Clinical trial NCT03394924
Conditions: Primary Biliary Cholangitis
Keywords: PBC Primary Biliary Cholangitis (PBC)
Sponsor: Enanta Pharmaceuticals, Inc
Start date: 2017-12-27; Completion date: 2020-01-16
Enrollment: 68 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 primary biliary cholangitis

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 two tablets once a day orally for 12 weeks
Interventions: intervention 1: EDP-305 1 mg intervention 2: EDP-305 2.5 mg 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, PLACEBO-
CONTROLLED STUDY EVALUATING THE SAFETY, TOLERABILITY,
PHARMACOKINETICS AND EFFICACY OF EDP-305 IN SUBJECTS WITH PRIMARY 
BILIARY CHOLANGITIS (PBC) WITH OR WITHOUT AN INADEQUATE RESPONSE TO
URSODEOXYCHOLIC ACID (UDCA)
Protocol Number:  EDP 305-201
   EudraCT Number: 2017-003528-62
Protocol Version:
Version 3.0 (Amendment 2.0, Global US and EU)
Date:
Amendment 2.0: 02 Apr 2018
Amendment 1.0 (US only): 12 Dec 2017
Original Protocol: 18 Oct 2017
Study Sponsor:
Enanta Pharmaceuticals, Inc.
500 Arsenal St.
Watertown, MA  02472
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.  
NCT03394924


Clinical Study Protocol
EDP 305-201 v3.0 (Amendment 2.0, Global US and EU)
Enanta Pharmaceuticals, Inc.
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CONTACT INFORMATION 


Clinical Study Protocol 
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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial 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
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Enanta Pharmaceuticals, Inc.
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TABLE OF CONTENTS 
CONTACT INFORMATION ................................................................................................... 2 
SIGNATURE PAGE ................................................................................................................ 3 
TABLE OF CONTENTS .......................................................................................................... 4 
LIST OF FIGURES.................................................................................................................. 8 
LIST OF TABLES ................................................................................................................... 8 
LIST OF APPENDICES........................................................................................................... 8 
LIST OF ABBREVIATIONS .................................................................................................... 9 
PROTOCOL SYNOPSIS........................................................................................................ 11 
1. 
INTRODUCTION ...................................................................................................... 18 
1.1 
OVERVIEW..........................................................................................................18 
1.2 
BACKGROUND......................................................................................................18 
1.2.1 
PBC and Farnesoid X Receptor (FXR) ............................................................18 
1.2.2 
Rationale for Development of EDP-305 for PBC................................................19 
1.3 
NONCLINICAL STUDIES...........................................................................................20 
1.3.1 
Mechanism of Action and Pharmacology.........................................................20 
1.3.2 
Safety Pharmacology..................................................................................21 
1.3.3 
Pharmacokinetics......................................................................................22 
1.3.4 
Toxicology ..............................................................................................23 
1.4 
CLINICAL STUDIES ................................................................................................26 
1.4.1 
Study EDP 305-001 ...................................................................................26 
 
 
1.5 
POTENTIAL RISKS AND BENEFITS...............................................................................35 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................... 36 
2.1 
OBJECTIVES ........................................................................................................36 
2.1.1 
Primary Objective.....................................................................................36 
2.1.2 
Secondary Objectives.................................................................................36 
2.2 
ENDPOINTS .........................................................................................................36 
2.2.1 
Primary Endpoints.....................................................................................36 
2.2.2 
Secondary Endpoints..................................................................................36 
3. 
SELECTION OF SUBJECTS ...................................................................................... 38 
3.1 
SUBJECT INCLUSION CRITERIA..................................................................................38 
3.2 
SUBJECT EXCLUSION CRITERIA.................................................................................39 
4. 
STUDY DESIGN ........................................................................................................ 41 
4.1 
DOSE AND TREATMENT SCHEDULE ............................................................................41 
4.2 
RATIONALE FOR STUDY DESIGN................................................................................42 
4.2.1 
Justification of Design and Control Group.......................................................42 
4.2.2 
Justification of EDP-305 Dose......................................................................42 
5. 
STUDY DRUG AND TREATMENT OF SUBJECTS .................................................... 45 


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5.1 
DESCRIPTION OF STUDY DRUG..................................................................................45 
5.2 
PACKAGING AND LABELING .....................................................................................45 
5.3 
STORAGE............................................................................................................45 
5.4 
ACCOUNTABILITY.................................................................................................45 
5.5 
HANDLING AND DISPOSAL.......................................................................................46 
5.6 
TREATMENT ASSIGNMENT AND RANDOMIZATION...........................................................46 
5.7 
STUDY DRUG DOSE AND ADMINISTRATION ..................................................................47 
5.7.1 
Dispensing of Study Drug............................................................................47 
5.7.2 
Treatment Compliance................................................................................47 
5.8 
CONCOMITANT MEDICATIONS ..................................................................................48 
5.8.1 
Co-administration of EDP-305 and Ursodiol (ursodeoxycholic acid, UDCA).............48 
5.9 
PROHIBITED MEDICATIONS......................................................................................49 
 
 
6. 
BLINDING ................................................................................................................ 50 
6.1 
BLINDING OF STUDY SAMPLES..................................................................................50 
6.1.1 
Blinding of Biomarker, Fibrosis and Inflammatory Markers and Laboratory 
Liver Test Results......................................................................................50 
6.1.2 
Blinding of Pharmacokinetic Samples.............................................................51 
6.2 
UNBLINDING .......................................................................................................51 
7. 
STUDY CONDUCT AND VISIT SCHEDULE.............................................................. 52 
7.1 
STUDY VISITS......................................................................................................52 
7.1.1 
Screening................................................................................................52 
7.1.2 
Rescreening.............................................................................................52 
7.1.3 
Baseline Visit (Day1) .................................................................................52 
7.1.4 
Treatment Period Visits (Day 3, Weeks 2, 4, 8 and 12 /EOT) .................................53 
7.1.5 
Safety Follow-up Period (End of Study Visit) ....................................................53 
7.2 
SUBJECT WITHDRAWAL / EARLY TERMINATION.............................................................54 
7.2.1 
Withdrawal Criteria...................................................................................54 
7.2.2 
Documentation of Withdrawal of Subjects........................................................55 
7.3 
SITE OR STUDY DISCONTINUATION ............................................................................55 
7.3.1 
Study Discontinuation.................................................................................55 
7.3.2 
Site Termination .......................................................................................55 
7.3.3 
Study Termination Procedures......................................................................56 
8. 
STUDY PROCEDURES/EVALUATIONS.................................................................... 57 
8.1 
DEMOGRAPHICS AND MEDICAL HISTORY.....................................................................57 
8.2 
CLINICAL EVALUATIONS .........................................................................................57 
8.2.1 
Vital Sign Measurements and ECGs...............................................................57 
8.2.2 
Physical Examination.................................................................................58 
8.2.3 
Weight and Body Mass Index (BMI) ...............................................................58 
8.2.4 
PBC-40 Quality of Life Assessment ................................................................58 
8.2.5 
Assessment of Pruritus................................................................................58 
8.2.6 
Adverse Events.........................................................................................59 
8.3 
CLINICAL LABORATORY AND DIAGNOSTIC PROCEDURES..................................................59 
8.3.1 
Safety Laboratory Assessments .....................................................................59 
8.3.2 
Pregnancy and Menopausal Laboratory Testing................................................61 
8.3.3 
Noninvasive Evaluations of Fibrosis...............................................................62 


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8.3.4 
Biomarkers..............................................................................................62 
 
 
8.3.6 
Liver Imaging...........................................................................................63 
8.4 
PHARMACOKINETIC SAMPLES...................................................................................64 
8.4.1 
Collection of Pharmacokinetic Samples...........................................................64 
8.4.2 
Handling and Bioanalysis of Pharmacokinetic Samples.......................................64 
9. 
SAFETY MONITORING AND REPORTING.............................................................. 66 
9.1 
DEFINITIONS........................................................................................................66 
9.1.1 
Pretreatment Events...................................................................................66 
9.1.2 
Adverse Events.........................................................................................66 
9.1.3 
Serious Adverse Events (SAEs)......................................................................66 
9.2 
DOCUMENTING AND REPORTING OF ADVERSE EVENTS (INCLUDING SERIOUS ADVERSE 
EVENTS).............................................................................................................67 
9.2.1 
Documenting and Reporting Adverse Events.....................................................67 
9.2.2 
Assigning Attribution of Adverse Events ..........................................................68 
9.2.3 
Classifying Action Taken with Study Drug........................................................69 
9.2.4 
Classifying Adverse Event Outcome................................................................69 
9.2.5 
Documenting and Reporting Serious Pretreatment Events and Serious Adverse 
Events....................................................................................................70 
9.2.6 
Documenting and Reporting of Pregnancy .......................................................71 
9.3 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.....................................71 
9.4 
SPONSOR’S REVIEW OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...........................71 
9.5 
DATA SAFETY MONITORING BOARD...........................................................................71 
10. 
SUBJECT SAFETY MANAGEMENT ......................................................................... 72 
10.1 
INDIVIDUAL SUBJECT STOPPING RULES .......................................................................72 
10.2 
MANAGEMENT OF LIVER ENZYME ELEVATIONS.............................................................72 
10.3 
MANAGEMENT OF PRURITUS....................................................................................73 
11. 
STATISTICAL CONSIDERATIONS........................................................................... 74 
11.1 
GENERAL CONSIDERATIONS.....................................................................................74 
11.2 
SAMPLE SIZE CONSIDERATIONS ................................................................................74 
11.3 
ANALYSIS POPULATIONS.........................................................................................74 
11.4 
SUBJECT DISPOSITION AND DEMOGRAPHIC DATA...........................................................75 
11.5 
EFFICACY ENDPOINTS ............................................................................................75 
11.5.1 Primary Efficacy Endpoints .........................................................................75 
11.5.2 Secondary Efficacy Endpoints.......................................................................75 
11.6 
SAFETY ENDPOINTS...............................................................................................76 
11.6.1 Adverse Events.........................................................................................76 
11.6.2 Clinical Laboratory Data ............................................................................76 
11.6.3 Electrocardiogram (ECG) Data ....................................................................77 
11.6.4 Vital Signs...............................................................................................77 
11.6.5 Concomitant Medications............................................................................77 
11.6.6 Physical Examinations................................................................................77 
11.7 
PHARMACOKINETIC ANALYSES.................................................................................77 
11.8 
INTERIM ANALYSES...............................................................................................78 
12. 
STUDY ADMINISTRATION ...................................................................................... 79 


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12.1 
ETHICAL CONSIDERATIONS ......................................................................................79 
12.1.1 Ethical Conduct of the Study ........................................................................79 
12.1.2 Ethical Review..........................................................................................79 
12.1.3 Written Informed Consent............................................................................79 
12.1.4 Investigator Compliance .............................................................................80 
12.2 
DATA COLLECTION ...............................................................................................80 
12.3 
STUDY MONITORING..............................................................................................80 
12.4 
QUALITY ASSURANCE ............................................................................................81 
12.5 
RECORDS RETENTION.............................................................................................81 
12.6 
INFORMATION DISCLOSURE .....................................................................................81 
12.6.1 Confidentiality..........................................................................................81 
12.6.2 Publication Policy .....................................................................................82 
13. 
REFERENCES ........................................................................................................... 83 
14. 
APPENDICES ............................................................................................................ 86 


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LIST OF FIGURES 
Figure 1: Study Design ..............................................................................................................41 
LIST OF TABLES 
Table 1: 
Safety Pharmacology Studies ...............................................................................22 
 
 
 
 
Table 4: 
Clinical Studies with EDP-305 .............................................................................26 
 
 
 
 
 
 
 
 
 
 
Table 10: 
EDP 305-005 Part 2 Activity and Treatment Schema ...............................................32 
 
 
 
 
 
 
Table 14: 
Laboratory Evaluations .......................................................................................61 
Table 15: 
Options for Action Taken with Study Drug ............................................................69 
Table 16:  
Classification and Definition of AE Outcomes ........................................................70 
Table 17: 
PK Parameters ...................................................................................................78 
LIST OF APPENDICES 
Appendix 1: 
Schedule of Assessments (SoA)............................................................................86 


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LIST OF ABBREVIATIONS 
ADaM 
analysis data model 
AE, AR 
adverse event(s), adverse reaction(s) 
ALT 
alanine aminotransferase 
APRI 
AST to platelet ratio index 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
BP 
blood pressure 
CL/F 
apparent total clearance after oral administration 
Cmax 
maximum concentration 
eCRF 
electronic case report form 
CRO 
contract research organization 
CS, NCS 
clinically significant, non-clinically significant 
CV 
cardiovascular 
CYP450, CYP3A4 
cytochrome P450, cytochrome P450 3A4 
CYP7A1 
cholesterol 7α-hydroxylase 
EC 
ethics committee 
ECG 
electrocardiogram 
EOS 
end-of-study 
EOT 
end-of-treatment 
F 
oral bioavailability 
FDA 
Food and Drug Administration 
FIB-4 
fibrosis 4 index 
FXR 
farnesoid X receptor 
GCP, GMP, GLP 
good clinical practice, good manufacturing practice, good laboratory practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol 
HDPE 
high density polyethylene 
hERG 
human Ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HR 
heart rate 
hs-CRP 
high-sensitivity C-reactive protein 
HV 
healthy volunteers 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
IU 
international units 
IUD, IUS 
intrauterine device, intrauterine system 
IWRS 
interactive web response system 
MAD 
multiple ascending dose 
MedDRA 
medical dictionary for regulatory activities 
NAFL, NAFLD 
non-alcoholic fatty liver, non-alcoholic fatty liver disease 


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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 
PBC-ANAb 
PBC-specific antinuclear antibodies 
PD 
pharmacodynamics 
P-gp 
P-glycoprotein 
PI 
principal investigator 
PK 
pharmacokinetics 
PN 
presumptive NAFLD (non-alcoholic fatty liver disease) 
po 
oral administration (by mouth, per os) 
PT/PTT 
prothrombin time / partial thromboplastin time 
QD 
once daily 
SAD 
single ascending dose 
SAE 
serious adverse event(s) 
SAP 
statistical analysis plan 
SHP 
small heterodimer partner 
SOC 
system organ class 
SUSAR 
suspected, unexpected, serious adverse reaction 
t1/2 
plasma half-life 
TB 
total bilirubin 
TEAE 
treatment emergent adverse event(s) 
Tmax 
time to maximum concentration 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 


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PROTOCOL SYNOPSIS  
Sponsor:  Enanta Pharmaceuticals, Inc. 
Name of Investigational Product:  EDP-305 
Study Title:  A Phase 2 Dose Ranging, Randomized, Double Blind, Placebo-Controlled Study 
Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects with 
Primary Biliary Cholangitis (PBC) with or without an Inadequate Response to Ursodeoxycholic 
Acid (UDCA) 
Protocol Number:  EDP 305-201 
Phase of Development: 2 
Study Centers:  The study will be conducted at approximately 65 sites located in both the US 
as well as international locations. 
Number of Subjects Planned: Approximately 119 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 1 mg, 2.5 mg, or 
placebo taken once daily (QD) for 12 weeks. 
Duration of Treatment:  12 weeks. 
Objectives: 
Primary Objective: 
x To evaluate the effect of EDP-305 on alkaline phosphatase (ALP) levels.  
Secondary Objective: 
x To evaluate the safety and tolerability of EDP-305  
x To evaluate the effect of EDP-305 on bilirubin levels 
x To evaluate the effects of EDP-305 on other markers of liver function 
x To evaluate the effects of EDP-305 on non-invasive markers of liver fibrosis 
x To evaluate the effects of EDP-305 on inflammatory markers 
x To evaluate the effects of EDP-305 on lipids  
x To evaluate the effects of EDP-305 on pruritus  
x To evaluate the effects of EDP-305 on Quality of Life (QoL) 
x To evaluate the pharmacokinetics (PK) of EDP-305 and metabolites in plasma 
x To evaluate the pharmacodynamics (PD) of EDP-305 
 
Criteria for Evaluation: 
Primary Endpoint: 
x Proportion of subjects with at least 20% reduction in ALP from pretreatment value or 
normalization of ALP at Week 12  
 
Secondary Endpoints: 
x Frequency of adverse events (AEs), serious AEs, and AEs leading to discontinuation 
through Week 12 


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x Bilirubin (Total, Conjugated, Unconjugated) decline from Baseline at Week 12 
x Change from Baseline in Alanine aminotransferase (ALT) and Aspartate 
aminotransferase (AST), Gamma-Glutamyl transferase (GGT) at Week 12 
x Change from Baseline of noninvasive liver fibrosis markers (Enhanced Liver Fibrosis 
[ELF] panel, PRO C3, AST to Platelet Ratio Index [APRI] and fibrosis-4 [FIB-4]) at 
Week 12  
x Change from Baseline in fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β , alpha2 
macroglobulin and haptoglobin levels at Week 12 
x Change from Baseline in Triglycerides (TG), Total Cholesterol (TC), High Density 
Lipoprotein Cholesterol (HDL-C), Low Density Lipoprotein Cholesterol (LDL-C) at 
Week 12 
x Change from Baseline in 5D-itch scale and Visual Analog Score (VAS) at Week 12 
x Change from Baseline in PBC-40 Quality of Life (QoL) at Week 12 
x Pharmacokinetic parameters of EDP-305 (and metabolites): Cmax, Tmax, and AUClast. 
x Pharmacodynamic  parameters of EDP-305: FGF19, C4 and Bile Acid (BA) at Week 12 
 
Study Design:   
This is a multicenter, double blind, placebo controlled, dose ranging Phase 2 study assessing the 
safety and efficacy of two doses of orally administered EDP-305. The total maximum length of 
time for participation for each subject enrolled in the study will be approximately 20 weeks. The 
study will consist of a Screening Period, Treatment Period and a Follow-up Period as shown in 
the following table. 
 
Study Period 
Duration  
Screening 
Up to 4 weeks (28 
Days) 
Treatment 
12 weeks 
Follow-up  
4 weeks 
Total approximate maximum duration of participation 
up to 20 weeks 
 
Screening Period:   After reviewing and signing the Informed Consent Form (ICF), subjects will 
be screened and must meet all criteria for entry into the study. The Screening Visit must occur 
between Days -28 and -1 (up to 4 weeks). All Screening assessments must occur within the -28 
to -1 window. 
Treatment Period: Subjects who have met all study criteria will report to the site on the morning 
of Day 1. Subjects must have fasted for at least 8 hours prior to dosing. Subjects will be 
randomized in a 3:3:1 manner to receive one of two doses of EDP-305 or placebo QD. 
Procedures performed are specified in the Schedule of Assessments (Appendix 1). Predose 
assessments will be conducted (including laboratory sample collection) before the subject 


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receives the first dose of study drug in the clinic. Following dosing, PK and biomarker samples 
will be collected. Prior to leaving the clinic on Day 1, study drug will be dispensed to the 
subjects and the subjects will be given instructions for taking study drug at home. Subjects will 
take study drug once daily for a total of 12 weeks returning to the clinic for efficacy and safety 
assessments on Day 3 and Weeks 2, 4, 8 and 12. On study days when there is a clinic visit, 
subjects will be administered their daily dose in the clinic. Additional PK and PD samples will 
be collected over a period of 8 hours on Day 1 and Week 12 (Day 84/End of Treatment, [EOT]) 
from subjects at a subset of sites that have the technical capability to collect and process 
intensive (longer duration) PK and PD samples (PK/PD Sub-study).  
Safety Follow-up and Early Termination Visit: The safety follow-up visit (or End of Study 
[EOS] visit) will occur 4 weeks after the last dose of study drug for all subjects, including those 
who discontinue treatment early (ie, prior to completing 12 weeks of dosing). Final study 
assessments will be completed at that visit.  
Subjects who discontinue treatment early should return to the clinic as soon as possible 
following the last dose of study drug for an EOT visit. They should then return for the EOS visit 
4 weeks following last dose of study drug. 
 Study Design: 
 
 
 
Abbreviations: D=Day; W=Week 
Eligibility Criteria:  
Inclusion Criteria  
Subjects must meet all of the following criteria to be eligible to participate: 
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 a diagnosis of PBC by at least two of the following criteria: 
x 
History of ALP above ULN for at least 6 months  


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x 
Positive Anti-Mitochondrial Antibodies (AMA) titers (>1/40 on immunofluorescence or M2 
positive by enzyme linked immunosorbent assay [ELISA] or positive PBC-specific antinuclear 
antibodies [PBC- ANAb]) 
x 
Documented liver biopsy result consistent with PBC (with no cirrhosis) 
4. For subjects with no documented liver biopsy performed within 2 years, subjects must undergo a 
transient elastography (Fibroscan) showing liver stiffness <14.0 kPA 
5. Must be on a stable dose of UDCA12-20 mg/kg/day for at least 6 months prior to Screening or 
intolerant of UDCA in the opinion of the Investigator (no UDCA for at least 12 weeks prior to 
Screening) 
6. Alkaline Phosphatase (ALP) ≥1.67 × ULN and/or total bilirubin >ULN but <2 × ULN (<2.4 mg/dL) 
7. Subjects must have Screening laboratory values for Hepatitis B surface antigen (HBsAg), anti-HCV 
antibodies and HCV RNA negative, 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. 
8. 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:  
x 
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 non-childbearing 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 postmenopausal (a demonstration of a total cessation of menses for ≥1 year with an FSH 
level of >35 mIU/mL).  
9. 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: 
x 
Intrauterine device 
x 
Oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive 
x 
Be of non-childbearing potential 
10. Male subjects must agree to refrain from sperm donation from the date of Screening until 90 days 
after their last dose of study drug 
11. Screening body mass index (BMI) of ≥18 kg/m2  
12. Subject must be willing and able to adhere to the assessments, visit schedule, prohibitions and 
restrictions, as described in this protocol 
Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible to participate: 
1. Laboratory Screening Results: 
x AST >5 × ULN 


