A Proof-of-Concept and Dose-Ranging Study Investigating the Efficacy and Safety of HTD1801 in Adults With NASH and T2DM
Phase: PHASE2
Conditions: Fatty Liver, Nonalcoholic, NAFLD, Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, Digestive System Diseases, Type 2 Diabetes Mellitus (T2DM)
Sponsor: HighTide Biopharma Pty Ltd

CONFIDENTIAL 
 
HighTide Biopharma Pty. Ltd. 
 
HTD1801 
Clinical Protocol 
IND 139502 
 
 
 
 
 
 
CONFIDENTIAL 
 
 
CLINICAL PROTOCOL 
 
 
 
 
 
TITLE OF STUDY: 
 
A Proof-of-Concept and Dose-Ranging Study Investigating the Efficacy and Safety of 
HTD1801 in Adults with Nonalcoholic Steatohepatitis (NASH) and Type 2 Diabetes Mellitus 
(T2DM) 
 
 
 
 
Protocol HTD1801.PCT012 
 
Trial Registration: NCT03656744 
 
 
 
 
 
 
 
 
 
 
 
Date of issue: 27 Mar 2019 
Version number: 3.0 
 
 
 
Sponsor: 
HighTide Biopharma Pty. Ltd. 
 
1 Melissa Street 
Mount Waverley, Vic 3149 
Australia 
 
 

CONFIDENTIAL 
 
HighTide Biopharma Pty. Ltd.
 
HTD1801
Clinical Protocol
IND 139502
 
 
 
Page 2 
Signatures of Approval of Protocol (Version 3.0) 
 
This protocol was subject to critical review and has been approved by the following persons:
 
Affiliation 
Name 
Signature 
Sponsor: 
Matthew R. Dauphin, MS 
 
Statistician: 
Eugene R. Heyman, PhD 
 
Medical Monitor: 
Jackson Snyder, MD, PhD, JD 
 
 
Sponsor: 
HighTide Biopharma Pty. Ltd.  
1 Melissa Street 
Mount Waverley, Vic 3149 
Australia 
 
 
Sponsor Contact: 
Matthew R. Dauphin, MS 
HighTide Biopharma Pty. Ltd. 
E-mail: mdauphin@hightidetx.com 
 
 
Medical Monitor: 
Jackson Snyder, MD, PhD, JD 
Clinical Research Physician 
Cato Research 
9605 Medical Center Drive 
Suite 350 
Rockville, MD 20850 USA 
Phone: 301-309-1260 
Fax: 919-361-2290 
E-mail: jsnyder@cato.com 
 
 

CONFIDENTIAL 
 
HighTide Biopharma Pty. Ltd. 
 
HTD1801 
Clinical Protocol 
IND 139502 
 
 
 
Page 3 
STUDY SYNOPSIS 
Name of sponsor company: HighTide BioPharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate (HTD1801) 
Title of study: A Proof-of-Concept and Dose-Ranging Study Investigating the Efficacy and Safety of 
HTD1801 in Adults with Nonalcoholic Steatohepatitis (NASH) and Type 2 Diabetes Mellitus (T2DM) 
Investigator(s): Multicenter 
Number of sites: Approximately 15 
Study periods: 
Screening: 28 days 
Double-blind Treatment: 18 weeks 
Follow-up: 30 days (after last dose of study drug) 
Phase of development: 2 
Study Design: This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
comparing multiple doses of investigational product (HTD1801) to placebo. Upon confirmation of 
eligibility, subjects will be randomized in a 1:1:1 ratio to HTD1801 500 mg twice daily (BID), HTD1801 
1,000 mg BID, or placebo BID for 18 weeks. 
Objectives: 
The primary objective of this study is to evaluate the effects of HTD1801 on liver fat content (LFC) in 
adults with NASH and T2DM. 
The secondary objectives of this study are to evaluate: 
1. The effects of HTD1801 on hemoglobin A1c (HbA1c) and glucose metabolism; 
2. The effects of HTD1801 on lipid profile; 
3. The effects of HTD1801 on liver associated enzymes; 
4. The effects of HTD1801 on biomarkers of liver inflammation and fibrosis; 
5. The effects of HTD1801 on bile acid homeostasis; 
6. The safety and tolerability of HTD1801. 
Methodology: This is an 18-week randomized, double-blind, parallel-group, proof-of-concept, and 
dose-ranging study comparing multiple doses of HTD1801 to placebo. Clinic visits for efficacy 
assessments and safety monitoring will occur at Week 2, then every 4 weeks throughout the 
Double-Blind Treatment Period. A follow-up safety telephone contact will take place at least 30 days 
after the last dose of study drug. An interim analysis will be conducted once a minimum of 51 subjects 
complete the assessment of the primary efficacy endpoint. An independent Data and Safety Monitoring 
Board will provide additional safety oversight. 
Number of subjects (planned): Approximately 117 
Inclusion criteria: 
1. Male or female between 18 and 75 years of age. 
2. Clinical diagnosis of NASH with at least stage F1 fibrosis as evident by: 

CONFIDENTIAL 
 
HighTide Biopharma Pty. Ltd. 
 
HTD1801 
Clinical Protocol 
IND 139502 
 
STUDY SYNOPSIS (continued) 
 
 
Page 4 
Name of sponsor company: HighTide BioPharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate (HTD1801) 
• 
Liver fat content ≥10% as assessed by magnetic resonance imaging-estimated proton density fat 
fraction (MRI-PDFF) and a corrected T1 (cT1) of ≥830 msec as assessed by multiparametric 
MRI. 
3. Aspartate aminotransferase (AST) ≥20 U/L. 
4. Clinically documented diagnosis of T2DM ≥6 months prior to randomization. 
5. If on a T2DM medication regimen, specifically thiazolidinediones, glucagon-like peptide-1 (GLP-1) 
agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sodium-glucose cotransporter-2 (SGLT-2) 
inhibitors, must be maintained on a stable dose regimen for ≥90 days prior to randomization. 
6. If on vitamin E, must be maintained on a stable dose of ≤400 IU for ≥90 days prior to randomization 
with no anticipated dose increases during the study. 
7. Regimens for other permitted concomitant medications, as described in Section 4.5 of the protocol, 
must be stable for ≥28 days prior to randomization. 
8. Body mass index (BMI) >25 kg/m2. 
9. Females of child-bearing potential (FOCP) and males participating in the study must either agree to 
use at least 2 approved barrier methods of contraception or be completely abstinent from sexual 
intercourse, if this is their usual and preferred lifestyle, throughout the duration of the study and for 
at least 90 days after the last dose of study drug. Females who are postmenopausal must have 
appropriate supporting documentation with a corresponding follicle-stimulating hormone (FSH) test 
result to support status. 
10. Ability to understand and sign a written informed consent form (ICF). 
Exclusion criteria: 
1. Clinically significant acute or chronic liver disease unrelated to NASH, including but not limited to 
primary sclerosing cholangitis (PSC), Wilson’s disease, alpha-1 antitrypsin (AAT) deficiency (MZ 
or ZZ phenotype), hepatitis B or C, hereditary hemochromatosis, alcoholic liver disease, and 
drug-induced liver disease. 
2. Clinically or histologically documented cirrhosis. 
3. Poorly controlled T2DM (HbA1c ≥9.5%) or Type 1 Diabetes Mellitus. 
4. Hepatitis B surface antigen positive. 
5. Hepatitis C antibody positive with active infection. 
6. Human immunodeficiency virus (HIV)-1 or HIV-2 infection. 
7. Glucose-6-phosphate dehydrogenase (G6PD) deficiency. 
8. Any prior history of hepatic decompensation (encephalopathy, ascites, gastroesophageal varices, 
hepatorenal syndrome), platelet count <150,000/mm3, international normalized ratio (INR) ≥1.3 
despite vitamin K supplementation, serum albumin <3.2 g/dL, or a prior or planned liver 
transplantation. 
9. History of alcohol or substance abuse or dependence. 
10. Hepatic steatosis that, in the opinion of the Investigator, is primarily related to alcohol consumption. 
11. Inability to undergo MRI for any reason. 

CONFIDENTIAL 
 
HighTide Biopharma Pty. Ltd. 
 
HTD1801 
Clinical Protocol 
IND 139502 
 
STUDY SYNOPSIS (continued) 
 
 
Page 5 
Name of sponsor company: HighTide BioPharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate (HTD1801) 
Note: Mild sedative use (if not prohibited as described in Section 4.6 of the protocol) for MRI 
procedures is permitted. 
12. Laboratory parameters within any of the following ranges: 
• 
AST >5 × ULN. 
• 
Alanine aminotransferase (ALT) ≥5 × ULN. 
• 
Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. 
• 
Hemoglobin <11 g/dL for males or females. 
• 
Direct bilirubin <LLN or >ULN. 
• 
Total bilirubin <LLN or >ULN. 
Note: Total bilirubin >ULN due to Gilbert’s syndrome is acceptable provided that direct 
bilirubin, reticulocyte count, and hemoglobin are within the laboratory defined normal ranges. 
• 
Thyroid-stimulating hormone (TSH) <LLN or >1.5 × ULN. 
Note: Subjects on a medication for a thyroid abnormality may enroll provided that they have 
been maintained on a stable dose for ≥90 days prior to randomization. 
13. Current use of oral prednisone/prednisolone (or prednisone/prednisolone equivalent) >10 mg/day. 
14. History of myocardial infarction, congestive heart failure, uncontrolled cardiac arrhythmia, unstable 
angina, coronary bypass surgery, or percutaneous coronary intervention ≤12 months prior to 
Screening. 
15. History of malignancy ≤2 years prior to Screening or ongoing malignancy other than basal cell 
carcinoma, or resected noninvasive cutaneous squamous cell carcinoma. 
16. Active, serious infections that require parenteral antibiotic or antifungal therapy ≤30 days prior to 
Screening. 
17. Major surgical procedure ≤30 days prior to Screening or prior organ transplantation. 
18. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents, and 
immune-modulating agents. 
19. Current use of prohibited medications as described in Section 4.6 of the protocol. 
20. Females who are pregnant or breastfeeding. 
21. Allergy to the study drug or its components. 
22. Use of any unapproved treatment for NASH, including but not limited to ursodeoxycholic acid 
(UDCA) and berberine containing agents, ≤30 days prior to Screening. 
23. Participation in other clinical trials of investigational drugs for NASH ≤6 months prior to Screening. 
24. Received any investigational drugs for any other condition ≤30 days or 5 half-lives (whichever is 
longer) prior to Screening. 
25. Any other clinically significant laboratory parameters, disorders, or prior or current therapy that, in 
the opinion of the Investigator, would make the subject unsuitable for the study, unable to comply 
with the dosing and protocol requirements, or could confound the study outcomes. 

CONFIDENTIAL 
 
HighTide Biopharma Pty. Ltd. 
 
HTD1801 
Clinical Protocol 
IND 139502 
 
STUDY SYNOPSIS (continued) 
 
 
Page 6 
Name of sponsor company: HighTide BioPharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate (HTD1801) 
Test product, dose, and mode of administration:  
• 
HTD1801: 250 mg tablets administered as 500 mg BID or 1,000 mg BID with food. 
• 
Placebo: HTD1801-matching tablets administered BID with food. 
Reference therapy, dose and mode of administration: 
Not applicable. 
Duration of treatment: 18 weeks 
Criteria for Evaluation: 
Efficacy Evaluation 
Primary Efficacy Endpoint: 
The primary endpoint for this study is the absolute change in LFC as measured by MRI-PDFF from 
Baseline to Week 18. 
Secondary Efficacy Endpoints: 
1. Changes in fasting glucose and HbA1c from Baseline to Week 18. 
2. Proportion of subjects who achieve ≥30% relative reduction in LFC as measured by MRI-PDFF 
from Baseline to Week 18. 
3. Relative change in LFC as measured by MRI-PDFF from Baseline to Week 18. 
4. Proportion of subjects who normalize LFC to <5% as measured by MRI-PDFF at Week 18. 
5. Proportion of subjects who achieve ≥5% absolute reduction in LFC as measured by MRI-PDFF from 
Baseline to Week 18. 
6. Change in homeostasis model assessment-estimated insulin resistance (HOMA-IR) from Baseline 
to Week 18. 
7. Change in low-density lipoprotein cholesterol (LDL-c) from Baseline to Week 18. 
8. Change in serum triglycerides from Baseline to Week 18. 
9. Change in high-density lipoprotein cholesterol (HDL-c) from Baseline to Week 18. 
10. Changes in AST and ALT from Baseline to Week 18. 
11. Proportion of subjects with elevated ALT at Baseline who normalize ALT at Week 18. 
12. Change in Pro-C3 from Baseline to Week 18 for subjects with elevated Pro-C3 at Baseline. 
13. Change in the enhanced liver fibrosis (ELF) score and each component of ELF (tissue inhibitor of 
metalloproteinases 1 [TIMP-1], N-terminal pro-peptide of type III collagen [PIIINP], and hyaluronic 
acid [HA]) from Baseline to Week 18. 
14. Changes in total bile acids, 7-hydroxy-4-cholesten-3-one (C4), and fibroblast growth factor 19 
(FGF19) from Baseline to Week 18. 

CONFIDENTIAL 
 
HighTide Biopharma Pty. Ltd. 
 
