guideline by the American Association for the Study of Liver Diseases, American 
College of Gastroenterology, and the American Gastroenterological Association. 
Hepatology, 55(6), 2005-2023. doi:10.1002/hep.25762. 
Ikenaga, N., Liu, S. B., Sverdlov, D. Y., Yoshida, S., Nasser, I., Ke, Q., . . . Popov, Y. (2015). A 
new Mdr2(-/-) mouse model of sclerosing cholangitis with rapid fibrosis progression, 
early-onset portal hypertension, and liver cancer. Am J Pathol, 185(2), 325-334. 
doi:10.1016/j.ajpath.2014.10.013 
McMahan, R. H., Wang, X. X., Cheng, L. L., Krisko, T., Smith, M., El Kasmi, K., . . . Rosen, H. 
R. (2013). Bile Acid Receptor Activation Modulates Hepatic Monocyte Activity and 
Improves Nonalcoholic Fatty Liver Disease. J Biol Chem, 288(17), 11761-11770  
Neuschwander-Tetri, B. A., Loomba, R., Sanyal, A. J., Lavine, J. E., Van Natta, M. L., 
Abdelmalek, M. F., . . . Doo, E. (2015). Farnesoid X nuclear receptor ligand obeticholic 
acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT); a multicentre, randomised, 
placebo-controlled trial. Lancet, 385(9972), 956-965 
Ratziu, V. (2013). Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol, 10(11), 
676-685. 
Wong, R. J., Aguilar, M., Cheung, R., Perumpail, R. B., Harrison, S. A., Younossi, Z. M., & 
Ahmed, A. (2015). Nonalcoholic steatohepatitis is the second leading etiology of liver 
disease among adults awaiting liver transplantation in the United States. 
Gastroenterology, 148(3), 547-555. doi:10.1053/j.gastro.2014.11.039 
Xu, J. Y., Li, Z. P., Zhang, L., & Ji, G. (2014). Recent insights into farnesoid X receptor in non-
alcoholic fatty liver disease. World J Gastroenterol, 20(37), 13493-13500. 
doi:10.3748/wjg.v20.i37.13493.




Clinical Study Protocol 
 
 
   
 
       Enanta Pharmaceuticals, Inc. 
EDP 305-101 v 3.0 (Amendment 2.0) 
 
  CONFIDENTIAL 
 
Page 86 of 86 
 
 
1. 
Screening assessments should be conducted within 28 days prior to the first dose of study drug (ie, Study Days -28 to -1) 
2. 
On Day 1, all samples are to be collected predose with the exception of post dose PK and PD samples 
3. 
Subjects should discontinue drug on Day 84. Subjects who return for their EOT Visit after Day 84, should stop dosing on Day 84 
4. 
For the treatment phase, indicates number of completed weeks of treatment 
5. 
For the EOT visit for subjects who discontinue early, all procedures for the Week 12 visit will be conducted; however, an MRI /MRE 
will not be performed if the subject has discontinued study drug prior to Day 14 and only 1 PK sample will be obtained. Subjects who 
discontinue the study early should complete the EOT procedures as soon as possible and return 4 weeks later for the EOS visit. For 
subjects with persistent transaminase elevations and who discontinue study drug with evidence of liver injury, additional PK samples 
will be collected at each visit where safety labs are obtained  
6. 
Informed consent must be obtained prior to conducting any study-specific procedures or assessments 
7. 
For post-menopausal women only 
8. 
Serum pregnancy test at Screening and Baseline, and urine pregnancy testing at Baseline and all other visits. If the urine pregnancy 
test is positive, a serum pregnancy test should be obtained as soon as possible to confirm.   
9. 
Height to be assessed at Screening only 
10. Full physical exam (PE) at screening and EOS Visit; subsequent PE should be targeted to review new signs and symptoms 
11. Vital Signs include heart rate, respiratory rate, blood pressure, and will be measured once in the morning before the morning dose of 
study drug 
12. Safety laboratory tests include chemistry (including liver function tests), hematology, and urinalysis and should be collected predose 
at all visits; See Table 15 for details. Creatinine clearance will be calculated based on serum creatinine value performed all visits.. 
HbA1c will be obtained at Screening, Baseline, and Week 12 only 
13. Lipids and CV risk markers to be collected are detailed in Table 15 
14. Markers of inflammation include fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β , alpha2 macroglobulin and haptoglobin (See Table 15) 
15. Samples will be collected from all subjects predose. Additional samples may be collected to further assess safety events. 
16. Samples should be collected after a minimum 8 hr fast and before the subject takes the daily dose of study drug.  All samples collected 
Day 1, Weeks 2, 4, 8 and 12 at predose and two samples postdose; with the first sample collected 1 to 3 hours postdose and the second 
sample collected at least 1 hour later 
17. Collect PK/PD samples after a minimum 8 hr fast and before the daily dose of study drug. PK/PD samples on Days 1 and 84 
(Week12) collected predose and 2, 6, and 8 hr postdose; Weeks 2, 4 and 8 at predose and two samples postdose with the first sample 
collected 1 to 3 hours postdose and the second sample collected at least 1 hr later 
18. PK predose samples should be collected after a minimum 8 hour fast before the daily dose of study drug. PK samples collected Day 1, 
Weeks 2, 4, 8 and 12 at predose and two samples postdose; the first sample collected 1 to 3 hours postdose and the second sample at 
least 1 hour later. For subjects with persistent transaminase or ALP elevations, and have evidence of liver injury and who remain on 
study drug, 
. 
19. Study drug given in the clinic on days where subject is seen in the clinic 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Protocol Number: EDP 305-101 
Version: Version 1.0, Date: 5JUN2019 
Page 1 of 58 
 
 
 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
 
 
Protocol Title: 
A Phase 2 Dose Ranging, Randomized, Double Blind, and 
Placebo-Controlled Study Evaluating the Safety, Tolerability, 
Pharmacokinetics and Efficacy of EDP-305 in Subjects with 
Non-Alcoholic Steatohepatitis (NASH) 
Protocol Number: 
EDP 305-101 
Protocol Version, Date 
Version 3.0 (Amendment 2.0), 21 Feb 2018 
Document Version, Date: 
Version 1.0, 5JUN2019 
 
 
Prepared by: 
 
 
 
On behalf of: 
ENANTA Pharmaceuticals Inc. 
 
 
 
 
 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential. The recipients of the SAP must not disclose 
the information contained within this document or any related information to other persons without the 
permission of the Sponsor. In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment which prevents unauthorized access to the document. 


Statistical Analysis Plan 
Protocol Number: EDP 305-101 
Version: Version 1.0, Date: 5JUN2019 
Page 2 of 58 
 
 
SIGNATURE PAGE 
 
 
 
Prepared at 
 by: 
 
 
 
 
 
 
Date 
(DD MMM YYYY) 
 
 
Reviewed at 
 by: 
 
 
 
 
 
 
 
 
(DD MMM YYYY) 
 
 
 
 
 
 
 
 
Date 
(DD MMM YYYY) 




Statistical Analysis Plan 
Protocol Number: EDP 305-101 
Version: Version 1.0 Date: 5JUN2019 
Page 4 of 58 
 
 
 
REVISION HISTORY 
 
 
Version/Date 
Version name 
Section 
Changes implemented 
Version 1.0/ 5JUN2019 
Initial Draft 
N/A 
N/A 


Statistical Analysis Plan 
Protocol Number: EDP 305-101 
Version: Version 1.0 Date: 5JUN2019 
Page 5 of 58 
 
 
TABLE OF CONTENTS 
SIGNATURE PAGE ............................................................................................................. 2 
REVISION HISTORY .......................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 5 
LIST OF ABBREVIATIONS................................................................................................ 8 
1 INTRODUCTION ......................................................................................................... 11 
2 STUDY OBJECTIVES ................................................................................................. 12 
2.1 Primary objective(s).............................................................................................. 12 
2.2 Secondary objective(s).......................................................................................... 12 
3 STUDY DESIGN .......................................................................................................... 13 
3.1 General study design ............................................................................................. 13 
3.2 Randomization and blinding ................................................................................. 13 
3.2.1 Randomization ............................................................................................. 13 
3.2.2 Blinding ....................................................................................................... 14 
3.2.3 Unblinding ................................................................................................... 14 
3.3 Study treatments and assessments ........................................................................ 15 
4 STUDY ENDPOINTS ................................................................................................... 18 
4.1 Primary efficacy endpoint(s) ................................................................................ 18 
4.2 Secondary efficacy endpoint(s) ............................................................................ 18 
4.3 Safety endpoint(s) ................................................................................................. 18 
5 SAMPLE SIZE AND POWER ..................................................................................... 19 
6 ANALYSIS POPULATIONS ....................................................................................... 20 
6.1 Safety population .................................................................................................. 20 
6.2 Efficacy Population .............................................................................................. 20 
6.3 Per Protocol Population ........................................................................................ 20 
6.4 Pharmacokinetic Population ................................................................................. 20 
6.5 Protocol deviations and exclusion from Per Protocol Analysis Set ..................... 20 
7 Statistical Considerations and analysis .......................................................................... 21 
7.1 Derived Variables ................................................................................................. 21 
7.2 Definition and Use of Visit Windows in Reporting Lab, Vital Signs .................. 22 
7.3 Handling of missing data and outliers .................................................................. 23 
7.3.1 Missing data analysis methods .................................................................... 23 
7.3.2 Handling of missing or incomplete dates .................................................... 24 
8 STATISTICAL METHODS .......................................................................................... 26 
8.1 General statistical conventions ............................................................................. 26 
8.2 Subject disposition ................................................................................................ 26 
8.3 Protocol violations/deviations .............................................................................. 27 
8.4 Demographics and Baseline characteristics ......................................................... 27 
8.4.1 Demographics .............................................................................................. 27 
8.4.2 Baseline and disease characteristics ............................................................ 27 
8.4.3 Medical history ............................................................................................ 28 
8.4.4 Prior and concomitant medications ............................................................. 28 


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8.5 Extent of exposure ................................................................................................ 28 
8.5.1 Treatment duration ...................................................................................... 28 
8.5.2 Treatment compliance ................................................................................. 29 
8.6 Efficacy analyses .................................................................................................. 29 
8.6.1 Analysis methods ......................................................................................... 29 
8.6.1.1 Multiplicity ....................................................................................................... 29 
8.6.1.2 Treatment by center interaction analysis (multi-center study) .......................... 29 
8.6.2 Analysis of primary efficacy endpoint(s) .................................................... 29 
8.6.3 Analysis of secondary efficacy endpoint(s) ................................................. 30 
8.6.3.1 Change from Baseline and percentage change from Baseline in percentage of 
fat in the liver as assessed by MRI-PDFF at Week 12 ......................................... 30 
8.6.3.2 Change from Baseline and percentage change from Baseline in liver stiffness 
as assessed by MRE at Week 12........................................................................... 31 
8.6.3.3 Change from Baseline and percentage change from Baseline of noninvasive 
liver fibrosis markers (ELF panel) and PRO C3 at Week 12 ............................... 31 
8.6.3.4 Change from Baseline and Percentage Change from Baseline in Fibrosis at 
Week 12 ................................................................................................................ 32 
8.6.3.5 Change from Baseline and Percentage Change from Baseline in Lipids by Visit 
and at Week 12 ..................................................................................................... 33 
8.6.3.6 Change from Baseline and percentage change from Baseline in Parameters of 
Glucose Metabolism by Visit and at Week 12 ..................................................... 36 
8.6.3.7 Change from Baseline and percentage change from Baseline in Laboratory 
Inflammation Parameter levels by Visit and at Week 12 ..................................... 38 
8.6.3.8 Change from Baseline and percentage change from Baseline in body weight by 
Visit and at Week ................................................................................................. 40 
8.6.3.9 Change from Baseline and percentage change from Baseline in Waist to Hip 
(WTH) ratio by Visit and at Week 12 .................................................................. 41 
8.6.3.1Change from Baseline and percentage change from Baseline in NASH 
biomarker by Visit and at Week 12 ...................................................................... 41 
8.6.4 Additional Analyses (Liver Tests) ............................................................... 41 
8.6.4.1 Change from Baseline and Percentage Change from Baseline in Additional 
Liver Parameters .......................................................................................... 41 
8.6.4.2 Subgroup Analyses ...................................................................................... 43 
8.6.4.3 Exploring Relationships between Endpoints ............................................... 43 
8.7 Safety analyzes ..................................................................................................... 44 
8.7.1 Adverse events ............................................................................................. 45 
8.7.2 Stopping Rules ............................................................................................. 46 
8.7.2.1 Close Monitoring for Drug Discontinuation due to Elevated ALT/AST ... 47 
8.7.3  Clinical laboratory evaluations ...................................................................... 47 
8.7.4 Vital signs ...................................................................................................... 47 
8.7.5 Physical examinations ................................................................................... 48 
8.7.6 Electrocardiograms (ECG) ............................................................................ 48 
8.8 Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD) 