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x ALT >5 × ULN  
x Patients with Gilbert’s syndrome will not be allowed due to interpretability of bilirubin levels 
x Total white blood cells (WBC) <3000 cells/mm3 
x Absolute neutrophil count (ANC) <1500 cells/mm3 
x Platelet count <140,000/mm3 
x Prothrombin time (international normalized ratio, INR) >1.2 
x Serum creatinine >2 mg/dL or creatinine clearance <60 mL/min (based on Cockroft-Gault 
Method) 
2. Suspected to have relevant nonalcoholic fatty liver disease (NAFLD) as based on the judgment 
of the Investigator at Screening 
3. Known history of alpha-1-Antitrypsin deficiency 
4. Use of immunosuppressants known to have an effect on the liver of patients with PBC (eg, 
colchicine, methotrexate, or azathioprine) in the 3 months preceding Screening. 
5. Current use of fibrates, including fenofibrates. NOTE: Subjects who discontinued fibrates for at 
least 3 months before Screening can participate 
6. Use of an experimental treatment for PBC within the past 6 months 
7. Prior use and/or concomitant treatment with obeticholic acid (OCA) 
8. Use of experimental or unapproved drugs within 1 year of Screening 
9. Any other condition(s) that would compromise the safety of the subject or compromise the 
quality of the clinical study, as judged by the Principal Investigator (PI) 
10. Pregnant or nursing females 
11. 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 
12. Co-existing liver or biliary diseases, such as primary sclerosing cholangitis, choledocholithiasis, 
acute or chronic hepatitis, autoimmune hepatitis, alcoholic liver disease, nonalcoholic 
steatohepatitis (NASH), acute infection of bile duct system or gall bladder, history of 
gastrointestinal bleeding (secondary to portal hypertension), cirrhosis, cholangiocarcinoma 
diagnosed or suspected liver cancers 
13. Cirrhosis with or without complications, including history or presence of: spontaneous bacterial 
peritonitis, hepatocellular carcinoma  
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. Patients with a history of severe pruritus requiring current or prior systemic treatment (e.g., with 
BAS or rifampicin) 
17. Medical conditions that may cause nonhepatic increases in ALP (e.g., Paget's disease)  
18. Any condition possibly affecting drug absorption (eg, gastrectomy <3 years prior to Screening. 
NOTE: Subjects who have undergone gastric surgeries known to not affect drug absorption such 
as gastric band or gastric sleeve will be allowed if they are stable for at least 1 year prior to 
Screening. 
19. 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 


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(150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) 
20. Participation in a clinical trial within 30 days prior to study drug administration 
21. 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 
22. Use of CYP3A4 and P-gp inducers and inhibitors within 14 days prior to the first dose of study 
medication and throughout study duration 
23. Clinically significant history of drug sensitivity or allergy, as determined by the PI 
24. Subject has received an investigational agent or investigational 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 
25. Use of a new statin regimen from Screening and throughout study duration. 
NOTE: Subjects on a stable dose of statins for at least 3 months prior to Screening are allowed. 
No dose modification during the study will be allowed. 
26. Use of immunosuppressants (eg, systemic corticosteroids) for more than 2 consecutive weeks in 
duration within 1 year prior to Screening. 
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 
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 and follow-up will be performed: 
x If ALT or aspartate aminotransferase (AST) increases to >5 × Baseline. 
x If ALT or AST increase >2 × Baseline AND the increase is accompanied by a 
concomitant total bilirubin (TB) increase >2 × Baseline OR the INR concomitantly 
increases by >0.2 
x 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).  
Analysis Populations 
x 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. 
x Efficacy Population: All subjects who receive at least one dose of study medication. 
Subjects will be included in the randomized treatment group. 


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x 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 adverse events (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 safety laboratory parameters by visit and treatment group. All 
laboratory data will be included in the data listings and all test values outside the normal range 
will be flagged. AEs will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term by treatment group. 
Efficacy Analyses:  Proportion of subjects with at least 20% reduction in ALP from pretreatment 
value or normalization of ALP at Week 12. Treatment comparisons will be made using a 
Mantel-Haenszel test comparing each of the active treatment groups to placebo, respectively.    
Pharmacokinetic Analyses:   Plasma PK parameters for each dose level will be calculated from 
the concentrations of EDP-305 and its major metabolites (as applicable) measured in predose 
and postdose plasma samples. For each EDP-305 dose level, descriptive statistics (sample size, 
arithmetic means, geometric means, standard deviation, % 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 following PK parameters will be calculated as indicated for plasma 
EDP-305 and its major metabolites: AUC0- t, Cmax, and Tmax. 
Sample Size Consideration:   The planned sample size is approximately 105 subjects. Group 
sample sizes of 45 in each active arm and 15 in the placebo arm achieve 83.552% power to 
detect a ratio of the group proportions of 40%. The proportion in the smallest active arm is 
assumed to be 0.4000 under the null hypothesis and 0.0400 under the alternative hypothesis. 
The proportion in the placebo arm is 10%. The test statistic used is the two-sided 
Mantel-Haenszel test. The significance level of the test is 0.05. To account for a 10% 
discontinuation rate, 14 additional subjects will be enrolled to attempt to have 105 who 
complete treatment, bringing the total number of subjects enrolled to 119.  


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1. 
INTRODUCTION 
1.1 
Overview 
EDP-305 (also known as EPS-2305, EPC-2305 or EP-022305) is a Farnesoid X Receptor (FXR) 
agonist being investigated as a potential treatment for Nonalcoholic Steatohepatitis (NASH) with 
liver fibrosis and Primary Biliary Cholangitis (PBC). This study, EDP 305-201, is a randomized, 
double-blind, placebo-controlled, Phase 2 study designed to assess the safety, tolerability, and 
effectiveness of EDP-305 in subjects with PBC with or without an inadequate response to 
ursodeoxycholic acid (UDCA). 
1.2 
Background  
1.2.1 
PBC and Farnesoid X Receptor (FXR) 
Bile acids 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 
(Matsubara, Li, & Gonzalez, 2013). FXR is a member of the nuclear hormone receptor 
superfamily and is considered a master regulator of many bile acid activities including feedback 
regulation of bile acid synthesis, gluconeogenesis and glycogenolysis in the liver, and peripheral 
insulin sensitivity in adipose tissue (McMahan et al., 2013). Given the critical role bile acids play 
in liver homeostasis and the role of FXR in regulating bile acid biosynthesis, FXR has become a 
target for therapeutic intervention in numerous liver diseases including NASH and PBC. 
Primary biliary cirrhosis is an important but uncommon autoimmune disease which 
predominantly affects women. Based on well-defined assessment of cases, the incidence and 
prevalence rates for PBC in Europe, North America, Asia, and Australia are reported as ranging 
from 0.33 to 5.8 per 100,000 inhabitants and 1.91 to 40.2 per 100,000 inhabitants, respectively 
(Boonstra, Beuers, & Ponsioen, 2012). Kim et al estimated that there were 47,000 prevalent 
cases of PBC in the United States white population and that approximately 3500 new cases are 
diagnosed each year (Kim et al., 2000). PBC disproportionately affects women (10:1 women to 
men ratio) although some recent data suggest an increasing male prevalence (Lleo et al., 2016). 
The typical age of diagnosis is between 40 and 60 years; recent data suggest that young age at 
diagnosis (ie, < 30 years of age) and male gender indicate a poor prognosis (Boonstra et al., 
2012). Racial and ethnic differences in PBC patients have not been clearly identified. It is a 
globally recognized autoimmune cholestatic liver disease (Beuers, Trauner, Jansen, & Poupon, 
2015; Hirschfield & Gershwin, 2013; Selmi, Mackay, & Gershwin, 2011; Webb & Hirschfield, 
2017) with several characteristics, including: cholestasis, serologic reactivity to 
antimitochondrial antibodies (AMA) or specific antinuclear antibody (ANA) reactivity, with 
accompanying histologic evidence of chronic non-suppurative, granulomatous, lymphocytic 
small bile duct cholangitis. Without treatment, the disease progresses to cirrhosis and, as the liver 


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fails, complications develop including those related to cirrhosis, portal hypertension and 
hepatocellular carcinoma (Carbone et al., 2013; Huet et al., 2008; Kuiper et al., 2010; Lammers 
et al., 2014; Trivedi et al., 2016), liver transplantation or death ensue.  
It is believed that a key result of the immunologic injury in PBC is a rise in the endogenous 
hepatocellular bile acids to cytotoxic levels, causing inflammatory damage, an increase in 
hepatocellular enzymes and apoptosis which over time results in hepatic fibrosis and cirrhosis 
(Beuers, 2006). Disease progression may take decades from diagnosis to the development of the 
clinical events associated with hepatic decompensation. Early on, patients are typically 
asymptomatic, and suspicion of a potential PBC diagnosis is raised by an elevation of alkaline 
phosphatase noted on screening blood tests obtained during routine office visits. Currently, 
patients are more likely to be diagnosed at earlier stages of the disease, secondary to the current 
practice guideline that include screening of liver biochemistries during routine physical exams 
(Floreani et al., 2011; Prince, Chetwynd, Craig, Metcalf, & James, 2004).  
Clinically, PBC is monitored by assessing alkaline phosphatase (ALP) levels. ALP is used 
universally in the diagnosis of the disease (as noted in both the US and recent European 
treatment guidelines (European Association for the Study of the Liver, 2017; Lindor et al., 2009). 
However, other liver enzymes including gamma-glutamyltransferase (GGT), alanine 
aminotransferases (ALT) and aspartate aminotransferase (AST) are also used in the clinical 
assessment and care of patients. As the disease progresses and hepatocellular function is 
impaired, bilirubin levels (a direct measurement of hepatic degradation) rise and albumin and 
prothrombin time (assays of hepatic synthesis) are impaired. 
1.2.2 
Rationale for Development of EDP-305 for PBC 
Until most recently, there has been one approved treatment for PBC, ursodeoxycholic acid 
(UDCA), which was approved by the FDA in 1997. UDCA is effective in more than 50 percent 
of patients, but up to 40 percent of patients do not achieve an adequate reduction in blood 
chemistries (eg, ALP and/or total bilirubin) with UDCA, while 5% to 10% are unable to tolerate 
UDCA. While UDCA therapy has a marked impact on clinical outcomes in PBC, up to 40% of 
UDCA-treated patients have a suboptimal or absent response to UDCA and, as such, are at 
significantly increased risk of an adverse outcome (death, requiring a liver transplant, or other 
clinical complications) (Carbone et al., 2013; Corpechot et al., 2008; ter Borg, Schalm, Hansen, 
& van Buuren, 2006). Several studies have shown that UDCA-treated patients with early stage 
disease, who respond biochemically to UDCA treatment, have survival rates comparable with a 
standardized general population (Carbone et al., 2013; Corpechot et al., 2008; ter Borg et al., 
2006). In 2016, the U.S. Food and Drug Administration granted accelerated approval for the 
FXR agonist Ocaliva® (obeticholic acid, OCA) for the treatment of PBC in combination with 
UDCA in adults with an inadequate response to UDCA, or as a single therapy in adults unable to 
tolerate UDCA (U.S. Food and Drug Administration, 2016). 


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Several animal models have demonstrated that the FXR has a protective effect in various 
diseases, including cholestatic and autoimmune liver diseases, alcoholic liver disease, fatty liver, 
gallstone formation, portal hypertension, and hepatocellular carcinoma. It has been recently 
reported that EDP-305 potently suppresses liver injury and fibrosis in mouse models of biliary 
and metabolic liver disease (An et al., 2017). Furthermore, in the MCD diet mouse model of 
steatohepatitis and perisinusoidal fibrosis, EDP-305 outperformed OCA in attenuating MCD 
diet-induced liver injury and fibrosis. 
In conclusion, there remains an unmet medical need for better therapies in patients with an 
inadequate response to UDCA or those who cannot tolerate the drug, and those with a more 
advanced fibrosis stage. Results from in vitro pharmacology and animal model studies suggest 
that EDP-305 has the potential to satisfy this unmet medical need. 
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 it’s close 
synthetic analog obeticholic acid (OCA), were used as controls. OCA has recently been 
approved for the treatment of PBC. 
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 bile acid biosynthesis. The efficacy and potency of EDP-305 was demonstrated in 
several in vitro assays.   
x 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. 
x In human Huh7.5 hepatocyte cells, EDP-305 effected a dose-dependent increase in SHP 
gene expression and decrease in CYP7A1 mRNA expression. 
x 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 bile acid and lipid metabolism, 
inflammation, fibrosis, and glucose metabolism was evaluated using in vitro systems. OCA 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 bile acid (5 genes) 


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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: 
x The regulation of FXR downstream genes critical for bile acid metabolism was assessed 
in C57BL/6 mice treated with EDP-305 or OCA orally for five days. EDP-305 induced a 
dose-dependent increase in FGF15 and SHP gene expression in the ileum, and dose-
dependent increases in SHP and BSEP mRNA and decreases in CYP7A1 mRNA in the 
liver. In all cases, EDP-305 was more active than OCA. 
x 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 non-fasted 
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. 
x 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 
HOMA-IR and plasma insulin levels in the therapeutic model, suggesting the potential 
for improvement in insulin sensitivity. 
x Mdr2-/- mice develop progressive biliary-type (periportal) fibrosis resembling that 
observed in PSC, PBC, 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 ALT and AST levels compared to vehicle 
controls. Mice receiving OCA (30 mg/kg) had a significant decrease in AST but not ALT 
levels. Histologically, treatment with EDP-305 resulted in a marked attenuation of 
fibrosis compared to placebo control mice with a 39% reduction in hepatic collagen 
content. Treatment with OCA at 30 mg/kg did not result in a histological improvement in 
fibrosis, and had no significant impact on hepatic collagen levels. Thus, treatment with 
EDP-305 potently improved pre-established liver injury and hepatic fibrosis in Mdr2-/- 
mice outperforming OCA in all parameters measured. 
1.3.2 
Safety Pharmacology  
EDP-305 was tested in a battery of safety and secondary pharmacology studies. The results of 
the safety pharmacology tests are shown below in Table 1. A detailed description of the studies 
and results can be found in the IB. 


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Table 1: 
Safety Pharmacology Studies 
System / Study
TestSystem
(route)
Dose or 
Concentration Results
CV/ Radioligand
hERG Binding Assay
HEK293 Cells
(in vitro)
3 and 10 μM
EDP-305 was inactive in this assay.
CV / hERG Patch
Clamp Assay
HEK293 Cells 
(in vitro)
0.3, 1, 3, 10
μM
IC50 was estimated to be >1 μM due to disruption of the 
giga-ohm seal required for successful recordings at 3 and 
CV / Pharmacology&
TK Study
Cynomolgus 
monkeys (oral)
100, 200, 400
mg/kg
NOEL was 400 mg/kg; EDP-305 did not elicit adverse 
clinical observations, alter body weight, or affect survival, 
body temperature, blood pressure, heart rate or ECG.
CNS / Safety
Pharmacology Study
Crl:CD1® (ICR) 
mice (oral)
25, 50, 100
NOEL was 100 mg/kg; EDP-305 did not elicit any 
adverse effects as assessed via FOB evaluations
Respiratory / Safety
Pharmacology Study
Crl:CD1® (ICR) 
mice (oral)
25, 50, 100
NOEL was 100 mg/kg; EDP-305 did not affect respiratory 
rate, tidal volume or minute volume
Abbreviations:  Human embryonic kidney (HEK), Cardiovascular (CV), Toxicokinetics (TK), No-observed-effect-level (NOEL), 
Central nervous system (CNS), Functional observation battery (FOB), Electrocardiogram (ECG)
1.3.3
Pharmacokinetics 
A series of nonclinical studies were conducted to assess the pharmacokinetics and metabolism of 
EDP-305.
1.3.3.1
Absorption 
The absorption of a single oral dose of EDP-305 was evaluated in CD-1 mice, Sprague-Dawley 
rats, Beagle dogs, and Cynomolgus monkeys. The studies showed that EDP-305 was well 
absorbed with a calculated oral bioavailability of 9.0% in monkeys, 26.0% in mice, 29.2% in 
dogs, and 33.3% in rats. An evaluation of membrane permeability to EDP-305 was performed 
using Caco-2 cells and showed a high in vitro permeability of 8.7 x 10-6 to 10.8 x 10-6 cm/sec at 
concentrations tested from 0.5 μM to 10 μM. Based on the outcome of these absorption studies, 
EDP-305 is projected to have a good oral absorption in humans. 
1.3.3.2
Distribution 
Drug concentrations in the plasma, liver, and kidney were measured following 5-day oral 
administrations of EDP-305 to mice at 25, 50 or 100 mg/kg. Results showed that EDP-305
preferentially penetrated into the liver, which is the target organ of NASH and PBC. The liver-
to-plasma exposure ratio ranged from 6.0 – 13.8. 
As determined by equilibrium dialysis, plasma protein binding of EDP-305 (1 μg/mL) was 
>99.9% in mouse, rat, dog, monkey, and human. The in vitro partitioning of EDP-305 between 
plasma and formed elements (erythrocytes, leukocytes, and platelets) of whole blood was also 
evaluated. The blood-to-plasma concentration ratios ranged from 0.46 –0.57 in human, 
indicating that EDP-305 had a preferential distribution into the plasma compartment. The blood 


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to plasma partition ratio was independent of the concentrations evaluated (0.1, 0.5, 1 and 2 
μg/mL). 
1.3.3.3
Metabolism 
The metabolic stability of EDP-305 was examined in liver microsomes across different species 
including rat, dog, monkey and human. Results showed that EDP-305 had the highest intrinsic 
clearance (Clint) of 41.0 μL/min/kg in monkey liver microsomes, and had the lowest intrinsic 
clearance of 6.5μL/min/kg and 6.9 μL/min/kg in rat and human liver microsomes, respectively.
 The human 
metabolites observed in in vitro liver microsome incubations were also formed in mouse and/or 
monkey, the primary species for general toxicology studies. Thus, no metabolites unique to 
humans have been observed to date. 
1.3.3.4
Drug Interactions 
Based on preclinical evaluation, EDP-305 has low potential to inhibit CYP 1A2, 2B6, 2C8, 2C9, 
2C19, 2D6, and 3A4 or to induce CYP 1A2, 2B6 and 3A4. However, incubation in the presence 
of EDP-305 resulted in a concentration-dependent down-regulation of mRNA for CYP1A2 and 
CYP3A4.
The in vitro studies suggest that there is potential for EDP-305 to inhibit organic anion-
transporting polypeptide (OATP)1B1 and OATP1B3. EDP-305 has low potential to inhibit 
BSEP, multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gP), and breast 
cancer resistance protein (BCRP) transporters. EDP-305 is unlikely to be a BCRP substrate but 
has potential to be a P-gP substrate. 
1.3.4
Toxicology 
The nonclinical safety assessment program evaluated the potential toxicity of EDP-305 in pivotal 
GLP studies (mouse and monkey) and in non-pivotal studies (rat, mouse, and monkey). In all 
studies, the vehicle was 0.5% (w/v) methylcellulose in water (ultrapure, reverse osmosis or 
NANOpure). The mouse was chosen as the rodent species for the definitive studies based on the 
presence of a gallbladder in this species versus the rat. The monkey was chosen as the non-
rodent species owing to the similar metabolic profiles between monkey and human. Results of 
key studies are presented below while details of all studies can be found in the IB. 
1.3.4.1
Repeat-dose Toxicology Studies 






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Thus, these 
results support the conclusion that EDP-305 is non-genotoxic. 
1.4
Clinical Studies 
Five Phase 1 clinical studies have been conducted and/or are ongoing with EDP-305 including a 
First-in-Human (FIH) study in healthy volunteers (HV) and in subjects with presumptive 
NAFLD (PN), a hepatic impairment study, two drug: drug interaction (DDI) studies, and a 
bioavailability (BA) study (Table 4).
Table 4: 
Clinical Studies with EDP-305
Study ID
Phase 
/ Type
Population
Planned/Actual 
(N)
Title
EDP 305-001
1 / FIH 
HV & PN / 
N=42/50(HV), 
N=48/96(PN)
A Randomized, Double-Blind, Placebo-Controlled, First-In-
Human Study of Orally Administered EDP-305 to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Single Ascending 
Doses (SAD), Multiple Ascending Doses (MAD) and the Effect of 
Food on EDP-305 Pharmacokinetics in Healthy Subjects, and of 
Multiple Ascending Doses (MAD) in Subjects with Presumptive 
NAFLD
EDP 305-003
1 / HI
HV, mild & 
moderate HI / 
N=30/29 
A Phase 1, Open-Label, Parallel Group, Single Dose Study to 
Evaluate the Pharmacokinetics, Safety and Tolerability of EDP-
305 in Subjects with Varying Degrees of Hepatic Function
EDP 305-004
1 / 
DDI
HV / N=24/24
A Non-Randomized, Multiple-Dose, Open-Label, Single 
Sequence Study to Evaluate the Effect of Concomitant 
Administration of EDP-305 on the Pharmacokinetics and Safety of 
Midazolam, Caffeine, and Rosuvastatin in Healthy Human 
Volunteers
EDP 305-005
1 / 
DDI
HV / N=48/48
A Non-Randomized, Open-Label, Two-Part, Drug-Drug 
Interaction Study to Evaluate the Effects of Itraconazole and 
Rifampin on the Pharmacokinetics and Safety of EDP-305 in 
Healthy Volunteers
EDP 305-006
1 / BA
HV / N=18/18
A Randomized, Single-Dose, Open-Label, 3-Way, 3-Period 
Crossover, 6-Sequence Bioavailability Study Comparing the 
Pharmacokinetics of EDP-305 Suspension (reference) to Tablet 
(test) in Healthy Human Volunteers under Fed and Fasted 
Conditions
Abbreviations:  Pop. (study population); FIH (first-in-human); HV (healthy volunteer(s)); PN (presumptive 
NAFLD); HI (hepatic impairment); DDI (drug:drug interaction); BA (bioavailability)
1.4.1
Study EDP 305-001
A Randomized, Double-Blind, Placebo-Controlled, First-In-Human Study of Orally Administered EDP-
305 to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses (SAD), 
Multiple Ascending Doses (MAD) and the Effect of Food on EDP-305 Pharmacokinetics in Healthy 
Subjects, and of Multiple Ascending Doses (MAD) in Subjects with Presumptive NAFLD 