HTD1801 
Clinical Protocol 
IND 139502 
 
STUDY SYNOPSIS (continued) 
 
 
Page 7 
Name of sponsor company: HighTide BioPharma Pty. Ltd. 
Name of finished product: HTD1801 Tablets 
Name(s) of active ingredient(s): Berberine Ursodeoxycholate (HTD1801) 
Analysis of Primary Endpoint: 
The primary endpoint is absolute change from Baseline to Week 18 in LFC, or absolute change from 
Baseline to the Early Termination (ET) visit for subjects who terminate the study prematurely. Absolute 
change from Baseline in LFC will be assessed by analysis of covariance that includes the effects of 
treatment group, Baseline LFC, and Baseline ALT. Comparison of each active treatment group to 
placebo will be tested at the 5% level of significance without adjustment for multiple tests.  Secondarily, 
comparison of the 2 active treatment groups with each other will be tested at the 5% level. 
Analysis of Secondary Endpoints: 
Relative (percent) change from Baseline in LFC will be analyzed by the same model described for the 
primary endpoint.  Normalization of LFC will be analyzed by logistic regression that includes the effects 
of treatment group, Baseline LFC, and Baseline ALT. 
All additional secondary endpoints are continuous and each will be assessed by analysis of covariance 
that includes treatment group and the Baseline value of the analysis variable.  All secondary analyses 
(except LFC) will have missing Week 18 values imputed using a multiple imputation procedure for all 
subjects with an available measurement prior to Week 18. 
Safety Evaluation 
Safety Endpoints: 
Adverse events and changes in physical examination, vital signs, electrocardiogram (ECG), and clinical 
laboratory values will be used to evaluate safety and tolerability. Adverse event incidence will be 
assessed during the Double-Blind Treatment Period. Adverse event type, relationship, severity, onset, 
and duration will be presented by treatment group within the Double-Blind Treatment Period. 
Safety Analysis: 
Changes in physical examination, vital signs, ECG, and clinical laboratory values will be presented using 
summary statistics. Numbers and percentages of the first occurrence for each adverse event will be 
presented. 
Sample Size: 
An absolute change in LFC of 5% as measured by MRI-PDFF has been reported to be the minimal 
clinically relevant difference between active treatment and placebo that correlates with histological 
improvement in NASH (Loomba et al., 2015, Patel et al., 2015). Furthermore, Harrison and colleagues 
reported a pooled standard deviation of 6.3% for changes from Baseline in LFC (Harrison et al., 2018). 
Based on this standard deviation, 35 subjects in each treatment group will provide 90% power to show 
a difference of 5 percentage points between any 2 treatment groups at the 5% level of significance.  To 
allow for a dropout rate of 10%, 39 subjects will be randomized to each of the 3 treatment groups. An 
interim analysis will be conducted after a minimum of 51 subjects complete the assessment of the 
primary efficacy endpoint to assess sample size assumptions and futility through conditional power; the 
study will not be stopped for efficacy. 
 
 
 
 

CONFIDENTIAL 
 
HighTide Biopharma Pty. Ltd. 
 
HTD1801 
Clinical Protocol 
IND 139502 
 
 
 
Page 8 
Figure 1. 
Study Design 
 
Screening 
Double-Blind Treatment 
Follow-up 
Baseline 
WK 2 
WK 6 
WK 10 
WK 14 
WK 18 
 
 
 
 
 
 
R
HTD1801 500 mg BID
HTD1801 1000 mg BID
Placebo

CONFIDENTIAL 
 
HighTide Biopharma Pty. Ltd. 
 
HTD1801 
Clinical Protocol 
IND 139502 
 
 
 
Page 9 
Table 1. 
Schedule of Time and Events 
 
Protocol 
Section(s) 
SCR 
Double-Blind Treatment 
ET 
Follow-up 
Baseline 
WK 2 
WK 6 
WK 10 
WK 14 
WK 18 
Visit Day 
- 
-28 to -1 
0 
14 
42 
70 
98 
126 
- 
+30d 
Procedure / Window 
- 
- 
±3d 
±3d 
±3d 
±3d 
±3d 
+7d 
Administrative Procedures 
Clinic visit 
5.1 
X 
X 
X 
X 
X 
X 
X 
X 
 
Informed consent 
10.1 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
3.3.1, 3.3.2 
X 
Xa 
 
 
 
 
 
 
 
Demographics 
6.1.1 
X 
 
 
 
 
 
 
 
 
Medical history 
6.1.1 
X 
Xa 
 
 
 
 
 
 
 
Randomization 
6.1.2 
 
X 
 
 
 
 
 
 
 
Dispense study drug 
6.1.2 
 
X 
X 
X 
X 
X 
 
 
 
Return study drug 
6.1.2 
 
 
X 
X 
X 
X 
X 
X 
 
Study discharge 
5.1.4, 5.1.5 
 
 
 
 
 
 
X 
X 
 
Telephone contact 
5.1.6 
 
 
 
 
 
 
 
 
X 
Clinical Assessments 
Comprehensive physical 
examination 
6.3.1 
X 
 
 
 
 
 
X 
X 
 
Targeted physical examinationb 
6.3.1 
 
Xa 
 
X 
 
X 
 
 
 
Vital signs 
6.3.2 
X 
Xa 
 
X 
 
X 
X 
X 
 
Weight 
6.3.2 
X 
Xa 
X 
X 
X 
X 
X 
X 
 
Height 
6.3.2 
X 
 
 
 
 
 
 
 
 
ECG 
6.3.3 
X 
Xa 
 
X 
 
X 
X 
X 
 
Laboratory Assessments 
Serum chemistry panelc 
6.2.2, 6.3.4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lipid panelc 
6.2.2, 6.3.4 
X 
X 
 
 
X 
 
X 
X 
 
Hematology with differentialc 
6.3.4 
X 
X 
 
 
X 
 
X 
X 
 
Coagulation panelc 
6.3.4 
X 
X 
 
 
X 
 
X 
X 
 

CONFIDENTIAL 
 
HighTide Biopharma Pty. Ltd. 
 
HTD1801 
Clinical Protocol 
IND 139502 
 
 
 
Page 10 
 
Protocol 
Section(s) 
SCR 
Double-Blind Treatment 
ET 
Follow-up 
Baseline 
WK 2 
WK 6 
WK 10 
WK 14 
WK 18 
Visit Day 
- 
-28 to -1 
0 
14 
42 
70 
98 
126 
- 
+30d 
Procedure / Window 
- 
- 
±3d 
±3d 
±3d 
±3d 
±3d 
+7d 
HbA1c 
6.2.2 
Xd 
 
 
X 
 
X 
X 
 
HOMA-IR 
6.2.2 
 
X 
 
 
 
 
X 
X 
 
HIV and Hepatitis B/C 
6.3.4 
X 
 
 
 
 
 
 
 
 
G6PD 
6.3.4 
X 
 
 
 
 
 
 
 
 
Pregnancy teste 
6.3.4 
X 
Xa,e 
 
 
 
 
X 
X 
 
FSH teste 
6.3.4 
X 
 
 
 
 
 
 
 
 
Urine drug test 
6.3.4 
X 
 
 
 
 
 
 
 
 
Imaging and Biomarker Assessments 
MRI-PDFF 
6.2.1 
Xd 
 
 
 
 
X 
X 
 
Corrected T1 and T2* 
6.2.1 
Xd 
 
 
 
 
 
 
 
Pro-C3 
6.2.2 
 
X 
 
 
 
 
X 
X 
 
ELF test 
6.2.2 
 
X 
 
 
 
 
X 
X 
 
Bile acid panelc 
6.2.2 
 
X 
 
 
X 
 
X 
X 
 
Safety Assessments 
Adverse event monitoring 
6.3.5, 7.0 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications 
4.5, 4.6, 
6.3.6 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
a Continued study eligibility confirmed based on updated medical history, targeted physical examination, vital signs, weight, ECG, negative urine pregnancy test (for FOCP), 
updated prior and concomitant medications, and any adverse events that have occurred since signing informed consent. 
b Targeted physical examination of body systems or organs performed on symptom-driven basis (e.g., adverse events or other findings). 
c See Table 2 for analytes tested as part of the serum chemistry, lipid, hematology, and coagulation panels. The serum chemistry panel performed at the Week 2, Week 6, and 
Week 14 visits only includes testing of alkaline phosphatase (ALP), ALT, AST, gamma-glutamyl transferase (GGT), total bilirubin, direct bilirubin, and fasting glucose. The 
Week 10 and Week 18 (or ET) bile acid panel applies only to subjects who have had the Baseline bile acid panel performed. 
d Assessments performed during Screening to confirm study eligibility; results applied as Baseline values. 
e Pregnancy test required for FOCP only; serum pregnancy test performed at Screening and Week 18 (or ET); urine and confirmatory serum pregnancy tests performed at 
Baseline. FSH test required for postmenopausal females only. 
ET = Early Termination; SCR = Screening 

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HighTide Biopharma Pty. Ltd. 
 
HTD1801 
Clinical Protocol 
IND 139502 
 
 
 
Page 11 
Table 2. 
Laboratory Analytes 
Serum Chemistry 
Hematology 
Lipids 
Coagulation 
Comprehensive metabolic panel: 
• 
Albumin 
• 
ALP 
• 
ALT 
• 
AST 
• 
Bicarbonate 
• 
Bilirubin, total 
• 
Bilirubin, direct 
• 
Blood urea nitrogen (BUN) 
• 
Calcium 
• 
Chloride 
• 
Creatinine 
• 
Creatine kinase 
• 
GGT 
• 
Glucose, fasting 
• 
Lactate dehydrogenase 
• 
Magnesium 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid 
 
Endocrinology: 
• 
Insulin, fasting 
• 
TSH 
Complete blood count, including: 
• 
Hemoglobin 
• 
Hematocrit 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count 
• 
Reticulocyte count 
 
White blood cell count differential, 
including: 
• 
Basophils 
• 
Eosinophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Neutrophils 
Total cholesterol 
LDL-c 
HDL-c 
Triglycerides 
Activated partial thromboplastin time 
(aPTT) 
Prothrombin time (PT) 
INR 
Other 
HbA1c 
HOMA-IR 
HIV and Hepatitis B/C 
G6PD 
Serum and urine pregnancy tests 
FSH test 
Urine drug test 
Pro-C3 
ELF 
Bile acid panel, including: 
• 
Bile acids, total 
• 
C4 
• 
FGF19 
 
 

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HighTide Biopharma Pty. Ltd. 
 
HTD1801 
Clinical Protocol 
IND 139502 
 
 
 
Page 12 
TABLE OF CONTENTS 
 
Page 
 
STUDY SYNOPSIS........................................................................................................................................................3 
LIST OF TABLES ........................................................................................................................................................15 
LIST OF FIGURES.......................................................................................................................................................15 
LIST OF APPENDICES ...............................................................................................................................................16 
LIST OF ABBREVIATIONS .......................................................................................................................................17 
1.0 
INTRODUCTION .................................................................................................................................19 
1.1 
BACKGROUND .....................................................................................................................................19 
1.1.1 
Nonalcoholic Steatohepatitis ................................................................................................19 
1.1.2 
Nonclinical Studies ...............................................................................................................22 
1.2 
STUDY RATIONALE ............................................................................................................................23 
1.2.1 
Rationale for Study Design ...................................................................................................23 
1.2.2 
Rationale for Dose and Duration ..........................................................................................24 
2.0 
OBJECTIVES ........................................................................................................................................26 
3.0 
STUDY DESIGN ...................................................................................................................................27 
3.1 
BASIC DESIGN CHARACTERISTICS ................................................................................................27 
3.2 
DURATION OF SUBJECT PARTICIPATION AND STUDY .............................................................27 
3.3 
STUDY POPULATION ..........................................................................................................................28 
3.3.1 
Inclusion Criteria ..................................................................................................................28 
3.3.2 
Exclusion Criteria .................................................................................................................29 
3.4 
ENDPOINTS ...........................................................................................................................................31 
3.4.1 
Efficacy .................................................................................................................................31 
3.4.2 
Safety ....................................................................................................................................33 
3.5 
SUBJECT NUMBERING, RANDOMIZATION, AND BLINDING ....................................................33 
3.6 
REPLACEMENT OF DROPOUTS ........................................................................................................34 
4.0 
STUDY DRUGS AND DOSAGES .......................................................................................................35 
4.1 
IDENTIFICATION AND DESCRIPTION OF INVESTIGATIONAL PRODUCT .............................35 
4.1.1 
Investigational Product .........................................................................................................35 
4.1.2 
Labeling ................................................................................................................................35 
4.2 
DOSING INSTRUCTIONS AND SCHEDULE.....................................................................................35 
4.3 
HANDLING OF INVESTIGATIONAL PRODUCT .............................................................................36 
4.4 
COMPLIANCE WITH INVESTIGATIONAL PRODUCT ...................................................................36 
4.5 
CONCOMITANT MEDICATIONS .......................................................................................................36 
4.6 
PROHIBITED CONCOMITANT MEDICATIONS ..............................................................................37 
4.7 
MANAGEMENT OF CONCOMITANT CONDITIONS ......................................................................39 
4.8 
LIFESTYLE CONSIDERATIONS.........................................................................................................39 
5.0 
EXPERIMENTAL PROCEDURES ....................................................................................................40 
5.1 
PROCEDURES, MEASUREMENTS, AND EVALUATIONS.............................................................40 

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HTD1801 
Clinical Protocol 
IND 139502 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
 
Page 13 
5.1.1 
Screening (Days -28 to -1) ....................................................................................................40 
5.1.2 
Baseline (Day 0) ...................................................................................................................41 
5.1.3 
Double-Blind Treatment Period (Weeks 2, 6, 10, 14, 18) ....................................................42 
5.1.4 
Study Discharge ....................................................................................................................44 
5.1.5 
Early Termination .................................................................................................................44 
5.1.6 
Follow-up Period ..................................................................................................................44 
6.0 
CONDUCT OF STUDY PROCEDURES AND ASSESSMENTS ....................................................45 
6.1 
ADMINISTRATIVE PROCEDURES ....................................................................................................45 
6.1.1 
Demographics and Medical History .....................................................................................45 
6.1.2 
Randomization and Study Drug Management ......................................................................45 
6.1.3 
Subject Reminder Cards .......................................................................................................45 
6.2 
EFFICACY ASSESSMENTS .................................................................................................................45 
6.2.1 
Magnetic Resonance Imaging ...............................................................................................45 
6.2.2 
Efficacy Related Laboratory and Biomarker Assessments...................................................46 
6.3 
SAFETY ASSESSMENTS .....................................................................................................................48 
6.3.1 
Physical Examinations ..........................................................................................................48 
6.3.2 
Vital Signs, Height, and Weight ...........................................................................................48 
6.3.3 
Electrocardiograms ...............................................................................................................48 
6.3.4 
Safety Related Laboratory Assessments ...............................................................................49 
6.3.5 
Adverse Events .....................................................................................................................49 
6.3.6 
Prior and Concomitant Medications .....................................................................................49 
7.0 
PROCEDURES FOR HANDLING ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS .................................................................................................................................................51 
7.1 
DEFINITION OF AN ADVERSE EVENT ............................................................................................51 
7.2 
DEFINITION OF A SERIOUS ADVERSE EVENT .............................................................................53 
7.3 
RECORDING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .......................................54 
7.4 
ASSESSMENT OF INTENSITY............................................................................................................54 
7.5 
ASSESSMENT OF CAUSALITY ..........................................................................................................55 
7.6 
EXPECTEDNESS OF SERIOUS ADVERSE EVENTS .......................................................................56 
7.7 
REPORTING OF SERIOUS ADVERSE EVENTS ...............................................................................56 
7.8 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .................................57 
7.9 
LIVER ADVERSE EVENTS..................................................................................................................58 
7.10 
PREGNANCY .........................................................................................................................................60 
7.11 
DATA AND SAFETY MONITORING BOARD ..................................................................................61 
8.0 
STUDY OR SITE TERMINATION AND SUBJECT DISCONTINUATION................................62 
8.1 
ADVERSE EVENT STOPPING RULES ...............................................................................................62 
8.2 
NONCOMPLIANCE ..............................................................................................................................62 
8.3 
WITHDRAWAL OF CONSENT............................................................................................................62 
8.4 
PREMATURE STUDY OR SITE TERMINATION ..............................................................................63 