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Analysis ................................................................................................................ 49 
8.8.1 Pharmacokinetic (PK) Analysis ................................................................... 50 
8.8.1.1 Analysis of Sparse PK Samples ................................................................ 50 
8.8.1.2 Analysis of Intensive PK samples ............................................................ 50 
8.8.2 Pharmacodynamic (PD) Analysis ................................................................ 51 
8.8.2.1 Analysis of Sparse PD Samples ................................................................... 52 
8.8.2.2 Analysis of Intensive PD Samples ............................................................... 52 
8.8.2.3 PK/PD Analysis at Week 12 for Subjects with Intensive Samples .......... 53 
8.8.2.4 PK/PD Analysis at Week 12 for All Subjects .......................................... 54 
8.9 
 56 
9 CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL ..................... 57 
10 REFERENCES .............................................................................................................. 58 


Statistical Analysis Plan 
Protocol Number: EDP 305-101 
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LIST OF ABBREVIATIONS 
The following abbreviations will be used within this SAP. 
 
AE 
adverse event(s) 
ATC 
anatomical therapeutic chemical 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
apo 
apolipoproteins 
APRI 
AST to Platelet Ratio Index 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BA 
bile acid 
BMI 
body mass index 
C4 
7α-OH-4-cholesten-3-one 
CI 
confidence interval 
CK18 
cytokeratin 18 
Cmax 
maximum concentration 
CRO 
contract research organization 
CSR 
clinical study report 
CV 
cardiovascular 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EENT 
eyes/ears/nose/throat 
ELF 
enhanced liver fibrosis 
EOS 
end-of-study 
EOT 
End-of-treatment 
FGF 
fibroblast growth factor 
FIB-4 
Fibrosis-4 
FSH 
follicle stimulating hormone 
FXR 
farnesoid X receptor 
GGT 
Gamma Glutamyl Transferase 
GLP-1 
glucagon-like peptide-1 
HbA1c 
glycated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol 
HIV 
Human Immunodeficiency Virus 


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Protocol Number: EDP 305-101 
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HOMA 
homeostasis model assessment 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IL 
interleukin 
INR 
international normalized ratio 
IWRS 
interactive web response system 
LDH 
Lactate Dehydrogenase 
LDL-C 
low density lipoprotein cholesterol 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCMC 
Markov Chain Monte Carlo 
MCV 
Mean corpuscular volume 
MI 
Multiple Imputation 
MRE 
magnetic resonance elastography 
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging - proton density fat fraction 
NAFLD 
non-alcoholic fatty liver disease 
NASH 
non-alcoholic steatohepatitis 
NFS 
NAFLD fibrosis score 
PBO 
placebo 
PD 
pharmacodynamics 
PIIINP 
procollagen III amino terminal peptide 
PK 
pharmacokinetics 
PR 
electrocardiographic interval occurring between the onset of the P wave 
and the QRS complex, representing time for atrial and ventricular 
depolarization, respectively 
PRO C3 
type 3 procollagen 
PT 
Prothrombin Time 
PTT 
Partial thromboplastin time 
QD 
once daily 
QRS 
electrocardiographic deflection between the beginning of the Q wave 
and termination of the S wave, representing the time for ventricular 
depolarization 
QT 
electrocardiographic interval between the beginning of the Q wave and 
termination of the T wave, representing the time for both ventricular 
depolarization and repolarization to occur 
QTcF 
QT interval corrected by Fridericia's formula 
RBC 
Red Blood Cell 
SAE 
serious adverse event(s) 
 


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SAP 
statistical analysis plan 
SD 
Standard Deviation 
T2DM 
type 2 diabetes mellitus 
TC 
total cholesterol 
TEAE 
treatment emergent adverse event 
TFLs 
Tables, Figures and Listings 
TG 
triglyceride(s) 
TIMP-1 
tissue inhibitor of metalloproteinase 1 
TNF 
tumor necrosis factor 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell (Count) 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
WTH 
waist to hip ratio 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Protocol Number: EDP 305-101 
Version: Version 1.0 Date: 5JUN2019 
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1 
INTRODUCTION 
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under Enanta Pharmaceuticals, Inc. Protocol EDP 
305-101 entitled “A Phase 2 Dose Ranging, Randomized, Double Blind, and Placebo- 
Controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of 
EDP-305 in Subjects with Non-Alcoholic Steatohepatitis (NASH)”. 
This SAP should be read in conjunction with the study protocol and case report form 
(CRF). This version of the plan has been developed using the protocol version 3.0 dated 
21Feb2018 (Amendment 2.0) and CRF dated 2NOV2018. Any further changes to the 
protocol or CRF may necessitate updates to the SAP. 
Changes following approval of this SAP will be tracked in the SAP Change Log and a final 
amended version will be issued for Sponsor approval prior to database lock, and 
subsequent unblinding of treatment codes, efficacy lab and imaging data for final study 
results delivery. 
Any change to the data analysis methods described in the protocol will require an 
amendment only if it changes a principal feature of the protocol. Any other change to the 
data analysis methods described in the protocol, and the justification for making the 
change, will be described in the clinical study report. Additional exploratory analysis of the 
data may be conducted as deemed appropriate. 
The preparation of this SAP has been based on International Conference on Harmonization 
(ICH) E9 guidelines. The table of contents and shells for the tables, figures and listings 
(TFLs) will be produced in a separate document. All data analyses and generation of TFLs 
will be performed using SAS 9.3®  or higher. 


Statistical Analysis Plan 
Protocol Number: EDP 305-101 
Version: Version 1.0 Date: 5JUN2019 
Page 12 of 58 
 
2 
STUDY OBJECTIVES 
2.1 
Primary objective(s) 
The primary objectives of the study are as follows: 
• To evaluate change in alanine aminotransferase (ALT) levels 
• To evaluate the safety and tolerability of EDP-305 
2.2 
Secondary objective(s) 
The secondary objectives of the study are as follows: 
• To evaluate the effect of EDP-305 on liver fat 
• To evaluate the effect of EDP-305 on fibrosis (“liver stiffness”) 
• To evaluate the effect of EDP-305 on non-invasive liver fibrosis markers 
• To evaluate the effects of EDP-305 on lipids 
• To evaluate the effects of EDP-305 on glucose metabolism 
• To evaluate the effects of EDP-305 on inflammatory markers 
• To evaluate the pharmacokinetics (PK) of EDP-305 and its metabolites in plasma 
• To evaluate the effect of EDP-305 on body weight 
• To evaluate the effect of EDP-305 on waist to hip (WTH) ratio 
• To evaluate the pharmacodynamics (PD) of EDP-305 


Statistical Analysis Plan 
Protocol Number: EDP 305-101 
Version: Version 1.0 Date: 5JUN2019 
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3 
STUDY DESIGN 
3.1 
General study design 
This is a Phase 2 dose-ranging, randomized, double blind, and placebo-controlled study 
evaluating the safety, tolerability, PK and efficacy of EDP-305 in subjects with NASH. 
The study is composed of 3 phases or periods: 
• Screening period which includes the Screening Visit and may occur over a period 
of 28 days prior to the first dose of study drug 
• Treatment period which begins with the first dose of study drug on Day 1 and 
concludes with the End of Treatment (EOT) Visit on Day 84 (Week12) 
• Safety Follow-up period which includes the End of Study (EOS) Visit on Day 112 
This proposed study will evaluate EDP-305 in patients with NASH who will be 
randomized to one of three treatment groups: (1) 1 mg EDP-305, (2) 2.5 mg EDP-305, or 
(3) placebo in a 2:2:1 ratio. Approximately 125 subjects will be enrolled into the study. 
The study will be conducted at approximately 65 US and ex-US sites. 
The Study Design is presented in Figure 1. 
 
Figure 1: Study Flow Chart 
Abbreviations: D=Day; W=Week 
3.2 
Randomization and blinding 
3.2.1 Randomization 
Subjects will be randomized to study treatment using an Interactive Web Response System 
(IWRS). Subjects will be stratified initially by prior liver biopsy vs no prior liver biopsy. 
Subjects will be randomized to the treatment groups shown below: 
• Treatment Group 1 (N=50); EDP-305 1 mg orally for 12 weeks 
• Treatment Group 2 (N=50); EDP-305 2.5 mg orally for 12 weeks 


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• Treatment Group 3 (N=25); Placebo (PBO) orally for 12 weeks 
A minimum of 10 subjects per treatment group will be included in the PK/PD substudy. 
The randomization code will be produced by Enanta (or designee). The Enanta unblinded 
biostatistician or designee will review and approve the final randomization list. 
During the Screening period, subjects will be identified by a unique screening number 
assigned by the clinical site. Subjects who have completed screening assessments and are 
eligible for participation in the study will be randomized before the first dose of study drug 
(Day −1 or Day 1) and assigned a unique subject number which will be used to identify the 
subject throughout the study. 
3.2.2 Blinding 
The study will be double-blinded meaning the subjects, Investigators, and site staff will be 
blinded to treatment assignment until the completion of the study. 
All study personnel will be blinded to treatment assignment except for the following 
individuals: 
• Unblinded Enanta/Clinical Research Organization (CRO) statistician for purpose of 
generating and monitoring the randomization list, working with the DSMB 
 
 
• Unblinded Drug Supply Chain personnel for the purpose of monitoring drug supplies 
• Enanta/CRO Pharmacovigilance Group and Regulatory Affairs representatives when 
required to satisfy regulatory reporting requirements 
• Bioanalytical Laboratory for the purpose of measuring drug concentrations 
3.2.3 Unblinding 
At the initiation of the study, the study site will be instructed on the method for breaking 
the blind. The unblinding method will use the IWRS process. 
Unblinding of individual subject treatment by the Investigator should be limited to medical 
emergencies or urgent clinical situations in which knowledge of the subject's study 
treatment is necessary for clinical management. In such cases, the Investigator should first 
attempt to contact the study medical monitor to discuss and agree to the need for 
unblinding. In situations in which Investigator have attempted and failed to contact the 
medical monitor, and/or the urgency of the case required immediate action, Investigators 
should use their best judgment, based on the nature and urgency of the clinical situation, 
and proceed with unblinding. 
For unblinding, in the event the local 
 medical monitor cannot be reached, sites at all 
locations should call the following 24/7 global medical coverage hotline: 
 
 
Once a subject's treatment assignment has been unblinded for a medical emergency or 
urgent clinical situation, the medical monitor and study coordinator should be notified 


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Protocol Number: EDP 305-101 
Version: Version 1.0 Date: 5JUN2019 
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within 24 hours of unblinding of the treatment. Information relating to unblinding (e.g., the 
reason, date) should be clearly recorded in the subject’s study file. In addition, the 
Investigator should consider whether the clinical event that prompted unblinding should be 
considered a serious adverse event (SAE), according to the regulatory definitions or 
criteria for SAEs, and if so, submit an SAE report. 
The Safety and Risk Management group will also unblind any SAE reports in compliance 
with regulatory reporting requirements. In addition, Enanta may unblind individual 
subjects at any time for matters relating to safety concerns. 
3.3 
Study treatments and assessments 
The maximum study duration from Screening period to end of the safety follow-up period 
is 20 weeks. The duration of treatment is 12 weeks. 
EDP-305 will be supplied as 1 mg and 2.5 mg tablets for oral administration; doses 
administered will be 1 mg, 2.5 mg or placebo taken once daily (QD) for 12 weeks. 
The subject will be instructed to take all study drug doses at home except when study drug 
will be administered in the clinic (i.e., at the Days 1 and 3, and Weeks 2, 4, 8 and 12 visits). 
The subject will be instructed to take the study drug approximately at the same time every 
day (i.e., orally in the morning after fasting overnight for a minimum of 8 hours). If a 
subject forgets to take their study drug at their scheduled time, the dose may be taken later 
that day following a minimum of 4 hours fast; however, no more than 1 dose should be 
taken on any calendar day and a minimum of 16 hours between doses should be 
maintained. 
A detailed description of procedures and assessments to be conducted during this study is 
summarized in the Scheduled of Study Assessments in the table below. 