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A Phase 1 FIH study (EDP 305-001) to evaluate the safety, tolerability, and pharmacokinetics of 
EDP-305 in healthy volunteers (HV) and subjects with presumptive NAFLD (PN) was 
conducted.  The study included 2 phases:  a Single Ascending Dose (SAD) phase enrolling 
healthy adult subjects, including a “fasted” versus “fed” two-part cohort to assess food effect 
(SAD/FE), and a Multiple Ascending Dose (MAD) phase enrolling healthy adult subjects into 3 
cohorts, and subjects with PN into 3 cohorts.  A total of 42 HV were planned to be enrolled into 
6 SAD cohorts at doses of 1, 5, 10, 20, and 40 mg EDP-305/placebo and a total of 48 subjects 
were planned to be enrolled into 3 MAD-HV cohorts (5, 10, 20 mg EDP-305/placebo) and 3 
MAD-PN cohorts (5, 10, 20 mg EDP-305/placebo).  The study was amended to add a 80 mg 
cohort in the SAD phase, and 6 MAD cohorts (3 HV and 3 PN) assessing 3 lower doses of EDP-
305, 0.5mg, 1mg, and 2.5mg, in each subject population.  In all cohorts except SAD/FE, 8 
subjects were enrolled at a randomization ratio of 3:1 (6 receiving EDP-305 and 2 receiving 
placebo (PBO)).  Ten subjects were enrolled in the SAD/FE cohort and randomized 4:1, EDP-
305 to PBO. 
A total of 146 subjects have been enrolled and received at least one dose of EDP-305 or placebo, 
and were included in the safety analyses: 50 healthy subjects in the SAD phase, and 48 healthy 
subjects and 48 subjects with presumptive NAFLD in the MAD phase. 
EDP-305 was generally well tolerated at single doses up to 80 mg and at multiple doses up to 20 
mg for 14 days. TEAEs occurring in ≥ 2 EDP-305 treated subjects in MAD were: headache and 
pruritus in HV, and constipation and pruritus in PN.  No SAEs or Grade 4 AEs were reported.  
Drug related pruritus was reported after multiple dosing at the higher doses of EDP-305 10 mg 
(n=2) and 20 mg (n=7), and PBO (n=1), with 1 discontinuation at 20 mg in HV (moderate).  
Majority of drug related pruritus were mild to moderate (except one subject with severe). No 
pruritus was observed at lower doses (below 10 mg). No clinically significant laboratories were 
reported except one transient Grade 2 ALT/AST elevation in one subject (MAD-HV-20 mg) that 
led to drug discontinuation. Total, LDL-, HDL- cholesterol and triglycerides did not differ 
between EDP-305 and placebo in either healthy or PN subjects at any dose, except at 20 mg in 
PN for cholesterol and HDL. 
A dose proportional increase in exposure was observed following single and multiple doses of 
EDP-305.  Pharmacokinetic (PK) profiles following single doses of EDP-305, indicated linear, 
one-compartment PK, with monophasic decline.  Half-life was similar following single doses 
with a mean ranging from 11 to 16 hours.  A high fat meal increased EDP-305 exposure by 
approximately 200%.  Half-life ranged from 10-23 hours following multiple doses of EDP-305.    
There was more drug accumulation (~3-fold) observed following 20 mg dose compared to lower 
doses. Similar exposures were observed in both HV and PN subjects.  The metabolite (EP-
022571, EP-022572 and EP-022679) levels were generally low (<5% of parent drug), following 
single and multiple doses of EDP-305.  EDP-305 and metabolite levels in the urine were low and 








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1.5
Potential Risks and Benefits 
Potential risks to subjects receiving EDP-305 have been estimated based on results from the 
repeat dose toxicity studies and safety data from the Phase 1 study (EDP 305-001) conducted in 
healthy volunteers and subjects with presumptive NAFLD (PN). 
Safety data from EDP 305-001:  
x
EDP-305 was generally well tolerated at single doses up to 80 mg and at multiple doses 
up to 20 mg for 14 days.  
x
TEAEs occurring in ≥ 2 EDP-305 treated subjects were: headache and pruritus in HV, 
and constipation and pruritus in PN.  
x
No clinically significant laboratories were reported except one transient Grade 2 
ALT/AST elevation in n=1 (MAD-HV-20mg) that led to drug discontinuation.  
x
No effects on lipids were observed after 14 days except for cholesterol and HDL at 20 mg 
in PN. 
x
Majority of drug related pruritus were mild to moderate (except n=1) and reported after 
multiple dosing at the higher doses of EDP-305 10 mg (n=2/12) and 20 mg (n=7/12), and 
PBO (n=1/24), with 1 drug discontinuation at 20 mg in HV. No pruritus was observed at 
any multiple doses below 10mg.  


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2. 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Objective 
The primary objective of the study is to evaluate the effect of EDP-305 on ALP levels. 
2.1.2 
Secondary Objectives 
The secondary objectives of the study are as follows: 
x To evaluate the safety and tolerability of EDP-305  
x To evaluate the effect of EDP-305 on bilirubin levels 
x To evaluate the effects of EDP-305 on other markers of liver function 
x To evaluate the effects of EDP-305 on non-invasive markers of liver fibrosis 
x To evaluate the effects of EDP-305 on inflammatory markers 
x To evaluate the effects of EDP-305 on lipids  
x To evaluate the effects of EDP-305 on pruritus  
x To evaluate the effects of EDP-305 on Quality of Life (QoL) 
x To evaluate the PK of EDP-305 and metabolites in plasma 
x To evaluate the PD of EDP-305 
2.2 
Endpoints 
2.2.1 
Primary Endpoints 
The primary endpoint of the study is the proportion of subjects with at least 20% reduction in 
ALP from pretreatment values or normalization of ALP at Week 12. 
2.2.2 
Secondary Endpoints 
The secondary endpoints are as follows: 
x Frequency of adverse events (AEs), serious AEs, and AEs leading to discontinuation 
through Week 12 
x Bilirubin (Total, Conjugated, Unconjugated) decline from Baseline at Week 12 
x Change from Baseline in Alanine aminotransferase (ALT) and Aspartate 
aminotransferase (AST), Gamma-Glutamyl transferase (GGT) at Week 12 
x Change from Baseline of noninvasive liver fibrosis markers (Enhanced Liver Fibrosis 
[ELF] panel, PRO C3, AST to Platelet Ratio Index [APRI] and fibrosis-4 [FIB-4]) at 
Week 12  


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x Change from Baseline in fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β , alpha2 
macroglobulin and haptoglobin levels at Week 12 
x Change from Baseline in Triglycerides (TG), Total Cholesterol (TC), High Density 
Lipoprotein Cholesterol (HDL-C), Low Density Lipoprotein Cholesterol (LDL-C) at 
Week 12 
x Change from Baseline in 5D-itch scale and Visual Analog Score (VAS) at Week 12 
x Change from Baseline in PBC-40 Quality of Life (QoL) at Week 12 
x Pharmacokinetic parameters of EDP-305 (and metabolites): Cmax, Tmax, and AUClast 
x 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 119 subjects with a diagnosis of PBC 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 a diagnosis of PBC by at least two of the following criteria: 
x History of ALP above ULN for at least 6 months  
x Positive Anti-Mitochondrial Antibodies (AMA) titers (>1/40 on immunofluorescence or 
M2 positive by enzyme linked immunosorbent assay [ELISA] or positive PBC-specific 
antinuclear antibodies [PBC-ANAb]) 
x Documented liver biopsy result consistent with PBC (with no cirrhosis) 
4. For subjects with no documented liver biopsy performed within 2 years, subjects must 
undergo a transient elastography (Fibroscan) showing liver stiffness <14.0 kPA 
5. Must be on a stable dose of UDCA 12-20 mg/kg/day for at least 6 months prior to Screening 
or intolerant of UDCA in the opinion of the Investigator (no UDCA for at least 12 weeks 
prior to Screening) 
6. Alkaline Phosphatase (ALP) ≥1.67 × ULN and/or total bilirubin >ULN but <2 × ULN 
(<2.4 mg/dL) 
7. Subjects must have Screening laboratory values for Hepatitis B surface antigen (HBsAg), 
anti-HCV antibodies and HCV RNA negative, 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. 
8. 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:  
x 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 non-childbearing 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 


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- 
is postmenopausal (a demonstration of a total cessation of menses for ≥1 year with an 
FSH level of >35 mIU/mL).  
9. 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: 
x Intrauterine device 
x Oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive 
x Be of non-childbearing potential 
10. Male subjects must agree to refrain from sperm donation from the date of Screening until 
90 days after their last dose of study drug 
11. Screening body mass index (BMI) of ≥18 kg/m2  
12. Subject must be willing and able to adhere to the assessments, visit schedule, prohibitions 
and restrictions, as described in this protocol 
3.2 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Laboratory Screening Results: 
x AST >5 × ULN 
x ALT >5 × ULN  
x Patients with Gilbert’s syndrome will not be allowed due to interpretability of bilirubin 
levels 
x Total white blood cells (WBC) <3000 cells/mm3 
x Absolute neutrophil count (ANC) <1500 cells/mm3 
x Platelet count <140,000/mm3 
x Prothrombin time (international normalized ratio, INR) >1.2 
x Serum creatinine >2 mg/dL or clearance creatinine <60 mL/min (based on Cockroft-
Gault Method) 
2. Suspected to have relevant nonalcoholic fatty liver disease (NAFLD) as based on the 
judgment of the Investigator at Screening 
3. Known history of alpha-1-Antitrypsin deficiency 
4. Use of immunosuppressants known to have an effect on the liver of patients with PBC (eg, 
colchicine, methotrexate, or azathioprine) in the 3 months preceding Screening. 
5. Current use of fibrates, including fenofibrates. NOTE: Subjects who discontinued fibrates for 
at least 3 months before Screening can participate 
6. Use of an experimental treatment for PBC within the past 6 months 
7. Prior use and/or concomitant treatment with OCA 
8. Use of experimental or unapproved drugs within 1 year of Screening 


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9. Any other condition(s) that would compromise the safety of the subject or compromise the 
quality of the clinical study, as judged by the Principal Investigator (PI) 
10. Pregnant or nursing females 
11. 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 
12. Co-existing liver or biliary diseases, such as primary sclerosing cholangitis, 
choledocholithiasis, acute or chronic hepatitis, autoimmune hepatitis, alcoholic liver disease, 
nonalcoholic steatohepatitis (NASH), acute infection of bile duct system or gall bladder, 
history of gastrointestinal bleeding (secondary to portal hypertension), cirrhosis, 
cholangiocarcinoma diagnosed or suspected liver cancers 
13. Cirrhosis with or without complications, including history or presence of: spontaneous 
bacterial peritonitis, hepatocellular carcinoma 
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. Patients with a history of severe pruritus requiring current or prior systemic treatment (e.g., 
with BAS or rifampicin) 
17. Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease)  
18. Any condition possibly affecting drug absorption (eg, gastrectomy <3 years prior to 
Screening). NOTE: Subjects who have undergone gastric surgeries known to not affect drug 
absorption such as gastric band or gastric sleeve will be allowed if they are stable for at least 
1 year prior to Screening. 
19. 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) 
20. Participation in a clinical trial within 30 days prior to study drug administration 
21. 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 
22. Use of CYP3A4 and P-gp inducers and inhibitors within 14 days prior to the first dose of 
study medication and throughout study duration 
23. Clinically significant history of drug sensitivity or allergy, as determined by the PI 
24. Subject has received an investigational agent or investigational 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  
25. Use of a new statin regimen from Screening and throughout study duration. 
NOTE: Subjects on a stable dose of statins for at least 3 months prior to Screening are 
allowed. No dose modification during the study will be allowed. 
26. Use of immunosuppressants (eg, systemic corticosteroids) for more than 2 consecutive weeks 
in duration within 1 year prior to Screening. 


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4. 
STUDY DESIGN  
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study assessing 
the safety, tolerability, pharmacokinetics, and efficacy of two doses of EDP-305 in subjects with 
PBC with or without an inadequate response to UDCA.  
The study is composed of 3 phases or periods:  
x 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   
x 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) 
x 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 in a 3:3:1 ratio to one of two doses of EDP-305 and 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 Assessment (SoA) in Appendix 1. 
Figure 1: Study Design 
 
 
Abbreviations: D=Day; W=Week 


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4.2 
Rationale for Study Design  
This proposed trial will evaluate EDP-305 in patients with PBC 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 3:3:1 
ratio. 
4.2.1 
Justification of Design and Control Group 
Until recently, ursodeoxycholic acid (UDCA) has been the only approved treatment for PBC, 
which was approved by the FDA in 1997.  While UDCA therapy has a marked impact on clinical 
outcomes in PBC, up to 40% of UDCA-treated patients have a suboptimal or absent response to 
UDCA and, as such, are at significantly increased risk of an adverse outcome (death, requiring a 
liver transplant, or other clinical complications) (Carbone et al., 2013; Corpechot et al., 2008; 
ter Borg et al., 2006) (U.S. Department of HHS Organ Procurement and Transplantation 
Network.) (https://optn.transplant.hrsa.gov, Sept 5, 2016). In May 2016, the U.S. Food and Drug 
Administration granted accelerated approval for the FXR agonist Ocaliva® (obeticholic acid, 
OCA) for the treatment of PBC in combination with UDCA in adults with an inadequate 
response to UDCA, or as a single therapy in adults unable to tolerate UDCA (U.S. Food and 
Drug Administration, 2016). The confirmatory trials are ongoing.  
This Phase 2 double-blind, parallel dose group study evaluating 3 doses of EDP-305 compared to 
placebo was designed to assess the safety, efficacy, and PK of EDP-305 for the treatment of 
subjects with PBC over a 12-week treatment period. This trial will establish the effect of adding 
EDP-305 to the PBC standard of care treatment, UDCA on the ALP change. Patients will 
continue their pre-study stable dose of UDCA throughout the trial. Accordingly, patients will not 
have any standard therapies withheld in the trial. The use of placebo is implemented to maintain 
the study blind and scientific validity of the trial. Some patients cannot tolerate UDCA; their 
standard of care does not include UDCA. Patients taking drugs that might have effects in PBC or 
recently conditionally approved (i.e., OCA) are being excluded from the trial to ensure that the 
trial provides the clearest comparison of the effects of EDP-305 with placebo. 
4.2.2 
Justification of EDP-305 Dose 
This phase 2 trial has been designed to assess the efficacy, safety and tolerability of 2 doses (1 
mg, and 2.5 mg) of EDP-305 in patients with PBC so as to provide proof of concept data to 
support Phase 3 in this indication. 
Study EDP 305-001 characterized a broad range of single and multiple doses: from 1 to 80 mg in 
the SAD part, and from 0.5 to 20 mg in the MAD part, and administered as an oral suspension.  
The safety and tolerability of EDP-305 has been established not only in healthy subjects but also 
in subjects with presumptive NAFLD at doses up to 80 mg single dose and up to 20 mg once 
daily for 14 consecutive days. 


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As demonstrated in study EDP 305-001, EDP-305 was generally well tolerated at single doses up 
to 80 mg and at multiple doses up to 20 mg for 14 days. No SAEs or Grade 4 AEs were reported.  
No clinically significant laboratories were reported except one transient Grade 2 ALT/AST 
elevation in n=1 (MAD-HV-20mg) that led to drug discontinuation. Drug related pruritus was 
reported after multiple dosing at the higher doses of EDP-305 10 mg (n=2) and 20 mg (n=7), and 
PBO (n=1), with 1 discontinuation at 20 mg in HV.  Total, LDL-, HDL- cholesterol and 
triglycerides did not differ between EDP-305 and placebo in healthy at any dose or PN subjects 
at any dose, except for cholesterol and HDL at 20mg.
The pharmacokinetics of EDP-305 was profiled over a broad range of single and multiple doses.  
A dose proportional increase in exposure was observed over the broad dose range studied.  Half-
life ranged from 11-16 hours and from 10-23 hours following single and multiple doses of EDP-
305, respectively.  There was more drug accumulation observed following 20 mg dose compared 
to lower doses, indicating a potential change in the PK profile at 20 mg.   
  
Based on observed safety profile to date, pharmacokinetics profile and changes in C4 and FGF-
19 in study EDP 305-001 and relative bioavailability data from study 006, (Section 1.4.2.4), 
EDP-305 doses of 1 and 2.5 mg once daily using the tablet formulation are selected for this 
study. The exposures associated with this dose range are expected to result in clinically 
meaningful changes in C4 and other relevant markers of FXR activity (FGF-19), while 
minimizing the incidence of potential adverse events (i.e. pruritus). 
Doses of 1 and 2.5 mg using the tablet formulation in the fasted state 
(comparable to approximately 2.5 and 5 mg using the suspension formulation in the fasted state) 


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are expected to provide exposures associated with clinically meaningful changes in C4 and FGF-
19, while minimizing the incidence of potential adverse events (i.e. pruritus). 
In summary, based on data from studies 001, 004, and 006, doses of 1 and 2.5 mg are expected to 
provide: 
x A safe and tolerable regimen with lowest chance to induce pruritus 
x Plasma exposures representing linear, time-independent PK and correlated with desirable 
dose dependent changes in PD markers suitable for a once daily dosing 
x Maximal decreases in C4 ranging from approximately 67% to 85% at steady state and 
associated increases in FGF-19 ranging from approximately 1000% to 1700% at steady 
state.  Given the similarity in the MOA between EDP-305 and OCA, the expected 
changes in C4/FGF-19 over the selected dose range for EDP-305 in phase 2 studies, are 
expected to be associated with relevant downstream pharmacological effects clinically 
relevant changes in liver markers. 
 


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5.
STUDY DRUG AND TREATMENT OF SUBJECTS 
5.1
Description of Study Drug 
EDP-305 drug product tablets consist of 1 mg, and 2.5 mg strengths supplied as round, white to 
off-white tablets debossed with I, and II respectively, to differentiate strength on one side of the 
tablet. Matching placebos for the two strengths will also be supplied as round, white to off-white 
tablets debossed with I, and II for 1mg, and 2.5 mg strengths respectively. Study drug and 
matching placebo tablets will be supplied by Enanta.  
The matching placebo will contain all the excipients present in the EDP-305 drug product tablets 
with the exception of the active drug. 
  
EDP-305 drug product tablets and matching placebo tablets should be stored under refrigerated 
conditions (2°C – 8°C) at all times. 
Additional information will be provided in the Pharmacy Manual. 
5.2
Packaging and Labeling 
EDP-305 tablets and matching placebo will be supplied in 
All bottles containing clinical trial material will be labeled 
according to study drug labeling in compliance with applicable local and national regulations for 
labeling of investigational products.  
EDP-305 tablets are packaged in a 
 The bottles will 
be induction sealed. 
5.3
Storage
EDP-305 drug product tablets and placebo tablets in bottles will be shipped to the clinical site 
and stored under refrigerated conditions (2°C–8°C).
5.4
Accountability 
Study drug may be dispensed only under the supervision of the Investigator or authorized 
designee and only to study subjects. The Pharmacist or designated study staff will maintain 


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adequate records of 1) study drug received, 2) study drug dispensed to the subjects, and 3) drug 
returned by the subjects. Subjects will be instructed to return all used and unused study drug to 
the site. All used and unused study drug will be retained at the site according to instructions 
provided by Enanta or designee until monitored by the study monitor. The study monitor will 
review study drug records and inventory throughout the study. 
5.5 
Handling and Disposal  
Study drug must not be used for any purpose other than for administration to subjects enrolled 
into this clinical study. All study drug bottles that are opened and returned by subjects as well as 
those that are not opened or assigned to subjects will be retained at the site according to 
instructions provided by Enanta or designee until monitored by the study monitor. Full 
accountability of all study drug distributed to subjects will be documented per Section 5.4. 
At the end of the study, Enanta will provide instructions for the destruction of any unused study 
drug.  If Enanta authorizes destruction at the study site, the Investigator must ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy and any special instructions provided by Enanta, and, that the destruction was adequately 
documented.   
5.6 
Treatment Assignment and Randomization 
Subjects will be randomized to study treatment using an Integrated Web Response System 
(IWRS). Subjects will be stratified initially by participation in the PK/PD substudy and then by 
a) prior use of fibrates and b) prior and/or current use of UDCA. Subjects will be randomized to 
the treatment groups shown below: 
x Treatment Group 1 (N=45); EDP-305 1 mg orally for 12 weeks 
x Treatment Group 2 (N=45); EDP-305 2.5 mg orally for 12 weeks 
x Treatment Group 3 (N=15); 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. 


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5.7 
Study Drug Dose and Administration 
Complete instructions for dispensing and administering study drug are presented in the study 
specific Pharmacy Manual.  
The subject will be instructed to take all study drug doses at home except when study drug will 
be administered in the clinic (ie, 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 (ie, 
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.   
Stopping rules for study drug administration are provided in Section 10.1. 
5.7.1 
Dispensing of Study Drug 
When drug is dispensed at the clinic, study drug may be dispensed only under the supervision of 
a qualified pharmacist or an authorized designee and only for administration to the study 
subjects.  
A 4-week supply of blinded study drug in individually labelled bottles will be dispensed by 
qualified site personnel to the subject at the visit on Day 1, Week 4, and 8. The bottle number 
dispensed to the subject and the number of tablets dispensed will be recorded in the site source 
documents.  Subjects will be instructed to store study drug in the original bottle under 
refrigerated conditions. Subjects will be provided with a cooler bag to bring the study drug 
home. Once returning home, the subject will be instructed to refrigerate the study medication, 
removing it only for dosing. 
5.7.2 
Treatment Compliance 
The subject will be instructed to bring all study drug (including empty bottles) to the clinic at 
each study visit. Both accountability and study drug compliance will be reviewed at each visit as 
indicated in the SoA (Appendix 1). The number of tablets will be counted and the study 
personnel will ask the subjects why any doses were missed, if applicable. Any potential reasons 
for lack of compliance with dosing will be monitored and followed up by the study personnel.   
For any subject demonstrating continued noncompliance of study drug dosing despite continued 
educational efforts, the Investigator should contact the study medical monitor to discuss possible 
discontinuation of the subject from the study. 