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9.0 
DATA COLLECTION AND PROCESSING AND STATISTICAL ANALYSIS ..........................65 
9.1 
DATA COLLECTION AND PROCESSING .........................................................................................65 
9.2 
STATISTICAL ANALYSIS ...................................................................................................................66 
9.2.1 
General Overview .................................................................................................................66 
9.2.2 
Analysis Datasets ..................................................................................................................66 
9.2.3 
Efficacy Analysis ..................................................................................................................67 
9.2.4 
Missing Data .........................................................................................................................68 
9.2.5 
Safety Analysis .....................................................................................................................68 
9.2.6 
Sample Size...........................................................................................................................69 
9.2.7 
Interim Analysis ....................................................................................................................69 
10.0 
STUDY ADMINISTRATION ..............................................................................................................71 
10.1 
INFORMED CONSENT AND AUTHORIZATION FOR USE AND DISCLOSURE OF 
PROTECTED HEALTH INFORMATION ............................................................................................71 
10.2 
STUDY DOCUMENTATION ................................................................................................................71 
10.2.1 
Investigator Information .......................................................................................................71 
10.2.2 
Investigator’s Study Files .....................................................................................................71 
10.2.3 
Case Report Forms and Source Documentation ...................................................................72 
10.2.4 
Retention of Study Documents .............................................................................................72 
10.3 
CONFIDENTIALITY .............................................................................................................................72 
10.3.1 
Data .......................................................................................................................................72 
10.3.2 
Subject Anonymity ...............................................................................................................73 
10.4 
PROTOCOL COMPLIANCE .................................................................................................................73 
10.5 
STUDY MONITOR FUNCTIONS AND RESPONSIBILITY ..............................................................74 
10.6 
GENERAL INFORMATION .................................................................................................................74 
11.0 
REFERENCES ......................................................................................................................................75 
APPENDICES...............................................................................................................................................................79 
 

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LIST OF TABLES 
 
Page 
 
Table 1. 
Schedule of Time and Events ....................................................................................................................9 
Table 2. 
Laboratory Analytes ................................................................................................................................11 
Table 3. 
Comparison of HTD1801 Clinical Dose with FDA Approved UDCA Dose and Clinical BBR Dose ...24 
Table 4. 
Prohibited Medications ............................................................................................................................38 
Table 5. 
Classification of AEs by Intensity ...........................................................................................................55 
Table 6. 
Assessment of Causality of AEs..............................................................................................................56 
Table 7. 
Timeline for Reporting SAEs ..................................................................................................................57 
Table 8. 
Algorithm to Monitor for DILI ................................................................................................................58 
 
 
 
 
LIST OF FIGURES 
 
 
Figure 1. 
Study Design .............................................................................................................................................8 
 
 
 
 
 

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LIST OF APPENDICES 
 
 
APPENDIX A  PROTECTION OF HUMAN SUBJECTS (International Conference on Harmonisation E6) 
APPENDIX B  REQUISITE DOCUMENTS FOR APPROVAL OF STUDY SITE 
APPENDIX C  RESPONSIBILITIES AND OBLIGATIONS  OF INVESTIGATORS AND SPONSORS 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
AAT 
alpha-1 antitrypsin 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BBR 
berberine 
BBR·Cl 
berberine chloride 
BID 
twice daily 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
C4 
7-hydroxy-4-cholesten-3-one 
cT1 
corrected T1 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP450 
cytochrome P450 
DILI 
drug induced liver injury 
DPP-4 
dipeptidyl peptidase-4 
DSHEA 
Dietary Supplement Health and Education Act 
DSMB 
Data and Safety Monitoring Board 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ELF 
enhanced liver fibrosis 
ET 
early termination 
FDA 
Food and Drug Administration 
FGF19 
fibroblast growth factor 19 
FOCP 
females of child-bearing potential 
FSH 
follicle-stimulating hormone 
FXR 
farnesoid X receptor 
G6PD 
glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP-1 
glucagon-like peptide-1 
HA 
hyaluronic acid 
HbA1c 
hemoglobin A1c 
HDL-c 
high-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HOMA-IR 
homoeostasis model assessment-estimated insulin resistance 
ICF 
informed consent form 

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ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent-to-treat 
LDL-c 
low-density lipoprotein cholesterol 
LFC 
liver fat content 
LMSD 
LiverMultiScan Discover™ 
MRI-PDFF 
magnetic resonance imaging-estimated proton density fat fraction 
NAFLD 
nonalcoholic fatty liver disease 
NASH 
nonalcoholic steatohepatitis 
P-gp 
P-glycoprotein 
PBC 
primary biliary cirrhosis  
PET/AL/PE 
polyethylene terephthalate/aluminum foil/polyethylene 
PIIINP 
N-terminal pro-peptide of type III collagen 
PK 
pharmacokinetic 
POC 
proof-of-concept 
PSC 
primary sclerosing cholangitis 
PT 
prothrombin time 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SGLT-2 
sodium-glucose cotransporter-2 
SPM 
Study Procedures Manual 
T2DM 
Type 2 Diabetes Mellitus 
TB 
total bilirubin 
TC 
total cholesterol 
TIMP-1 
tissue inhibitor of metalloproteinases-1 
TSH 
thyroid-stimulating hormone 
UDCA 
ursodeoxycholic acid 
UGT 
uridine diphosphate glucuronosyltransferase 
ULN 
upper limit of normal 
US 
United States 
 
 

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1.0 
INTRODUCTION 
HTD1801 is a novel salt formed between berberine (BBR) and ursodeoxycholic acid 
(UDCA) with a stoichiometry of 1:1.  HTD1801 is currently being developed as an oral 
treatment for nonalcoholic steatohepatitis (NASH). HTD1801 is expected to dissociate 
into BBR salt and UDCA after oral administration, which suggests that the efficacy 
and safety profiles of HTD1801 can be predicted by those of the individual components 
(see Section 1.1.1.1). 
Berberine and UDCA have displayed wide-ranging biologic activity relative to liver 
dysfunction in nonclinical and clinical settings, including immunomodulatory, 
anti-inflammatory, anti-fibrotic, anti-microbial, and hepatoprotective effects. 
Furthermore, their effects on serum lipid, hepatic lipid, and/or glucose metabolism, all 
of which are implicated in the pathogenesis of NASH, have been well studied and 
reported in the literature. 
Given the reported hepatotherapeutic mechanisms of BBR and UDCA, the 
pharmacologic profile of HTD1801 (see Section 1.1.1.2) may offer patients with 
NASH a safe and effective therapy. HighTide Biopharma Pty. Ltd. (HighTide) is 
conducting this proof-of-concept (POC) study to evaluate HTD1801 in adults with 
NASH and Type 2 Diabetes Mellitus (T2DM) by assessing changes in liver fat content 
(LFC) over 18 weeks. 
1.1 
BACKGROUND 
1.1.1 
Nonalcoholic Steatohepatitis 
Nonalcoholic steatohepatitis is a progressive form of nonalcoholic fatty liver disease 
(NAFLD) characterized by the presence of hepatic steatosis and inflammation with 
hepatocyte injury (i.e., ballooning) with or without fibrosis. While the prevalence of 
NAFLD in the general population is estimated at 20-30%, NASH has been reported to 
affect approximately 5% of the general population. It is generally agreed that patients 
with NASH can exhibit histological progression to cirrhotic-stage disease. 
Furthermore, several studies have reported that the most common cause of death in 
patients with NAFLD/NASH is cardiovascular disease, while patients specifically 
with NASH have an increased liver-related mortality rate (Chalasani et al., 2012, NICE 

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2016). The most common comorbidities associated with NASH are reported to include 
obesity, T2DM, insulin resistance, hypertension, and dyslipidemia (Rinella 2015). 
It is hypothesized that different pathogenic factors lead to “multiple hits” during the 
disease progression from hepatic steatosis to the hepatic inflammatory and 
hepatocellular damage components that define NASH (Adams and Angulo 2006, 
Weiss et al., 2014). Accumulation of hepatic fat linked to insulin resistance is 
considered the “first hit.”  Hyperinsulinemia in the context of insulin resistance leads 
to an increased release of free fatty acids from adipocytes and myocytes, which are then 
absorbed by and accumulate in the liver resulting in steatosis. Insulin resistance also 
promotes de novo triglyceride synthesis within the liver and inhibits fatty acid oxidation 
thereby promoting triglyceride accumulation (Adams and Angulo 2006). Additional 
oxidative injury has been proposed as a “second hit,” which manifests the 
necroinflammatory component of steatohepatitis. Factors associated with obesity and 
metabolic syndrome, such as increased circulating free fatty acids, excess iron, and 
intestinal bacterial overgrowth, increase levels of reactive oxygen species and produce 
cytotoxic aldehydes, which further contribute to oxidative stress and promote 
hepatocyte injury, inflammation, and apoptosis (Basaranoglu et al., 2013). As 
hepatocyte injury becomes repetitive and repair dysregulated, the liver’s normal 
wound-healing process stalls during tissue reconstruction and progression to fibrosis 
and cirrhosis ensues (Diehl and Day 2017). 
Despite the investigation of multiple therapies, there are no approved drugs for the 
treatment of NAFLD, or more specifically, NASH. Currently, weight loss is the only 
therapy with reasonable evidence suggesting that it is safe, beneficial, and may result in 
improved histologic features of NASH. Many patients, however, do not 
achieve or cannot maintain goals of lifestyle modification for a long-term period 
(Vilar-Gomez et al., 2015). Novel pharmacologic therapies that comprehensively 
ameliorate the pathological spectrum of NASH are therefore needed. 
1.1.1.1 
Berberine and Ursodeoxycholic Acid 
Berberine is an isoquinoline alkaloid found in many different plants, with a long history 
of use in traditional Chinese medicine (Caliceti et al., 2016, Kumar et al., 2015).  
Berberine chloride (BBR·Cl) is an approved antiseptic drug in China, Japan, and 
Taiwan. In the United States (US) and Australia, BBR is widely used in various dietary 
supplements for a number of advertised health benefits and is grandfathered under the 

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Dietary Supplement Health and Education Act (DSHEA) in the US (Council for 
Responsible Nutrition 1998). The reported multi-spectrum activity of BBR, including 
effects on glucose and lipid metabolism, hepatic steatosis, oxidative stress, 
inflammation, and  fibrosis suggests that BBR has the potential to treat NAFLD/NASH. 
Furthermore, clinical studies of BBR for the treatment of T2DM, hyperlipidemia, 
hypertension, and NAFLD have yielded favorable results (Cicero and Ertek 2009, Lan 
et al., 2015). 
Ursodeoxycholic acid is a secondary bile acid produced by intestinal bacteria as a 
metabolic by-product, which is approved by the US Food and Drug Administration 
(FDA) for the non-surgical treatment of cholesterol gallstone dissolution (Actigall®, 
NDA 019594) and the treatment of primary biliary cirrhosis (PBC) (URSO 250® and 
URSO Forte®, NDA 020675). Similar to BBR, UDCA activity is reported to include 
anti-oxidative stress, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects, as 
well as improvement in liver injury caused by microbial dysbiosis. In the clinical 
setting, favorable results were reported for UDCA combination therapy compared to 
UDCA monotherapy in the treatment of NASH (Xiang et al., 2013). 
Based on the pharmacological properties and clinical evaluations of BBR and UDCA 
relative to NASH and conditions that are most commonly attributed to its development, 
BBR and UDCA may present as good “partners” for effectively treating this advanced 
liver disease. More information about the activity, safety, and efficacy of BBR and 
UDCA can be found in the HTD1801 Investigator’s Brochure. 
1.1.1.2 
HTD1801 
HTD1801 is expected to demonstrate a multi-functional pharmacologic profile 
reflecting the individual actions of its active components, BBR and UDCA. These 
agents target multiple aberrant pathways that may contribute to the pathogenesis of 
NASH. The beneficial effects of HTD1801 in patients with NASH are expected to 
include, but may not be limited to: 
• 
Improved insulin resistance and regulation of lipid and glucose metabolism; 
• 
Reduction of fat deposition in the liver; 
• 
Restoration of the intestinal barrier function; 