Statistical Analysis Plan 
Protocol Number: EDP 305-101 
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3. Subjects should discontinue drug on Day 84. Subjects who return for their EOT Visit after Day 84, should stop dosing 
on Day 84 
4. For the treatment phase, indicates number of completed weeks of treatment 
5. For the EOT visit for subjects who discontinue early, all procedures for the Week 12 visit will be conducted; however, 
an MRI /MRE will not be performed if the subject has discontinued study drug prior to Day 14 and only 1 PK sample 
will be obtained. Subjects who discontinue the study early should complete the EOT procedures as soon as possible and 
return 4 weeks later for the EOS visit. For subjects with persistent transaminase elevations and who discontinue study 
drug with evidence of liver injury, additional PK samples will be collected at each visit where safety labs are obtained 
6. Informed consent must be obtained prior to conducting any study-specific procedures or assessments 
7. For post-menopausal women only 
8. Serum pregnancy test at Screening and Baseline, and urine pregnancy testing at Baseline and all other visits. If the 
urine pregnancy test is positive, a serum pregnancy test should be obtained as soon as possible to confirm. 
9. Height to be assessed at Screening only 
10. Full physical exam (PE) at screening and EOS Visit; subsequent PE should be targeted to review new signs and 
symptoms 
11. Vital Signs include heart rate, respiratory rate, blood pressure, and will be measured once in the morning before the 
morning dose of study drug 
12. Safety laboratory tests include chemistry (including liver function tests), hematology, and urinalysis and should be 
collected predose at all visits; See Table 2 for details. Creatinine clearance will be calculated based on serum creatinine 
value performed all visits. HbA1c will be obtained at Screening, Baseline, and Week 12 only 
13. Lipids and CV risk markers to be collected are detailed in Table 2 
14. Markers of inflammation include fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β, alpha2 macroglobulin and haptoglobin 
(See Table 2) 
15. Samples will be collected from all subjects predose Additional samples may be collected to further assess safety 
events 
16. Samples should be collected after a minimum 8 hr fast and before the subject takes the daily dose of study drug. All 
samples collected Day 1, Weeks 2, 4, 8 and 12 at predose and two samples post dose; with the first sample collected 1 to 
3 hours postdose and the second sample collected at least 1 hour later 
17. Collect PK/PD samples after a minimum 8 hr fast and before the daily dose of study drug. PK/PD samples on Days 1 
and 84 (Week 12) collected predose and 2, 6, and 8 hr post dose; Weeks 2, 4 and 8 at predose and two samples post dose 
with the first sample collected 1 to 3 hours postdose and the second sample collected at least 1 hr late 
18. PK predose samples should be collected after a minimum 8 hour fast before the daily dose of study drug. PK samples 
collected Day 1, Weeks 2, 4, 8 and 12 at predose and two samples post dose; the first sample collected 1 to 3 hours 
postdose and the second sample at least 1 hour later. For subjects with persistent transaminase or ALP elevations and 
have evidence of liver injury and who remain on study drug, additional PK samples will be collected at each visit where 
safety labs are obtained. 
19. Study drug given in the clinic on days where subject is seen in the clinic 


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4 
STUDY ENDPOINTS 
4.1 
Primary efficacy endpoint(s) 
The primary efficacy endpoint of the study is the change from Baseline in ALT levels at 
Week 12. 
4.2 
Secondary efficacy endpoint(s) 
The secondary efficacy endpoints are as follows: 
• Change from Baseline in percentage of fat in the liver as assessed by MRI-PDFF at 
Week 12 
• Change from Baseline in liver stiffness as assessed by magnetic resonance 
elastography (MRE) at Week 12 
• Change from Baseline of noninvasive liver fibrosis markers (ELF panel) and PRO 
C3 at Week 12 
• Change from Baseline in NFS, APRI, and FIB-4 at Week 12 
• Change from Baseline in TG, TC, HDL-C, LDL-C, adiponectin, and ApoA1, B, C3 
at Week 12 
• Change from Baseline in fasting glucose and insulin, HOMA index (in nondiabetic 
subjects) and HbA1c in subjects with T2DM at Week 12 
• Change from Baseline in fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β, alpha2 
macroglobulin and haptoglobin levels at Week 12 
• Pharmacokinetic parameters of EDP-305 (and metabolites): Cmax, Tmax, and AUClast 
• Change from Baseline in body weight at Week 12 
• Change in waist to hip WTH ratio at Week 12 
• Pharmacodynamic parameters of EDP-305: FGF19, C4, and bile acid (BA) at 
Week 12 
In addition, the percentage change from Baseline in the primary endpoint and all secondary 
endpoints will be summarized (as applicable). 
4.3 
Safety endpoint(s) 
The primary safety endpoint of the study is the frequency of Adverse Events (AEs), 
Serious Adverse Events (SAEs), and AEs leading to discontinuation through Week 12 


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5 
SAMPLE SIZE AND POWER 
Group sample sizes of 44 (in each dose group) and 22 placebo subjects achieves 80.438% 
power to reject the null hypothesis of equal means when the population mean difference in 
ALT is (−40.0) – (−10.0) = −30.0 with a standard deviation for both groups of 40.0 and 
with a significance level (alpha) of 0.050 using a two-sided two-sample equal-variance t- 
test. To account for a 10% discontinuation rate, 15 additional subjects will be enrolled to 
attempt to have at least 110 subjects who complete treatment bringing the total number of 
subjects enrolled to 125. 


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6 
ANALYSIS POPULATIONS 
6.1 
Safety population 
All subjects who receive at least one dose of study drug. Subjects will be included in the 
treatment group that corresponds to the study drug received during the study. 
6.2 
Efficacy population 
All subjects who receive at least one dose of study drug. Subjects will be included in the 
randomized treatment group. 
Subjects will be included in the analysis according to the treatment to which they were 
randomized. 
6.3 
Per protocol population 
All subjects in the efficacy population who enter the study without a protocol violation and 
did not have a major (key) protocol deviation as defined below will be included in the per 
protocol population. This population will be reviewed and finalized prior to locking the 
database and unblinding the study. 
6.4 
Pharmacokinetic population 
All subjects receiving active study drug and having any measurable plasma concentration 
of study drug at any timepoint. 
Subjects will be included in the analysis according to the study drug received during the 
study. 
6.5 
Protocol deviations and exclusion from Per protocol analysis aet 
Protocol deviations will be identified following the 
, and after review and 
validation of the Enanta study team prior to locking the database and unblinding the 
treatment codes. If necessary, a meeting will be held to discuss and adjudicate any 
deviations that need classification (major vs. minor). Deviations will be identified using 
data listings provided by 
 and from the deviation log maintained by 
. 
The listing of protocol deviations will be reviewed by Enanta team with focus from 
Biometrics/Medical in order to define the Per Protocol population. Subjects with a 
protocol violation or a major protocol deviation will be thus identified for exclusion from 
the per protocol population. 




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ULN = upper limit of normal 
Fibrosis-4 score (FIB-4) 
FIB-4 = [Age (years) × AST (IU/L)] / [Platelets (109/L) × (√ 
ALT (IU/L) ) 
NAFLD fibrosis score (NFS) 
NFS = -1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m2) + 
1.13 × IFG/Diabetes (yes = 1, no = 0) + 0.99 × AST/ALT 
ratio – 0.013 × Platelets (109/L) – 0.66 × Albumin (g/dL) 
 
7.2 
Definition and use of visit windows in reporting lab, vital signs 
Note that Day 1 in the table below is taken as the first day of dosing with study drug. It 
may not be the same as the first study date which is the randomization date. Also note 
that Day 0 does not exist, so Day -1 is the day before Day 1. Also, the relative days 
(rel_day) from Day 1 are defined as the visit date minus first dosing date plus one. For 
treatment-free follow-up period, the rel_days is computed from the date of last dose. 
Unless otherwise specified in specific analyses, the analysis visit windows will follow 
the rules in the following table. 
Table 4. 
 
Analysis Visit No. Analysis Visit Label Target Day 
Visit Window 
1 
Screening 
N/A 
-28≤rel_day≤-1 
2 
Baseline 
1 
Rel_day= 1* 
3 
Day 3 
3 
Rel_day= 3 
4 
Week 2 
14 
4<rel_day≤21 
5 
Week 4 
28 
22≤rel_day≤42 
6 
Week 8 
56 
43≤rel_day≤70 
7 
Week 12 
84 
71≤rel_day≤end of 
treatment+7 
8 
Follow-up Week 4 
21** 
End of treatment+7<=rel_day 
<end of study 
* Baseline analysis visit window may be considered as Rel_day≤1 in some analyses (e.g., 
those involving change from Baseline). That is, in case that Day 1 observation is missing, 
the  last non-missing observation before or on the first dosing date may be considered as 


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mis 
miss 
miss 
the Baseline. For Lab values, average of all values collected prior to the first dose of study 
drug will be considered Baseline. 
** computed from the date of last dose. 
7.3 
Handling of missing data and outliers 
7.3.1 Missing data analysis methods 
In general, missing data for the primary endpoint and secondary endpoint are not imputed, 
with the exception being a secondary analysis on the primary endpoint. The extent and 
pattern of missing data for primary endpoints will be summarized by treatment group. All 
missing Week 12 values for the primary efficacy endpoint will be estimated by multiple 
imputation (MI). The Markov Chain Monte Carlo (MCMC) method (Dong et al, 2013) 
will be used to impute the missing Week 12 values. The least squares mean and standard 
error for the change from Baseline in Week 12 analysis values will also be derived from an 
analysis using the MCMC method of MI. 
Multiple Imputation Method 
MI handles missing data in three steps: 
Step 1: Imputation using MCMC Method 
For MI analysis first uses MCMC method to impute the missing data through SAS Proc 
MI. The goal of the imputation step is to draw random samples of missing data based on 
information contained in the observed data. Since the parameter (θ) of the data is also 
unknown, the imputation step actually draws random samples of both missing data and θ 
based on the observed data. 
The MCMC method draws samples in two steps. At step one (I-Step), given the current 
estimate of θ(t) at the tth  iteration, a random sample Yt+l  is drawn from the conditional 
predictive distribution of P(Ymis|Yobs, 0t).  At step two (P-step), given Yt+l , a random 
sample of θ(t + 1) is drawn from the distribution of  P(0IYobs, Yt+l). Starting with an initial 
value θ(0) (usually an arbitrary guess), MCMC iterates between the I-step and the P-step, 
leading to a Markov Chain: 
It can be shown that this Markov Chain converges in distribution to P(θ,Ymis|Yobs). It 
follows that the sequence θ(1), θ(2),…, θ(t),… converges to P(θ|Yobs) and the sequence 
Yl    , Y2    ,…, Yt 
… converges to P(Ymis|Yobs). Thus, after the Markov Chain converges, 
mis 
mis 
mis 
m draws of Ymis can form m imputations for the missing data. At the end of the first step in 
MI, missing data will be imputed m times to produce m sets of complete data. 
Step 2: Statistical Analysis 
The second step of MI analyzes the m sets of data separately using Proc Mixed to estimate 
the relevant standard errors and least square means. At the end of the second step, m sets of 
parameter estimates are obtained from separate analyses of m data sets. 
Step 3: Combining Results 