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5.8
Concomitant Medications 
Subjects taking UDCA at the start of the study must remain on the same dose of UDCA 
throughout the 12-week dosing period. If the Investigator believes that dosing with UDCA 
should be stopped due to adverse reactions, then the Medical Monitor should be consulted prior 
to discontinuing the drug. Subjects who were not taking UDCA at the start of the study will not 
be allowed to initiate treatment during the study. 
All subjects enrolled in the study must abstain from taking any prohibited concomitant 
medication through the end of study.  
Details of prior and concomitant medication use will be recorded in the source documentation 
and the electronic case report form (eCRF) as indicated in the SoA (Appendix 1). 
5.8.1
Co-administration of EDP-305 and Ursodiol (ursodeoxycholic acid, UDCA) 
Drug-drug interaction between EDP-305 and UDCA is not anticipated based on available 
EDP-305 drug-drug interaction (see Section 1.4.2), and on UDCA metabolic profile from the 
literature. In the liver, ursodiol is conjugated with glycine or taurine, then secreted into bile. 
These conjugates of ursodiol are absorbed in the small intestine by passive and active 
mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, 
leading to the formation of free ursodiol that can be reabsorbed and reconjugated in the liver. 
Nonabsorbed ursodiol passes into the colon where it is mostly 7- dehydroxylated to lithocholic 
acid. Some ursodiol is epimerized to chenodiol (CDCA) via a 7-oxo intermediate. Chenodiol 
also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble 
and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the 
liver with glycine, or taurine and sulfated at the 3 position. The resulting sulfated lithocholic acid 
conjugates are excreted in bile and then lost in feces (Axcan Scandipharm Inc., 2007).
As UDCA is primarily metabolized through conjugation, EDP-305 is not expected to have an 
impact on the metabolism of UDCA.  
Available data from Study EDP 305-005 indicated that CYP3A4 is a major pathway for EDP-
305 metabolism, as is also supported by preclinical phenotyping data (refer to the Investigator’s 
Brochure for additional detail). As reported in the literature, UDCA did not have an effect on 
midazolam pharmacokinetics (a sensitive CYP3A4 substrate) (Becquemont et al., 2006; Dilger, 
Denk, Heeg, & Beuers, 2005).  
UDCA had limited effect on digoxin (a sensitive P-gp
substrate) (Becquemont et al., 2006). Based on this information, UDCA is not expected to have an 
effect on EDP-305 pharmacokinetics during co-administration.  


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5.9
Prohibited Medications 
  
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. 
5.10


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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:  
x Unblinded Enanta/CRO statistician for purpose of generating and monitoring the 
randomization list 
x Unblinded Drug Supply Chain personnel for the purpose of monitoring drug supplies 
x Enanta/CRO Pharmacovigilance Group and Regulatory Affairs representatives when 
required to satisfy regulatory reporting requirements 
x Bioanalytical Laboratory for the purpose of measuring drug concentrations  
6.1 
Blinding of Study Samples 
6.1.1 
Blinding of Biomarker, Fibrosis and Inflammatory Markers and Laboratory 
Liver Test Results 
Investigators, site personnel and CRO/Sponsor will be blinded to the following laboratory tests 
post-Baseline:   
x Biomarker laboratory data  
o FGF19,  
o total bile acids (BA),  
o C4 [7α-OH-4-cholesten-3-one],  
x 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 AST to Platelet Ratio Index (APRI) 
o Fibrosis 4 (FIB-4) Index 
x Liver Tests  
o ALP 


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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 
the Investigator has attempted and failed to contact the Medical Monitor, and/or the urgency of 
the case required immediate action, he/she should use his/her best judgment, based on the nature 
and urgency of the clinical situation, and proceed with unblinding. 
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 (the reason, date, etc.) 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.
CRO pharmacovigilance will also unblind any SAE reports in compliance with Regulatory 
reporting requirements. In addition, Enanta may unblind individual subjects at any time for 
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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 (Appendix 1).  
7.1.1 
Screening  
Screening procedures will occur after the subject signs and dates an Institutional Review Board 
(IRB) or Ethics Committee (EC) approved 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 (Appendix 1). 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 re screened under the following circumstances and with the approval of the medical monitor: 
x 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.  
x Subjects who are eligible, but transiently (for personal reasons) unable to commit to all 
study procedures  
7.1.3 
Baseline Visit (Day1) 
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 


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of applicable inclusion/exclusion criteria, subjects who continue to satisfy eligibility 
requirements will be randomized in a 3:3:1 ratio to their treatment group. Predose assessments 
and procedures will be conducted as noted in the SoA (Appendix 1) and considered Baseline 
values.  
After predose/Baseline study procedures are completed, subjects will receive the first dose of 
study drug in the clinic on Day 1 followed by PK and biomarker blood draws. Additional PK, 
C4, FGF19 and Bile Acid samples will be collected from subjects at a subset of sites (PK/PD 
Substudy) that have the technical capability to collect and process intensive (longer duration) 
sampling. PK and PD samples will be collected as described in Section 8.4. 
Before leaving the clinic, subjects will receive study medication and instructions on how to take 
the medication at home.   
7.1.4 
Treatment Period Visits (Day 3, Weeks 2, 4, 8 and 12 /EOT) 
Except for days when there is a clinic visit, subjects will take their daily dose of study drug at 
home for 12 weeks. Throughout the 12-week treatment period, subjects will return to the clinic 
as shown in the SoA (Appendix 1) for study assessments.  Prior to each visit, subjects will be 
instructed to fast for a minimum of 8 hrs prior to the scheduled visit time. 
At the end of the treatment period, subjects will complete the EOT visit. Subjects who complete 
12 weeks of treatment will complete the EOT assessments at the Day 84 visit/Week 12. Subjects 
who discontinue treatment early should complete EOT assessments at the time of discontinuation 
(if in the clinic) or as soon thereafter as possible if the subject discontinues treatment while not in 
the clinic. Procedures performed are specified in the SoA (Appendix 1). 
Population PK and PK/PD samples will be collected as specified in the SoA (Appendix 1) and as 
described in Section 8.4.  
Subjects should discontinue drug on Day 84. Subjects, who return for their EOT Visit after Day 
84, should stop dosing on Day 84 (Week 12 Visit).   
7.1.5 
Safety Follow-up Period (End of Study Visit) 
All subjects, including those who discontinue treatment early, should return to the clinic for the 
End of Study (EOS) visit 4 weeks after the last dose of study drug for safety assessments 
(Appendix 1). For subjects who complete the study, the EOS visit would be scheduled on Day 
112. Following completion of study procedures, subjects will be terminated from the study.   
Any subject with ongoing AEs/SAEs (serious adverse events) at the EOS visit should be 
followed until resolution of their AE/SAE or until the Investigator has determined that the event 
has stabilized as discussed in Section 9.3. 


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7.2 
Subject Withdrawal / Early Termination 
Subjects are free to withdraw their participation at any time during this clinical trial. The 
Investigator has the right to remove any subject from treatment with study drug or participation 
in the study. However, the Investigator should consult with the Sponsor’s Medical Monitor 
before prematurely removing a subject. For any subject who decides to withdraw from the study, 
the Investigator should inquire about the reason for withdrawal, request that the subject to return 
all unused investigational product(s), request that the subject return for a final visit, if applicable, 
and follow-up with the subject regarding any unresolved adverse events. Although a subject may 
discontinue study treatment, every effort must be made to continue the subject on the study, 
returning for the EOT visit (if prematurely discontinuing treatment) and the safety follow-up 
visit.  
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 , Appendix 1). 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 the EOS 
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 11.3. 
7.2.1 
Withdrawal Criteria 
The primary consideration in any determination to discontinue a subject’s participation must be 
the health and welfare of the subject. Reasons for withdrawal may include, but are not limited, to 
the following: 
x Adverse Event 
x Noncompliance with study drug dosing or study procedures 
x Lack of efficacy 
x Lost to follow-up 
x Withdrawal by subject 
x Protocol deviation  


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x Pregnancy 
x Sponsor’s decision to terminate the study 
x 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. 
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: 
x The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects. 
x Subject enrollment is unsatisfactory. 
x 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: 
x Failure of the site to enroll subjects into the study at an acceptable rate. 
x Failure of the site to comply with pertinent governmental regulations as appropriate. 
x Submission of knowingly false information from the research facility to the Sponsor, 
clinical monitor, or governmental authority. 


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x Failure to adhere to the protocol requirements. 
x Data recording is inaccurate or incomplete. 
x PI 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: 
x Return of all study data to Enanta Pharmaceuticals, Inc. or designee. 
x Respond to and complete all requests for data clarifications. 
x Accountability and final disposition of used and unused study drug. 
x Review of site records for completeness. 
x Shipment of all applicable biological samples (including PK samples) to the designated 
laboratory. 


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8. 
STUDY PROCEDURES/EVALUATIONS  
All visits and assessments should be conducted as shown in the SoA (Appendix 1). 
8.1 
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 PBC should be recorded. 
8.2 
Clinical Evaluations 
8.2.1 
Vital Sign Measurements and ECGs 
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 (Appendix 1) after the 
subject has been supine for 5 minutes. 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. 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). Clinical interpretation of the ECGs by the Investigator or designee should be recorded 
on a hard copy of the ECGs.  
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. 
 


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Prior to dosing the Baseline ECG must be reviewed to confirm that no clinically significant 
cardiac abnormalities are present.  
8.2.2 
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 (Appendix 1) and will include 
examination 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. 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). 
8.2.3 
Weight and Body Mass Index (BMI) 
Height should be recorded once at the Screening visit while weight should be recorded at the 
Screening and EOS visits. BMI should be calculated at the times shown in the SoA (Appendix 1) 
according to the following equation:  BMI=weight (kg)/height (m)2.   
8.2.4 
PBC-40 Quality of Life Assessment 
The PBC-40 Quality of Life Assessment (PBC-40 QoL) is a study of health-related quality of 
life (HRQOL). It is a survey containing domains of PBC-40 relate to fatigue, emotional, social, 
and cognitive function, general symptoms, and itch. This measure has been validated for PBC 
and the survey will be provided to sites by Enanta. The PBC-40 QoL will be performed as 
indicated in the SoA (Appendix 1). 
8.2.5 
Assessment of Pruritus  
Pruritus will be monitored in this study. As listed below, two separate scales will be used to 
assess pruritus in subjects.  
x An itch visual analog scale (VAS) will be used to record the intensity of the event (Furue 
et al., 2013). Site personnel should instruct the subject to draw a line on the scale 
corresponding to the maximum intensity of itch.   
x The 5-D itch scale is a multidimensional questionnaire completed by subjects assessing 
pruritus. The 5D-itch scale includes a range of 0 (no itch) to 10 (worst imaginable itch) 
covering five dimensions: degree, duration, direction, disability and distribution. 
The scales should be completed by the subject as indicated in the SoA (Appendix 1). 
 


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8.2.6 
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 PI 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 (Appendix 1). 
8.3 
Clinical Laboratory and Diagnostic Procedures 
All laboratory samples will be analyzed by a centralized 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 clinically 
significant. Clinically significant laboratory findings in the opinion of the Investigator should be 
recorded as an AE (or SAE as appropriate).   
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 Biomarker analysis, fasting serum or plasma samples should be collected before the daily 
dose of study drug for analysis of FGF19, bile acids, C4, and at visits indicated in the SoA 
(Appendix 1). Samples should be collected after an overnight fast of a minimum of 8 hours. 
8.3.1 
Safety Laboratory Assessments 
Blood and urine samples for clinical laboratory assessments will be collected according to the 
SoA (refer to Table 14). Subjects should be instructed to fast for at least 8 hours prior to the 


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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. 
Creatinine clearance will be calculated using the Cockcroft Gault equation as indicated in the 
Laboratory Manual.     


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Table 14: 
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 
BUN 
BUN/Creatinine Ratio (calculation) 
Calcium, (Serum) 
Creatine Kinase  
Creatinine, Serum (creatinine clearance) 
Uric Acid 
Electrolyte Panel (Na+, K+, Cl-, Bicarb.) 
Phosphorus 
Gamma Glutamyl Transferase (GGT) 
Globulin, Total 
Glucose, Serum 
Cholesterol, serum 
Lactate Dehydrogenase (LDH) 
Lipase 
Protein, Total, Serum 
TG (triglycerides) 
Coagulation tests 
INR – PT/PTT 
HEMATOLOGY PANEL 
Hemoglobin 
Hematocrit 
Differential WBC Count (percentage and absolute): 
Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils 
MCH 
MCHC 
MCV 
Platelets 
Red Blood Count 
RBC Morphology 
White Blood Count 
SCREENING TESTS 
Viral serology:  HIV-1, HIV-2, HBV (HBsAg), anti-HCV 
antibodies and HCV RNA 
PBC diagnostic (if needed): AMA/M2/PBC-ANAb 
MARKERS OF CV RISKS AND LIPIDS 
hs-CRP  
HDL and LDL-P (high and low-density lipoprotein 
particles using a lipoprotein subfractions test; eg, 
LIPOPROFILE)  
lipoprotein (a) [Lp(a)] assay  
apoA-I, apoB, apoB/A Ratio, apoC3, apoE isoforms (E2, 
E3, E4) Total Cholesterol (TC) 
High Density Lipoprotein – Cholesterol (HDL-C) 
Low-Density-Lipoprotein – Cholesterol (LDL-C) 
TG (triglycerides) 
Total/HDL Cholesterol (CT) Ratio 
Adiponectin 
URINALYSIS  
Routine urinalysis to include: Color and appearance, 
pH, SG, Bilirubin, Glucose, Ketones, Leukocytes, 
Nitrite, Occult blood, Protein, Urobilinogen, 
Microscopic (including RBCs and WBCs) 
MARKERS OF FIBROSIS AND INFLAMMATION 
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, β) 
IL-6. IL1β 
AST to Platelet Ratio Index (APRI) 
Fibrosis 4 (FIB-4) Index 
PREGNANCY AND MENOPAUSE TESTS  
Serum pregnancy test  
Follicle-StimulatingHormone (FSH)  
BIOMARKERS 
FGF19 (fasting plasma) 
Total bile acids (fasting serum) 
C4 (7α-OH-4-cholesten-3-one) 
 
8.3.2 
Pregnancy and Menopausal Laboratory Testing 
All female subjects will undergo a serum pregnancy test at Screening and Baseline, and a urine 
pregnancy test at Baseline and all other visits according to the SoA. If the results of the urine 
pregnancy test are positive, a serum pregnancy test should be conducted as soon as possible. A 
urine pregnancy test must be conducted and confirmed negative on Day 1 prior to the first dose 
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To confirm childbearing status for women claiming that they are postmenopausal, follicle 
stimulating hormone (FSH) will be measured at Screening. Additionally, a serum pregnancy test 
should also be drawn in the event the woman is found to be of childbearing potential based on 
the FSH results. 
8.3.3 
Noninvasive Evaluations of Fibrosis 
The ELF panel combines 3 biomarkers that have been shown to be 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 Appendix 1.  
Fibrosis will be estimated using the APRI and the fibrosis 4 (FIB-4) formulae. The APRI will be 
calculated by the central laboratory using the following formula: 
([AST IU/L / AST ULN] / [Platelet count 109/L]) × 100 = APRI 
An online calculator can be found at:  
 https://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])) 
An online calculator can be found at: 
 http://www.hepatitisc.uw.edu/page/clinical-calculators/fib-4 
Refer to the SoA (Appendix 1) for the timing of these tests. 
8.3.4 
Biomarkers 
See Table 14 for full list of biomarkers to be collected in this study. 
Fasting serum or plasma samples should be collected before the daily dose of study drug for 
analysis of FGF19, bile acids, and C4 at visits indicated in the SoA (Appendix 1) at Day 1, and 
Week 2, 4, 8 and 12 after a fast of a minimum of 8 hours. 
For all subjects, samples for FGF19, bile acids, and C4 will be collected predose at the noted 
visits as indicated in the SoA (Appendix 1).  
PK/PD Substudy (select subjects to consent to participate): Additional samples will be 
collected from subjects at a subset of sites that have the technical capability to collect and 
process intensive (longer duration) sampling (those also collecting intensive PK) at Day 1 and 
Day 84 (Week 12). Biomarker samples will be collected at predose and 2, 6, and 8 hours 
postdose. Additionally, an ALP sample will be collected at the same time points for subjects 


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participating in the PK/PD substudy (ie, predose and at 2, 6, and 8 hours postdose). On scheduled 
visits on Week 2, 4 and 8, samples (FGF19, bile acids, C4 and ALP) will be collected at three 
timepoints: predose and at two timepoints postdose; the first samples collected 1 to 3 hours 
postdose and the second postdose samples collected at least 1 hour later. Where possible, the 
samples at each visit should be obtained at different times postdose relative to each other. 
8.3.6
Liver Imaging 
To exclude cirrhosis and/or advanced fibrosis, a liver Fibroscan will be conducted prior to 
Baseline in subjects for whom documented fibrosis stage on a recent liver biopsy (<2 years) 
result is not available and once a subject is considered eligible based on Screening laboratory 
values. 


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8.4 
Pharmacokinetic Samples 
8.4.1 
Collection of Pharmacokinetic Samples 
Plasma samples will be collected and processed to define the PK parameters according to the 
procedures provided and/or approved by Enanta Pharmaceuticals, Inc. Plasma PK samples will 
be collected as shown in the SoA (Appendix 1). More detailed information will be given in the 
Laboratory Manual.   
Population PK( all Subjects): On scheduled visits at Day 1, and Weeks 2, 4, 8 and 12, PK 
samples will be collected at three timepoints: predose and at two timepoints postdose; the first 
postdose sample collected 1 to 3 hours postdose and the second postdose sample collected at 
least one hour later. Where possible, the samples at each visit should be obtained at different 
times postdose relative to each other. 
PK/PD Substudy (select subjects to consent to participate): Additional samples will be 
collected from subjects at a subset of sites that have the technical capability to collect and 
process intensive (longer duration) PK samples. At Day 1 and Day 84 (Week 12) PK samples 
will be collected at predose and 2, 6, and 8 hours postdose. On scheduled visits on Week 2, 4 and 
8, PK samples will be collected at three timepoints: predose and at two timepoints postdose; the 
first samples collected 1 to 3 hours postdose and the second postdose samples collected at least 
1 hour later. Where possible, the samples at each visit should be obtained at different times 
postdose relative to each other.  
More detailed information will be provided in the Study Manual. It is important that the date and 
time of collection of each of the PK blood samples are accurately recorded in the source 
document. Within 8 hours postdose, an acceptable window around each PK draw is 
± 10 minutes. Predose PK samples should be drawn within 30 minutes of the next scheduled 
dosing time. Actual date and time of PK sample collection will be recorded in the eCRF. In 
addition, the site should record the time of last dose taken at home prior to the visit. 
PK samples may be stored and used for future metabolite identification and/or further evaluation 
of the bioanalytical method. These data will be used for internal exploratory purposes and will 
not be included in the clinical study report. 
8.4.2 
Handling and Bioanalysis of Pharmacokinetic Samples 
EDP-305 and its major metabolites (EP-022571, EP-022572, and EP-022679) in human plasma 
will be quantified by high performance liquid chromatography (HPLC) with tandem mass 
spectrometric (LC-MS/MS) detection. The method will be fully validated by assessment of 
precision, accuracy, sensitivity, and specificity of EDP-305 and its major metabolites by a 
laboratory selected by Enanta Pharmaceuticals, Inc.   


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Detailed procedures for the collection of blood samples and further procedures for processing, 
handling and shipping of samples for PK analysis will be provided in the Laboratory Manual.   
The lab performing bioanalytical analysis will be provided the randomization scheme and will 
generally analyze all samples for subjects randomized to EDP-305 plus a few samples for 
subjects randomized to placebo as a control. 


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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 trial 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:  
x Results in death: This includes deaths that appear to be completely unrelated to study 
medication (eg, a car accident).  
x 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.  
x 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 pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the ICF 


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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 
o social reasons and respite care in the absence of any deterioration in the subject's 
general condition 
x Results in permanent or prolonged (at least 28 days in duration) disability or incapacity.  
x Is a congenital anomaly or birth defect in the offspring of a study subject.  
x 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 (ie, randomized), record all AEs in the subject’s AE eCRF and Clinical Trials SAE 
Form (if applicable). The AE CRF 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:  
x Mild (Grade 1) asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
x Moderate (Grade 2) minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 


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x 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 
x Life-threatening (Grade 4) Life-threatening consequences; urgent intervention indicated  
x 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:  
x 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.  
x Pre-existing event that increases in frequency or intensity.  
x 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.  
x Laboratory abnormalities outside of normal limits and requiring therapeutic intervention.  
x An overdose of the study drug without any signs or symptoms will be considered an AE. 
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:  
x 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.  
x 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 


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also be alternative etiology, such as characteristics of the subject’s clinical status or underlying 
disease.  
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 15. 
Table 15: 
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 16. 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. 