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• 
Anti-inflammatory, anti-oxidative, and anti-apoptotic effects; 
• 
Anti-fibrotic effects. 
Given the unique pharmacologic profiles of BBR and UDCA, both additive and 
synergistic effects are expected to occur when the 2 products are administered together 
as HTD1801. More information about the activity, safety, and efficacy of HTD1801 
can be found in the HTD1801 Investigator’s Brochure. 
1.1.2 
Nonclinical Studies 
The pharmacology of HTD1801 was evaluated in vivo in rodent and primate models of 
hyperlipidemia/NAFLD: 
• 
HTD1801 was evaluated in a pilot study of high-fat diet-induced Golden Syrian 
hamsters. After 8 weeks, hamsters administered HTD1801 100 mg/kg or a 
physical mixture of BBR·Cl and UDCA 100 mg/kg (molar ratio of 1:1) had 
decreased serum levels of total cholesterol (TC), triglycerides, and 
malondialdehyde compared to those of a model (untreated) control group; 
however, the effects were enhanced with HTD1801 compared to the physical 
mixture of BBR·Cl and UDCA. Hamsters treated with the physical mixture of 
BBR·Cl and UDCA also exhibited greater decreases in body weight and more 
serious adverse effects than the group treated with HTD1801. 
• 
HTD1801 was further evaluated in a high-fat diet-induced Golden Syrian hamster 
model of hyperlipidemia/NAFLD. At doses of 50 mg/kg or 200 mg/kg 
administered intragastrically for 7 weeks, HTD1801 significantly reduced serum 
levels of TC, triglyceride, and low-density lipoprotein cholesterol (LDL-c), the 
ratio of TC/high-density lipoprotein cholesterol (HDL-c), and the atherosclerotic 
index value, as well as the risk of atherosclerosis, in a dose-dependent manner. 
Hepatic lipidosis and body lipidosis also were significantly reduced, while 
hepatic inflammation was ameliorated. 
• 
HTD1801 was evaluated in male Rhesus monkeys with naturally-occurring 
NAFLD. Study results indicated a dose-dependent reduction of liver steatosis. At 
30 mg/kg (equivalent to a clinical proposed dose of 1,050 mg/70 kg person/day), 
HTD1801 significantly reduced liver steatosis, while at 15 mg/kg (equivalent to 
a clinical proposed dose of 525 mg/70 kg person/day), a decreasing trend in 

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steatosis was observed after 69 days of administration. Significant lowering of 
LDL-c, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) 
levels was noted, while a treatment-related decreasing trend was observed for TC, 
apolipoprotein B, and blood glucose levels. 
The nonclinical toxicity profiles of both BBR and UDCA have been extensively 
documented. A full International Conference on Harmonisation (ICH) M3 battery of 
nonclinical studies of UDCA was submitted in support of NDA 020675. The toxicity 
profile of BBR was assessed in a battery of nonclinical studies conducted and/or 
reviewed by the National Toxicology Program. These studies include single-dose oral 
studies in mice and rats, in vitro and in vivo genotoxicity studies, and reproductive and 
developmental toxicity studies in mice and rats (National Toxicology Program 2002, 
2003c, a, b, 2010). 
The pharmacokinetic (PK) and toxicity profiles of HTD1801 have been evaluated in 
both rats and dogs. Toxicology studies of up to 2 weeks in rats (non-GLP) and up to 
13 weeks in dogs (GLP) have been conducted. Combined administration of BBR and 
UDCA as HTD1801 yielded PK and toxicity profiles similar to those of the individual 
components UDCA and BBR. In addition, a 13-week GLP dog study provided data to 
qualify the toxicity profile of BBR in non-rodents and the safety of the combination of 
BBR and UDCA when administered as HTD1801. 
Available nonclinical study data for HTD1801, together with cumulative nonclinical 
study data and clinical experience for BBR and UDCA individually, support the safety 
and tolerability of HTD1801 for this POC study. More information about the 
nonclinical evaluation of HTD1801 can be found in the HTD1801 Investigator’s 
Brochure. 
1.2 
STUDY RATIONALE 
1.2.1 
Rationale for Study Design 
This 18-week randomized, double-blind, parallel-group, POC, dose-ranging study will 
compare multiple doses of HTD1801 to placebo. A randomized, double-blind design 
will enhance study rigor and quality relative to assessment of the pre-specified 
endpoints (see Section 3.4). In the absence of approved or recognized therapeutics for 
NASH, a placebo control group will be utilized, as has been reported for several prior 

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randomized, placebo-controlled assessments of various pharmacologic agents 
(Loomba et al., 2008). 
Since accumulation of hepatic fat is considered the “first hit” in the pathogenesis of 
NASH (Adams and Angulo 2006), change in LFC by magnetic resonance 
imaging-estimated proton density fat fraction (MRI-PDFF) is an appropriate primary 
endpoint and is consistent with that used in recent Phase 2 POC studies in NASH 
(Harrison et al., 2018, Madrigal Pharmaceuticals 2018). 
1.2.2 
Rationale for Dose and Duration 
Ursodeoxycholic acid is approved by the US FDA at a dose of 13-15 mg/kg/day (URSO 
250® and URSO FORTE®), or approximately 1 g/day for a 70 kg individual. Berberine 
is widely used in dietary supplements in the US at a recommended dose of 
17-33 mg/kg/day, or approximately 1-2 g/day for a 70 kg individual. Furthermore, New 
Tantose A®, an over-the-counter combination including BBR (adult dose of 
0.300 g/day) and UDCA (0.030 g/day), has been approved in Japan for acute diarrheal 
illness (New Tantose A®), while the therapeutic dosage in most of BBR’s clinical 
experience is around 0.4-2.7 g/day orally for exposures up to 181 days (Cicero and 
Ertek 2009, Lan et al., 2015). As shown in Table 3, the UDCA and BBR content of 
HTD1801 are comparable to doses associated with clinical safety. 
Table 3. 
Comparison of HTD1801 Clinical Dose with FDA Approved 
UDCA Dose and Clinical BBR Dose 
Compound 
FDA Approved Clinical Dose (UDCA) / 
Dose Used in Clinical Experience (BBR) 
HTD1801 Clinical Dose 
(29 mg/kg/day; 2,000 mg/day)a,d 
UDCAa 
13-15 mg/kg/day (910-1,050 mg/day)b 
15 mg/kg/day (1,078 mg/day) 
BBRa 
6-38 mg/kg/day (400-2,700 mg/day)c 
15 mg/kg/day (1,022 mg/day) 
a mg/kg doses calculated assuming a 70 kg adult. 
b Safety at doses up to 25 mg/kg/day is supported by the published literature for PBC patients 
(Angulo et al., 1999). 
c Therapeutic dosage in most of BBR’s clinical experience (Cicero and Ertek 2009, Lan et al., 
2015). 
d HTD1801 dose of 2,000 mg/day is equivalent to 1,022 mg/day BBR and 1,078 mg/day UDCA. 
Furthermore, data from a first-in-human, single ascending dose study of HTD1801 in 
healthy subjects (Protocol HTD1801.PCT002) demonstrated dose proportionality for 

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UDCA and BBR exposure parameters at orally administered HTD1801 doses of 
0.5-4.0 g/day. Single doses of HTD1801 were also safe and well tolerated. 
Lastly, recent Phase 2 POC studies in NASH (Harrison et al., 2018, Madrigal 
Pharmaceuticals 2018) show clinically meaningful absolute and relative reductions in 
LFC assessed by MRI-PDFF over 12-week treatment periods. An 18-week HTD1801 
treatment period is therefore adequate to assess the study’s primary endpoint and to 
maximize collection of exposure and safety related data.

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2.0 
OBJECTIVES 
The primary objective of this study is to evaluate the effects of HTD1801 on LFC in 
adults with NASH and T2DM. 
The secondary objectives of this study are to evaluate: 
1. The effects of HTD1801 on hemoglobin A1c (HbA1c) and glucose metabolism; 
2. The effects of HTD1801 on lipid profile; 
3. The effects of HTD1801 on liver-associated enzymes; 
4. The effects of HTD1801 on biomarkers of liver inflammation and fibrosis; 
5. The effects of HTD1801 on bile acid homeostasis; 
6. The safety and tolerability of HTD1801. 
 

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3.0 
STUDY DESIGN 
3.1 
BASIC DESIGN CHARACTERISTICS 
This multicenter, randomized, double-blind, parallel-group, POC and dose-ranging 
study will compare multiple doses of HTD1801 to placebo. Upon confirmation of 
eligibility, subjects will be randomized in a 1:1:1 ratio to receive 1 of 2 doses of 
HTD1801 or placebo for 18 weeks. 
Subjects will receive 500 mg HTD1801, 1,000 mg HTD1801, or placebo (collectively, 
the study drug or study drugs), administered twice daily (BID) during the 18-week 
Double-Blind Treatment Period. Clinic visits for efficacy assessments and safety 
monitoring will occur at Week 2, then every 4 weeks throughout the Double-Blind 
Treatment Period. A follow-up safety telephone contact for an assessment of adverse 
events (AEs) and concomitant medications will take place at least 30 days after the last 
dose of study drug. An interim analysis will be conducted after a minimum of 51 
subjects complete the assessment of the primary efficacy endpoint to assess sample size 
assumptions and futility through conditional power; the study will not be stopped for 
efficacy. An independent Data and Safety Monitoring Board (DSMB) will provide 
additional safety oversight. 
3.2 
DURATION OF SUBJECT PARTICIPATION AND STUDY 
Once the informed consent form (ICF) is signed, Screening assessments 
(see Section 5.1.1) may be performed over a 28-day period prior to randomization at 
the Baseline visit. Subjects will then be randomized to receive their assigned study drug 
during the 18-week Double-Blind Treatment Period (see Section 5.1.3). If a subject 
completes the Double-Blind Treatment Period or discontinues his/her assigned study 
drug early, the subject will complete follow-up assessments (see Section 5.1.5) at least 
30 days after the last dose of study drug. Overall subject participation, from Screening 
through the follow-up assessments, may last for up to approximately 6 months. 
The study begins when the first subject signs the ICF. The end of the study will occur 
when all subjects have discontinued taking their assigned study drug (i.e., either at the 
end of the Double-Blind Treatment Period or earlier) and have completed the follow-up 
assessments. 

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3.3 
STUDY POPULATION 
Approximately 117 patients with NASH and T2DM will be enrolled as subjects from 
approximately 15 investigational sites in the US. Eligibility will be established by the 
Investigator on the basis of the inclusion and exclusion criteria. 
3.3.1 
Inclusion Criteria 
To be considered eligible to participate in this study, a subject must meet the inclusion 
criteria listed below: 
1. Male or female between 18 and 75 years of age. 
2. Clinical diagnosis of NASH with at least stage F1 fibrosis as evident by: 
• Liver fat content ≥10% as assessed by MRI-PDFF and a corrected T1 (cT1) of 
≥830 msec as assessed by multiparametric MRI. 
3. Aspartate aminotransferase ≥20 U/L. 
4. Clinically documented diagnosis of T2DM ≥6 months prior to randomization. 
5. If on a T2DM medication regimen, specifically thiazolidinediones, glucagon-like 
peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, or 
sodium-glucose cotransporter-2 (SGLT-2) inhibitors, must be maintained on a 
stable dose regimen for ≥90 days prior to randomization. 
6. If on vitamin E, must be maintained on a stable dose of ≤400 IU for ≥90 days prior 
to randomization with no anticipated dose increases during the study. 
7. Regimens for other permitted concomitant medications, as described in Section 4.5 
of the protocol, must be stable for ≥28 days prior to randomization. 
8. Body mass index (BMI) >25 kg/m2. 
9. Females of child-bearing potential (FOCP) and males participating in the study 
must either agree to use at least 2 approved barrier methods of contraception or be 
completely abstinent from sexual intercourse, if this is their usual and preferred 
lifestyle, throughout the duration of the study and for at least 90 days after the last 

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dose of study drug. Females who are postmenopausal must have appropriate 
supporting documentation with a corresponding follicle-stimulating hormone 
(FSH) test result to support status. 
10. Ability to understand and sign a written ICF. 
3.3.2 
Exclusion Criteria 
To be eligible for entry into the study, the subject must not meet any of the exclusion 
criteria listed below: 
1. Clinically significant acute or chronic liver disease unrelated to NASH, including 
but not limited to primary sclerosing cholangitis (PSC), Wilson’s disease, alpha-1 
antitrypsin (AAT) deficiency (MZ or ZZ phenotype), hepatitis B or C, hereditary 
hemochromatosis, alcoholic liver disease, and drug induced liver disease. 
2. Clinically or histologically documented cirrhosis. 
3. Poorly controlled T2DM (HbA1c ≥9.5%) or Type 1 Diabetes Mellitus. 
4. Hepatitis B surface antigen positive. 
5. Hepatitis C antibody positive with active infection. 
6. Human immunodeficiency virus (HIV)-1 or HIV-2 infection. 
7. Glucose-6-phosphate dehydrogenase (G6PD) deficiency. 
8. Any prior history of hepatic decompensation (encephalopathy, ascites, 
gastroesophageal varices, hepatorenal syndrome), platelet count <150,000/mm3, 
international normalized ratio (INR) ≥1.3 despite vitamin K supplementation, 
serum albumin <3.2 g/dL, or a prior or planned liver transplantation. 
9. History of alcohol or substance abuse or dependence. 
10. Hepatic steatosis that, in the opinion of the Investigator, is primarily related to 
alcohol consumption. 
11. Inability to undergo MRI for any reason. 

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Note: Mild sedative use (if not prohibited as described in Section 4.6 of the 
protocol) for MRI procedures is permitted. 
12. Laboratory parameters within any of the following ranges: 
• AST >5 × ULN. 
• ALT ≥5 × ULN. 
• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. 
• Hemoglobin <11 g/dL for males or females. 
• Direct bilirubin <LLN or >ULN. 
• Total bilirubin <LLN or >ULN. 
Note: Total bilirubin >ULN due to Gilbert’s syndrome is acceptable provided 
that direct bilirubin, reticulocyte count, and hemoglobin are within the 
laboratory defined normal ranges. 
• Thyroid-stimulating hormone (TSH) <LLN or >1.5 × ULN. 
Note: Subjects on a medication for a thyroid abnormality may enroll provided 
that they have been maintained on a stable dose for ≥90 days prior to 
randomization. 
13. Current use of oral prednisone/prednisolone (or prednisone/prednisolone 
equivalent) >10 mg/day. 
14. History of myocardial infarction, congestive heart failure, uncontrolled cardiac 
arrhythmia, unstable angina, coronary bypass surgery, or percutaneous coronary 
intervention ≤12 months prior to Screening. 
15. History of malignancy ≤2 years prior to Screening or ongoing malignancy other 
than basal cell carcinoma, or resected noninvasive cutaneous squamous cell 
carcinoma. 
16. Active, serious infections that require parenteral antibiotic or antifungal therapy 
≤30 days prior to Screening. 