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The third step of MI combines the m estimates into one using PROC MIANALYZE. 
7.3.2 Handling of missing or incomplete dates 
Imputation rules for missing or partial AE start dates are defined below: 
If only Day of AE start date is missing: 
If the AE start year and month are the same as that for the first dose date, then: 
 If the full (or partial) AE end date is NOT before the first dose date or AE end date 
is missing, then impute the AE start day as the day of first dose date; 
 Otherwise, impute the AE start day as 1. 
If Day and Month of AE start date are missing: 
If AE start year = first dose year, then: 
 If the full (or partial) AE end date is NOT before the first dose date or AE end date 
is missing, then impute the AE start Month and Day as the Month and Day of first 
dose date 
 Otherwise, impute the AE start MONTH as January and the DAY as 1. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing, then query site 
and leave as missing. 
For missing and partial adverse event end dates, imputation will be performed as follows: 
If only the day of the month is missing, the last day of the month will be used to replace 
the missing day. If the day and month are missing or a date is completely missing, it will 
be considered as missing. 
Imputation rules for missing or partial medication start/stop dates are defined below: 
If only Day of CM start date is missing: 
If the CM start year and month are the same as that for the first dose date, then: 
 If the full (or partial) CM end date is NOT before the first dose date or CM end date 
is missing, then impute the CM start day as the day of first dose date; 
 Otherwise, impute the CM start day as 1. 
If Day and Month of CM start date are missing: 
If CM start year = first dose year, then: 
 If the full (or partial) CM end date is NOT before the first dose date or CM end date 
is missing, then impute the CM start Month and Day as the Month and Day of first 
dose date 
 Otherwise, impute the CM start MONTH as January and the DAY as 1. 


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If Year of CM start date is missing: 
If the year of CM start is missing or CM start date is completely missing, then query site 
and leave as missing. 


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8 
STATISTICAL METHODS 
8.1 
General statistical conventions 
All statistical procedures will be completed using SAS version 9.3 or higher. 
Unless otherwise stated, all statistical testing will be two-sided and will be performed using 
a significance (alpha) level of 0.05. Two-sided 95 % confidence intervals (CI) will be 
provided when relevant. Any p-value below 0.05 will be displayed to 4 decimal places. 
Any p-value less than 0.0001 will be displayed as <0.0001. Any p-value between 0.05 
(inclusive) and 0.10 will be displayed to 3 decimal places and any p-value greater than 
0.10 will be displayed to two decimal places. Any p-value greater than 0.9999 will be 
displayed as >0.9999. 
All quantitative endpoints will be summarized using an 8-number summary (n, mean, 
standard deviation, median, 25th percentile, 75th  percentile, minimum and maximum 
values). The mean and median and the percentiles will be rounded to one decimal place 
beyond the precision of the values being summarized, the standard deviation will be 
rounded to 2 additional decimal places beyond this precision and the minimum and 
maximum values will be displayed in the same precision. All qualitative endpoints will be 
summarized by the number of subjects meeting the endpoint and the percentage of subjects 
out of the appropriate population. The denominator will be displayed when needed and the 
percentage will be rounded to one decimal place 
All subject data, including those derived, will be presented in individual subject data 
listings. Unless otherwise stated, unscheduled visit results will be included in date/time 
chronological order, within subject listings only. All listings will be sorted by 
investigational site, patient number, date/time and visit. The treatment group as well as 
patient’s sex and age will be stated on each listing. Unless otherwise stated, data listings 
will be based on all subjects randomized. 
Descriptive statistics in tables will include a pooled EDP-305 group (Combined EDP-305) 
except PK information. No inferential analysis will be performed using the combined 
group. No figures or listings will include the combined group.  The overall (totals) will 
only be presented for study disposition. 
8.2 
Subject disposition 
All subjects who provided informed consent will be included in a summary of subject 
accountability. The number and percentage of subjects screened, randomized, and treated, 
randomized and not treated, as well as the number and percentage of subjects in each 
analysis population (safety, efficacy, per protocol, and PK) will be summarized. The 
denominator for the calculation of percentages will be from the number of subjects 
randomized. 
The following categories will also be summarized for subject disposition by treatment 
group and overall: 
• Completed study drug per protocol 


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• Discontinued study drug early and the primary reason for discontinuation 
• Completed the study 
• Discontinued from the study early and the main reason for discontinuation 
The denominator used for the calculation of percentages will be the number of subjects 
randomized. 
In addition, the number of subjects excluded from Safety, Efficacy and PK analysis sets 
and reasons for exclusion will be summarized by treatment group and overall. 
8.3 
Protocol violations/deviations 
All protocol deviations identified will be summarized by treatment group and overall, all 
protocol deviations will be listed. 
Summaries will be conducted on all subjects that were randomized. 
8.4 
Demographics and baseline characteristics 
No statistical testing will be performed for the comparison between treatment groups on 
demographics and Baseline characteristics. 
8.4.1 Demographics 
Subject demographics will be summarized by randomized treatment group for all subjects 
in the safety population. Age, height, weight and BMI at Baseline will be summarized 
using an 8-number summary (n, mean, standard deviation, median, 25th percentile, 75th 
percentile, minimum and maximum values). Qualitative variables such as gender, ethnicity 
and race will be summarized using count and percentage. 
A by-subject listing will be provided. 
8.4.2 Baseline and disease characteristics 
The categorical Baseline characteristics such as Baseline ECG and other Baseline lab 
parameters will be summarized using frequency counts for the safety population. NASH 
relevant comorbidities, and concomitant medications in the past 6 months will also be 
summarized. 
A summary of NASH diagnosis will be provided for the safety population. 
The following are summarized using count and percentage: 
• Liver Biopsy <= 24 mths of screening consistent with NASH AND Elevated ALT 
defined as 50 <= ALT (IU/L) <= 200 at Screening AND MRI-PDFF with >8% 
steatosis 
 
OR 


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• Type II Diabetes Mellitus / Pre-Diabetes defined as Glucose >200mg/dL or fasting 
glucose >126mg/dL and HB1AC at least 6% AND Elevated ALT at Screening, 
where elevated ALT is defined as 50 <= ALT (IU/L) <= 200 AND MRI-PDFF with 
>8% steatosis. 
Subjects will be considered diagnosed with NASH based on a liver biopsy within the last 
24 months, prior to the present study. Otherwise, it will be assumed that subjects were 
diagnosed as having NASH by phenotype. 
A by-subject listing will be provided. 
8.4.3 Medical history 
A summary of medical and surgical history will be presented by system organ class (SOC) 
and preferred term (PT) using Medical Dictionary for Regulatory Affairs® (MedDRA) 
Version 19.0 or higher for the safety population. 
A by-subject listing will be provided. 
8.4.4 Prior and concomitant medications 
Medications used in this study will be coded by using the latest available version of the 
World Health Organization Drug Dictionary Enhanced (WHODDE). 
Prior medications: are defined as those medications with a start date prior to the first dose 
of study drug. 
Concomitant medications: are defined as those medications with a start date on or after 
the first dose of study drug and within 30 days after the last dose. A medication which 
started prior to dosing and continued after dosing will also be considered as concomitant 
medications. 
Concomitant medications will be summarized descriptively using frequency tables by 
anatomical therapeutic chemical (ATC) class and preferred name by treatment group on 
the safety population. Concomitant diabetes medications will be summarized using the 
same format. 
A by-subject listing will be provided for prior and concomitant medications. 
Details for imputing missing or partial start and/or stop dates of medication are described 
in Section 7.2.2. 
8.5 
Extent of exposure 
8.5.1 Treatment duration 
Duration of study drug (in days) will be calculated as: last dose date – first dose 
date + 1 day, regardless of study drug interruption. 
Study drug exposure will be summarised by treatment group on the Safety Population 
using descriptive statistics. A categorical (0-2 Weeks, 2-4 Weeks, 4-6 Weeks, 6-8 Weeks, 
8-10 Weeks, 10-12 Weeks 12-16) summary will be provided. 


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8.5.2 Treatment compliance 
Study drug compliance based on the number of tablets taken will be calculated as: 
100 x [(total number of tablets dispensed) – (total number of tablets returned)]/ (total 
number of tablets planned to be taken per day x duration of study drug exposure in days). 
The maximum percentage of tablets taken will be 100%. 
Study drug compliance based on study drug exposure will be calculated as: 
100 x [1 − (total number of days of any study drug interruption) / (duration of study drug 
exposure in days)]. 
Study drug compliance will be summarized by treatment group using 8-number summary. 
They will also be summarized in categories “<80%, 80% - <90%, 90% - <100% and 
“≥100% compliant” using frequency tables. 
Study drug compliance summaries will be based on the Safety Population. 
8.6 
Efficacy analyses 
This section addresses separately the analyses to be conducted on the primary, secondary, 
and additional efficacy variables. All the efficacy analyses will be performed using 
efficacy population as primary analysis. 
8.6.1 Analysis methods 
Analysis of Covariance (ANCOVA) Model for Change from Baseline 
In summaries of efficacy endpoints examining changes from Baseline at Week 12, 
ANCOVA of the differences between post-Baseline and Baseline measurements will be 
performed, with treatment group as fixed effects and the Baseline measurement as a 
covariate. 
The model will be used to derive least squares estimates of the treatment differences (each 
active treatment group versus placebo) in mean change and two-sided 95% confidence 
intervals. Where applicable, t-statistics corresponding to the type III sums of squares for 
the differences in the least squares means will be used to obtain p-values for treatment 
group comparisons (each active treatment group versus placebo). Moreover, two-sided 
95% confidence intervals for the mean change within each treatment group will be 
calculated. 
8.6.1.1 Multiplicity 
No adjustment will be made for multiple comparisons. 
8.6.1.2 Treatment by center interaction analysis (multi-center study) 
No analysis will be made to assess the treatment-by-center interaction. 
8.6.2 Analysis of primary efficacy endpoint(s) 
The primary efficacy endpoint of the study is the change from Baseline in ALT at Week 
12. All subjects in the efficacy population will be included, with a secondary analysis 


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performed on the per protocol population. 
Baseline in ALT will be derived based on three different methods (see Table 3): Baseline 
(Average), Baseline (Last value pre-dose), and Baseline (Screening). 
A descriptive summary table will be presented for ALT values, change from Baseline and 
percentage change from Baseline in ALT by treatment group and visit using the 8-number 
summary.  Percent change from baseline will be analyzed similarly as the change results. 
Change from Baseline in ALT at Week 12 will be analysed using an ANCOVA model 
with treatment as a fixed effect and the associated Baseline value as a covariate. Least 
squares means and standard errors will be presented for each visit, p-value and 2-sided 
95% confidence interval for treatment differences will be presented for each visit. 
Significance tests will be based on least-squares means using a two-sided α = 0.05. As an 
additional analysis, the primary endpoint will be analysed using the Multiple Imputation 
method as described in section 7.2.1. 
A by-subject listing will be provided for observed and derived variables. 
8.6.3 Analysis of secondary efficacy endpoint(s) 
All analysis of secondary efficacy endpoints will be performed on the efficacy population. 
Additional analyses will be performed on the per protocol population. All secondary 
endpoint related to PK data will be analysed using subjects in the PK population. 
Endpoints related to PD data will be analyzed using subjects in the efficacy population 
unless otherwise specified. 
8.6.3.1 Change from baseline and percentage change from baseline in percentage of 
fat in the liver as assessed by MRI-PDFF at week 12 
Percentage of fat in the liver assessed by MRI-PDFF at Screening and Week 12, change 
from Baseline and percentage change from Baseline will be summarized using an 8- 
number summary by visit and treatment group. 
The screening visit will be considered the Baseline value for this endpoint. 
Change from Baseline and percentage change from Baseline in percentage of fat in the 
liver at Week 12 will be analysed using an ANCOVA model with treatment as fixed effect 
and the associated Baseline value as covariate. Least squares mean and standard errors will 
be presented for each visit, p-value and 2-sided 95% confidence interval for treatment 
differences will be presented for each visit. Significance tests will be based on least- 
squares means using a two-sided α = 0.05. 
In addition, the proportion of subjects who show at least a 30% reduction versus those less 
than a 30% reduction from Baseline in liver fat assessed by MRI-PDFF at Week 12 will be 
summarized (Loomba et.al, 2018)￼ Inferential testing will be performed using a Fisher’s 
Exact test to compare each of the active arms to the placebo arm. All subjects in the 
efficacy population will be included in this analysis, with those subjects with missing 
Week 12 MRI-PDFF results included in the denominator (i.e., Missing=failure).  The ALT 
value change from Baseline in ALT and percentage change from Baseline in ALT at week 
 