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Table 16:  
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 (eg, a subject lost to follow up) 
9.2.5
Documenting and Reporting Serious Pretreatment Events and Serious 
Adverse Events 
All SAEs that occur after obtaining informed consent through the EOS visit, regardless of 
causality, must be reported by the Investigator to 
 and Enanta 
Pharmaceuticals, Inc. In addition, all SAEs, including those that result in death, that occur after 
the EOS visit and that are considered related to study drug(s) must be reported to 
 
 and Enanta within 24 hours of learning of its occurrence. Additional 
details are provided in the Safety Management Plan.  
The electronic SAE Form should be sent to the Study SAE e-mail address to be distributed to all 
recipients:  
SAEs will be recorded on the Clinical Trials 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. On the Clinical 
Trials SAE Form, relationship to study drug(s) will be assessed only as related or not related. 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 
 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.  


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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, 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.
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 non-serious) until resolution or otherwise explained (see Table 16),
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 (see Section 8.2.4). 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 PBC. 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:  
x If ALT or AST increases to >5 × Baseline. 
x If ALT or AST increase >2 × Baseline AND the increase is accompanied by a 
concomitant TB increase to >2 × Baseline OR the INR concomitantly increases by >0.2 
x 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.  
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 TB.  
The protocol also includes an algorithm to respond to changes in liver enzymes and functions as 
follow:  
x To establish a baseline utilizing at least 2 lab values at least several weeks apart. 
x 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 
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. 


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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. 
x
If a subject lives in a remote area, they can be tested locally with the results promptly 
communicated to the Investigator site.
10.3
Management of Pruritus  
If an event of pruritus is reported by subjects in this study, the location and intensity of the event 
must be captured on the eCRF as an AE. In addition, as listed below, two separate scales will be 
used to assess pruritus in subjects who report itching.  
x
An itch visual analog scale (VAS) will be used to record the intensity of the event (Furue 
et al., 2013). Site personnel should instruct the subject to draw a line on the scale 
corresponding to the maximum intensity of itch.   
x
The 5-D itch scale is a multidimensional questionnaire completed by subjects assessing 
pruritus. The 5D-itch scale includes a range of 0 (no itch) to 10 (worst imaginable itch) 
covering five dimensions: degree, duration, direction, disability and distribution. 
If reported, pruritus should be assessed at each visit until resolution of the event. The scales 
should be completed by the subject/site personnel during each assessment/visit where pruritus is 
reported.   
   


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11. 
STATISTICAL CONSIDERATIONS 
11.1 
General Considerations 
All data will be mapped into the appropriate SDTM domains per version 3.2. All analysis 
datasets will be in the appropriate ADaM data structure. Pinnacle21 will be used to ensure 
compliance of the SDTM domains and ADaM datasets to 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 
 
The planned sample size is approximately 105 subjects. Group sample sizes of 45 in each active 
arm and 15 in the placebo arm achieve 83.552% power to detect a ratio of the group proportions 
of 40%. The proportion in the smallest active arm is assumed to be 0.4000 under the null 
hypothesis and 0.0400 under the alternative hypothesis. The proportion in the placebo arm is 
10%. The test statistic used is the two-sided Mantel-Haenszel test. The significance level of the 
test is 0.05. To account for a 10% discontinuation rate, 14 additional subjects will be enrolled to 
attempt to have 105 who complete treatment, bringing the total number of subjects enrolled to 
119. 
11.3 
Analysis Populations 
The following analysis populations are planned:  
x 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. 
x Efficacy Population: All subjects who receive at least one dose of study medication. 
Subjects will be included in the randomized treatment group. 
x Pharmacokinetic Population: All subjects receiving active study medication and having 
any measurable plasma concentration of study medication at any timepoint. 


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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: 
x Completed study drug per protocol 
x Discontinued study drug early and the reason for discontinuation 
x Completed the study  
x 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. 
11.5 
Efficacy Endpoints 
11.5.1 
Primary Efficacy Endpoints 
The primary efficacy endpoint of the study is the proportion of subjects with at least 20% 
reduction in ALP from pre-treatment values or normalization of ALP at Week 12. The 
denominator will be the number of subjects in the efficacy population (missing=failure). 
Treatment comparisons will be made using a Mantel-Haenszel test comparing each of the active 
treatment arms to placebo, separately. 
11.5.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
x Bilirubin (Total, Conjugated, Unconjugated) decline from Baseline at Week 12 
x Change from Baseline in Alanine aminotransferase (ALT), Aspartate aminotransferase 
(AST), and Gamma-Glutamyl transferase (GGT) at Week 12 
x Change from Baseline of noninvasive liver fibrosis markers (Enhanced Liver Fibrosis 
[ELF] panel, PRO C3, AST to Platelet Ratio Index [APRI] and fibrosis-4 [FIB-4]) at 
Week 12  
x Change from Baseline in fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β , alpha2 
macroglobulin and haptoglobin levels at Week 12 


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x Change from Baseline in Triglycerides (TG), Total Cholesterol (TC), High Density 
Lipoprotein Cholesterol (HDL-C), Low Density Lipoprotein Cholesterol (LDL-C) at 
Week 12 
x Change from Baseline in 5D-itch scale and Visual Analog Score (VAS) at Week 12 
x Change from Baseline in PBC-40 Quality of Life (QoL) at Week 12 
x Pharmacodynamic parameters of EDP-305: FGF19, C4 and Bile Acid (BA) at week 12 
 
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 analysis 
of covariance (ANCOVA) model with treatment and baseline values included in the model 
where appropriate.   
11.6 
Safety Endpoints 
11.6.1 
Adverse Events 
Adverse events will be summarized by 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 Adverse Events will include the following: 
x An overall summary of AEs with a line for each of the categories provided below. 
x Treatment-emergent adverse events 
x Treatment-emergent treatment-related adverse events 
x Treatment-emergent adverse events leading to study drug discontinuation 
x Serious adverse events 
x Serious treatment-related adverse events 
x Adverse events leading to death 
11.6.2 
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. 
Change from Baseline will be included in summary tables for laboratory parameters. Shift tables 
will also be generated for safety laboratory parameters by visit and treatment group. All 


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laboratory data will be included in the data listings and all test values outside the normal range 
will be flagged. 
11.6.3 
Electrocardiogram (ECG) Data 
ECG data will be summarized using an 8-number summary by visit and treatment. Change from 
Baseline will be included in summary tables for ECG parameters. 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. 
11.6.4 
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. Change from Baseline will be included in summary tables for vital 
signs. No statistical testing will be performed. 
11.6.5 
Concomitant Medications 
The number and percentage of subjects taking concomitant medications will be summarized by 
drug class and drug name. Subjects in the safety population will be summarized by treatment 
group. No statistical testing will be performed. 
11.6.6 
Physical Examinations 
Physical examination data will be provided in data listings. 
11.7 
Pharmacokinetic Analyses 
The following PK parameters (Table 17) will be calculated as indicated for plasma EDP-305 and 
its major metabolites as applicable: 


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Table 17: 
PK Parameters 
PK 
Parameter 
Description 
AUClast: 
The area under the plasma concentration-time curve from time zero to the 
time of the last quantifiable concentration. 
Cmax: 
Maximum observed concentration. 
Tmax: 
Time to reach Cmax. If the maximum value occurs at more than one time 
point, Tmax is defined as the first time point with this value. 
For each EDP-305 dose level, descriptive statistics (sample size, arithmetic means, geometric 
means, standard deviation, % 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. 
11.8 
Interim Analyses 
An interim analysis may be conducted after 25% of the planned total number of subjects have 
been enrolled and completed 12 weeks of treatment. Additional information will be provided in 
the Statistical Analysis Plan (SAP). 


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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 national 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 21CFR, 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 IND 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.   


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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 
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. 


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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 
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, 
eCRFs, and other study documentation for source data check and/or on-site audit inspection.  
12.5 
Records Retention 
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. 


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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 trial. 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: 
x Modify or amend study material to ensure that no confidential or proprietary information 
is disclosed. 
x Ensure that the reported data are factually correct. 
x 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. 
x 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. 


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13. 
REFERENCES 
An, P., Vald, K., Wei, G., Chau, M., Li, Y., Or, Y., . . . Popov, Y. (2017). A novel FXR agonist 
EDP-305 potently suppresses liver injury and fibrosis in mouse models of biliary and 
metabolic liver disease. Paper presented at the EASL.  
Axcan Scandipharm Inc. (2007). URSO 250 / URSO Forte. Retrieved from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020675s013lbl.pdf 
Becquemont, L., Glaeser, H., Drescher, S., Hitzl, M., Simon, N., Murdter, T. E., . . . Fromm, M. 
F. (2006). Effects of ursodeoxycholic acid on P-glycoprotein and cytochrome P450 3A4-
dependent pharmacokinetics in humans. Clin Pharmacol Ther, 79(5), 449-460. 
doi:10.1016/j.clpt.2006.01.005 
Beuers, U. (2006). Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in 
cholestasis. Nat Clin Pract Gastroenterol Hepatol, 3(6), 318-328. 
doi:10.1038/ncpgasthep0521 
Beuers, U., Trauner, M., Jansen, P., & Poupon, R. (2015). New paradigms in the treatment of 
hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol, 62(1 Suppl), S25-
37. doi:10.1016/j.jhep.2015.02.023 
Boonstra, K., Beuers, U., & Ponsioen, C. Y. (2012). Epidemiology of primary sclerosing 
cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol, 56(5), 1181-
1188. doi:10.1016/j.jhep.2011.10.025 
Carbone, M., Mells, G. F., Pells, G., Dawwas, M. F., Newton, J. L., Heneghan, M. A., . . . Jones, 
D. E. (2013). Sex and age are determinants of the clinical phenotype of primary biliary 
cirrhosis and response to ursodeoxycholic acid. Gastroenterology, 144(3), 560-569.e567; 
quiz e513-564. doi:10.1053/j.gastro.2012.12.005 
Corpechot, C., Abenavoli, L., Rabahi, N., Chretien, Y., Andreani, T., Johanet, C., . . . Poupon, R. 
(2008). Biochemical response to ursodeoxycholic acid and long-term prognosis in 
primary biliary cirrhosis. Hepatology, 48(3), 871-877. doi:10.1002/hep.22428 
Dilger, K., Denk, A., Heeg, M. H., & Beuers, U. (2005). No relevant effect of ursodeoxycholic 
acid on cytochrome P450 3A metabolism in primary biliary cirrhosis. Hepatology, 41(3), 
595-602. doi:10.1002/hep.20568 
European Association for the Study of the Liver. (2017). EASL Clinical Practice Guidelines: The 
diagnosis and management of patients with primary biliary cholangitis. J Hepatol.  
Floreani, A., Caroli, D., Variola, A., Rizzotto, E. R., Antoniazzi, S., Chiaramonte, M., . . . Baldo, 
V. (2011). A 35-year follow-up of a large cohort of patients with primary biliary cirrhosis 
seen at a single centre. Liver Int, 31(3), 361-368. doi:10.1111/j.1478-3231.2010.02366.x 
Furue, M., Ebata, T., Ikoma, A., Takeuchi, S., Kataoka, Y., Takamori, K., . . . Ständer, S. (2013). 
Verbalizing extremes of the visual analogue scale for pruritus: a consensus statement. 
Acta Derm Venereol, 93(2), 214-215.  
Hirschfield, G. M., & Gershwin, M. E. (2013). The immunobiology and pathophysiology of 
primary biliary cirrhosis. Annu Rev Pathol, 8, 303-330. doi:10.1146/annurev-pathol-
020712-164014 
Huet, P. M., Vincent, C., Deslaurier, J., Cote, J., Matsutami, S., Boileau, R., & Huet-van 
Kerckvoorde, J. (2008). Portal hypertension and primary biliary cirrhosis: effect of long-


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term ursodeoxycholic acid treatment. Gastroenterology, 135(5), 1552-1560. 
doi:10.1053/j.gastro.2008.07.019 
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 
Kim, W. R., Lindor, K. D., Locke, G. R., 3rd, Therneau, T. M., Homburger, H. A., Batts, K. P., . 
. . Dickson, E. R. (2000). Epidemiology and natural history of primary biliary cirrhosis in 
a US community. Gastroenterology, 119(6), 1631-1636. doi:10.1053/gast.2000.20197 
Kuiper, E. M., Hansen, B. E., Adang, R. P., van Nieuwkerk, C. M., Timmer, R., Drenth, J. P., . . . 
van Buuren, H. R. (2010). Relatively high risk for hepatocellular carcinoma in patients 
with primary biliary cirrhosis not responding to ursodeoxycholic acid. Eur J 
Gastroenterol Hepatol, 22(12), 1495-1502. doi:10.1097/MEG.0b013e32834059e7 
Lammers, W. J., van Buuren, H. R., Hirschfield, G. M., Janssen, H. L., Invernizzi, P., Mason, A. 
L., . . . Hansen, B. E. (2014). Levels of alkaline phosphatase and bilirubin are surrogate 
end points of outcomes of patients with primary biliary cirrhosis: an international follow-
up study. Gastroenterology, 147(6), 1338-1349.e1335; quiz e1315. 
doi:10.1053/j.gastro.2014.08.029 
Lindor, K. D., Gershwin, M. E., Poupon, R., Kaplan, M., Bergasa, N. V., & Heathcote, E. J. 
(2009). Primary biliary cirrhosis. Hepatology, 50(1), 291-308. doi:10.1002/hep.22906 
Lleo, A., Jepsen, P., Morenghi, E., Carbone, M., Moroni, L., Battezzati, P. M., . . . Invernizzi, P. 
(2016). Evolving Trends in Female to Male Incidence and Male Mortality of Primary 
Biliary Cholangitis. Sci Rep, 6, 25906. doi:10.1038/srep25906 
Matsubara, T., Li, F., & Gonzalez, F. (2013). FXR signaling in the enterohepatic system. Mol 
Cell Endocrinol, 38(1-2), 17-29.  
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.  
Prince, M. I., Chetwynd, A., Craig, W. L., Metcalf, J. V., & James, O. F. (2004). Asymptomatic 
primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large 
population based cohort. Gut, 53(6), 865-870.  
Selmi, C., Mackay, I. R., & Gershwin, M. E. (2011). The autoimmunity of primary biliary 
cirrhosis and the clonal selection theory. Immunol Cell Biol, 89(1), 70-80. 
doi:10.1038/icb.2010.126 
ter Borg, P. C., Schalm, S. W., Hansen, B. E., & van Buuren, H. R. (2006). Prognosis of 
ursodeoxycholic Acid-treated patients with primary biliary cirrhosis. Results of a 10-yr 
cohort study involving 297 patients. Am J Gastroenterol, 101(9), 2044-2050. 
doi:10.1111/j.1572-0241.2006.00699.x 
Trivedi, P. J., Lammers, W. J., van Buuren, H. R., Pares, A., Floreani, A., Janssen, H. L., . . . 
Hirschfield, G. M. (2016). Stratification of hepatocellular carcinoma risk in primary 
biliary cirrhosis: a multicentre international study. Gut, 65(2), 321-329. 
doi:10.1136/gutjnl-2014-308351 
U.S. Food and Drug Administration. (2016). FDA approves Ocaliva for rare, chronic liver 
disease [Press release]. Retrieved from 
https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm503964.htm 


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Webb, G. J., & Hirschfield, G. M. (2017). Primary biliary cholangitis in 2016: High-definition 
PBC: biology, models and therapeutic advances. Nat Rev Gastroenterol Hepatol, 14(2), 
76-78. doi:10.1038/nrgastro.2016.201 
 
 
 


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14.
APPENDICES   
Appendix 1: Schedule of Assessments (SoA) 
Study Event
Scr.1
Study Assessments per Planned Study Day
EOS
Visit Day (D-28
to -1)
D12
D3
D14±2
D28±2
D56±2
D843±2
D112±2
Treatment Week4
W2
W4
W8
EOT5/W12
W16
ICF6; Demography; Medical History
x
Inclusion/Exclusion 
x
FSH7; HIV/HCV/HBV
x
AMA/M2/PBC-ANAb8
x
Pregnancy Test9
x
x
x
x
x
x
Height10, Weight, BMI
x
x
PT/PTT and INR
x
x
Oral Temperature
x
x
x
Physical Exam11
x
x
x
x
x
x
x
x
Vital Signs12
x
x
x
x
x
x
x
x
ECG
x
x
x
x
x
Safety Lab. Tests13
x
x
x
x
x
x
x
x
PBC-40 QoL
x
x
x
x
x
VAS and 5-D Itch
x
x
x
x
x
Biomarkers (FGF19, C4, BA)14
x
x
x
x
x
CV Markers15
x
x
x
x
x
x
Fibroscan 
x
ELF panel, PRO-C3, Inflammatory Markers16
x
x
x
APRI, FIB-4
x
x
PK/PD Substudy (PK, C4, FGF19, BA, ALP)17
x
x
x
x
x
Population PK Samples18
x
x
x
x
x
Dispense Study Drug
x
x
x
Study Drug Dosing19
daily dosing
Drug Accountability
x
x
x
x
x
AEs & Con Meds20
x
x
x
x
x
x
x
x
                                             
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 respective 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 8 4.
4 For the treatment phase, indicates number of completed weeks of treatment  
5 Subjects who discontinue treatment early should complete the EOT procedures as soon as possible and return 4 weeks later for the EOS visit 
6 Informed consent must be obtained prior to conducting any study-specific procedures or assessments 
7 For post-menopausal women only 
8 Only if historical values are not available; one test must be positive for study entry to confirm PBC diagnosis (see Inclusion Criterion #3) 
9 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.   
10 Height should only be measured at Screening 
11 Full PE at Screening and EOS; all other exams should be targeted to review of new signs and symptoms 
12 Vital Signs include HR, respiratory rate, and BP and will be measured once in the morning before the morning dose of study drug 
13 Safety laboratory tests include chemistry (including liver function tests), hematology, and urinalysis and should be collected predose at all 
visits; See Table 14 for details 


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14 Biomarkers include fasting plasma FGF19, fasting serum bile acids, fasting C4 (7α-OH-4-cholesten-3-one). Samples should be collected 
after a minimum 8 hr fast and before the subject takes the daily dose of study drug 
15 Lipids and CV risk markers to be collected are detailed in Table 14
16 Markers of inflammation include fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β, alpha2 macroglobulin and haptoglobin (see Table 14) 
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; the first sample collected 1 to 3 hours 
postdose and the second sample at least 1 hour later. 
18 PK predose samples should be collected after a minimum 8 hr 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. 
19 Study drug given in the clinic on days where subject is seen in the clinic 
20 Additional samples may be collected to further assess safety events e.g. pruritus 

SAP_001.pdf: 
NCT03394924


Sponsor: Enanta Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol no: EDP 305-201 
Version Date: 09-MAR-2020 
PRS 005 T 17 F 
Page 2 of 57 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Table of Contents 
Approvals .................................................................................................................................................................................... 1 
Table of Contents ..................................................................................................................................................................... 2 
1 
Purpose .............................................................................................................................................................................. 4 
2 
Scope ................................................................................................................................................................................... 4 
3 
Introduction ..................................................................................................................................................................... 4 
4 
Study Objectives ............................................................................................................................................................. 4 
5 
Study Design .................................................................................................................................................................... 5 
6 
Statistical Considerations ........................................................................................................................................... 6 
6.1 
Study Analysis Populations .............................................................................................................................. 6 
6.2 
Baseline .................................................................................................................................................................... 7 
6.3 
Study Day Windows ............................................................................................................................................ 7 
6.4 
Multiplicity .............................................................................................................................................................. 9 
7 
Subject Disposition ........................................................................................................................................................ 9 
7.1 
Disposition of Subjects ....................................................................................................................................... 9 
7.2 
Important Protocol Deviations ....................................................................................................................... 9 
7.3 
Extent of Study Drug Exposure and Compliance .................................................................................... 9 
8 
Demographic and Baseline Characteristics....................................................................................................... 10 
8.1 
Demographic and Baseline Characteristics ............................................................................................. 10 
8.2 
Medical History ................................................................................................................................................... 10 
8.3 
Prior and Concomitant Medications ........................................................................................................... 10 
9 
Efficacy Analysis ........................................................................................................................................................... 11 
9.1 
Primary Endpoint ............................................................................................................................................... 11 
9.1.1 
Definition of Primary Endpoint .......................................................................................................... 11 
9.1.2 
Analysis of Primary Endpoint .............................................................................................................. 11 
9.1.3 
Imputation of Missing Data .................................................................................................................. 12 
9.1.4 
Change from Baseline and Percent Change from Baseline for ALP ..................................... 13 
9.2 
Secondary Efficacy Endpoints ....................................................................................................................... 14 
9.2.1 
Change from Baseline and Percentage Change from Baseline in Liver-Related 
Secondary Endpoints.................................................................................................................................................. 14 
9.2.2 
Change from Baseline and percentage change from Baseline of noninvasive liver 
fibrosis markers (ELF panel) and PRO C3 at Week 12 ................................................................................. 15 
9.2.3 
Change from Baseline and Percentage Change from Baseline in Fibrosis at Week 12 16 
9.2.4 
Change from Baseline and percentage change from Baseline in Laboratory Fibrosis 
Parameter levels by Visit and at Week 12 ......................................................................................................... 16 
9.2.5 
Change from Baseline and Percentage Change from Baseline in Lipids by Visit and at 
Week 12 18 
9.2.6 
Adiponectin ................................................................................................................................................. 20 
9.2.7 
ApoA-I ............................................................................................................................................................ 20 
9.2.8 
ApoB ............................................................................................................................................................... 20 
9.2.9 
ApoC3 ............................................................................................................................................................ 20 
9.2.10 
ApoB/A Ratio ............................................................................................................................................. 20 
9.2.11 
Pruritis .......................................................................................................................................................... 21 
9.2.12 
Quality of Life ............................................................................................................................................. 21 


 
 
 
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9.3 
PK/PD Analysis ................................................................................................................................................... 22 
9.3.1 
Pharmacokinetic (PK) Analysis .......................................................................................................... 22 
9.3.2 
Pharmacodynamic (PD) Analysis....................................................................................................... 24 
9.3.3 
PK/PD Analysis at Week 12 (Correlations) ................................................................................... 27 
 
 
10 
Safety Analyses ........................................................................................................................................................ 30 
10.1 
Treatment Emergent Adverse Events........................................................................................................ 31 
10.2 
Laboratory Data .................................................................................................................................................. 32 
10.2.1 
Subject Safety Monitoring ..................................................................................................................... 32 
10.3 
Vital Signs ......................................................................................................................................................... 33 
10.4 
Physical Exam Data ........................................................................................................................................... 33 
10.5 
ECG Results ........................................................................................................................................................... 34 
11 
Interim Analyses...................................................................................................................................................... 34 
12 
Data Safety Monitoring Board ........................................................................................................................... 34 
13 
References .................................................................................................................................................................. 35 
Appendix 1 Glossary of Abbreviations ......................................................................................................................... 36 
Appendix 2 Adverse Event Start/Stop Date Imputation ....................................................................................... 38 
Appendix 3 Prior and Concomitant Medication Start/Stop Date Imputation .............................................. 39 
Appendix 4 Tables, Figures, Listings ............................................................................................................................. 40 
Appendix 5 Schedule of Assessments (SoA) ............................................................................................................... 54 
 
 
 


 
 
 
Sponsor: Enanta Pharmaceuticals, Inc. 
Statistical Analysis Plan 
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Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
1 Purpose  
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 305-201. 
2 Scope 
This plan is a living document that is created during the study start-up.  The SAP will be drafted within three 
months of final CRF and maintained throughout the lifecycle of the study. The SAP will be amended with 
any changes that occurred during the course of the study and finalized prior to database lock. The SAP and 
amended SAP will be approved and signed off by the Project Manager and the Sponsor.   
The SAP outlines the following: 
• 
Study objectives 
• 
Study design 
• 
Variables analyzed and analysis populations 
• 
Applicable study definitions 
• 
Statistical methods regarding important protocol deviations, study drug exposure, efficacy 
analysis, concomitant medications, adverse events handling, laboratory data and physical 
examinations  
• 
Study conduct methods for maintaining blinding of efficacy lab data during the course of the study 
3 Introduction 
This SAP describes the statistical methods to be used during the reporting and analyses of data collected 
under Enanta Pharmaceuticals, Inc.’s Protocol EDP 305-201, titled “A Phase 2 Dose Ranging, 
Randomized, Double Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics 
and Efficacy of EDP-305 in Subjects with Primary Biliary Cholangitis (PBC) with or without an Inadequate 
Response to Ursodeoxycholic Acid (UDCA).” The study protocol provides conduct for a phase 2 
randomized, double blind, dose-ranging placebo-controlled study to evaluate the safety, tolerability, 
efficacy, and pharmacokinetics of compound EDP-305 in subjects with PBC, with or without inadequate 
response to UDCA. Both males and females may be enrolled in the study, though the condition PBC is 
mainly found in women (10:1 women versus men). Suspicion of a potential PBC diagnosis is raised by an 
elevation of alkaline phosphatase (ALP) noted on screening blood tests obtained during routine office visits.  
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 dated 02Apr2018 (Amendment 2.0) and CRF dated 
01Aug2018. 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 
and efficacy lab 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. 
  