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17. Major surgical procedure ≤30 days prior to Screening or prior organ transplantation. 
18. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic 
agents, and immune-modulating agents. 
19. Current use of prohibited medications as described in Section 4.6 of the protocol. 
20. Females who are pregnant or breastfeeding. 
21. Allergy to the study drug or its components. 
22. Use of any unapproved treatment for NASH, including but not limited to UDCA 
and berberine containing agents, ≤30 days prior to Screening. 
23. Participation in other clinical trials of investigational drugs for NASH ≤6 months 
prior to Screening. 
24. Received any investigational drugs for any other condition ≤30 days or 5 half-lives 
(whichever is longer) prior to Screening. 
25. Any other clinically significant laboratory parameters, disorders, or prior or current 
therapy that, in the opinion of the Investigator, would make the subject unsuitable 
for the study, unable to comply with the dosing and protocol requirements, or could 
confound the study outcomes. 
3.4 
ENDPOINTS 
3.4.1 
Efficacy 
3.4.1.1 
Primary Endpoint 
The primary endpoint for this study is the absolute change in LFC as measured by 
MRI-PDFF from Baseline to Week 18. Analysis of the primary endpoint is described 
in Section 9.2.3.1. 
3.4.1.2 
Secondary Endpoints 
The secondary endpoints of this study include the following: 

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1. Changes in fasting glucose and HbA1c from Baseline to Week 18. 
2. Proportion of subjects who achieve ≥30% relative reduction in LFC as measured 
by MRI-PDFF from Baseline to Week 18. 
3. Relative change in LFC as measured by MRI-PDFF from Baseline to Week 18. 
4. Proportion of subjects who normalize LFC to <5% as measured by MRI-PDFF at 
Week 18. 
5. Proportion of subjects who achieve ≥5% absolute reduction in LFC as measured by 
MRI-PDFF from Baseline to Week 18. 
6. Change in homeostasis model assessment-estimated insulin resistance (HOMA-IR) 
from Baseline to Week 18. 
7. Change in LDL-c from Baseline to Week 18. 
8. Change in serum triglycerides from Baseline to Week 18. 
9. Change in HDL-c from Baseline to Week 18. 
10. Changes in AST and ALT from Baseline to Week 18. 
11. Proportion of subjects with elevated ALT at Baseline who normalize ALT at 
Week 18. 
12. Change in Pro-C3 from Baseline to Week 18 for subjects with elevated Pro-C3 at 
Baseline. 
13. Change in the enhanced liver fibrosis (ELF) score and each component of ELF 
(tissue inhibitor of metalloproteinases 1 [TIMP-1], N-terminal pro-peptide of type 
III collagen [PIIINP], and hyaluronic acid [HA]) from Baseline to Week 18. 
14. Changes in total bile acids, 7-hydroxy-4-cholesten-3-one (C4), and fibroblast 
growth factor 19 (FGF19) from Baseline to Week 18. 
Analysis of the secondary endpoints is described in Section 9.2.3.2. 

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3.4.2 
Safety 
Adverse events and changes in physical examination, vital signs, electrocardiogram 
(ECG), and clinical laboratory values will be used to evaluate safety and tolerability. 
Adverse event incidence will be determined during the Double-Blind Treatment 
Period. Adverse event type, relationship, severity, onset, and duration will be presented 
by treatment group within the Double-Blind Treatment Period. 
3.5 
SUBJECT NUMBERING, RANDOMIZATION, AND BLINDING 
After signing the ICF, subjects will be assigned a unique subject ID number, which is 
a combination of the investigational site ID number and a sequential subject number. 
The subject ID number will be maintained throughout the course of the study and will 
be the primary number used to manage subject-related operations and documentation. 
The process for subjects who fail Screening but then repeat the Screening process due 
to a change in their eligibility status (see Section 5.1.1) will be described in the Study 
Procedures Manual (SPM) or other applicable instructions. 
Upon confirmation of subject eligibility at the Baseline visit (see Section 5.1.2), 
investigational site staff will login to the designated automated system to randomize 
the subject. Subjects will be randomized in equal numbers to 1 of 3 treatment groups: 
HTD1801 500 mg BID, 1,000 mg BID, or placebo BID. In addition to the subject ID 
number, subjects will be assigned a randomization number, as well as a kit ID number 
corresponding to a pre-packaged and numbered study drug kit (see Section 4.1.2). 
All subjects and study personnel will remain blinded to the treatment administered 
throughout the study. All study drugs will be provided in matching white tablets, 
4 tablets to a pouch, 2 pouches to be administered each day, 1 pouch in the morning 
and 1 pouch in the evening. An adequate supply of study drug will be provided to each 
subject at each clinic visit to cover the next 2- or 4-week period with additional days 
of coverage, as applicable (e.g., to provide for possible scheduling conflicts). 
In this double-blind study, if a medical emergency occurs and a decision about a 
subject’s condition requires knowledge of the study drug assignment in order to 
properly treat the subject, the study blind may be broken for that specific subject only.  
The decision to break the blind for a subject should only be made after consultation 
with the Medical Monitor or Sponsor representative. 

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Any broken blind must be clearly justified and explained by a note in the subject's 
source documents. 
3.6 
REPLACEMENT OF DROPOUTS 
Subjects who do not complete the Double-Blind Treatment Period may be replaced at 
the Sponsor's discretion.

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4.0 
STUDY DRUGS AND DOSAGES 
4.1 
IDENTIFICATION AND DESCRIPTION OF INVESTIGATIONAL PRODUCT 
4.1.1 
Investigational Product 
The HTD1801 drug substance, berberine ursodeoxycholate, is the salt formed between 
BBR and UDCA with a stoichiometry of 1:1. The HTD1801 drug product is a 
film-coated tablet containing 250 mg of berberine ursodeoxycholate. HTD1801 is 
expected to dissociate into BBR salt and UDCA after oral administration. 
4.1.2 
Labeling 
The study drugs (HTD1801 500 mg, HTD1801 1,000 mg, and placebo) will be supplied 
by HighTide and packaged into polyethylene terephthalate/aluminum foil/polyethylene 
(PET/AL/PE) pouches. Each pouch will contain 4 HTD1801 250 mg and/or 
HTD1801-matching placebo tablets and be affixed with a single-panel label that will 
describe the following information at a minimum: study drug, dose, kit number, 
Sponsor name, instructions for storage between 36°F and 46°F (2°C and 8°C), and 
includes the statements “Caution: New Drug - Limited by United States law to 
investigational use” and “Keep out of reach of children.” 
An adequate supply of pouches will be placed into kits packaged for weekly use, and 
each subject will receive the appropriate number of kits to provide enough supplies 
until their next scheduled visit to the investigational site. Each kit will bear a label 
describing the following information at a minimum: kit number, Sponsor name, 
instructions for storage between 36°F and 46°F (2°C and 8°C), and includes the 
statements “Caution: New Drug - Limited by United States law to investigational use” 
and “Keep out of reach of children.” 
4.2 
DOSING INSTRUCTIONS AND SCHEDULE 
Subjects are instructed to take the entire contents of 1 pouch of study drug each morning 
and each evening with water and food (e.g., meal or snack) during the Double-Blind 
Treatment Period.  Each pouch will contain 4 identical white tablets.  Subjects should 
retain the empty pouches and return them to the investigational site on their next visit 

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along with any unused study drug. Returned unused study drug must not be 
re-dispensed to subjects. 
4.3 
HANDLING OF INVESTIGATIONAL PRODUCT 
The Investigator will be fully responsible for the security, accessibility, and storage of 
the study drugs while they are at the investigational site.  The Investigator is also 
responsible for the education of site staff in the correct administration of the study drugs 
and must ensure that appropriate study drug accountability records are maintained. 
4.4 
COMPLIANCE WITH INVESTIGATIONAL PRODUCT 
At 
applicable 
clinic 
visits 
during 
the 
Double-Blind 
Treatment 
Period 
(see Section 5.1.3), subjects will be queried about their compliance with taking their 
assigned study drug as instructed. The number of full and empty study drug pouches 
will be captured on the electronic case report form (eCRF). 
4.5 
CONCOMITANT MEDICATIONS 
The use of permitted concomitant medications may continue during the study at the 
same dosage strength and frequency. If subjects are receiving permitted medications, 
doses and regimens should be stable as described in Section 3.3.1: 
• 
Thiazolidinediones, GLP-1 agonists, DPP-4 inhibitors, or SGLT-2 inhibitors 
must be stable for ≥90 days prior to randomization; 
• 
Vitamin E dose of ≤400 IU must be stable for ≥90 days prior to randomization 
with no anticipated dose increases during the study; 
• 
Regimens for other concomitant medications must be stable for ≥28 days prior to 
randomization. 
Changes to permitted concomitant medications are not to be made unless medically 
necessary. The Medical Monitor may be consulted, as needed, on such changes. The 
need for medication or dose changes must be documented in the subject’s source 
documents (e.g., in response to an AE). 

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During the Double-Blind Treatment Period, concomitant medications should not be 
taken within 1 hour prior to dosing of study drug or up to 6 hours following dosing of 
study drug. 
Note the following for specific concomitant medications: 
• 
Dose adjustments for T2DM medication regimens, including those for metformin 
and insulin, will primarily be made in consultation with the subject’s primary care 
physician. 
• 
Short courses of oral prednisone/prednisolone (or prednisone/prednisolone 
equivalent) ≤10 mg/day for conditions unrelated to NASH (e.g., allergic reaction) 
are permitted. 
• 
The study drug should be taken >1 hour before or 4-6 hours after taking any of 
the following: bile acid sequestering agents (e.g., cholestyramine and colestipol), 
aluminum-based antacids (e.g., aluminum hydroxide), or traditional Chinese 
medicines. 
• 
Based on HTD1801 human PK data and in vitro inhibition of cytochrome P450 
(CYP450) and uridine diphosphate glucuronosyltransferase (UGT) enzymes, a 
meaningful inhibition of CYP2D6, CYP3A4, and UGT enzymes at the doses used 
in this study is not expected. Other than those listed in Section 4.6, Table 4, the 
concomitant use of statins, selective serotonin reuptake inhibitors, serotonin and 
norepinephrine reuptake inhibitors, and other antidepressants (i.e., agomelatine, 
mirtazapine, reboxetine, vilazodone, and vortioxetine) is permitted. 
4.6 
PROHIBITED CONCOMITANT MEDICATIONS 
Certain concomitant medications have been identified for exclusion from this study 
and are not to be taken at any time during the entire study (i.e., from Screening through 
the Follow-up Period).  These exclusions are primarily due to the potential drug 
interaction profile of the BBR component of HTD1801. Table 4 lists medications 
known to be strong inhibitors of P-glycoprotein (P-gp), CYP3A4, and CYP2D6; strong 
inducers of CYP3A4; as well as P-gp substrates with a narrow therapeutic index, and 
that are prohibited from concomitant use during this study. 

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Table 4. 
Prohibited Medications 
Single Agents: 
P-glycoprotein 
CYP3A4 
CYP2D6 
clarithromycin 
clarithromycin 
ritonavir 
bupropion 
erythromycin 
telithromycin 
saquinavir 
fluoxetine 
amiodarone 
troleandomycin 
telaprevir 
fluvoxamine 
digitalis 
nefazodone 
tipranavir 
paroxetine 
dronedarone 
St. John's wort 
chloramphenicol 
quinidine 
carvedilol 
itraconazole 
rifampin 
terbinafine 
propafenone 
ketoconazole 
cobicistat 
 
quinidine 
posaconazole 
grapefruit juice 
 
ranolazine 
voriconazole 
conivaptan 
 
verapamil 
atazanavir 
diltiazem 
 
sildenafil 
boceprevir 
idelalisib 
 
itraconazole 
darunavir 
enzalutamide 
 
ketoconazole 
indinavir 
mitotane 
 
ritonavir 
lopinavir 
carbamazepine 
 
saquinavir 
nelfinavir 
phenytoin 
 
telaprevir 
 
 
 
lapatinib 
 
 
 
Combination Agents: 
P-glycoprotein 
CYP3A4 
lopinavir and ritonavir 
danoprevir and ritonavir 
saquinavir and ritonavir 
elvitegravir and ritonavir 
tipranavir and ritonavir 
indinavir and ritonavir 
 
lopinavir and ritonavir 
 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
 
saquinavir and ritonavir 
 
tipranavir and ritonavir 
Source: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLa
beling/ucm093664.htm (Tables 2-2, 2-3, 3-2, 3-3, and 5-2) 
The Investigator should consult the Medical Monitor, as needed, on the concomitant 
use of any additional medications. 

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4.7 
MANAGEMENT OF CONCOMITANT CONDITIONS 
In general, the Investigator should advise subjects to consult their primary care 
physician as medically warranted. 
Specifically for the management of T2DM, the Investigator will instruct study subjects 
to visit or consult their primary care physician if clinical laboratory results or other 
symptomatology indicate a hypoglycemic or hyperglycemic state. The Investigator will 
advise subjects on routine blood glucose monitoring and follow-up with their primary 
care physician, consistent with the subjects’ standard T2DM management practices, as 
well as instruct subjects to report any signs or symptoms of low or high blood glucose 
for appropriate management and follow-up. 
4.8 
LIFESTYLE CONSIDERATIONS 
All subjects will receive a hand-out of standard recommendations about lifestyle 
modification, including, but not limited to: dietary modification, weight loss, exercise, 
the use of dietary supplements, and alcohol consumption. Subject adherence to diet and 
lifestyle recommendations will not specifically be assessed. 

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5.0 
5.1 
5.1.1 
EXPERIMENTAL PROCEDURES 
PROCEDURES, MEASUREMENTS, AND EVALUATIONS 
Study procedures are summarized across all scheduled study visits as indicated in the 
Study Design (Figure 1) and the Schedule of Time and Events (Table 1). Unscheduled 
visits may also occur at any time if medically warranted. Study related assessments 
performed at all visits will be recorded in the eCRF. 
Throughout the study, clinical laboratory (blood and urine) samples will be 
collected during a fasting state (i.e., at least 8 hours prior to sample collection) and 
sent to the designated central laboratory for analysis.  Study drug should be taken 
with water and food (e.g., meal or snack). 
For subjects who cannot be contacted for either a return for a scheduled clinic visit or 
for follow-up assessments as described in this section, and who may be considered “lost 
to follow-up,” at least 3 documented attempts should be made to establish contact with 
and to instruct the subject on how to complete study procedures. In the final attempt to 
contact the subject, a letter should be sent by certified mail to the subject’s last known 
address. 
Screening (Days -28 to -1) 
Prior to any clinical procedures and evaluations, written signed informed consent must 
be obtained. Screening procedures must be completed within 28 days prior to the 
Baseline visit and can be performed across multiple days during this period. Screening 
clinical laboratory tests (see Sections 6.2.2 and 6.3.4) may be repeated once during 
Screening if the Investigator believes the results to be erroneous. In the event that 
Screening tests are repeated, the most current results will be used to determine 
eligibility. Potential subjects who do not meet all eligibility criteria at Screening will 
be allowed to re-screen once if the Investigator believes that there has been a change 
in eligibility status. If a potential subject fails to meet eligibility criteria upon re-screen, 
he/she will remain ineligible for the study. 
During Screening, the following procedures must be conducted and assessments 
obtained.  The information will be collected in the investigational site’s standard source 
documents or in source document templates provided by the Sponsor. 