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12 will be summarized by treatment and liver fat response rate. The ANCOVA model will 
be repeated as described above, adding in the subgroup as a fixed effect. 
A by-subject listing will be provided for observed and derived variables. 
8.6.3.2 Change from baseline and percentage change from baseline in liver stiffness 
as assessed by MRE at week 12 
The liver stiffness as assessed by MRE at the Screening visit and Week 12, change from 
Baseline and percentage change from Baseline will be summarized using an 8-number 
summary by visit and treatment group. 
The screening visit will be considered the Baseline value for this endpoint. 
Change from Baseline and percentage change from Baseline in liver stiffness at Week 12 
will be analysed using an ANCOVA model with treatment as fixed effect and the 
associated Baseline value as covariate. Least squares means and standard errors will be 
presented for each visit, p-value and 2-sided 95% confidence interval for treatment 
differences will be presented for each visit. Significance tests will be based on least- 
squares means using a two-sided α = 0.05. 
In addition, the proportion of subjects who show at least a 15% reduction versus those less 
than a 15% reduction from Baseline in liver stiffness will be summarized by visit and 
treatment group (Loomba et.al, 2018). Inferential testing will be performed using a 
Fisher’s Exact test to compare each of the active arms to the placebo arm. The ALT value 
change from Baseline in ALT and percentage change from Baseline in ALT will be 
summarized by treatment and liver stiffness response rate. 
By-subject listing will be provided for observed and derived variables. 
8.6.3.3 Change from baseline and percentage change from baseline of noninvasive 
liver fibrosis markers (ELF panel) and PRO C3 at week 12 
ELF Panel at Week 12 
The ELF panel combines 3 biomarkers that have been shown to correlate with the level of 
liver fibrosis assessed by a liver biopsy. These biomarkers include HA, PIIINP, and 
TIMP-1. 
A descriptive summary will be provided for noninvasive liver fibrosis markers (ELF panel) 
values, change from Baseline and percentage change from Baseline using 8-number 
summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline of noninvasive liver fibrosis 
markers (ELF panel) at Week 12 will be analysed using an ANCOVA model with 
treatment as fixed effect and the associated Baseline value as covariate. Least squares 
means and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 


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A by-subject listing will be provided for observed and derived variables. 
PRO C3 at Week 12 
A descriptive summary will be provided for PRO C3 values, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline PRO C3 at Week 12 will be 
analysed using an ANCOVA model with treatment as fixed effect and the associated 
Baseline value as covariate. Least squares means and standard errors will be presented for 
each visit, p-value and 2-sided 95% confidence interval for treatment differences will be 
presented for each visit. Significance tests will be based on least-squares means using a 
two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
8.6.3.4 Change from baseline and percentage change from baseline in fibrosis at 
week 12 
Fibrosis will be estimated using the APRI, the fibrosis 4 (FIB-4) formulae, and the NAFLD 
fibrosis score (NFS). 
NFS at Week 12 
The NFS will be calculated by the central laboratory using the following formula: 
-1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG/Diabetes (yes = 1, no = 
0) + 0.99 × AST/ALT ratio – 0.013 × Platelets (109/L) – 0.66 × Albumin (g/dL) 
NFS online calculator reference: 
https://www.mdcalc.com/nafld-non-alcoholic-fatty-liver-disease-fibrosis-score 
A descriptive summary will be provided for NFS values, change from Baseline and the 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in NFS at Week 12 will be 
analysed using an ANCOVA model with treatment as fixed effect and the associated 
Baseline value as covariate. Least squares means and standard errors will be presented for 
each visit, p-value and 2-sided 95% confidence interval for treatment differences will be 
presented for each visit. Significance tests will be based on least-squares means using a 
two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
APRI at Week 12 
The APRI will be calculated by the central laboratory using the following formula: 
([AST IU/L / AST ULN] / [Platelet count 109/L]) × 100 = APRI 
Online calculator can be found at: http://www.hepatitisc.uw.edu/page/clinical- 
calculators/apri 


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A descriptive summary will be provided for APRI, change from Baseline and the 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in APRI at Week 12 will be 
analysed using an ANCOVA model with treatment as fixed effect and the associated 
Baseline value as covariate. Least squares means and standard errors will be presented for 
each visit, p-value and 2-sided 95% confidence interval for treatment differences will be 
presented for each visit. Significance tests will be based on least-squares means using a 
two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
FIB-4 at Week 12 
The FIB-4 score will be calculated using the following formula: 
[Age (years) × AST (IU/L)] / [Platelets (109/L) × (√ ALT (IU/L)))] 
FIB-4 online calculator reference: http://www.hepatitisc.uw.edu/page/clinical- 
calculators/fib-4 
A descriptive summary will be provided for FIB-4 values, change from Baseline and the 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in FIB-4 at Week 12 will be 
analysed using an ANCOVA model with treatment as fixed effect and the associated 
Baseline value as covariate. Least squares mean and standard errors will be presented for 
each visit, p-value and 2-sided 95% confidence interval for treatment differences will be 
presented for each visit. Significance tests will be based on least-squares means using a 
two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
8.6.3.5 Change from baseline and percentage change from baseline in lipids by visit 
and at week 12 
Lipids will be evaluated using the regular lipid panel obtained in the biochemistry panel 
from the standard blood draw. In addition, a special LIPO Profile assay will be used to 
further evaluate the number of particles in each of the lipid parameters. This section will 
describe the parameters obtained from this standard lipid profile and from the LIPO 
profile, where applicable. 
Triglycerides by Visit and at Week 12 
Triglycerides are captured in the general lab biochemistry panel and also in the LIPO 
profile panel. Both measurements of triglycerides will be summarized separately. 
A descriptive summary will be provided for triglyceride values, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in triglycerides at each visit, 
with Week 12 as the visit of primary interest, will be analysed using an ANCOVA model 


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with treatment as fixed effect and the associated Baseline value as covariate. Least squares 
mean and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
Total Cholesterol by Visit and at Week 12 
Total cholesterol is captured in the general lab biochemistry panel and also in the LIPO 
profile panel.  Both measurements of total cholesterol will be summarized separately. 
A descriptive summary will be provided for total cholesterol values, change from Baseline 
and percentage change from Baseline using 8-number summary by visit and treatment 
group. 
Change from Baseline and percentage change from Baseline in total cholesterol at each 
visit, with Week 12 as the primary visit of interest, will be analysed using an ANCOVA 
model with treatment as fixed effect and the associated Baseline value as covariate. Least 
squares mean and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
HDL by Visit and at Week 12 
HDL is captured in the general lab biochemistry panel and also in the LIPO profile panel 
(as HDL-C).  Both measurements of HDL will be summarized separately. 
A descriptive summary will be provided for HDL values, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in HDL at each visit, with the 
Week 12 being the primary visit of interest, will be analysed using an ANCOVA model 
with treatment as fixed effect and the associated Baseline value as covariate. Least squares 
means and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
LDL by Visit and at Week 12 
LDL is captured in the general lab biochemistry panel and also in the LIPO profile panel 
(as LDL-C).  Both measurements of LDL will be summarized separately. 
A descriptive summary will be provided for LDL values, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in LDL at each visit, with the 
Week 12 being the primary visit of interest, will be analysed using an ANCOVA model 


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with treatment as fixed effect and the associated Baseline value as covariate. Least squares 
mean and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
 
 
 
 
 
 
 
 
Total/HDL Cholesterol (CT) Ratio by Visit and at Week 12 
A descriptive summary will be provided for total cholesterol/HDL Ratio values, change 
from Baseline and percentage change from Baseline using 8-number summary by visit and 
treatment group. Ratio will be also obtained from LIPO profile. 
Change from Baseline and percentage change from Baseline in total cholesterol/HDL ratio 
at each visit, with Week 12 as the primary visit of interest, will be analysed using an 
ANCOVA model with treatment as fixed effect and the associated Baseline value as 
covariate. Least squares mean and standard errors will be presented for each visit, p-value 
and 2-sided 95% confidence interval for treatment differences will be presented for each 
visit. Significance tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
Adiponectin by Visit and Week 12 
A descriptive summary will be provided for adiponectin values, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in adiponectin values by visit, 
with the Week 12 being the primary visit of interest, will be analysed using an ANCOVA 
model with treatment as fixed effect and the associated Baseline value as covariate. Least 
squares mean and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
ApoA-1 by Visit and at Week 12 
A descriptive summary will be provided for ApoA-1 values, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in ApoA-1 by visit, with the 
Week 12 being the primary visit of interest, will be analysed using an ANCOVA model 
with treatment as fixed effect and the associated Baseline value as covariate. Least squares 
mean and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 


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ApoB by Visit and at Week 12 
A descriptive summary will be provided for ApoB values, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in ApoB by visit, with the 
Week 12 being the primary visit of interest, will be analysed using an ANCOVA model 
with treatment as fixed effect and the associated Baseline value as covariate. Least squares 
mean and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
ApoC3 by Visit and at Week 12 
A descriptive summary will be provided for ApoC3 values, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in ApoC3 by visit, with the 
Week 12 being the primary visit of interest, will be analysed using an ANCOVA model 
with treatment as fixed effect and the associated Baseline value as covariate. Least squares 
mean and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
ApoB/A-1 Ratio by Visit and at Week 12 
A descriptive summary will be provided for ApoB/A-1 ratio values, change from Baseline 
and percentage change from Baseline using 8-number summary by visit and treatment 
group. 
Change from Baseline and percentage change from Baseline in ApoB/A-1 ratio by visit, 
with the Week 12 being the primary visit of interest, will be analysed using an ANCOVA 
model with treatment as fixed effect and the associated Baseline value as covariate. Least 
squares mean and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
8.6.3.6 Change from baseline and percentage change from baseline in parameters of 
glucose metabolism by visit and at week 12 
Fasting Glucose by Visit and at Week 12 
A descriptive summary will be provided for fasting glucose, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline will be analysed by visit, with 