4 Study Objectives 
The primary objective of the study is to evaluate the effect of EDP-305 on alkaline phosphatase (ALP) 
levels.  
The secondary objectives of the study are as follows: 
• 
To evaluate the safety and tolerability of EDP-305 


 
 
 
Sponsor: Enanta Pharmaceuticals, Inc. 
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Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
• 
To evaluate the effects of EDP-305 on bilirubin levels 
• 
To evaluate the effects of EDP-305 on other markers of liver function 
• 
To evaluate the effects of EDP-305 on non-invasive markers of liver fibrosis 
• 
To evaluate the effects of EDP-305 on inflammatory markers 
• 
To evaluate the effects of EDP-305 on lipids 
• 
To evaluate the effects of EDP-305 on pruritus 
• 
To evaluate the effects of EDP-305 on Quality of Life (QoL) 
• 
To evaluate the pharmacokinetics (PK) of EDP-305 and metabolites in plasma 
• 
 To evaluate the pharmacodynamics (PD) of EDP-305 
5 Study Design 
The study is a double blind, placebo-controlled study to compare 2 orally-administered dose levels (1 and 
2.5 mg, respectively) of EDP-305 versus placebo for treatment of PBC. 
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 (Week 12) 
• 
Safety Follow-up period which includes the End of Study (EOS) Visit on Day 112. 
 
  
Given that knowledge of ALP levels and other laboratory test results may lead to unblinding of treatment 
assignment, laboratory assessment data will remain blinded to the Enanta and PRA study blinded staff 
members by exclusion from scheduled data transfers, until after database lock. See Section 6.1.1 for a list 
of blinded laboratory test parameters. 
  
Total planned enrollment is approximately 119 subjects based on a target of 105 after a 10% 
discontinuation rate.  Enrollment will take place at approximately 90 sites located in the US as well as 
international locations (Australia, Austria, Belgium, Canada, France, Germany, Netherlands, Spain, and 
Great Britain). 
 
The total maximum length of time of participation for each subject enrolled in the study will be approximately 
20 weeks based on a maximum of 28 days for the Screening Period, 12 weeks for the Treatment Period 
and 4 weeks for the Follow-up Period. 
 
The planned sample size is approximately 105 subjects. Group sample sizes of 45 in each active arm and 
15 in the placebo arm achieve 83.552% power to detect a ratio of the group proportions of 40%. The 
proportion in the smallest active arm is assumed to be 0.4000 under the null hypothesis and 0.0400 under 
the alternative hypothesis. The proportion in the placebo arm is 10%. The test statistic used is the two-
sided Mantel-Haenszel test. The significance level of the test is 0.05.  
To account for a 10% discontinuation rate, 14 additional subjects will be enrolled to attempt to have 105 
who complete treatment, bringing the total number of subjects enrolled to 119. 
PASS software version 14 was used to calculate the sample size. 
Subjects will be asked to participate in the PK/PD substudy. The randomization schedule will be developed 
to allow for balance between the treatment groups within the substudy. For all non-PK/non-PD analysis 
purposes, the subjects in the substudy will be combined with the subjects not in the substudy. 
In order to achieve this balance subjects will be stratified by:  


 
 
 
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1) prior use of fibrates   
2) prior and/or current use of UDCA 
Note that both 1) and 2) may be applicable for a given subject.  In addition, a subset of subjects 
will be included in the PK/PD substudy. 
Subjects will be randomized to 3 treatment groups in a 3:3:1 ratio after stratification: 
• 
Treatment Group 1:  EDP-305 1 mg orally for 12 weeks 
• 
Treatment Group 2:  EDP-305 2.5 mg orally for 12 weeks 
• 
Treatment Group 3:  Placebo (PBO) orally for 12 weeks 
 
A minimum of 10 subjects per treatment group will be included in the PK/PD substudy. 
 
Triangle Biostatistics generated the randomization schedule and provided it to Bioclinica as the IWRS 
vendor, for incorporation into the IWRS 
6 Statistical Considerations 
All analyses will use SAS version 9.4 or higher. 
Continuous and discrete variables will be summarized using an 8-number summary (n, mean, standard 
deviation, median, 25th quartile, 75th quartile, minimum and maximum values). The median, minimum 
and maximum values will be displayed to the same level of precision as the raw data, the mean to one 
additional decimal place and the SD to two additional decimal places. 
 
Categorical variables will be summarized using frequencies and percentages based on the specified 
population total. Variables will be summarized by treatment group. 
 
Statistical hypothesis testing will be conducted to compare treatment groups, using 2-sided tests at alpha 
= 0.05. 
6.1 Study Analysis Populations   
The following analysis populations are planned: 
• 
Safety population: All subjects who received 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. 
• 
Full Efficacy (FE) population: All subjects who received at least one dose of study drug.  Subjects 
will be included in the treatment group that corresponds to the planned randomized study drug. 
• 
Per Protocol (PP) population: All subjects who receive at least one dose of study drug; did not have 
any important protocol deviations (IPDs) during the course of the study; and have ALP data at 
Baseline and Week 12.  Since misallocation of study drug is always an IPD, planned treatment will 
always match actual treatment received in this population, which these subjects will be grouped 
according to. 
• 
Pharmacokinetic (PK) Population: All subjects receiving active study drug and having any 
measurable plasma concentration of study drug at any timepoint. This includes subjects in the 
PK/PD substudy population.  
o 
The PK/PD Substudy Population consists of subjects who have additional PK and PD 
samples at a subset of study sites; and an additional ALP sample will be collected at these 
timepoints. 


 
 
 
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6.1.1 Blinded Laboratory Parameters 
The following laboratory parameters are considered potentially unblinding (as to study treatment) when 
values would be viewed, and therefore need to remain unseen and inaccessible by the Enanta and PRA 
blinded staff until the official unblinding of the study following database lock. 
• 
ALP Levels; 
• 
The Laboratory parameters for Chemistry panel and Hematology panel are listed in the Appendix 
6. 
 
6.2 Baseline 
For the primary endpoint, baseline will be defined in 3 ways: 1.) the average between the screening and 
the day 1 visits.  If either is missing, the non-missing value will be considered baseline for this approach.  
This is the primary definition for the study 2.) The Day 1 value or the last value prior to first dose of study 
drug.  3.) The value from the screening visit as the baseline.  The primary endpoint will be evaluated using 
all 3 baseline calculations.  For all secondary and safety endpoints, baseline will be defined using method 
2.) above. 
6.3 Study Day Windows 
The windows for all visits including PK draws appear in table below: 
Visit  
Target Day 
Time window 
Screening 
Day -1  
Day -28 to Day -1 
Day 1 
Day 1 
N/A 
Day 3 
Day 3 
N/A 
Week 2 
Day 14 
Day 4 to Day 21 
Week 4 
Day 28 
Day 22 to Day 42 
Week 8 
Day 56 
Day 43 to Day 70 
Week 12 
Day 84 
Day 71 to less than or equal to End of 
Treatment+7 days 
Treatment-Free 
Follow-up Week 4 
Day 112 
Greater than End of Treatment+7 days to last 
visit 
a. Samples at each visit should be obtained at different times postdose relative to each of the other 
visits (2, 4, and 8) 
b.  The target day for the screening visit is Day -1 during the period of Day -28 to Day -1 
The relative day will be computed for each laboratory, vitals, ECG and PD data point.  The relative day will 
be calculated as visit date-date of first dose+1.  For data collected prior to first dose, the relative day will be 
calculated as visit date-date of first dose.  When there are multiple observations within a visit window, the 
value closest to the target day will be analyzed.. 
 
 
 
 


 
 
 
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PK/PD Draw Timing 
 
 
Population 
Visit 
Target Day 
PK/PD Substudy 
(PK, C4, FGF19, BA, and 
additional ALP samples) 
 
 For subjects not substudy 
PK 
PD (FGF19, BA, C4) 
Day 1 
Day 1 
At predose and 2, 6, and 8 
hr postdose   
at predose and two samples 
postdose;  
• First sample collected 1 
to 3 hours postdose 
• Second sample at least 
1 hour later   
At predose 
Week 2 
Day 14 
at predose and two 
samples postdose;  
• First sample collected 
1 to 3 hours postdose 
• Second 
sample 
at 
least 1 hour later   
at predose and two samples 
postdose;  
• First sample collected 1 
to 3 hours postdose 
• Second sample at least 
1 hour later   
At predose 
Week 4 
Day 28 
at predose and two 
samples postdose;  
• First sample collected 
1 to 3 hours postdose 
• Second 
sample 
at 
least 1 hour later   
at predose and two samples 
postdose;  
• First sample collected 1 
to 3 hours postdose 
• Second sample at least 
1 hour later   
At predose 
Week 8 
Day 56 
at predose and two 
samples postdose;  
• First sample 
collected 1 to 3 hours 
postdose 
• Second 
sample 
at 
least 1 hour later   
at predose and two samples 
postdose;  
• First sample collected 1 
to 3 hours postdose 
• Second sample at least 
1 hour later   
At predose 
Week 12 
Day 84 
At predose and 2, 6, and 8 
hr postdose   
at predose and two samples 
postdose;  
• First sample collected 1 
to 3 hours postdose 
• Second sample at least 
1 hour later   
At predose 
 
 
 


 
 
 
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6.4 Multiplicity 
No adjustments for multiplicity will be performed. 
7 Subject Disposition 
7.1 Disposition of Subjects 
The number of subjects screened, randomized, randomized and treated, randomized and not treated, and 
the number of subjects in the analysis populations will be summarized.  
 
The number and percentage of subjects will also be summarized for the following subject disposition 
categories: 
• 
Completed study drug treatment per protocol 
• 
Discontinued study drug early and the reason for discontinuation 
• 
Completed the study including follow-up period 
• 
Discontinued from the study early and the reason for discontinuation 
7.2 Important Protocol Deviations 
 As a guideline, important protocol deviations (IPDs) are: 
• 
Non-compliance with study drug 
• 
Pregnancy 
• 
Other deviations that violate inclusion or exclusion criteria 
• 
Outside Study Windows  
The occurrence of protocol deviations will inform which subjects to include in the Per Protocol population.  
The Per Protocol population must be finalized prior to the post-freeze data review meeting (or earlier), prior 
to database lock 
 
Subjects indicating reason for discontinuation at end of treatment visit as Other Protocol Deviation will be 
listed along with their deviation reason, demographics and study drug group for inclusion in the CSR based 
on the deviation data entered into CTMS. 
7.3 Extent of Study Drug Exposure and Compliance 
  
Exposure to study drug, number of days dose is taken and compliance with study drug dosing will be  
summarized by treatment group using the Safety Population. Study drug accountability including bottle  
types, dispensed tablets and returned tablets will be listed. Study drug not returned will be assumed to have  
been taken.  
Study drug compliance will be calculated using values from the Study Drug Accountability and Exposure 
– Oral CRF pages as shown below: 
 (Number of Tablets Dispensed – Number of Tablets Returned) / (End Date –  Start Date + 1) 
Percentage of subjects meeting Study Drug Compliance will be presented in the following categories: at 
least 85% of dispensed tablets (coded as yes/no), and, < 80%, ≥ 80% to < 85%, ≥ 85% to < 90%, and ≥ 
90%. 


 
 
 
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8 Demographic and Baseline Characteristics 
8.1 Demographic and Baseline Characteristics 
Baseline data will be summarized for continuous and categorical variables as applicable. 
 
The following subject demographics and pre-dose values will be summarized in the Full Efficacy 
population: 
• 
Age, and Age group (< 45 years, 45 to < 65 years, and  65 years); 
• 
PBC Diagnosis Age, and PBC Diagnosis Age group (<45, ≥45) 
(Age at diagnosis will be calculated as [year of diagnosis] minus [year of birth].  If only the 
subject’s age at screening is available (rather than year of birth), then [year of signing consent 
(first consent)] minus [age at consent] will be used in place of [year of birth]); 
• 
Duration of PBC, and Duration of PBC category(<7.5 years vs ≥7.5 years); 
• 
Sex, and Females of Child-Bearing Potential; 
• 
Ethnicity, Race; 
• 
Height, Weight, BMI; 
• 
liver stiffness score; 
• 
documented fibrosis stage; 
• 
UDCA usage (Yes/No), UDCA Total Daily Dose (will be derived as the total daily dose recorded 
immediately prior to first dose of study drug - as an ongoing concomitant medication at that time; 
any changes in UDCA use are not expected and will not affect the derivation of this baseline 
characteristic); 
• 
UDCA response status; 
• 
ApoE Isoform (Genomics) as resulted at Day 1, if no Day 1 value is present reported as the next 
result available in the progression of study visits (i.e. Day 1, Week 2, Week 4, Week 8, Week 12, 
and EOS); 
• 
Alkaline phosphatase (ALP): screening value, baseline (last pre-dose) value, average of all pre-
dose values; 
• 
Alanine Aminotransferase (ALT); 
• 
Conjugated (direct), Unconjugated (indirect), and Total Bilirubin (unconjugated will be derived as 
total minus conjugated). 
• 
Gamma-Glutamyl Transferase (GGT) 
No statistical testing will be performed on the aforementioned demographic data. 
8.2 Medical History 
Subjects medical history will be summarized by treatment group for all subjects in the safety population.  
Medical history data will be coded using MedDRA 20.1 and summarized by system organ class and 
preferred term.  No inferential testing will be performed in this section. 
8.3 Prior and Concomitant Medications 
Subjects taking UDCA at the start of the study must remain on the same dose of UDCA throughout the 12-
week dosing period. Subjects who were not taking UDCA at the start of the study will not be allowed to 
initiate treatment during the study. Subjects will be classified as taking or not taking UDCA. 


 
 
 
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Medications will be categorized by medication group and subgroup according to WHODRUG (Version 
Global B3 2017SEP01 DDE+HD (Enhanced + Herbals)).  Refer to the Coding Conventions document for 
this study. 
A medication will be considered concomitant if started or continued to be taken after first dose of study drug 
through 30 days after the last dose of study drug.  Otherwise if a medication was stopped prior to first dose 
of study drug then it will be consider prior.   
Prohibited medications are inhibitors and inducers of CYP3A4 and P-gp (taken between 14 days prior to 
first dose through 30 days after last dose of study drug). Any medication that inhibit or induce the transporter 
proteins P-gp are also prohibited during the study. Use of a new statin regimen is prohibited from Screening 
and throughout study duration. Additional details of prohibited medications please see protocol section 5.9. 
For protocol restrictions other than prohibited medications, please see the protocol section 5.10 
In order to flag prohibited medications taken in the study, each medication taken will be compared against 
a pre-specified list of all prohibited medications. Prior, Concomitant and Prohibited medications will be 
summarized based on the number and percentage of subjects using each medication along with the number 
and percentage of subjects using at least one medication within each medication group and subgroup. 
Prior, concomitant, and prohibited medications will be summarized for the Safety Population.  All 
medications will be listed per subject. 
9 Efficacy Analysis 
The variables from the data to be used to produce the analysis of the objectives and corresponding 
endpoints are presented below.  All efficacy endpoints will be evaluated using the Full Efficacy population. 
9.1 Primary Endpoint 
9.1.1 Definition of Primary Endpoint 
The primary endpoint is defined as the proportion of subjects who have either a 20% reduction in ALP from 
pre-treatment values or normalization of ALP at Week 12. All subjects in the Full Efficacy population will be 
included in the analysis of the primary endpoint. Meeting either of these conditions will be considered 
meeting the primary endpoint of ALP response.  Subjects who are missing either Baseline or Week 12 ALP 
results cannot have either condition evaluated, and will therefore be counted as failure (non-responder).  
Subjects having both Baseline and Week 12 ALP results will each be evaluated as follows: 
1. Percent change will be calculated as [(ALP at Week 12 – ALP at Baseline)/ALP at Baseline] *100.  
The subject will be considered to have successfully achieved 20% reduction in ALP if the result is 
≤ -20. 
2. The subject will be considered to have successfully achieved ALP normalization if ALP was 
abnormal at baseline and normal at week 12. 
If either condition is met, the subject is a responder (ALP Response = YES); if the subject fails both 
conditions, the subject is a non-responder (ALP Response = NO).  The proportion of subjects with a ‘Yes’ 
for ALP Response will be compared among the 3 study treatment groups.  The denominator for this 
calculation is the number of subjects in the Full Efficacy population.  
9.1.2 Analysis of Primary Endpoint 
For the primary endpoint, the Cochran-Mantel-Haenszel (CMH) test will be used to compare the proportion 
of subjects with ALP Response = ” Yes” (percent improvement < -0.20 and/or normalization at Week 12 
from Baseline) for each of the active treatment groups to placebo.  The CMH test will be stratified, two-
sided with an alpha level at 0.05.  For the stratification in this analysis, the two randomization strata (fibrates 
and UDCA use) will be combined to create one strata variable.  The code used to generate the p-value for 
each active treatment vs the placebo will be (with necessary output steps added): 


 
 
 
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Proc freq data=indata; 
Tables strata*treatment*response/cmh; 
Run;  
The primary analysis of the primary endpoint will be performed using the Full Efficacy population.  The 
analysis will be repeated on the Per-Protocol (PP) population, including only subjects with Baseline and 
Week 12 ALP results. 
Subgroup analysis will be performed for ALP Response for the following subgroups: 
• 
Age (<65 vs ≥65) 
• 
gender 
• 
UDCA strata 
• 
Prior use of Fibrates strata 
• 
ALP baseline categories [1.67xULN,2xULN), [2xULN,3xULN), [3xULN,4xULN), [4xULN,5xULN), 
and ≥5xULN (categories are data dependent) 
• 
Total Bilirubin baseline categories [1xULN,2xULN), [2xULN,3xULN), ≥3xULN (categories are data 
dependent) 
• 
ALP/Total Bilirubin/UDCA baseline subgroup (categories are data dependent, cut points should 
be based on median baseline values)  
o 
ALP≤3xULN, Total Bilirubin≤2xULN, UDCA usage,  
o 
ALP≤3xULN, Total Bilirubin>2xULN, UDCA usage 
o 
ALP>3xULN, Total Bilirubin≤2xULN, UDCA usage,  
o 
ALP>3xULN, Total Bilirubin>2xULN, UDCA usage 
o 
ALP≤3xULN, Total Bilirubin≤2xULN, No UDCA usage,  
o 
ALP≤3xULN, Total Bilirubin>2xULN, No UDCA usage 
o 
ALP>3xULN, Total Bilirubin≤2xULN, No UDCA usage,  
o 
ALP>3xULN, Total Bilirubin>2xULN, No UDCA usage 
The code used to generate the p-value for each active treatment vs the placebo will be: 
Proc freq data=indata; 
Tables subgroup*treatment*response/cmh;. 
Run;  
The subgroup analysis will be performed using the Full Efficacy population 
The proportion of responders will be summarized and plotted by Visit. 
9.1.3 Imputation of Missing Data 
To account for missing data, a sensitivity analysis will be performed using the multiple imputation Markov 
Chain method.  
MMRM Using Multiple imputation (MI)  
To assess robustness of the efficacy analysis, sensitivity analysis with missing values imputed by MI will 
be performed on ALP change from baseline data.  In the first stage, missing values will be imputed by 
Markov Chain Monte Carlo (SAS PROC MI, MCMC) to make the missing pattern monotone (by filling in 