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• 
Informed consent 
• 
Confirm eligibility criteria 
• 
Demographic information 
• 
Medical history 
• 
Comprehensive physical examination 
• 
Vital signs 
• 
Weight and height 
• 
12-lead ECG 
• 
Serum chemistry panel 
• 
Lipid panel 
• 
Hematology with differential 
• 
Coagulation panel 
• 
HbA1c 
• 
HIV and Hepatitis B/C 
• 
G6PD 
• 
Serum pregnancy test (for FOCP) 
• 
FSH test (for postmenopausal females) 
• 
Urine drug test 
• 
MRI-PDFF 
• 
Corrected T1 and T2* 
• 
AEs 
• 
Prior and concomitant medications 
Potential subjects who have successfully completed all of the Screening procedures and 
who have met all the eligibility criteria (see Sections 3.3.1 and 3.3.2) will be eligible 
for enrollment in the study. Eligible subjects will be instructed to stop all prohibited 
medications (see Section 4.6) prior to beginning Baseline procedures. 
5.1.2 
Baseline (Day 0) 
Prior to randomization, potential subjects will undergo the following Baseline 
procedures and assessments: 
• 
Updated medical history 
• 
Targeted physical examination 
• 
Vital signs 
• 
Weight 
• 
12-lead ECG 
• 
Urine pregnancy test (for FOCP) 
• 
Updated 
prior 
and 
concomitant 
medications 
• 
AEs that have occurred since signing 
informed consent 
If potential subjects continue to satisfy the eligibility criteria based upon the procedures 
and assessments stated above, those data will become part of the Baseline visit.  Those 
potential subjects may then be randomized and officially become subjects in the study.  
Subjects will again be instructed to avoid any use of the prohibited medications listed 
in Section 4.6 for the entire duration of the study, or until formally instructed otherwise. 

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Prior to dosing, the following additional Baseline procedures and assessments will be 
conducted at the investigational site. The Baseline central laboratory data will not be 
used to determine eligibility in the study as the newly enrolled subject has already been 
randomized. The additional pre-dose Baseline procedures include: 
• 
Serum chemistry panel 
• 
Lipid panel 
• 
Hematology with differential 
• 
Coagulation panel 
• 
HOMA-IR 
• 
Serum pregnancy test (for FOCP) 
• 
Pro-C3 
• 
ELF test 
• 
Bile acid panel 
Following the successful completion of all Baseline procedures, the subject will 
self-administer the first dose of the study drug, consisting of 4 tablets (1 pouch), under 
the supervision of investigational site staff. A 2-week supply of study drug will be 
dispensed to the subject to take home, and the dosing instructions and schedule will be 
provided (see Section 4.2).  Subjects will be instructed to contact the investigational 
site immediately if any problems or concerns arise. 
5.1.3 
Double-Blind Treatment Period (Weeks 2, 6, 10, 14, 18) 
During the Double-Blind Treatment Period, the following procedures and assessments 
will be conducted during the visits to the investigational site on: 
Week 2 – 
• 
Weight 
• 
Serum chemistry panel 
• 
AE monitoring 
• 
Concomitant medications 
Weeks 6 and 14 – 
• 
Targeted physical examination 
• 
Vital signs 
• 
Weight 
• 
12-lead ECG 
• 
Serum chemistry panel 
• 
AE monitoring 
• 
Concomitant medications 

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Week 10 – 
•
Weight
•
Serum chemistry panel
•
Lipid panel
•
Hematology with differential
•
Coagulation panel
•
HbA1c
•
Bile acid panel
•
AE monitoring
•
Concomitant medications
Week 18 – 
•
Comprehensive physical examination
•
Vital signs
•
Weight
•
12-lead ECG
•
Serum chemistry panel
•
Lipid panel
•
Hematology with differential
•
Coagulation panel
•
HbA1c
•
HOMA-IR
•
Serum pregnancy test (for FOCP)
•
MRI-PDFF
•
Pro-C3
•
ELF test
•
Bile acid panel
•
AE monitoring
•
Concomitant medications
Note: The serum chemistry panel performed at the Week 2, Week 6, and Week 14 
visits only includes testing of alkaline phosphatase (ALP), ALT, AST, 
gamma-glutamyl transferase (GGT), total bilirubin, direct bilirubin, and fasting 
glucose. The Week 10 and Week 18 bile acid panel applies only to subjects who have 
had the Baseline bile acid panel performed. Refer to Table 1 and Table 2 for the clinical 
laboratory collection schedule and corresponding analytes, respectively. 
At the completion of the Weeks 2, 6, 10 and 14 clinic visits, the next 4-week supply of 
study drug will be dispensed to the subject. At all visits, used and unused study drug 
pouches will be collected from the subject; compliance with taking the study drug will 
be assessed. 
Prior and concomitant medications will be reviewed and any changes will be recorded 
on the appropriate eCRF page.  Generally, any new medications that are being taken 
are, by default, to be considered as being necessitated by an AE.  Rarely, a previously 
unmentioned prior medication may be disclosed, and that eCRF page should be 
updated. 

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The subject is to be queried for any changes to existing AEs or any additional AEs that 
may have occurred during the intervening period. 
5.1.4 
Study Discharge 
Following the successful completion of all procedures at the Week 18 visit of the 
Double-Blind Treatment Period, all subjects are to undergo study discharge procedures.  
This will include instructions to the subject to contact the investigational site 
immediately if any problems or concerns arise during the next 30 days of follow-up 
(see Section 5.1.6). 
5.1.5 
Early Termination 
Should a subject permanently discontinue taking his/her assigned study drug, an Early 
Termination (ET) visit should be performed. The ET visit procedures and assessments 
are the same as those performed at the Week 18 visit (see Section 5.1.3).  If the ET visit 
coincides with a regularly scheduled study visit, the ET visit procedures and 
assessments will be performed in its place. The subject will then be instructed to contact 
the investigational site immediately if any problems or concerns arise during the next 
30 days of follow-up (see Section 5.1.6). 
5.1.6 
Follow-up Period 
All subjects will undergo follow-up evaluations at least 30 days after the last dose of 
study drug. The follow-up can be via telephone, provided that the subject has no health 
concerns related to the study.  The subject may be asked to return to the investigational 
site if the Investigator thinks it is advisable for safety reasons. The following 
assessments will be conducted by telephone (or other) contact: 
• 
AE monitoring 
• 
Concomitant medications (query for any possible relationship to an AE) 
Following the completion of the follow-up procedures, the subject is officially 
discharged from the study. 
 

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6.0 
6.1 
6.1.1 
6.1.2 
6.1.3 
CONDUCT OF STUDY PROCEDURES AND ASSESSMENTS 
For all study procedures and assessments described in this section, refer to the Schedule 
of Time and Events (Table 1) and Section 5.0. 
ADMINISTRATIVE PROCEDURES 
Demographics and Medical History 
The Investigator or qualified designee will obtain demographic data, medical history, 
and medication history for each potential subject at Screening. Demographic data will 
include, at a minimum, the subject’s age and/or date of birth, sex, race, and ethnicity. 
Medical and medication history will include relevant medical conditions and 
treatments, including surgical procedures, within the last 10 years of Screening that the 
Investigator considers clinically significant. 
Randomization and Study Drug Management 
Upon confirmation of subject eligibility at the Baseline visit (see Section 5.1.2), 
investigational site staff will login to the designated automated system to randomize 
the subject and to dispense the assigned study drug kits. The designated automated 
system will also be used throughout the study to enter study visit data, update the 
subject’s study disposition, and for study drug supply management. Refer to the SPM 
or applicable instructions for further system and process related details. 
Subject Reminder Cards 
Subject reminder cards will be provided to all (potential) subjects at each study visit. 
The reminder cards will inform the subject of the date and time of his/her next 
scheduled visit and will include any necessary instructions. 
6.2 
EFFICACY ASSESSMENTS 
6.2.1 
Magnetic Resonance Imaging 
Magnetic resonance imaging-estimated proton density fat fraction will be utilized as 
the primary efficacy measure to quantify LFC. Proton density fat-fraction, which is a 
fundamental property of tissue that measures hepatic fat concentration based on the 

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6.2.2 
density of mobile protons from fat (triglycerides) compared to the total density of 
protons from mobile triglycerides and mobile water, is well-accepted as a standardized 
non-invasive biomarker of LFC (Reeder et al., 2012). 
Corrected T1 (or iron-corrected T1) is an MRI-based technique that characterizes 
tissue in vivo based on the fluidity of water protons within the tissue. Relative to liver 
tissue, the T1 measurement of free water increases with inflammation and fibrosis, but 
must be corrected due to the confounding effect of iron (Banerjee et al., 2014). While 
cT1 will not be utilized as an efficacy measure for this study, it will be utilized as a 
biomarker of fibrosis to qualify potential subjects given its reported correlation with 
histological parameters of liver disease (Pavlides et al., 2016). 
Investigational sites will utilize their local MRI facility, which will be qualified 
according to a study-specific image acquisition protocol, to acquire the MRI-PDFF and 
cT1 scans. Magnetic resonance imaging scans will be performed on the subjects’ 
abdominal region and will last approximately 10 minutes. Scan data will then be 
transmitted electronically via a secure portal to a central imaging laboratory for 
analysis. Central imaging specialists blinded to the clinical data will use the 
LiverMultiScan Discover™ (LMSD; Perspectum Diagnostics, Oxford, United 
Kingdom) investigational device to analyze the scans and report the MRI-PDFF, cT1, 
and T2* results to the investigational sites. The MRI-PDFF, cT1, and T2* results will 
be reported at Screening, with MRI-PDFF and cT1 as part of the eligibility criteria. At 
a minimum, clinical metrics for the MRI-PDFF will be reported at the Week 18 or ET 
visit. Technical and analysis specifications and procedures, including the blinded 
reporting of any results, will be detailed in the central imaging manual, imaging charter, 
and/or SPM. 
Efficacy Related Laboratory and Biomarker Assessments 
A central laboratory will be utilized to perform efficacy related clinical laboratory and 
biomarker assessments as specified in Table 1 and Table 2 and as described in this 
section. Samples for laboratory and biomarker assessments performed at Baseline must 
be collected prior to study drug dosing. The Investigator or qualified designee must 
review the results of all central laboratory testing to assess subject eligibility at 
Screening and Baseline, as well as continued study participation for the duration of the 
Double-Blind Treatment Period. Procedures for sample collection and handling, 

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including the blinded reporting of any results, will be detailed in the central laboratory 
manual and/or SPM. 
The following laboratory and biomarker assessments will be utilized as secondary 
efficacy measures: 
Fasting glucose, HbA1c, HOMA-IR, serum triglycerides, LDL-c, and HDL-c will be 
utilized in this study to assess glucose metabolism, insulin resistance, and lipid 
metabolism. These measures are routinely performed in the management of metabolic 
abnormalities that underlie the pathogenesis of NAFLD, including dyslipidemia and 
T2DM, the latter of which is recognized as a risk factor for progressive hepatic fibrosis 
(Adams and Angulo 2006). 
Aspartate aminotransferase and ALT are liver-associated enzymes that will be utilized 
in this study to assess liver biochemistry. These enzymes are markers of liver injury 
that may be useful surrogate measures of NAFLD and NASH, particularly in T2DM 
patients (Sanyal et al., 2015). 
Pro-C3 and the ELF score are biomarkers that will be utilized in this study to assess 
liver inflammation and fibrosis. Pro-C3 is a neo-epitope of PIIINP, which has been 
reported to reflect the true formation of collagen and to potentially be an accurate 
biomarker for the formation of fibrotic tissue in the liver (Nielsen et al., 2013). The 
ELF score is a set of extracellular matrix markers that consists of TIMP-1, PIIINP, and 
HA, and has been reported to show good correlations with fibrosis stages in chronic 
liver disease (Lichtinghagen et al., 2013). 
Total bile acids, C4, and FGF19 are biomarkers that will be utilized in this study to 
assess bile acid homeostasis. Factors implicated in the pathogenesis of NASH, such as 
obesity or increased BMI, insulin resistance, and elevated AST and ALT serum 
concentrations to the dysregulation and increase of serum bile acids. Likewise, 
elevations in serum C4, an indicator of bile acid synthesis in vivo, have been observed 
in NASH patients. Conversely, reduced serum concentrations of FGF19, which inhibits 
the rate-limiting enzyme CYP7A1 to regulate bile acid synthesis, have also been 
observed in NASH patients (Zhang and Deng 2018). Furthermore, the results of a 
recent study of BBR administered to wild type and farnesoid X receptor (FXR) 

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knockout mice suggest that BBR may exert its lipid-lowering effect by modulating bile 
acid turnover and activating the FXR-FGF19 signaling pathway (Sun et al., 2017). 
6.3 
SAFETY ASSESSMENTS 
6.3.1 
Physical Examinations 
Physical examinations must be performed at investigational sites by medically 
qualified individuals according to local requirements. Abnormal physical examination 
findings that the Investigator considers clinically significant are to be reported as AEs. 
The comprehensive physical examination will include the assessment of the following: 
skin; head, neck, eyes, ears, nose, throat; upper and lower extremities; chest and lungs; 
abdomen; cardiovascular system; and a brief neurological examination. The targeted 
physical examination will be a symptom-driven assessment of body systems or organs 
as indicated by AEs or other findings. 
6.3.2 
Vital Signs, Height, and Weight 
Vital sign measurements must be performed at investigational sites by medically 
qualified individuals according to local requirements. Measurements include blood 
pressure, pulse, respiratory rate, and body temperature. Blood pressure and pulse will 
be taken in a recumbent, semirecumbent, or sitting position after 5 minutes of rest. 
Height (at Screening only) and weight will also be performed. Abnormal findings that 
the Investigator considers clinically significant are to be reported as AEs. 
6.3.3 
Electrocardiograms 
Twelve-lead ECGs will be performed at the investigational site with the subject in a 
recumbent or semirecumbent position after 5 minutes of rest. Local institutional 
standards for QT interval corrections should be utilized. Interpretation of ECG results 
for the ongoing assessment of safety will be performed by the Investigator or qualified 
designee during the scheduled visit. Abnormal ECG readings that the Investigator 
considers clinically significant are to be reported as AEs. Additionally, the Investigator 
should consult the Medical Monitor, when possible, for any abnormal, clinically 
significant ECG findings that may result in a change to the subject’s treatment or 
management. 