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the Week 12 visit being the primary visit of interest, will be analysed using an ANCOVA 
model with treatment as fixed effect and the associated Baseline value as covariate. Least 
squares mean and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
Fasting Insulin by Visit and at Week 12 
A descriptive summary will be provided for fasting insulin, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline will be analysed by visit, with 
the Week 12 visit being the primary visit of interest, will be analysed using an ANCOVA 
model with treatment as fixed effect and the associated Baseline value as covariate. Least 
squares means and standard errors will be presented for each visit, p-value and 2-sided 
95% confidence interval for treatment differences will be presented for each visit. 
Significance tests will be based on least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
HOMA Index for Non-Diabetic Subjects by Visit and at Week 12 
Subjects who are not considered having type 2 diabetes will be identified using the NASH 
history page in the CRF. A descriptive summary will be provided for HOMA index for the 
non-diabetic subjects, change from Baseline and percentage change from Baseline using 8- 
number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline will be analysed by visit, with 
the Week 12 visit being the primary visit of interest, will be analysed using an ANCOVA 
model with treatment as fixed effect and the associated Baseline value as covariate. Least 
squares means and standard errors will be presented for each visit, p-value and 2-sided 
95% confidence interval for treatment differences will be presented for each visit. 
Significance tests will be based on least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
HOMA Index for Diabetic Subjects by Visit and at Week 12 
Subjects who are considered as having type 2 diabetes will be identified using the NASH 
history page in the CRF. 
A descriptive summary will be provided for HOMA index for the diabetic subjects, change 
from Baseline and percentage change from Baseline using 8-number summary by visit and 
treatment group. 
Change from Baseline and percentage change from Baseline will be analyzed by visit, with 
the week 12 visit being the primary visit of interest, will be analyzed using an ANCOVA 
model with treatment as fixed effect and the associated Baseline value as covariate. Least 
squares means and standard errors will be presented for each visit, p-value and 2-sided 


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95% confidence interval for treatment differences will be presented for each visit. 
Significance tests will be based on least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
HbA1C for Subjects with Type 2 Diabetes by Visit and at Week 12 
Subjects who are considered as having type 2 diabetes will be identified using the NASH 
history page in the CRF. 
A descriptive summary will be provided for HbA1c for subjects with type 2 diabetes, 
change from Baseline and percentage change from Baseline using 8-number summary by 
visit and treatment group. 
Change from Baseline and percentage change from Baseline will be analysed by visit, with 
the Week 12 visit being the primary visit of interest, will be analysed using an ANCOVA 
model with treatment as fixed effect and the associated Baseline value as covariate. Least 
squares means and standard errors will be presented for each visit, p-value and 2-sided 
95% confidence interval for treatment differences will be presented for each visit. 
Significance tests will be based on least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
8.6.3.7 Change from baseline and percentage change from baseline in laboratory 
Inflammation parameter levels by visit and at week 12 
Fibrinogen by Visit and at Week 12 
A descriptive summary will be provided for fibrinogen levels, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in fibrinogen levels by visit, 
with the Week 12 will be analysed using an ANCOVA model with treatment as fixed 
effect and the associated Baseline value as covariate. Least squares means and standard 
errors will be presented for each visit, p-value and 2-sided 95% confidence interval for 
treatment differences will be presented for each visit. Significance tests will be based on 
least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
CRP (hs-CRP) by Visit and at Week12 
A descriptive summary will be provided for CRP (hs-CRP) levels, change from Baseline 
and percentage change from Baseline using 8-number summary by visit and treatment 
group. 
Change from Baseline and percentage change from Baseline in CRP (hs-CRP) levels at 
Week 12 will be analysed using an ANCOVA model with treatment as fixed effect and the 
associated Baseline value as covariate. Least squares means and standard errors will be 
presented for each visit, p-value and 2-sided 95% confidence interval for treatment 
differences will be presented for each visit. Significance tests will be based on least- 


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squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
IL6 by Visit and at Week 12 
A descriptive summary will be provided for IL6 levels, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in IL6 levels at Week 12 will 
be analysed using an ANCOVA model with treatment as fixed effect and the associated 
Baseline value as covariate. Least squares means and standard errors will be presented for 
each visit, p-value and 2-sided 95% confidence interval for treatment differences will be 
presented for each visit. Significance tests will be based on least-squares means using a 
two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
IL1β by Visit and at Week 12 
A descriptive summary will be provided for IL1β levels, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in IL1β levels at Week 12 will 
be analysed using an ANCOVA model with treatment as fixed effect and the associated 
Baseline value as covariate. Least squares means and standard errors will be presented for 
each visit, p-value and 2-sided 95% confidence interval for treatment differences will be 
presented for each visit. Significance tests will be based on least-squares means using a 
two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
TNF-α by Visit and at Week 12 
A descriptive summary will be provided for TNF-α levels, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in TNF-α levels at Week 12 
will be analysed using an ANCOVA model with treatment as fixed effect and the 
associated Baseline value as covariate. Least squares means and standard errors will be 
presented for each visit, p-value and 2-sided 95% confidence interval for treatment 
differences will be presented for each visit. Significance tests will be based on least- 
squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
TNF-β by Visit and at Week 12 
A descriptive summary will be provided for TNF-β levels, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change  from  Baseline  and  percentage  change  from  Baseline  in  TNF-β  levels  at  Week  12 
will be analysed using an ANCOVA model with treatment as fixed effect and the 
 


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associated Baseline value as covariate. Least squares means and standard errors will be 
presented for each visit, p-value and 2-sided 95% confidence interval for treatment 
differences will be presented for each visit. Significance tests will be based on least- 
squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
Haptoglobin by Visit and at Week 12 
A descriptive summary will be provided for haptoglobin levels, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in haptoglobin levels at Week 
12 will be analysed using an ANCOVA model with treatment as fixed effect and the 
associated Baseline value as covariate. Least squares means and standard errors will be 
presented for each visit, p-value and 2-sided 95% confidence interval for treatment 
differences will be presented for each visit. Significance tests will be based on least- 
squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
Alpha2 Macroglobulin by Visit and at Week 12 
A descriptive summary will be provided for alpha2 macroglobulin levels, change from 
Baseline and percentage change from Baseline using 8-number summary by visit and 
treatment group. 
Change from Baseline and percentage change from Baseline in alpha2 macroglobulin 
levels at Week 12 will be analysed using an ANCOVA model with treatment as fixed 
effect and the associated Baseline value as covariate. Least squares means and standard 
errors will be presented for each visit, p-value and 2-sided 95% confidence interval for 
treatment differences will be presented for each visit. Significance tests will be based on 
least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
8.6.3.8 Change from baseline and percentage change from baseline in body weight 
by visit and at week 
A descriptive summary will be provided for body weight, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in body weight by visit, with 
the Week 12 visit as the primary visit of interest, will be analysed using an ANCOVA 
model with treatment as fixed effect and the associated Baseline value as covariate. Least 
squares mean and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 


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8.6.3.9 Change from baseline and percentage change from baseline in waist to hip 
(WTH) ratio by visit and at week 12 
A descriptive summary will be provided for Waist Circumference, Hip Circumference, and 
WTH ratio using 8-nummer summary by visit and treatment group. In addition, change 
from Baseline and percentage change from Baseline in WTH ratio will be summarized. 
Change from Baseline and percentage change from Baseline in waist to hip WTH ratio by 
visit, with the Week 12 visit as the primary visit of interest, will be analysed using an 
ANCOVA model with treatment as fixed effect and the associated Baseline value as 
covariate. Least squares mean and standard errors will be presented for each visit, p-value 
and 2-sided 95% confidence interval for treatment differences will be presented for each 
visit. Significance tests will be based on least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
8.6.3.1Change from Baseline and percentage change from Baseline in NASH 
biomarker by Visit and at Week 12 
Cytokeratin (CK) 18  by Visit and at Week 12 
A descriptive summary will be provided for CK18 levels, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in CK18 levels by visit, with 
the Week 12 will be analysed using an ANCOVA model with treatment as fixed effect and 
the associated Baseline value as covariate. Least squares means and standard errors will be 
presented for each visit, p-value and 2-sided 95% confidence interval for treatment 
differences will be presented for each visit. Significance tests will be based on least- 
squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
GLP-1 by Visit and at Week 12 
A descriptive summary will be provided for GLP-1 levels, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in GLP-1 levels by visit, with 
the Week 12 will be analysed using an ANCOVA model with treatment as fixed effect and 
the associated Baseline value as covariate. Least squares means and standard errors will be 
presented for each visit, p-value and 2-sided 95% confidence interval for treatment 
differences will be presented for each visit. Significance tests will be based on least- 
squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
8.6.4 Additional Analyses (Liver Tests) 
8.6.4.1 Change from Baseline and Percentage Change from Baseline in Additional 


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Liver Parameters 
AST by Visit and at Week 12 
A descriptive summary will be provided for AST values, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in AST at each visit, with the 
Week 12 being the primary visit of interest, will be analysed using an ANCOVA model 
with treatment as fixed effect and the associated Baseline value as covariate. Least squares 
mean and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
Total Bilirubin by Visit and at Week 12 
A descriptive summary will be provided for Total Bilirubin values, change from Baseline 
and percentage change from Baseline using 8-number summary by visit and treatment 
group. 
Change from Baseline and percentage change from Baseline in Total Bilirubin at each 
visit, with the Week 12 being the primary visit of interest, will be analysed using an 
ANCOVA model with treatment as fixed effect and the associated Baseline value as 
covariate. Least squares means and standard errors will be presented for each visit, p-value 
and 2-sided 95% confidence interval for treatment differences will be presented for each 
visit. Significance tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
GGT by Visit and at Week 12 
A descriptive summary will be provided for GGT values, change from Baseline and 
percentage change from Baseline using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline in GGT at each visit, with the 
Week 12 being the primary visit of interest, will be analysed using an ANCOVA model 
with treatment as fixed effect and the associated Baseline value as covariate. Least squares 
means and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
Alkaline Phosphatase by Visit and at Week 12 
A descriptive summary will be provided for alkaline phosphatase values, change from 
Baseline and percentage change from Baseline using 8-number summary by visit and 
treatment group. 
Change from Baseline and percentage change from Baseline in alkaline phosphatase at 


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each visit, with the Week 12 being the primary visit of interest, will be analysed using an 
ANCOVA model with treatment as fixed effect and the associated Baseline value as 
covariate. Least squares means and standard errors will be presented for each visit, p-value 
and 2-sided 95% confidence interval for treatment differences will be presented for each 
visit. Significance tests will be based on least-squares means using a two-sided α = 0.05. 
By-subject listing will be provided for observed and derived variables. 
8.6.4.2 Subgroup Analyses 
Subgroup analyses will be performed on selected outcomes in subgroups of interest. All 
subgroup analyses will be exploratory in nature. As the interest will be on how different 
treatment regimens work in a specific subgroup, instead of whether the treatment 
differences are the same across different subgroups, the subgroup analyses will be 
performed by analyzing the outcome data in different subgroups, instead of analyzing the 
outcome data in the whole population with subgroup factors included in the analyses 
model. 
Subgroup analyses will be performed for the primary endpoint and the secondary endpoints 
to determine whether significant differences exist in primary and secondary endpoint 
results between subgroups. 
These subgroup analyses will be carried out using the subjects from the efficacy 
population. 
The list of potential subgroups (with applicable definitions in parentheses) includes the 
following: 
• MRE Week 12 response: (<15% reduction vs ≥15% reduction in percentage of change 
from baseline) 
• MRI-PDFF Week 12 response: (<30% reduction vs ≥30% reduction in percentage of 
change from baseline) 
• 
Both MRE Week 12 response (≥15% reduction in percentage of change from 
baseline) and MRI-PDFF Week 12 response (≥30% reduction in percentage of change 
from baseline) vs non-response 
•NASH 
Diagnosis (biopsy vs phenotype) 
• ALT Week 12 Category (>=0 change from baseline 
(0--10] change from baseline 
(-10--20] change from baseline 
(-20--30] change from baseline 
(-30--40] change from baseline 
<-40 change from baseline) AND same ALT categories for percent 
change from baseline 
 
8.6.4.3 Exploring Relationships between Endpoints 
Relationships between the endpoints will be evaluated as follows: 


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• Comparing the percentage change in ALT to the proportion of subjects with at least 
a 30% reduction in the percentage change from baseline in the MRI-PDFF score 
• Comparing the percentage change in the WTH ratio to the proportion of subjects 
with at least a 30% reduction in the percentage change from baseline the MRI- 
PDFF at Week 12 
• Comparing the percentage change in PRO-C3 to the proportion of subjects with at 
least a 30% reduction in the percentage change from baseline the MRI-PDFF at 
Week 12 
• Comparing the percentage change in ALT to the proportion of subjects with at least 
a 15% reduction in the percentage change from baseline in the MRE at Week 12 
• Comparing the percentage change in the WTH ratio to the proportion of subjects 
with at least a 15% reduction in the percentage change from baseline the MRE at 
Week 12 
• Comparing the percentage change in PRO-C3 to the proportion of subjects with at 
least a 30 point reduction in ALT at Week 12 
• Comparing the percentage change in body weight to the proportion of subjects with 
at least a 30 point reduction in ALT at Week 12 
• Comparing the percentage change in PRO-C3 to the proportion of subjects with at 
least a 20 percent reduction in ALT at Week 12 
• Comparing the percentage change in body weight to the proportion of subjects with 
at least a 20 percent reduction in ALT at Week 12 
• Comparing the percentage change in body weight to the proportion of subjects with 
at least a 30% reduction in the percentage change from baseline in MRI-PDFF at 
Week 12 
• Comparing the percentage change in body weight to the proportion of subjects with 
at least a 15% reduction in the percentage change from baseline in MRE at Week 
12 
In addition, relationships between the primary and secondary endpoints will be explored 
using scatterplots (and correlation coefficients) using various change and percent change 
from baseline. All data points will be included for all visits on a single plot, with separate 
color for each treatment group. 
8.7 
Safety analyzes 
All safety analyzes will be based on the Safety population and will be performed for all 
safety variables specified below. 
No statistical tests will be performed. 