 
 
 
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imputed values of ALP between 2 non-missing values).  In the second stage, monotone linear regression 
will fill in missing values through Week 12.  SAS PROC MI and PROC MIXED will be used to obtain MMRM 
estimates of treatment difference.  SAS PROC MIANALYZE will be used to combine estimates and to 
generate the average test statistics for hypothesis testing.  The Missing at Random method will be used 
with the following parameters 
MAR – assume missing at random, number of imputation=100, seed= 
SEED11 (for MCMC) and SEED12 (for MONOTONE REG) for imputation. 
9.1.4 Change from Baseline and Percent Change from Baseline for ALP 
A descriptive summary will be provided for ALP 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 at Week 12 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 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. 
Mean ± SD ALP values and change from baseline by visit and treatment group will be plotted and also 
separately for the subgroups of UDCA and Fibrates strata.  Scatterplots of the percentage change from 
baseline in ALP at Week 12 against the baseline ALP will also be produced. 
Additional ALP endpoints investigated include: 
• 
Decrease in ALP ≥10% at 12 weeks 
• 
Decrease in ALP ≥15% at 12 weeks 
• 
Decrease in ALP ≥20% at 12 weeks 
• 
Decrease in ALP ≥40% at 12 weeks 
• 
ALP < ULN and Decrease in ALP ≥10% at 12 weeks 
• 
ALP < ULN and Decrease in ALP ≥20% at 12 weeks 
• 
ALP < ULN and Decrease in ALP ≥40% at 12 weeks 
• 
ALP < 1.67xULN and Decrease in ALP ≥10% at 12 weeks 
• 
ALP < 1.67xULN and Decrease in ALP ≥20% at 12 weeks 
• 
ALP < 1.67xULN and Decrease in ALP ≥40% at 12 weeks 
• 
ALP < 2xULN and Decrease in ALP ≥10% at 12 weeks 
• 
ALP < 2xULN and Decrease in ALP ≥20% at 12 weeks 
• 
ALP < 2xULN and Decrease in ALP ≥40% at 12 weeks 
• 
Proportion of subjects at Week 12 with ALP <ULN, ≥ ULN and <1.67xULN, ≥ to 1.67xULN and < 
2xULN and ≥2xULN 
ALP Shifts from baseline endpoints will also be evaluated as follows: 
• 
Baseline ALP category ([1.67xULN,2xULN), [2xULN,3xULN), [3xULN,4xULN), [4xULN,5xULN), 
and ≥5xULN) shifting to Normal, [1*ULN,1.67xULN), [1.67xULN,2xULN), and ≥2xULN (baseline 
categories are data dependent) 
 


 
 
 
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9.2 Secondary Efficacy Endpoints 
9.2.1 Change from Baseline and Percentage Change from Baseline in Liver-
Related Secondary Endpoints 
9.2.1.1 Bilirubin 
A descriptive summary will be provided for Total, Conjugated and Unconjugated 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 at Week 12 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 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. 
Additional endpoints for Bilirubin will include the following: 
• 
Proportion of subjects at Week 12 with Total Bilirubin <ULN, ≥ULN and <1.5xULN, ≥1.5xULN and 
<2xULN and ≥2xULN. 
• 
Shift in total bilirubin from baseline to Week 12 using the same categories as the endpoint in the 
previous bullet. 
A by-subject listing will be provided for observed and derived variables. 
Scatterplots of the change from baseline in total bilirubin versus the baseline total Bilirubin value will be 
produced. 
9.2.1.2 Alanine Aminotransferase 
A descriptive summary will be provided for ALT 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 at week 12 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 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.  
Mean ± SD and change from baseline for ALT values by visit and treatment group will be plotted. 
9.2.1.3 Aspartate Aminotransferase 
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 at week 12 will be analyzed using an 
ANCOVA model with treatment as fixed effect and the associated baseline value as covariate. Least 


 
 
 
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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. 
Mean ± SD and change from baseline for AST values by visit and treatment group will be plotted. 
9.2.1.4 Gamma-Glutamyl Transferase  
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 at week 12 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 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. 
Mean ± SD and change from baseline for GGT values by visit and treatment group will be plotted. 
9.2.2 Change from Baseline and percentage change from Baseline of 
noninvasive liver fibrosis markers (ELF panel) and PRO C3 at Week 12 
9.2.2.1 Enhanced Liver Fibrosis (ELF) Panel  
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.  
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 at week 12 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 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. 
9.2.2.2 PRO C3  
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 at week 12 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 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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9.2.3 Change from Baseline and Percentage Change from Baseline in Fibrosis at 
Week 12 
9.2.3.1 APRI  
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 
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 at week 12 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 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. 
9.2.3.2 FIB-4 
The FIB-4 score will be calculated using the following formula:  
[Age (years) × AST (IU/L)] / [Platelets (109/L) × (√ ALT (IU/L)))] 
Online calculator can be found at: 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 at week 12 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 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. 
9.2.4 Change from Baseline and percentage change from Baseline in Laboratory 
Fibrosis Parameter levels by Visit and at Week 12 
9.2.4.1 Fibrinogen 
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 by visit, with the week 12 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 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. 
9.2.4.2 CRP 
A descriptive summary will be provided for CRP levels, change from Baseline and percentage change from 
Baseline using 8-number summary by visit and treatment group. 


 
 
 
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Change from Baseline and percentage change from Baseline in at week 12 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 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. 
9.2.4.3 IL6 
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 at week 12 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 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. 
9.2.4.4 IL1β 
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 at week 12 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 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. 
9.2.4.5 TNF-α 
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 at week 12 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 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. 
9.2.4.6 TNF-β 
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 at week 12 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 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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9.2.4.7 Haptoglobin 
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 levels at week 12 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 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. 
9.2.4.8 Alpha2 Macroglobulin 
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 levels at week 12 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 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. 
9.2.5 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 LipoProfile 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. 
9.2.5.1 Triglycerides by Visit and Week 12 
Triglycerides are captured in the general lab biochemistry panel and also in the LipoProfile panel.  Both 
measurements of triglycerides will be summarized separately.  
A descriptive summary will be provided for Triglycerides 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 at each visit, with week 12 as the visit of 
primary 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 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. 
9.2.5.2 Total Cholesterol by Visit and Week 12 
Total cholesterol is captured in the general lab biochemistry panel and also in the LipoProfile 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 at each visit, with week 12 as 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-


 
 
 
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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. 
9.2.5.3 hs-CRP by Visit and Week 12 
A descriptive summary will be provided for hs-CRP 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 by visit, with the week 12 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 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. 
9.2.5.4 HDL by Visit and Week 12  
HDL is captured in the general lab biochemistry panel and also in the LipoProfile 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 at each visit, with the week 12 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 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. 
9.2.5.5 LDL by Visit and Week 12 
LDL is captured in the general lab biochemistry panel and also in the LipoProfile panel (as LDL-C).  Both 
measurements of triglycerides 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 at each visit, with the week 12 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 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. 
9.2.5.6 Total Cholesterol/HDL (CT Ratio) by Visit and 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. 
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 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 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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By-subject listing will be provided for observed and derived variables. 
9.2.6 Adiponectin 
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 by visit, with the week 12 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 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. 
9.2.7 ApoA-I 
A descriptive summary will be provided for ApoA-I 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 by visit, with the week 12 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 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. 
9.2.8 ApoB 
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 by visit, with the week 12 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 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. 
9.2.9 ApoC3 
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 by visit, with the week 12 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 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. 
9.2.10 ApoB/A Ratio 
A descriptive summary will be provided for ApoB/A 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 by visit, with the week 12 being the primary 
visit of interest, will be analyzed using an ANCOVA model with treatment as fixed effect and the associated 


 
 
 
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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. 
Correlation scatterplots for all combinations of Primary (ALP) and Secondary Efficacy variables (sections 
9.2.1 through 9.2.10) by visit for each treatment group will be presented. 
9.2.11 Pruritis 
9.2.11.1 
5D-Itch Scale 
The 5-D questionnaire (Elman 2010) is a specific tool used to quantify the magnitude of pruritus in PBC 
(and other diseases).  It consists of 5 domains:  duration, degree, direction, disability, distribution, as well 
as the total score.  Each of the domains and the total score will be summarized by visit and treatment, with 
the week 12 visit being considered as the primary visit of interest.   
The disability domain will be the highest score obtained from the daily activities of sleep, leisure/social 
activities, housework/errands, and work/school.  The disability domain will only be calculated if at least 3 
daily activities are documented. 
The distribution domain includes 16 locations of itch and is the categorized to a scale of 0 to 5, based on 
the sum of the number of affected locations: sum of 0 to 2 = score of 1, sum of 3 to 5 = score of 2, sum of 
6 to 10 = score of 3, sum of 11 to 13 = score of 4, sum of 14 to 16 = score of 5. 
The total 5D score is obtained by summing up the domain scores and ranges between 5 (no pruritus) and 
25 (most severe pruritus).  The total score will not be calculated if any of the domain scores is missing. 
For each of the domains and the total score, the value at each visit, the change from Baseline and 
percentage change from Baseline will be summarized for each of the domains.  Statistical inference will be 
tested 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.   
9.2.11.2 
Visual Analog Scale 
A descriptive summary will be provided for the VAS 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 by visit, with the week 12 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 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. 
Mean ± SD and change from baseline for 5D-Itch Scale Total Score and VAS values by visit and treatment 
group will be plotted. 
9.2.12 Quality of Life 
9.2.12.1 
PBC-40 
PBC-40 Quality of Life questionnaire for this study does not collect an overall score. The 40 questions from 
the PBC-40 questionnaire will be scored from 1-5, with 5 representing the highest impact and 1 the lowest 
impact of PBC on the quality of life.  The direction is reversed to reflect this impact.   There will be 6 domains 
computed from the 40 questions in the following manner: 


 
 
 
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1.) Symptoms:  Sum of questions 1-7.  Question 1 will be scored with ‘Never’=5 to ‘Always’=1.  The 
remaining questions will be scored with ‘Never’=1 to ‘Always’=5.  If 4 or more of the 7 questions 
are missing, then the domain will be left as missing.  If 4 or more questions are answered, any 
missing answered will be imputed using the median value of the non-missing questions used for 
this domain.  The range of possible scores for this domain are [7,35]. 
2.) Itch: Sum of questions 8-10.  All 3 questions will be scored with ‘Never’=1 to ‘Always’=5 and ‘Did 
not apply/no itch’=0.  If 2 or more of the questions are missing, then the domain will be left as 
missing, otherwise, all missing values will be imputed using the median of the other non-missing 
values used in this question.  The possible range of scores for this domain are [0,15]. 
3.) Fatigue: Sum of questions 11-21.  All questions will be scored as ‘Never’=1 to ‘Always’=5.  If 6 or 
more of the 11 questions are missing, then the domain will be left as missing.  If 6 or more questions 
are answered, any missing answered will be imputed using the median value of the non-missing 
questions used for this domain.  The range of possible scores for this domain are [11,55]. 
4.) Cognition: Sum of questions 22-27.  All questions will be scored as ‘Never’=1 to ‘Always’=5.  If 4 or 
more of the 6 questions are missing, then the domain will be left as missing.  If 4 or more questions 
are answered, any missing answered will be imputed using the median value of the non-missing 
questions used for this domain.  The range of possible scores for this domain are [6,30]. 
5.) Social: Sum of questions 29, 31, 32, 34, 35, 36, 37, 38, 39, and 40.  Questions 29, 31 and 32 will 
be scored from ‘Not at all’=1 to ‘Very Much’=5.  Questions 29 and 31 will also include ‘Does not 
apply’=0.  The remaining questions will be scored from ‘Strongly agree’=5 to ‘Strongly disagree=1’.  
If 6 or more of the 10 questions are missing, then the domain will be left as missing.  If 6 or more 
questions are answered, any missing answered will be imputed using the median value of the non-
missing questions used for this domain.  The range of possible scores for this domain are [8,50]. 
6.) Emotional: Sum of questions 28, 30, and 33.  Questions 28 and 30 will be scored from ‘Not at all’=1 
to ‘Very Much’=5 and ‘Does not apply’=0.  The remaining question will be scored from ‘Strongly 
agree’=5 to ‘Strongly disagree=1’.  If 2 or more of the 3 questions are missing, then the domain will 
be left as missing.  If 2 or more questions are answered, any missing answered will be imputed 
using the median value of the non-missing questions used for this domain.  The range of possible 
scores for this domain are [1, 15]. 
A descriptive summary will be provided for the domains, the change from Baseline and percentage change 
from Baseline for each domain, using 8-number summary by visit and treatment group. 
Change from Baseline and percentage change from Baseline by visit, with the week 12 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 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. 
9.3 PK/PD Analysis 
9.3.1 Pharmacokinetic (PK) Analysis 
 
For subjects who agree to participate in the PK/PD substudy, PK samples will be drawn at Day 1 and Day 
84 (Week 12) at predose, and 2, 6, and 8 hours postdose.   
For subjects who are not in the PK/PD substudy, on Day 1 and Day 84 (Week 12), PK samples will be 
drawn on predose, between 1 to 3 hours postdose and then the last sample at least 1 hour after the second 
collection, for a total of 3 samples 


 
 
 
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For all subjects (including those in the PK/PD substudy), at visits on Week 2, 4, and 8, PK sampling will be 
collected predose, between 1 to 3 hours postdose and then the last sample at least 1 hour after the second 
collection, for a total of 3 samples at each visit. 
9.3.1.1 PK/PD Substudy Analysis (Day 1 and Day 84) 
For subjects who agree to participate in the PK/PD substudy, concentration data will be summarized by 
active treatment arm, visit and hours since last dose for post-baseline visits for EDP-305 and each 
metabolite. Concentrations that are below the limit of quantitation (BLQ) will be treated as zero for the 
computation of descriptive statistics. The number of observations, mean, standard deviation, % coefficient 
of variation, geometric mean, % geometric coefficient of variation, median, minimum, maximum values will 
be displayed. Figures will be created to display mean (+/- SD) and individual subject EDP-305 concentration 
time curves in plasma on both a linear and semi-logarithmic scale (for semi-logarithmic plots, no SD will be 
presented).   
The PK parameters listed in Table 4 will be calculated as indicated for plasma EDP-305 and its metabolites, 
as applicable. PK parameters will be calculated by noncompartmental methods (AUC by linear up/log down 
method) (only on Day 1 and Day 84).  
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 (sample size, arithmetic means, geometric means, standard deviation (SD), % 
coefficient of variation (%CV), %GCV, minimum, median, and maximum) will be presented.  
Individual data will be presented in listing. 
 
Table 4: 
PK/PD Substudy Parameters 
PK Parameter 
Description 
AUClast 
The area under the plasma concentration-time curve from time zero to the time of the 
last quantifiable concentration. 
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. 
 
 
9.3.1.2 Population PK Analysis (Day 1 and Day 84) 
For subjects not in the PK/PD substudy, the concentration data will be summarized by active treatment 
arm, visit and hours since last dose for EDP-305 and each metabolite. Concentrations that are below the 
limit of quantitation (BLQ) will be treated as zero for the computation of descriptive statistics. The number 
of observations, mean, SD, % CV, geometric mean, % GCV, median, minimum and maximum values will 
be displayed. Figures will be created to display mean and individual subject EDP-305 concentration time 
curves in plasma on both a linear and semi-logarithmic scale (for semi-logarithmic plots, no SD will be 
presented).   
Individual data will be presented in listing. 


 
 
 
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9.3.1.3 PK Population Analysis  
For Week 2, 4, and 8: For all subjects in the PK population (PK/PD substudy subjects and population PK 
subjects), the concentration data will be summarized by active treatment arm, visit and hours since last 
dose for post-baseline visits for EDP-305 and each metabolite for visits at Week 2, 4, and 8. Concentrations 
that are below the limit of quantitation (BLQ) will be treated as zero for the computation of descriptive 
statistics.  The number of observations, mean, SD, % CV, geometric mean, % GCV, median, minimum, 
maximum values will be displayed.  Figures will be created to display mean and individual subject EDP 305 
concentration time curves in plasma on both a linear and semi-logarithmic scale (for semi-logarithmic plots, 
no SD will be presented).   
For all visits: A summary plot of the means and standard deviations of the pre-dose concentrations at each 
visit (Day 1, Week 2, 4, 8, and 12) will be provided by treatment on both a linear and semi-logarithmic scale 
(for semi-logarithmic plots, no SD will be presented).     
Individual data will be presented in listing. 
9.3.2 Pharmacodynamic (PD) Analysis 
The PD analysis will use the efficacy population and will include active treatment arms and placebo arms.  
For subjects who agree to participate in the PK/PD substudy, PD samples (FGF19, C4, bile acids (BA), and 
ALP) will be drawn at Day 1 and Day 84 (Week 12) at predose, 2, 6, and 8 hours postdose. At visits on 
Week 2, 4, and 8, PD sampling will be collected predose, between 1 to 3 hours postdose and then the last 
sample at least 1 hour after the second collection, for a total of 3 samples at each visit. 
 
For subjects who are not in the PK/PD substudy, PD samples (FGF19, C4, bile acids (BA)) will be drawn  
predose. 
 
9.3.2.1 PD Substudy Analysis (Day 1 and Day 84) 
9.3.2.1.1 FGF19  
A descriptive summary will be provided for the PD parameters such as AUC0-8 and AUC2-8 for FGF19 at 
Day 1 and Day 84 (Week 12), change from Baseline in the AUC values at Week 12 and percentage change 
from baseline in the AUC values at Week 12 using 8-number summary by visit and treatment group. 
Change from Baseline and the percentage change from baseline in the AUC0-8 and the AUC2-8 for FGF19 
at Week 12, 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 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 above analysis will be repeated for the actual FGF19 values (concentrations), the change from 
Baseline and the percentage change from Baseline values at time point and each visit for the PD substudy 
subjects.  
Individual Plasma Concentrations as well as Mean ± SD and change from baseline for FGF19 values by 
visit and treatment group will be plotted.  
A by-subject listing will be provided for observed and derived variables. 
9.3.2.1.2 C4 
A descriptive summary will be provided for the PD parameters such as AUC0-8 and AUC2-8 for C4 at Day 1 
and Day 84 (Week 12), change from Baseline in AUC at Week 12 and percentage change from baseline in 
the AUC at Week 12 values using 8-number summary by visit and treatment group. 


 
 
 
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Change from Baseline and the percentage change from baseline in the AUC0-8 and the AUC2-8 for C4 at 
Week 12, 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 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 above analysis will be repeated for the actual C4 values (concentrations), the change from Baseline 
and the percentage change from Baseline values at time point and each visit for the PD substudy subjects. 
Individual Plasma Concentrations as well as Mean ± SD and change from baseline for C4 values by visit 
and treatment group will be plotted. 
A by-subject listing will be provided for observed and derived variables. 
9.3.2.1.3 Bile Acid  
A descriptive summary will be provided for the bile acid concentrations, change from Baseline and the 
percentage change from baseline using 8-number summary by visit and treatment group. 
Change from Baseline and the percentage change from baseline in the bile acid for each time point by visit, 
with the Week 12 visit being considered 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 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. 
Individual Plasma Concentrations as well as Mean ± SD and change from baseline for Bile Acid values by 
visit and treatment group will be plotted. 
A by-subject listing will be provided for observed and derived variables. 
9.3.2.2 Population PD Analysis (Day 1 and Day 84) 
9.3.2.2.1 FGF19  
A descriptive summary will be provided for FGF19 concentrations, change from Baseline and the 
percentage change from baseline using 8-number summary by visit and treatment group. 
Change from Baseline and the percentage change from baseline in the FGF19 for each time point by visit, 
with the week 12 visit being considered 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 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. 
Mean ± SD and change from baseline for FGF19 values by visit and treatment group will be plotted. 
A by-subject listing will be provided for observed and derived variables. 
9.3.2.2.2 C4  
A descriptive summary will be provided for C4 concentrations, change from Baseline and the percentage 
change from baseline using 8-number summary by visit and treatment group. 
Change from Baseline and the percentage change from baseline in the C4 for each time point by visit, with 
the week 12 visit being considered 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 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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Mean ± SD and change from baseline for C4 values by visit and treatment group will be plotted. 
A by-subject listing will be provided for observed and derived variables. 
9.3.2.2.3 Bile Acid  
A descriptive summary will be provided for bile acid concentrations, change from Baseline and the 
percentage change from baseline using 8-number summary by visit and treatment group. 
Change from Baseline and the percentage change from baseline in the bile acid for each time point by visit, 
with the week 12 visit being considered 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 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. 
Mean ± SD and change from baseline for Bile Acid values by visit and treatment group will be plotted. 
A by-subject listing will be provided for observed and derived variables. 
9.3.2.3 PD Population Analysis (Weeks 2, 4, 8 and 12) 
9.3.2.3.1 FGF19  
A descriptive summary will be provided for FGF19 concentrations, change from Baseline and the 
percentage change from baseline using 8-number summary by visit and treatment group. 
Change from Baseline and the percentage change from baseline in the FGF19 for each time point by visit, 
with the week 12 visit being considered 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 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. 
Mean ± SD and change from baseline for FGF19 values by visit and treatment group will be plotted. 
A by-subject listing will be provided for observed and derived variables. 
9.3.2.3.2 C4  
A descriptive summary will be provided for C4 concentrations, change from Baseline and the percentage 
change from baseline using 8-number summary by visit and treatment group. 
Change from Baseline and the percentage change from baseline in the C4 for each time point by visit, with 
the week 12 visit being considered 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 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. 
Mean ± SD and change from baseline for C4 values by visit and treatment group will be plotted. 
A by-subject listing will be provided for observed and derived variables. 
9.3.2.3.3 Bile Acid  
A descriptive summary will be provided for bile acid concentrations, change from Baseline and the 
percentage change from baseline using 8-number summary by visit and treatment group. 
Change from Baseline and the percentage change from baseline in the bile acid for each time point by visit, 
with the week 12 visit being considered 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 


 
 
 
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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. 
Mean ± SD and change from baseline for Bile Acid values by visit and treatment group will be plotted. 
A by-subject listing will be provided for observed and derived variables. 
 