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6.3.4 
6.3.5 
6.3.6 
Safety Related Laboratory Assessments 
A central laboratory will be utilized to perform safety related clinical laboratory 
assessments as specified in Table 1 and Table 2 and as described in this section. 
Samples for laboratory assessments performed at Baseline must be collected prior to 
study drug dosing. The Investigator or qualified designee must review the results of 
all central laboratory testing to assess subject eligibility at Screening and Baseline, as 
well as continued study participation for the duration of the Double-Blind Treatment 
Period. Procedures for sample collection and handling, including the blinded reporting 
of any results, will be detailed in the central laboratory manual and/or SPM. 
In addition to standard serum chemistry, lipid, hematology, and coagulation panels 
(see Table 2) conducted at specific visits throughout the study, samples to assess HIV 
and Hepatitis B/C, G6PD, and recreational drug use will only be collected at Screening 
to determine those factors that could render the subject unsuitable for the study or 
confound study results. 
A local laboratory will perform serum pregnancy testing at Screening, Baseline, and at 
the Week 18 visit for all FOCP. A locally performed urine pregnancy test will also be 
done at Baseline. A local laboratory will perform FSH testing at Screening for all 
postmenopausal females. 
Adverse Events 
Adverse events will be collected from the time at which the potential subject signs the 
ICF. Subjects will be instructed to report all AEs during the study and will be assessed 
for the occurrence of AEs throughout the study until at least 30 days after discontinuing 
the study drug. General and non-leading questions such as “How are you feeling?” 
should be asked when assessing the occurrence of AEs. The definition, reporting, and 
recording requirements for AEs are described in Section 7.0. 
Prior and Concomitant Medications 
Prior and concomitant medications will be reviewed to determine study eligibility for 
potential subjects and to monitor continued study participation. In addition to 
medication history (see Section 6.1.1), any medication, including prescription, 
over-the-counter, or natural/herbal preparations, received within 28 days of 

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randomization and the first dose of study drug through at least 30 days after 
discontinuing the study drug must be recorded in the eCRF. Changes to medication 
doses or regimens, e.g., in response to an AE, must also be recorded in the eCRF. See 
Sections 4.5 and 4.6 for details on non-prohibited and prohibited medications. 
 

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7.0 
PROCEDURES FOR HANDLING ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS 
7.1 
DEFINITION OF AN ADVERSE EVENT 
The following definition of an AE will be used for this study: Adverse event means any 
untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of the investigational product, regardless of whether it is considered to be related to the 
investigational product. 
The following are examples of AEs: 
• 
Significant or unexpected worsening or exacerbation of the indication under 
study. 
• 
Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in frequency or intensity of the condition. 
• 
New conditions detected or diagnosed after investigational product 
administration, even if they were present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction with another 
medical product. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concurrent medication. 
Overdose should not be reported as an AE or serious adverse event (SAE), but rather 
the symptoms resulting from the overdose should be reported as such. 
Examples of AEs do not include the following: 
• 
Medical or surgical procedures (e.g., endoscopy, appendectomy). The medical 
condition that led to the procedure as the AE should be reported. 

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• 
Situations that are unwanted by the subject but in which an untoward medical 
occurrence did not occur, for example social inconvenience after admission to a 
hospital. 
• 
Anticipated day-to-day fluctuations of a pre-existing disease or condition (present 
or detected before enrollment) that does not worsen overall. 
• 
Expected progression of the disease being studied, including signs or symptoms 
of the disease, unless progression is more severe than expected for the subject’s 
condition. 
Adverse events may include pre-treatment or post-treatment events that occur as a 
result of protocol-mandated procedures (e.g., invasive procedures, modification of the 
subject’s previous therapeutic regimen). 
Adverse events should be captured even if they occur during periods without drug 
treatment, post-treatment periods, known placebo treatment, or in a reference or control 
group receiving drug or nondrug therapy. 
The Investigator is responsible for all AE assessments. The Investigator and 
investigational site staff will note all AEs mentioned by the subject at Baseline and 
during study drug administration. All clinical complaints volunteered by or elicited 
from the subject during the study will be recorded on the appropriate page of the eCRF 
for the study period indicated (see Section 6.3.5). The subject will receive appropriate 
treatment and medical supervision for any AE that occurs. 
All AEs judged to be clinically significant, including clinically significant laboratory 
abnormalities, will be followed until resolution. All AEs will be summarized in the 
annual report or more frequently if requested by the regulatory agency. Serious adverse 
events require special reporting in addition to documentation in the eCRF as described 
in Section 7.7. 
 

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7.2 
DEFINITION OF A SERIOUS ADVERSE EVENT 
In this study, an SAE is defined as an AE that meets any of the following criteria: 
• 
Results in death. 
• 
Is life-threatening.  The term life-threatening in the definition of an SAE refers to 
an event in which the subject was at risk of death at the time of the event. The 
term life-threatening does not refer to an event that, had it occurred in a more 
severe form, might have caused death.  
• 
Requires hospitalization or a prolongation of an existing hospitalization. In 
general, hospitalization signifies that the subject has been detained at the hospital 
or emergency ward for observation or treatment that would not have been 
appropriate in the physician’s office or out-patient setting. Complications that 
occur during hospitalization are AEs, but not necessarily SAEs. A medical 
occurrence or complication that prolongs hospitalization is an SAE. When there 
is doubt as to whether hospitalization occurred or was necessary, the AE should 
be considered an SAE. Hospitalization for elective treatments of a preexisting 
condition that did not worsen from its original Baseline level is not considered an 
SAE. 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. This does not include AEs of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza and accidental trauma (e.g., sprained ankle) that may interfere 
or prevent everyday life functions but do not constitute a substantial disruption. 
• 
A congenital anomaly or birth defect. This refers to the offspring of a study 
subject. 
• 
An other important medical event. Medical or scientific judgment should be 
exercised when deciding whether reporting is appropriate for other important 
medical events that may not result in death, be life-threatening, or require 
hospitalization but still may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed in this definition. These events 
should also be considered serious. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 

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dyscrasias, or convulsions that do not result in hospitalization or in the 
development of drug dependency or drug abuse. 
7.3 
7.4 
An SAE requires additional detailed reports and follow-up. The content of these 
detailed reports must address the Investigator’s estimate of causality. The Medical 
Monitor will review the SAE to determine if it is an expected SAE (i.e., whether or not 
the SAE is identified in nature, severity, and frequency in the Investigator’s Brochure). 
RECORDING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
When an AE or SAE occurs, the Investigator is responsible for reviewing all 
documentation (e.g., hospital progress notes, laboratory, and diagnostic reports) 
relative to the event(s). The Investigator will record all relevant information about any 
AE (including SAEs) on the AE page of the eCRF. It is not acceptable for the 
Investigator to send photocopies of the subject’s medical records in lieu of the properly 
completed AE or SAE pages of the eCRF. These documents should not be sent unless 
they are specifically requested by the Sponsor’s or designee’s pharmacovigilance 
department. If this request occurs, all subject identifiers and protected health 
information should be blinded on the copies of the medical records before submission 
to the pharmacovigilance department and to the appropriate authorities. 
The Investigator will also attempt to report a diagnosis, instead of signs, symptoms, or 
other clinical information, for the AE. The diagnosis, not the individual signs and 
symptoms, should be documented on the appropriate page of the eCRF as the AE or 
SAE. In addition, SAEs need to be reported in the SAE report. Adverse events being 
processed as SAEs will also require additional documentation. The SPM (or other 
applicable instructions) provides additional guidelines about reporting SAEs. 
ASSESSMENT OF INTENSITY 
The Investigator will assess the intensity for each AE and SAE reported during the 
study on the basis of his or her clinical judgment.  The classifications in Table 5 should 
be used in assigning intensity of each AE recorded in the eCRF. 

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Table 5. 
Classification of AEs by Intensity 
Intensitya 
Definition 
Mild AE 
(Grade 1) 
An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities 
Moderate AE 
(Grade 2) 
An event that is sufficiently discomforting to the extent of interfering with 
normal everyday activities 
Severe AE 
(Grade 3) 
An event that prevents the subject from performing normal everyday 
activities 
Life-threatening or 
disabling AE 
(Grade 4) 
An event that, at the time of occurrence, put the subject at risk of death or 
resulted in a persistent or significantly disability or incapacity 
Death related to AE 
(Grade 5) 
An event that resulted in death 
a From Common Terminology Criteria for Adverse Events, Version 4.0 
Any AE that changes in intensity or grade during a single occurrence of an AE will be 
recorded in the eCRF at the highest level experienced by the subject. 
An AE that is assessed as severe should not be confused with an SAE. Severity is a 
category used for rating the intensity of an AE (such as mild, moderate, or severe 
myocardial infarction). However, an AE itself may be of relatively minor medical 
significance, such as a severe headache. Both AEs and SAEs can be assessed as severe. 
An AE is considered serious when it meets one of the predefined outcomes described 
in Section 7.2. 
7.5 
ASSESSMENT OF CAUSALITY 
The Investigator must estimate the relationship between the investigational product and 
the occurrence of each AE or SAE by using his or her best clinical judgment. Elements 
to consider for this estimate include the history of the underlying disease, concomitant 
therapy, other risk factors, and the temporal relationship of the AE or SAE to the 
investigational product. The Investigator will also consult the Investigator’s Brochure 
or product label for marketed products in estimating the relationship. 
Because of reporting timelines, the Investigator might have minimal information to 
include in the initial SAE report. However, the Investigator must always make an 
assessment of causality for every SAE before the transmission of the SAE report. The 

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Investigator may change his or her opinion of the causality in light of follow-up 
information, with subsequent amendment of the SAE report. Causality assessment is a 
criterion used to determine regulatory reporting requirements and should not be left 
blank on the eCRF. The same applies to AEs that are to be processed as SAEs. 
Table 6 provides some definitions to use in the assessment. 
Table 6. 
Assessment of Causality of AEs 
Term 
Definition 
Possibly related 
The AE may be related to the investigational agent(s) or intervention: the AE 
has a temporal relationship to the administration of the investigational 
agent(s) or research intervention. 
Unrelated 
(or not related) 
The AE is clearly not related to the investigational agent(s) or intervention: 
the AE has no temporal relationship to the administration of the 
investigational agent(s) or research intervention, and follows no known or 
suspected pattern of response, and an alternative cause is present.  
7.6 
EXPECTEDNESS OF SERIOUS ADVERSE EVENTS 
An expected AE is one that is consistent with the known risk information described in 
the product label (if applicable) or the current Investigator’s Brochure. The 
expectedness of an SAE will be assessed by the Medical Monitor and Sponsor on 
receipt of the initial SAE report. 
7.7 
REPORTING OF SERIOUS ADVERSE EVENTS 
1. Any SAE occurring after the subject signs the ICF and the study drug has been
administered, as described in Section 7.1, must be reported to the Sponsor’s or
designee’s pharmacovigilance department by phone, fax, or e-mail within 24 hours
of the time the Investigator becomes aware of the SAE (Table 7).  Any SAE
reported by phone should be immediately followed up with the submission of the
completed SAE report form.  Urgent reporting of SAEs is required for the following
reasons:
a.
To enable the Sponsor to fulfill the reporting requirements to the appropriate
regulatory authority;

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b. To facilitate discussion between the Sponsor and the Investigator about 
appropriate follow-up measures (if necessary); 
c. To facilitate the Sponsor’s rapid dissemination of information about AEs to 
other investigators or sites in a multicenter study; 
d. To facilitate reporting unanticipated problems involving risk to subjects to the 
institutional review board (IRB) or independent ethics committee (IEC). 
Table 7. 
Timeline for Reporting SAEs 
Initial SAE Report 
Follow-up SAE Report 
Time Frame 
Documents 
Time Frame 
Documents 
24 hours 
SAE report 
7 days 
Updated SAE report 
The SAE report will be completed as thoroughly as possible, including the following: 
• 
Subject identification information; 
• 
Event term; 
• 
All available details about the SAE; 
• 
Causality of each SAE; 
• 
Signature of the Investigator. 
The SAE report will be forwarded to the Sponsor’s or designee’s pharmacovigilance 
department within the designated time frames. If additional information to complete 
the SAE report is needed, the Investigator will not wait before notifying the 
pharmacovigilance department of the SAE. The SAE report will be updated by the 
Investigator when additional information is received. 
7.8 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
After the initial AE or SAE report, the Investigator is required to proactively follow 
each subject and provide further information to the Sponsor about the subject’s 
condition. All AEs and SAEs will be followed until the occurrence of one of the 
following: 