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8.7.1 Adverse events 
The primary safety endpoint of the study is the frequency of AEs, SAEs, and AEs leading 
to discontinuation through Week 12. 
All Adverse Events (AEs) will be classified by Primary System Organ Class (SOC) and 
Preferred Term (PT) according to the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 19.0 or higher. All subjects in the safety analysis set will be included 
in the summaries. 
AEs will be classified as pre-treatment AEs and treatment emergent adverse events 
(TEAEs) and are defined as follows: 
Pre-treatment AE: A pre-treatment event is any event that meets the criteria for an 
AE/SAE and occurs after the subject signs the ICF but before receiving the first 
administration of study drug. 
TEAE: A TEAE is defined as an AE occurring or worsening on or after the first dose of 
study drug within 7 days after the last dose of study drug. 
Post-treatment AE: any AE that was newly developed after the last dose date + 7 days. 
Treatment-Related AEs: AE will be defined as related if causality is either probable or 
possible. AEs where the causality is missing will be assumed to have “Reasonable 
possibility of relatedness. 
Grade AEs: 
Grade AEs (serious and non-serious) in accordance with the NCI/CTCAE scale (available 
at 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06- 
14_QuickReference_8.5x11.pdf) as presented below: 
• Mild (Grade 1) asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
• Moderate (Grade 2) minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• Severe (Grade 3) Severe or medically significant but not immediately life 
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living 
• Life-threatening (Grade 4) Life-threatening consequences; urgent intervention 
indicated 
• Death (Grade 5) Death related to the AE. 
Details for imputing missing or partial start dates of adverse events are described in 
Section 7.2.2. Imputed Adverse Event dates will be used for determining treatment- 
emergence. 


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Summaries of AEs will include the following: 
• Treatment-emergent AEs 
• Treatment-emergent AEs by severity 
• Treatment-emergent treatment-related AEs 
• Treatment-emergent AEs leading to study drug discontinuation 
• SAEs 
• Treatment-related SAEs 
• AEs leading to death 
All TEAEs will be summarized by SOC, PT and treatment group using frequency counts 
and percentages. In addition, an overall summary for the categories above will be prepared 
by treatment group and overall. On-treatment AEs will be summarized separately from 
those events that occurred during treatment-free follow-up. Those events that occurred 
during treatment-free follow-up will be summarized by randomized treatment group. The 
denominator for these events will be only those subjects who entered into the 4 week 
treatment free follow-up period. 
Where a subject has the same adverse event, based on preferred terminology, reported 
multiple times in the treatment period, the subject will only be counted once at the 
preferred terminology level in adverse event frequency tables. 
Where a subject has multiple adverse events within the same system organ class in the 
treatment period, the subject will only be counted once at the system organ class level in 
adverse event frequency tables. 
When reporting adverse events by severity, in addition to providing a summary table based 
on the event selection criteria detailed above, summary table will also be provided based 
on the most severe event during the treatment period - independent of relationship to study 
treatment. 
8.7.2 Stopping Rules 
Summaries will be provided using counts and percentages for subjects who meets the 
stopping rules as described below: 
• ALT or AST > 5 x Baseline 
• ALT or AST > 2 x Baseline AND concomitant total bilirubin > 2 x Baseline 
OR Concomitant INR > 0.2 from Baseline 
• ALT or AST > Baseline AND Right Upper Quadrant Abdominal Pain, 
Anorexia, Nausea, Vomiting, Fever, Eosinophilia, and/or Rash 


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8.7.2.1  Close Monitoring for Drug Discontinuation due to Elevated ALT/AST 
The following close observation guidelines applies to subjects that repeat assessments 
show persistent elevations of transaminases, but who do not meet drug discontinuation 
criteria, and for subjects who discontinue study drug due to ALT/AST elevations. 
A listing will be used to track and evaluate subjects that are part of the close observation 
guidelines. Monitoring of these subjects will be ongoing throughout the study. 
8.7.3 Clinical laboratory evaluations 
Summaries of clinical laboratory results will be performed using an 8-number summary by 
visit and treatment. All subjects in the safety population will be included in these 
summaries.  Baseline is defined as the last value collected prior to first dose of study drug. 
The number and percentage of subjects with treatment-emergent laboratory abnormalities 
within 7 days of last dose of study drug will be summarized by treatment group. In 
addition, shift from Baseline tables will be generated by visit and treatment group. All 
summary tables will be repeated for abnormalities that occur during the treatment-free 
follow-up which is defined as occurring more than 7 days after the date of last dose. The 
denominator for these will include any subject who entered into the 4 week treatment-free 
follow-up phase. 
All laboratory data will be included in the data listings and all test values outside the 
normal range will be flagged. 
Pregnancy test and FSH will be listed separately. 
The laboratory parameters listed in Table 2 on the following page will be assessed for each 
patient. 
Creatinine clearance will be calculated by the central laboratory using the Cockcroft Gault 
equation and actual body weight: 
CLCr (mL/min) = {((140 − Age [years]) × weight[kg]) / (72 × SCr[mg/dL])} × 0.85 (if 
female). 
where SCr =serum creatinine 
Online calculator can be found at: 
https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc 
8.7.4 Vital signs 
Vital signs will include systolic blood pressure (mmHg), diastolic blood pressure (mmHg), 
respiratory rate (breaths/min), heart rate (beats/min), and oral temperature (°C). Vital signs 
data will be summarized using an 8-number summary by visit and treatment. In addition, 
the number and percentage of subjects with significant changes in vital signs from Baseline 
will be summarized by treatment. No statistical testing will be performed. Baseline is 
defined as the last value collected prior to first dose of study drug. 


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Criteria for clinically significant changes in vital signs parameters. 
Pulse Rate 
• < 50 bpm 
• >120 bpm 
• 30 bpm increase from Baseline 
• 30 bpm decrease from Baseline 
Blood Pressure 
• SBP > 150 mmHg or DBP > 100 mmHg 
• SBP > 200 mmHg or DBP > 110 mmHg 
Respiration Rate 
• < 8 breaths/min 
• 40 breaths/min 
Temperature 
• 38.3°C 
• 1.1°C increase from Baseline (Baseline > 36.8°C) 
Change in Weight 
• 5% increase from Baseline 
• 5% decrease from Baseline 
A by-subject listing will be provided. 
8.7.5 Physical examinations 
A full physical examination will be conducted at Screening and EOS as indicated in the 
Schedule of Assessments and will include a review of the following systems: 
head/neck/thyroid; eyes/ears/nose/throat (EENT); respiratory; cardiovascular; chest, lymph 
nodes; abdomen; skin; musculoskeletal; and neurological. Breast, anorectal, and genital 
examinations will be performed when medically indicated. 
Physical examination data will be provided in data listings. 
8.7.6 Electrocardiograms (ECG) 
12-lead ECG measurements include (Heart Rate (bpm), QRS Duration (msec), PR Interval 
(msec), QT Interval (msec) and QTcF (msec)) and will be summarized using an 8-number 
summary by visit and treatment for all safety subjects for observed values and changes 
from Baseline. The overall ECG interpretation (Normal, Abnormal Not Clinically 
Significant, Abnormal Clinically Significant) will be summarized by presenting the 
number and percentage of subjects for each treatment group and time-point. In addition, 


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the number and percentage of subjects with significant changes in ECG parameters will be 
summarized by treatment. Change from Baseline in QTcF > 60 msec or a QTcF interval > 
500 msec and QTcF > 450 msec for males and 470 msec for females at either screening or 
Baseline are considered as significant changes in ECG parameters. 
Baseline is defined as the last value collected prior to first dose of study drug. 
No statistical testing will be performed. 
A by-subject listing will be provided. 
8.8 
Pharmacokinetics (PK) and Pharmacokinetics/Pharmacodynamics (PK/PD) 
Analysis 
During the study, PK samples and PD samples for FGF19, C4, bile acid, and ALT will be 
collected according to one of two schedules on Days 1 and 84. Subjects agreeing to 
participate in the PK/PD substudy will have samples collected at four discrete times: 
predose and 2, 6, and 8 hours after administration of EDP-305 on Days 1 and 84. This 
scheme will be referred to as “intensive” sampling in this SAP. On Days 1 and 84, all other 
subjects will have a sample collected predose, a second sample collected 1 to 3 hours after 
administration of EDP-305, and a third sample collected at least 1 hour after the second 
sample. This scheme will be referred to as “sparse” sampling. Additionally, all subjects 
will have PK, FGF19, C4, bile acid, and ALT samples collected according to the sparse 
scheme on Weeks 2, 4, and 8. 
For the sparse sampling scheme, the nominal window for the first post-dose sample is 
defined relative to the time of EDP-305 administration while the nominal window for the 
second post-dose sample is defined relative to the time of collection of the first post-dose 
sample. As a consequence, actual sampling times for the second post-dose sample may fall 
within the 1- to 3-hour window described for the first post-dose sample. For example, if  
the first post-dose sample is collected 1 hour after EDP-305 administration and the second 
post-dose sample is collected 1 hour later, then the both samples would fall within the 1- to 
3-hour window. In addition, actual sampling times relative to EDP-305 administration for 
post-dose samples collected according to the sparse scheme may vary between subjects and 
study visits. To permit more meaningful summarization, post-dose samples collected 
according to the sparse scheme will be binned by actual elapsed time since the time of the 
reference dose of EDP-305 for each visit. Bins for sparse post-dose samples are described 
in Table 3. Bins may be modified based on the distribution of the data. 
Table 3: Bin Time for Post-Dose Sparse Samples 
 
Bin Time Midpoint 
(hr) 
Range for actual post-dose sample time 
(relative to time of EDP-305 dose) 
0.5 
0 to < 1 h 
2.0 
≥ 1 to < 3 h 