9.3.3 PK/PD Analysis at Week 12 (Correlations) 
Scatterplots (including correlations) will be generated comparing the PD parameters or concentration to the 
PK parameter or concentration data or relevant lab data by treatment group.   
9.3.3.1 PK/PD Subgroup Analysis 
This will be done for all subjects in the PK/PD substudy.  The following scatterplots with one regression line 
and additional plots will be generated: 
• 
AUC0-8 in FGF19 with PK parameter AUClast (Day 1 and Day 84) 
• 
AUC2-8 in FGF19 with PK parameter AUClast (Day 1 and Day 84) 
• 
AUC0-8 in C4 with PK parameter AUClast (Day 1 and Day 84) 
• 
AUC2-8 in C4 with PK parameter AUClast (Day 1 and Day 84) 
• 
Percentage change from Baseline in AUC0-8 FGF19 with PK parameter,  AUClast (Week 12) 
• 
Percentage change from Baseline in AUC2-8 FGF19 with PK parameter  AUClast (Week 12) 
• 
Percentage change from Baseline in AUC0-8 C4 with PK parameter  AUClast (Week 12) 
• 
Percentage change from Baseline in AUC2-8 C4 with PK parameter  AUClast (Week 12) 
• 
Percentage change from Baseline in Bile Acid (predose Week 12) with PK parameter 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 percentage change from 
Baseline in PK parameter AUClast (Week 12) 


 
 
 
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• 
Percentage change from Baseline in FGF19 (predose Week 12) with PK parameter Cmax (Week 
12) 
• 
Percentage change from Baseline in C4 (predose Week 12) with PK parameter Cmax (Week 12) 
• 
Percentage change from Baseline in Bile Acid (predose Week 12) with PK parameter Cmax (Week 
12) 
• 
Box Plot Comparison of EDP-305 AUClast and Cmax at Day 1 and Week 12 by Pruritus Status  
• 
Box Plot Comparison of Percent Change from Baseline in C4 AUC0-8 by Pruritus Status 
• 
Box Plot Comparison of Percent Change from Baseline in C4 AUC2-8 by Pruritus Status 
 
9.3.3.2 PK/PD Population Analysis 
This will be done for all subjects (PK/PD substudy and population PK/PD). The following 
scatterplots with one regression line will be generated: 
• 
Percentage change from Baseline in ALT (Predose Week 12) with the percentage change from 
Baseline in FGF19 (Predose Week 12) 
• 
Percentage change from Baseline in ALT (Predose Week 12) with the percentage change from 
Baseline in C4 (Predose Week 12) 
• 
Percentage change from Baseline in ALT (Predose Week 12) with the percentage change from 
Baseline in Bile Acid (Predose Week 12) 
• 
Percentage change from Baseline in ALT (Predose Week 12) with EDP-305 concentration value 
(predose at Week 12) 
• 
Percentage change from Baseline in AST (Predose Week 12) with the percentage change from 
Baseline in FGF19 (Predose Week 12) 
• 
Percentage change from Baseline in AST (Predose Week 12) with the percentage change from 
Baseline in C4 (Predose Week 12) 
• 
Percentage change from Baseline in AST (Predose Week 12) with the percentage change from 
Baseline in Bile Acid (Predose Week 12) 
• 
Percentage change from Baseline in AST (Predose Week 12) with the EDP-305 concentration 
value (Predose Week 12) 
• 
Percentage change from Baseline in GGT (Predose Week 12) with the percentage change from 
Baseline in FGF19 (Predose Week 12) 
• 
Percentage change from Baseline in GGT (Predose Week 12) with the percentage change from 
Baseline in C4 (Predose Week 12) 


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


 
 
 
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• 
Percentage change from Baseline in Cholesterol (Predose Week 12) with EDP-305 concentration 
value (Predose Week 12) 
• 
Percentage change from Baseline in HDL (Predose Week 12) with EDP-305 concentration value 
(Predose Week 12) 
• 
Percentage change from Baseline in LDL (Predose Week 12) with EDP-305 concentration value 
(Predose Week 12) 
• 
Percentage change from Baseline in triglycerides (Predose Week 12) with EDP-305 
concentration value (Predose Week 12) 
• 
Correlation between Week 12 Predose EDP-305 concentrations and Adverse events occurring in 
at least 5% of the combined active subjects. 
 
• 
Summary of Week 12 Predose  EDP-305 concentrations for subjects with Grade 3 of Higher 
Adverse Events or Serious Adverse Events 
 
• 
Summary of Week 12 Predose (or last predose) EDP-305 concentrations for subjects with week 
12 completion by pruritus status 
• 
Summary of Week 12 Predose (or last predose) EP-022679 concentrations subjects with week 12 
completion by pruritus status 
• 
Summary of Week 12 Predose (or last predose) EDP-305 concentrations for all subjects by pruritus 
status 
• 
 Summary of Week 12 Predose (or last predose) EP-022679 concentrations for all subjects by 
pruritus status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 Safety Analyses   
All safety analyses will be performed using all subjects in the safety population. 


 
 
 
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10.1 Treatment Emergent Adverse Events 
Adverse events will be coded using MedDRA 20.1 (September 01, 2017) and graded by CTCAE version 
5 (November 27, 2017).  All safety analyses and listings will be reported using the safety population. An 
AE will be considered a Treatment-emergent AE (TEAE)  if it first occurs or begins previous to and 
worsens on or after the first dose date and before the last dose date + 30 days.  All TEAEs will be 
classified as being during the on-treatment period or during the follow-up period as follows: 
• 
Events that occurred between first dose and 7 days after last dose are classified as on-treatment; 
• 
Events occurring between 8-30 days after last dose are classified as follow-up. 
Adverse Events will be summarized for the safety population by both on-treatment period and follow-up 
period separately by dose group. 
The following events will not be identified as AEs in this study: 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, etc.).  The condition (the 
“triggering event”) that leads to the procedure are adverse events and will be reported as such. 
• 
Pre-existing conditions present or detected prior to the first dose of study drug that do not worsen 
during the study. 
Summaries of Adverse Events will include the following: 
• 
AEs that occur during the screening period will be listed in the Medical History for each subject. 
• 
An overall summary of all TEAEs. The number of events and the number and percentage of subjects 
reporting at least one TEAE will be reported 
• 
The number and percentage of subjects reporting each TEAE, categorized by MedDRA system organ 
class and preferred term. Note that frequencies will be by subject not event.  
• 
The number and percentage of subjects reporting each TEAE, categorized by MedDRA system organ 
class, preferred term and maximum CTCAE grade 
• 
TEAEs experienced by ≥ 5% of Subjects will be summarized by preferred term   
• 
TEAE experienced by ≥ 5% of Subjects categorized by MedDRA system organ class, preferred term 
and maximum CTCAE grade 
• 
Treatment Related Adverse Events categorized by MedDRA system organ class and preferred term 
• 
The number and percentage of TEAEs with outcome of death 
• 
Serious TEAEs categorized by MedDRA system organ class and preferred term 
• 
Serious TEAEs categorized by relationship to study drug, subjects with multiple events within each 
SOC or preferred term will be counted under the category of their most drug-related event within that 
SOC or preferred term 
• 
TEAEs leading to study drug discontinuation categorized by MedDRA system organ class and 
preferred term 


 
 
 
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• 
Treatment Related TEAEs leading to study drug discontinuation categorized by MedDRA system 
organ class and preferred term 
• 
Treatment Related TEAEs experienced by ≥ 5% of Subjects will be summarized by preferred term   
• 
Treatment Related TEAE experienced by ≥ 5% of Subjects categorized by MedDRA system organ 
class, preferred term and maximum CTCAE grade 
All adverse events (including non-treatment-emergent events) recorded on the eCRF will be listed for the 
Safety population 
A summary of the number of subject deaths will be presented by treatment group. All death data will be 
listed. 
10.2 Laboratory Data 
Laboratory test results for Baseline, Week 12 visits, change from Baseline at Week 12 and change to 
abnormal status of either below LLN (“Low”) or above ULN (“High”) from Baseline at Week 12 for all Safety 
Lab tests (Appendix 6) will be summarized by treatment groups. Shift tables will be used to present change 
in status (normal to abnormal or abnormal to normal) from Baseline at Week 12. All lab values will be listed 
and all test values outside the normal range will be flagged. Urinalysis results will be summarized separately 
for continuous and categorical variables. Pregnancy test results will be listed only. 
The pre-dose laboratory test results only within the time window will be considered for analyses safety 
laboratory data summaries. 
For average baseline, it is considered the average of the latest (closest to the target day Day -1) laboratory 
test result in the screening window (from Day -28 to Day -1) and the pre-dose Day 1 laboratory test result. 
For Day 1 value or the latest value prior to the first dose of study drug as baseline, it is considered the 
laboratory test result in the screening window (from Day -28 to Day -1) not beyond Day -28 laboratory test 
result. 
For screening visit as baseline, it is considered the laboratory test result in the screening window (from Day 
-28 to Day -1) and the latest laboratory test result. 
If the recorded the laboratory test result (<XX.xx) is below the lower limit, then the value 0.0 is considered 
for the laboratory test result. 
If the recorded laboratory test result (>XX.xx) is above the upper limit, then the value of the (XX.xx) is 
considered for the laboratory test result. 
For the purposes of summarization in both the tables and listings, all laboratory values will be converted 
to standardized units. Reference Covance Lab Manual for schedule of testing. 
10.2.1 Subject Safety Monitoring 
Subjects will be monitored throughout the study for the following: 
• 
 ALT or AST increase to >5 x Baseline 
•        ALT or AST increase >2 × Baseline AND the increase is accompanied by a concomitant Total 
Bilirubin increase to >2 × Baseline OR the INR (prothrombin time / partial thromboplastin time) 
concomitantly increases from Baseline by >0.2 
•          Elevated Baseline liver chemistry (AST or ALT elevations 2 × Baseline) will require subjects to be 
reassessed promptly (within 48–72 hours) with full liver biochemistry and physical exam 


 
 
 
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•          Elevations of ALT/AST accompanied by preferred terms indicating: signs or symptoms of right 
upper quadrant abdominal pain, anorexia, nausea, vomiting fever, eosinophilia, and/or rash 
Incidence of these safety categories will be summarized by treatment group and identified on the listings 
with laboratory data parameters 
10.3 Vital Signs 
Vital signs will include heart rate (HR), respiratory rate (RR), blood pressure (BP) and oral temperature. 
Vital signs results will be summarized by timepoint where it shows change from Baseline, and significant 
changes in vital signs by treatment. Significant vital signs to be included are: 
 
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 
 
All vital sign results will be listed. 
Weight may be collected in kilograms (kg) or pounds (lb) and height may be collected in centimeters (cm) 
or inches (in).  BMI will be reported in kg/m2. 
For metric measurements kg and cm: 
BMI = Weight/[(Height*100)2]. 
For English measurements lb and in: 
BMI = [Weight/(Height)2] x 703. 
10.4 Physical Exam Data 
All physical exam results will be listed along with descriptions of any abnormality. 
 
 


 
 
 
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10.5 ECG Results 
ECG results including PR, QRS, QT, RR, and QTc (QTcF) intervals will be summarized by timepoint 
where it shows change from Baseline with a summary for defined thresholds: 
 
QTcF Maximum value  
   450 msec 
  > 450 to  480 
  > 480 to  500 msec 
  > 500 msec 
 
QTcF Maximum change from Baseline 
   30 msec 
  > 30 to  60 msec 
  > 60 msec 
 
Females with Screening or Baseline < 470 msec 
Males with Screening or Baseline < 450 msec 
 
ECG results will be listed for all timepoints and clinically significantly results will be flagged. The ECG 
parameter, QT interval (msec) will be adjusted for the length of the RR interval (msec) using the Fridericia 
correction (QT interval length divided by cube root of the interval from the onset of one QRS complex to the 
next) as follows: 
QTcF= QT / cube root(RR). 
RR will be converted to seconds for the calculation.  
11 Interim Analyses 
An administrative interim analysis may be conducted after approximately 25% of the planned total number 
of subjects (~30 subjects) have been enrolled and completed 12 weeks of treatment.  
No study stopping rules have been established and no inferential testing will be performed.  
Reporting for interim analysis will include the subject disposition, demographics, the primary endpoint, and 
secondary efficacy variables. See Appendix 4 for the list of outputs. 
Results of the interim analysis will remain blinded to all blinded team members at Enanta and PRA. PRA 
will create the reporting with blinded treatment codes, and an unblinded PRA team will merge the data with 
the actual treatment codes for delivery of the unblinded interim analysis to the appropriate members of the 
Enanta management. 
12 Data Safety Monitoring Board 
The DSMB will meet on a periodic basis to review safety data. Refer to the DSMB charter for this study for 
information on the content and conduct for these meetings. Data review meetings will occur after groups of 
20 subjects have completed 4 weeks of study drug treatment. The DSMB will receive fully unblinded results.  
The same team described in the above section will be responsible for providing unblinded outputs to the 
DSMB independent, unblinded statistician who will distribute the results to the DSMB members. 
See Appendix 4 for the list of outputs. 


 
 
 
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13 References 
1. ICH Harmonized Tripartite Guideline. Statistical Principles for Clinical Studys E9. International 
conference on harmonisation of technical requirements for registration of pharmaceuticals for 
human use. 05 February 1998. 
http://www.ich.org/fileadmin/Public Web Site/ICH Products/Guidelines/Efficacy/E9/Step4/E9 Gu
ideline.pdf 
2. ICH Harmonized Tripartite Guideline. Structure and Content of Clinical Study Reports E3. 
International conference on harmonisation of technical requirements for registration of 
pharmaceuticals for human use. 30 November 1995. 
http://www.ich.org/fileadmin/Public Web Site/ICH Products/Guidelines/Efficacy/E3/E3 Guideline
.pdf 
 
 




 
 
 
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PBO 
Placebo 
P-gp 
p-glycoprotein 
PK 
Pharmacokinetics 
PP 
Per Protocol 
QoL 
Quality of Life 
QTcF 
QT interval, Fridericia correction 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
TFL 
Table, Figure and Listing 
Tmax 
time to maximum concentration 
UDCA 
Ursodeoxycholic Acid 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Score 
WHODRUG 
World Health Organization Drug Dictionary 
 
 
 


 
 
 
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Appendix 2 Adverse Event Start/Stop Date Imputation 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for 
AEs 
D 
M and Y same as M and Y of first dose 
of study drug 
Date of first dose of study drug 
M and/or Y not same as date of first 
dose of study drug 
First day of month 
D and M 
Y same as Y of first dose of study 
drug 
Date of first dose of study drug 
Y prior to Y of first dose of study drug 
but same as Y of screening date 
Date of screening date 
D, M, Y 
None - date completely missing 
Date of first dose of study drug 
Stop date for 
AEs 
D 
M and Y same as M and Y of last dose 
of study drug 
Date of last dose of study drug 
M and/or Y not same as date of last 
dose of study drug 
Use last day of month 
D and M 
Y same as Y of last dose of study drug 
Date of last dose of study drug 
Y not same as Y of last dose of study 
drug 
Use Dec 31 
D, M, Y 
None - date completely missing 
No imputation, but assume 
ongoing 
Note:  In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date 
month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day 
month. 
 


 
 
 
Sponsor: Enanta Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol no: EDP 305-201 
Version Date: 09-MAR-2020 
PRS 005 T 17 F 
Page 39 of 57 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Appendix 3 Prior and Concomitant Medication Start/Stop Date 
Imputation 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for 
con meds  
D only 
M and Y same as M and Y of first dose 
of study drug 
Date of first dose of study 
drug 
M and/or Y not same as date of first 
dose of study drug 
First day of month 
M and D 
Y same as Y of first dose of study 
drug 
Date of first dose of study 
drug 
Y not same as Y of first dose of study 
drug 
Use Jan 01 of Y 
M, D, and Y 
None - date completely missing 
Day prior to date of first dose 
of study drug 
Stop date for 
con meds  
D only 
M and Y same as M and Y of last dose 
of study drug 
Date of last dose of study 
drug 
M and/or Y not same as date of last 
dose of study drug 
Last day of month 
M and D 
Y same as Y of last dose of study drug 
Date of last dose of study 
drug 
Y not same as Y of last dose of study 
drug 
Use Dec 31 of Y 
M, D, and Y 
None - date completely missing and 
NOT ongoing 
Date of last dose of study 
drug 
Note:  In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date 
month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day 
month. 
 
































 
 
 
Sponsor: Enanta Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol no: EDP 305-201 
Version Date: 09-MAR-2020 
PRS 005 T 17 F 
Page 55 of 57 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
14 Biomarkers include fasting plasma FGF19, fasting serum bile acids, fasting C4 (7α-OH-4-cholesten-3-one). Samples should be collected after a 
minimum 8 hr fast and before the subject takes the daily dose of study drug 
15 Lipids and CV risk markers to be collected are detailed in Section 12.6.3.2 
16 Markers of inflammation include fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β, alpha2 macroglobulin and haptoglobin see Section 12.6.3.2 
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; the first sample collected 1 to 3 hours 
postdose and the second sample at least 1 hour later. 
18 PK predose samples should be collected after a minimum 8 hr 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. 
19 Study drug given in the clinic on days where subject is seen in the clinic 
20 Additional samples may be collected to further assess safety events e.g. pruritus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Sponsor: Enanta Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol no: EDP 305-201 
Version Date: 09-MAR-2020 
PRS 005 T 17 F 
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Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Appendix 6 Laboratory Evaluations 
Chemistry Panel 
Hematology 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 
• 
BUN 
• 
BUN/Creatinine Ratio (calculation) 
• 
Calcium, (Serum) 
• 
Creatine Kinase 
• 
Creatinine, Serum (creatinine clearance) 
• 
Uric Acid 
• 
Electrolyte Panel (Na+, K+, Cl-, Bicarb.) 
• 
Phosphorus 
• 
Gamma Glutamyl Transferase (GGT) 
• 
Globulin, Total 
• 
Glucose, Serum 
• 
Cholesterol, serum 
• 
Lactate Dehydrogenase (LDH) 
• 
Lipase 
• 
Protein, Total, Serum 
• 
TG (triglycerides) 
• 
HDL Cholesterol 1 
• 
LDL Cholesterol 1 
• 
Apolipoprotein E (ApoE) 
 
 
 
 
 
• 
Hemoglobin 
• 
Hematocrit 
• 
Differential WBC Count (percentage and absolute): 
     Basophils, Eosinophils, Lymphocytes,  
     Monocytes, Neutrophils 
• 
MCH 
• 
MCHC 
• 
MCV 
• 
Platelets 
• 
Red Blood Count 
• 
RBC Morphology 
• 
White Blood Count 
• 
Absolute Neutrophil count) 
Urinalysis Panel 
• 
Color and appearance 
• 
PH 
• 
SG 
• 
 Bilirubin 
• 
 Glucose  
• 
Ketones  
• 
Leukocytes  
• 
Nitrite  
• 
Occult blood  
• 
Protein  
• 
Urobilinogen 
• 
Microscopic (including RBCs and WBCs) 
• 
Bacteria 
• 
Leukocyte  Esterase 
Coagulation 
Safety Monitoring 
• 
INR 
• 
PT 
• 
PTT 
• 
Liver Enzymes 
o 
Total Bilirubin, Direct Bilirubin, Alkaline 
Phosphatase, ALT(SGPT), AST(SGOT), GGT 
• 
Liver Hematology 
o 
RBC, Neutrophils(abs, %), Lymphocytes(abs, %), 
Monocytes(abs, %), Eosinophils(abs,%), 
Basophils(abs,%), Platelets 
• 
Elevated Liver Coagulation 
o 
INR, PT 
• 
Albumin 
 


 
 
 
Sponsor: Enanta Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Protocol no: EDP 305-201 
Version Date: 09-MAR-2020 
PRS 005 T 17 F 
Page 57 of 57 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Appendix 7 Markers of CV Risks and Lipids and Markers of Fibrosis and 
Inflammation 
Markers of CV Risks and Lipids 
Markers of Fibrosis and Inflammation 
• 
hs-CRP 
• 
HDL-P 
• 
LDL-P 
• 
apoA-I  
• 
apoB  
• 
apoB/A Ratio  
• 
apoC3  
• 
apoE isoforms (E2, E3, E4)  
• 
Total Cholesterol (TC) 
• 
High Density Lipoprotein – Cholesterol 
(HDL-C)  
• 
Low-Density-Lipoprotein 
– 
Cholesterol 
(LDL-C)  
• 
TG (triglycerides) 
• 
Total /HDL Cholesterol (CT) Ratio 
• 
Adiponectin 
 
 
• 
Enhanced Liver Fibrosis (ELF) Panel 
o 
Hyaluronic acid (HA), 
o 
Procollagen III amino terminal peptide 
(PIIINP) 
o 
Tissue inhibitor of metalloproteinase 1 
(TIMP-1) 
• 
PRO-C3 
• 
Fibrinogen 
• 
CRP 
• 
alpha2 macroglobulin 
• 
haptoglobin 
• 
TNF-α 
• 
TNF-β 
• 
IL-6 
• 
IL1β 
• 
AST to Platelet Ratio Index (APRI) 
• 
Fibrosis 4 (FIB-4) Index