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4.0 
≥ 3 to < 5 h 
6.0 
≥ 5 to < 7 h 
8.0 
≥ 7 to < 9 h 
For plotting purposes, sparse predose samples collected prior to administration of the 
reference dose of EDP-305 at each study visit will be assigned to a 0-hour bin. In the event 
that a predose sample is collected after administration of the reference dose of EDP-305 at 
a particular study visit, this sample will be assigned to a bin in the same manner as 
described above for sparse post-dose samples. 
8.8.1 Pharmacokinetic (PK) Analysis 
The PK analysis will use the pharmacokinetic population and will include only subjects in 
active treatment arms. 
8.8.1.1 Analysis of Sparse PK Samples 
The concentration data for EDP-305 and each metabolite collected according to the sparse 
sampling scheme will be summarized by active treatment arm, visit, and bin time midpoint. 
Concentrations that are below the limit of quantitation (BLQ) will be treated as zero for the 
computation of descriptive statistics. If more than 50% of subjects have postdose 
concentration values below BLQ, descriptive statistics will not be presented except for 
maximum and BLQ will be displayed for mean and minimum. The number of observations, 
arithmetic mean, standard deviation (SD), % coefficient of variation (%CV), median, 
minimum, maximum, geometric mean, and %CV of the geometric mean (%GCV) will be 
displayed. Linear and semi-log plots of the arithmetic mean concentration versus bin time 
will be created. The linear plots of mean concentrations will include the SD (±) for each 
mean. Composite (i.e. “spaghetti”) plots of individual subject EDP-305 and metabolite 
plasma concentrations versus time data will be created on both the linear and semi-
logarithmic scales. A summary plot of the means and SD of the pre-dose concentrations at 
each visit will be provided by treatment. 
Individual data will be presented in listing. 
8.8.1.2 Analysis of Intensive PK samples 
The concentration data for EDP-305 and each metabolite collected according to the 
intensive sampling scheme will be summarized by active treatment arm, visit and nominal 
time since the reference dose. Concentrations that are BLQ will be treated as zero for the 
computation of descriptive statistics. If more than 50% of subjects have postdose 
concentration values below BLQ, descriptive statistics will not be presented except for 
maximum and BLQ will be displayed for mean and minimum. The number of 
observations, arithmetic mean, SD, %CV, median, minimum, maximum, geometric mean, 
and %GCV values will be displayed. Linear and semi-log plots of the arithmetic mean 
concentration versus nominal sampling time will be created. The linear plots of mean 


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concentrations will include the SD (±) for each mean. Composite (i.e. “spaghetti”) plots of 
individual subject EDP-305 and metabolite plasma concentrations versus time will be 
created on both the linear and semi-logarithmic scales. Predose samples collected under to 
the intensive sampling scheme will be pooled with those collected under the sparse 
sampling scheme for the purpose of creating the longitudinal summary plot of the means 
and standard deviations of the pre-dose concentrations (See Section 8.8.1.1). Linear and 
semi-logarithmic plots of the individual plasma concentration by actual sampling time will 
be provided by subject (one subject per page, Day 1 and Day 84 on same plot). 
 
The PK parameters listed in Table 6 will be calculated as indicated for plasma EDP-305 
and its metabolites, as applicable. PK parameters will be calculated by noncompartmental 
methods (only on Day 1 and Day 84). 
 
Table 6: PK/PD Parameters for Subjects with Intensive Samples 
 
PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve from time zero to the 
time of the last quantifiable concentration computed using the 
linear up/log down trapezoidal rule. 
Cmax 
Maximum observed concentration. 
Tlast 
Time to last quantifiable concentration. 
Tmax 
Time to reach Cmax. If the maximum value occurs at more than one timepoint, 
Tmax  is defined as the first time point with this value. 
Plasma PK parameters for each dose level will be calculated from the concentrations of 
EDP-305 and its metabolites measured in predose and post-dose plasma samples. For each 
EDP-305 dose level, descriptive statistics of AUClast and Cmax (sample size, arithmetic 
means, geometric means, standard deviation (SD), %CV, minimum, median, maximum, 
and %GCV) will be presented. Only the minimum, median, and maximum will be 
presented for Tmax. Tlast will be presented as a diagnostic parameter in the listing of 
individual PK parameters, but will not be included in summary tables with other PK 
parameters. 
 
Individual data will be presented in listing. 
 
8.8.2 Pharmacodynamic (PD) Analysis 
The PD analysis will use the efficacy population and will include all treatment arms (active 
and placebo). 


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8.8.2.1 Analysis of Sparse PD Samples 
A descriptive summary will be provided for the FGF19, C4, and bile acid endpoints 
including measured concentrations, change from baseline, and percentage change from 
baseline using the 8-number summary by visit, treatment group, and bin time midpoint. 
Change from baseline and percentage change from baseline in the FGF19, C4, and bile 
acid concentrations for each bin time midpoint by visit will be analysed using an 
ANCOVA model with treatment as fixed effect and the associated baseline value as 
covariate with the Week 12 visit being considered the primary visit of interest. Least 
squares means and standard errors will be presented for each visit, p-value and 2-sided 
95% confidence interval for treatment differences will be presented for each visit. 
Significance tests will be based on least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. 
8.8.2.2 Analysis of Intensive PD Samples 
A descriptive summary will be provided for the FGF19, C4, and bile acid endpoints 
including measured concentrations, change from baseline, and percentage change from 
baseline using 8-number summary by visit, treatment group, and nominal time. For Days 1 
and 84 (overlaid), linear plots of the arithmetic mean concentration (±SD) versus nominal 
sampling time figures will be created for FGF19, C4, and bile acid endpoints. 
Change from baseline and the percentage change from baseline in the FGF19, C4, and bile 
acid concentrations for each nominal time by visit will be analysed using an ANCOVA 
model with treatment as fixed effect and the associated baseline value as covariate with the 
Week 12 visit being considered the primary visit of interest. Least squares means and 
standard errors will be presented for each visit, p-value and 2-sided 95% confidence 
interval for treatment differences will be presented for each visit. Significance tests will be 
based on least-squares means using a two-sided α = 0.05. 
The area under the curve from 0 to 8 hours (AUC0-8) and from 2 to 8 hours (AUC2-8) will 
be computed for FGF19 and C4 at Days 1 and 84 using the linear trapezoidal rule. 
Descriptive summaries of AUC0-8 and AUC2-8 (sample size, arithmetic means, geometric 
means, standard deviation (SD), %CV, minimum, median, maximum, and %GCV) for 
FGF19 and C4 will be presented by visit and treatment group. 
The change from baseline and percent change from baseline for AUC0-8 and AUC2-8 will 
be computed for Day 84 using the parameter value at Day 1 as the baseline value. 
Change from baseline and the percentage change from baseline in the AUC0-8 and the 
AUC2-8 for FGF19 and C4 at Day 84 will be analysed using an ANCOVA model with 
treatment as fixed effect and the associated baseline value as covariate. Least squares 
means and standard errors will be presented for each visit, p-value and 2-sided 95% 
confidence interval for treatment differences will be presented for each visit. Significance 
tests will be based on least-squares means using a two-sided α = 0.05. 
A by-subject listing will be provided for observed and derived variables. Composite (i.e. 


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“spaghetti”) plots of individual subject FGF19, C4, and bile acid concentrations versus 
time will be created on the linear scale. 
8.8.2.3 PK/PD Analysis at Week 12 for Subjects with Intensive Samples 
Correlation and PK/PD plots will be created using all subjects in the PK population. 
Correlation and other PD plots will be created using all subjects in the efficacy population, 
including placebo, as applicable. The following scatterplots will be generated: 
• AUC0-8 in FGF19 with EDP-305 AUClast for Day 1 and Day 84 (Week 12) 
• AUC2-8 in FGF19 with EDP-305 AUClast for Day 1 and Day 84 (Week 12) 
• AUC0-8 in C4 with EDP-305 AUClast for (Day 1 and Day 84 [Week 12]) 
• AUC2-8 in C4 with EDP-305 AUClast for (Day 1 and Day 84 [Week 12]) 
• Percentage change from Baseline in AUC0-8 FGF19 with EDP-305 AUClast (Week 
12) 
• Percentage change from Baseline in AUC2-8 FGF19 with EDP-305 AUClast (Week 
12) 
• Percentage change from Baseline in AUC0-8 C4 with EDP-305 AUClast (Week 12) 
• Percentage change from Baseline in AUC2-8 C4 with EDP-305 AUClast (Week 12) 
• Percentage change from Baseline in Bile Acid (predose) with EDP-305 AUClast 
(Week 12) 
• Percentage change from Baseline in ALT (predose Week 12) with percentage 
change from Baseline in AUC0-8  FGF19 (Week 12) 
• Percentage change from Baseline in ALT (predose Week 12) with percentage 
change from Baseline in AUC2-8  FGF19 (Week 12) 
• Percentage change from Baseline in ALT (predose Week 12) with percentage 
change from Baseline in AUC0-8  C4 (Week 12) 
• Percentage change from Baseline in ALT (predose Week 12) with percentage 
change from Baseline in AUC2-8  C4 (Week 12) 
• Percentage change from Baseline in ALT (predose Week 12) with EDP-305 
AUClast  (Week 12) 
• Percentage change from Baseline in FGF19 (predose) with EDP-305 Cmax (Week 
12) 
• Percentage change from Baseline in C4 (predose) with EDP-305 Cmax  (Week 12) 
• Percentage change from Baseline in Bile Acid (predose) with EDP-305 Cmax (Week 
12) 


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8.8.2.4 PK/PD Analysis at Week 12 for All Subjects 
Correlation and PK/PD plots will be created using all subjects in the PK population. 
Correlation and other PD plots will be created using all subjects in the efficacy population, 
including placebo, as applicable. The following scatterplots will be generated: 
• Percentage change from Baseline in ALT with the percentage change from 
Baseline in FGF19 (Predose Week 12) 
• Percentage change from Baseline in ALT with the percentage change from 
Baseline in C4 (Predose Week 12) 
• Percentage change from Baseline in ALT with the percentage change from 
Baseline in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in ALT with EDP-305 concentration value 
(predose at Week 12) 
• Percentage change from Baseline in AST with the percentage change from Baseline 
in FGF19 (Predose Week 12) 
• Percentage change from Baseline in AST with the percentage change from Baseline 
in C4 (Predose Week 12) 
• Percentage change from Baseline in AST with the percentage change from Baseline 
in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in AST with EDP-305 concentration value 
(Predose Week 12) 
• Percentage change from Baseline in GGT with the percentage change from 
Baseline in FGF19 (Predose Week 12) 
• Percentage change from Baseline in GGT with the percentage change from 
Baseline in C4 (Predose Week 12) 
• Percentage change from Baseline in GGT with the percentage change from 
Baseline in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in GGT with EDP-305 concentration value 
(Predose Week 12) 
• Percentage change from Baseline in Total Bilirubin with the percentage change 
from Baseline in FGF19 (Predose Week 12) 
• Percentage change from Baseline in Total Bilirubin with the percentage change 
from Baseline in C4 (Predose Week 12) 


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• Percentage change from Baseline in Total Bilirubin with the percentage change 
from Baseline in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in Total Bilirubin with EDP-305 concentration 
value (Predose Week 12) 
• Percentage change from Baseline in Alkaline Phosphatase with the percentage 
change from Baseline in FGF19 (Predose Week 12) 
• Percentage change from Baseline in Alkaline Phosphatase with the percentage 
change from Baseline in C4 (Predose Week 12) 
• Percentage change from Baseline in Alkaline Phosphatase with the percentage 
change from Baseline in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in Alkaline Phosphatase with EDP-305 
concentration value (Predose Week 12) 
• Percentage change from Baseline in FGF19 with the percentage change from 
Baseline in C4 (Predose Week 12) 
• Percentage change from Baseline in FGF19 with the percentage change from 
Baseline in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in FGF19 with EDP-305 concentration value 
(Predose Week 12) 
• Percentage change from Baseline in C4 with the percentage change from Baseline 
in Bile Acid (Predose Week 12) 
• Percentage change from Baseline in C4 with EDP-305 concentration value 
(Predose Week 12) 
• Percentage change from Baseline in Bile Acid with EDP-305 concentration value 
(Predose Week 12) 
• Percentage change from Baseline in Cholesterol with EDP-305 concentration value 
(Predose Week 12) 
• Percentage change from Baseline in HDL with EDP-305 concentration value 
(Predose Week 12) 
• Percentage change from Baseline in LDL with EDP-305 concentration value 
(Predose Week 12) 
• Percentage change from Baseline in triglycerides with EDP-305 concentration 
value (Predose Week 12) 






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