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•
The condition resolves;
•
The AE or SAE is considered not causally related to investigational product;
•
The subject is lost to follow-up;
•
The subject is followed for at least 30 days after the last dose of study drug (or
other appropriate time frame);
•
The subject starts another investigational product.
7.9 
The appropriate SAE report will be updated once the SAE resolves, stabilizes, or is 
otherwise explained, or until the subject is lost to follow-up. The Investigator also will 
ensure that updates include any supplemental data that may explain causality of the 
SAE(s). 
New or updated information will be recorded on a copy of the initial SAE report form; 
all incorrect data should be marked out (by a single line), initialed, and dated by the 
Investigator or designee, with the new information clearly recorded. The updated SAE 
report form will then be signed and dated by the Investigator and resubmitted to the 
Sponsor’s or designee’s pharmacovigilance department as outlined in Table 7. 
LIVER ADVERSE EVENTS 
The algorithm (Chalasani and Regev 2016) described in Table 8 will be used to monitor 
for drug-induced liver injury (DILI). 
Table 8. 
Algorithm to Monitor for DILI 
Treatment Emergent 
ALT 
Treatment Emergent 
Total Bilirubin (TB) 
Liver Symptoms 
Actions 
Normal Baseline: 
ALT >2x ULN 
Normal 
None 
• Repeat ALT, AST,
ALP, TB, in 2-5
days after receipt of
the scheduled ALT
results (Table 1).
• Follow up for
symptoms.
Elevated Baseline: 
ALT >2x Baseline or 
>300 U/L (whichever
occurs first)
Patients with Gilbert’s 
syndrome: No change 
in Baseline TB 

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Treatment Emergent 
ALT 
Treatment Emergent 
Total Bilirubin (TB) 
Liver Symptoms 
Actions 
Normal Baseline: 
ALT >5x ULN 
Normal 
None 
• Interrupt study
drug.
• Initiate close
monitoring and
workup for
competing
etiologies.
• Study drug can be
restarted only if
another etiology is
identified and liver
enzymes return to
baseline.
Elevated Baseline: 
ALT >5x Baseline or 
>500 U/L (whichever
occurs first)
Patients with Gilbert’s 
syndrome: No change 
in Baseline TB 
Normal Baseline: 
ALT >2x ULN 
TB >2x ULN 
None 
• Interrupt study
drug.
• Initiate close
monitoring and
workup for
competing
etiologies.
• Study drug can be
restarted only if
another etiology is
identified and liver
enzymes return to
baseline.
Elevated Baseline: 
ALT >2x Baseline or 
>300 U/L (whichever
occurs first)
Patients with Gilbert’s 
syndrome: Doubling 
of direct bilirubin 
Normal Baseline: 
ALT >2x ULN 
Normal or elevated 
Severe fatigue, nausea, 
vomiting, right upper 
quadrant pain 
• Interrupt study
drug.
• Initiate close
monitoring and
workup for
competing
etiologies.
• Study drug can be
restarted only if
another etiology is
identified and liver
enzymes return to
baseline.
Elevated Baseline: 
ALT >2x baseline or 
>300 U/L (whichever
occurs first)
- 
Note: Baseline is the average of the Screening and Baseline visit ALT measurements. 
As described in Table 8, close monitoring of the subject must be initiated if certain 
signals of a possible DILI are detected. At a minimum, close monitoring includes: 

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• 
Repeating liver enzyme and serum bilirubin tests 2-3 times weekly. The 
frequency of retesting can decrease to once a week or less if abnormalities 
stabilize or if the study drug has been discontinued and the subject is 
asymptomatic. 
• 
Obtaining a more detailed history of the subject’s symptoms and prior or 
concurrent diseases. 
• 
Obtaining a history of the subject’s concomitant medication use (including 
non-prescription medications and herbal/dietary supplement preparations), 
alcohol use, recreational drug use, and special diets. 
• 
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease. 
• 
Obtaining a history of the subject’s exposure to environmental chemical agents. 
• 
Obtaining additional tests to evaluate the subject’s liver function, as appropriate 
(e.g., INR, direct bilirubin). 
• 
Considering gastroenterology or hepatology consultations. 
At a minimum, the Medical Monitor should be consulted on events that may be 
considered DILI. Rechallenge is not recommended if it is determined that the subject 
has experienced DILI. 
7.10 
PREGNANCY 
When any member of the investigational site staff becomes aware of a subject’s (or 
subject’s partner’s) pregnancy, the site staff must report the pregnancy to the Sponsor’s 
or designee’s pharmacovigilance department within 24 hours by using the Pregnancy 
Notification Form.  The female subject will discontinue study drug. The pregnancy will 
be followed until there is an outcome and the outcome is reported to the Sponsor.  
Pregnancy is not to be reported as an AE. 

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7.11 
DATA AND SAFETY MONITORING BOARD 
Safety oversight will be under the direction of a DSMB composed of individuals with 
the appropriate expertise, including 2 physicians and a statistician. Members of the 
DSMB should be independent from the study conduct and free of conflict of interest, 
or measures should be in place to minimize perceived conflict of interest. The 
composition of the DSMB, procedures, meeting frequency, and operating guidelines 
will be detailed in a separate DSMB charter. Each data element that the DSMB needs 
to assess or be informed of will also be clearly defined in the DSMB charter. 

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8.0 
STUDY OR SITE TERMINATION AND SUBJECT DISCONTINUATION 
8.1 
ADVERSE EVENT STOPPING RULES 
If a subject experiences an AE that, in the judgment of the Investigator, the Sponsor, 
or the Medical Monitor, presents an unacceptable consequence or risk to the subject, 
the subject may be discontinued from the study. The Investigator should consult the 
Medical Monitor, when possible, for any situations (e.g., abnormal, clinically 
significant findings) that may result in a change to the subject’s treatment or 
management. 
8.2 
NONCOMPLIANCE 
After the Investigator, the Medical Monitor, and/or Study Monitor consult (and the 
Sponsor, if appropriate), a subject may be discontinued from the study for the following 
administrative reasons: 
• 
Failure to take the assigned study drug as mandated by the instructions provided 
in Section 4.2. 
• 
Failure to comply with protocol requirements. 
• 
Unauthorized, subject-initiated changes in the study drug dosing regimen. 
8.3 
WITHDRAWAL OF CONSENT 
Any subject who withdraws consent for any reason at any time during the study will be 
discontinued from the study, and the reason(s) will be documented on the appropriate 
eCRF page.  Subjects will be encouraged to complete the study; however, they may 
voluntarily withdraw at any time. The Investigator will provide a written explanation 
of the reason for discontinuation in a source document and this information will be 
recorded on the appropriate eCRF page. Subjects will be specifically queried to 
determine whether or not withdrawal of consent might have been due to an AE.  If a 
subject withdraws before completion, every effort should be made to complete the ET 
visit and follow-up assessments (see Sections 5.1.5 and 5.1.6). A subject may be 
removed from the study for the reasons described in Section 8.1 through Section 8.3. 

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8.4 
PREMATURE STUDY OR SITE TERMINATION 
If the Sponsor, Investigator, Medical Monitor, Study Monitor, and/or appropriate 
regulatory officials discover conditions arising during the study that indicate that the 
study should be halted or that the investigational site should be terminated, this action 
may be taken after appropriate consultation among the Sponsor, Investigator, Medical 
Monitor, and/or Study Monitor. The Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.0, will be used for assessment of trial stopping criteria. 
The study will be stopped if: 
• 
Three patients develop the same Grade 3 CTCAE, or 
• 
Two patients develop any Grade 4 CTCAE, or 
• 
One patient develops a Grade 5 CTCAE. 
Additional conditions that may warrant termination of the study include, but are not 
limited to, the following: 
• 
The discovery of an unexpected, serious, or unacceptable risk to the subjects 
enrolled in the study; 
• 
A decision on the part of the Sponsor to suspend or discontinue testing, 
evaluation, or development of the investigational product. 
A study conducted at a single investigational site in a multicenter study may also 
warrant termination under the following conditions: 
• 
Failure of the Investigator to enroll subjects into the study at an acceptable rate; 
• 
Failure of the Investigator to comply with pertinent regulations of appropriate 
regulatory authorities; 
• 
Submission of knowingly false information from the investigational site to the 
Sponsor, Study Monitor, or appropriate regulatory authority; 
• 
Insufficient adherence to protocol requirements. 

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Study termination and follow-up will comply with conditions set forth in ICH E6, 
Guideline for Good Clinical Practice (GCP), Sections 4.12, 4.13, 5.20, and 5.21. 
 

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9.0 
DATA COLLECTION AND PROCESSING AND STATISTICAL ANALYSIS 
9.1 
DATA COLLECTION AND PROCESSING 
Electronic case report forms will be used to capture study assessments and data. The 
study coordinator or other delegated study staff at the investigational site will enter data 
from source documents into the eCRFs. All eCRFs will be reviewed and 
source-verified by the Study Monitor during periodic site visits, and the Study Monitor 
will ensure that all data in the eCRFs are correct and complete. Before or between visits, 
the Medical Monitor or Study Monitor may conduct a preliminary medical review of 
the eCRFs. Once the eCRFs are completed and source-verified, the Investigator must 
electronically sign all required eCRF pages, verifying the accuracy of all data contained 
in the eCRFs. 
Training will be provided for the electronic data capture (EDC) system. All study staff 
at the investigational site using the EDC system must have the necessary education, 
training, and experience or any combination of these. The Investigator will be 
responsible for documenting employee education, training, and previous experience 
that pertain to the EDC system for all investigational site staff using the EDC system.  
The Investigator must maintain adequate security of the EDC system, including 
documentation that all users have been trained on the appropriate standard operating 
procedure and a list of authorized users. To ensure all data entries can be tracked, all 
personnel responsible for data entry must obtain a unique user ID and password before 
any data can be entered in the eCRFs. Authorized study staff at the investigational site 
will be assigned a unique user ID only after receiving standard operating procedure 
training. 
If electronic data systems other than those provided and maintained by the Sponsor are 
used for documentation and data capture, the Investigator must ensure that the systems 
are validated and that data are backed up as described in Section 10.2. 

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9.2 
STATISTICAL ANALYSIS 
9.2.1 
General Overview 
The study analyses will be conducted in a GCP controlled environment and will be 
described in detail in a Statistical Analysis Plan (SAP).  The SAP will also include the 
analysis table, listing, and figure specifications. 
A Biostatistics Data Review Meeting will be conducted to prior to database lock in 
order to determine which protocol deviations are major vs. minor. 
The data will be summarized in tables and listings according to nominal study visit and 
treatment group. As appropriate, tables will display the number of subjects with 
non-missing data (n), mean, standard deviation, median, minimum, and maximum for 
continuous data and showing counts and percentage for categorical data. All statistical 
analyses will be performed and data appendices will be created by using SAS (version 
9.2 or later, Cary NC). 
All statistical tests will be two-sided with a 0.05 alpha (α) level. 
No alpha adjustments for multiplicity will be made for analysis of efficacy endpoints 
for this POC study. 
9.2.2 
Analysis Datasets 
The efficacy dataset will consist of all randomized subjects who meet the following 
conditions: 
• 
For analysis of the primary efficacy endpoint, randomized subjects who complete 
at least 80 days of study drug dosing and have a Week 18 (or ET) visit MRI-PDFF 
assessment. 
• 
For analysis of the secondary efficacy endpoints, randomized subjects who 
receive at least one dose of study drug and have at least one post-dose assessment. 
The safety dataset will include all randomized subjects who receive at least one dose 
of study drug. 

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9.2.3 
Efficacy Analysis 
9.2.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the absolute change from Baseline to Week 18 in 
LFC, or absolute change from Baseline to the ET visit for subjects who terminate the 
study prematurely. Absolute change from Baseline in LFC will be assessed by analysis 
of covariance that includes the effects of treatment group, Baseline LFC, and Baseline 
ALT. Comparison of each active treatment group to placebo will be tested at the 5% 
level of significance without adjustment for multiple tests. Secondarily, comparison of 
the 2 active treatment groups with each other will be tested at the 5% level. 
9.2.3.2 
Secondary Efficacy Endpoints: 
The secondary efficacy endpoints of this study include the following: 
1. Absolute and relative (percent) change in fasting glucose and HbA1c from Baseline 
to Week 18, or to the ET visit for dropouts. 
2. A ≥30% reduction in LFC from Baseline to Week 18, or to the ET visit for dropouts. 
3. Percent change in LFC from Baseline to Week 18, or to the ET visit for dropouts. 
4. Normalization of LFC to <5% at Week 18, or to the ET visit for dropouts. 
5. A ≥5-percentage point reduction in LFC from Baseline to Week 18, or to the ET 
visit for dropouts. 
6. Absolute and percent change in HOMA-IR from Baseline to Week 18, or to the ET 
visit for dropouts. 
7. Absolute and percent change in LDL-c, serum triglycerides, and HDL-c from 
Baseline to Week 18, or to the ET visit for dropouts. 
8. Absolute and percent change in AST and ALT from Baseline to Week 18, or to the 
ET visit for dropouts. 

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9. Normalization of ALT (according to clinical laboratory reference ranges) to 
Week 18, or to the ET visit for dropouts, among subjects with elevated ALT at 
Baseline. 
10. Absolute and percent change in Pro-C3 from Baseline to Week 18, or to the ET 
visit for dropouts, among subjects with elevated Pro-C3 at Baseline. 
11. Absolute and percent change in the ELF score and each component of ELF 
(TIMP-1, PIIINP, and HA) from Baseline to Week 18, or to the ET visit for 
dropouts. 
12. Absolute and percent change in total bile acids, C4, and FGF19 from Baseline to 
Week 18, or to the ET visit for dropouts. 
Percent change from Baseline in LFC will be analyzed by the same model described 
for the primary efficacy endpoint. Normalization of LFC, a ≥30% reduction in LFC, 
and a 5-percentage point reduction in LFC will each be analyzed by a logistic 
regression that includes the effects of treatment group, Baseline LFC, and Baseline 
ALT. 
All additional secondary efficacy endpoints are continuous and each will be assessed 
by analysis of covariance that includes treatment group and the Baseline value of the 
analysis variable. All secondary analyses (except LFC) will have missing Week 18 
values imputed using a multiple imputation procedure for all subjects with an available 
measurement prior to Week 18. 
9.2.4 
Missing Data 
It is unlikely that all subjects will complete the 18-week evaluation. Endpoints that will 
only be measured at Week 18 or the ET visit (i.e., LFC) will have the value at the ET 
visit imputed for the missing Week 18 visit.  All other efficacy endpoints will have 
their Week 18 value imputed using a multiple imputation procedure. 
9.2.5 
Safety Analysis 
The safety dataset will be used for all safety analyses. Safety analyses will address AEs, 
physical examinations, vital signs, ECGs, and clinical laboratory assessments. 

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Adverse event type will be coded using MedDRA. Adverse event data will be listed 
individually; AE incidence will be summarized by system organ class and preferred 
terms within a system organ class for each treatment group. Adverse event type, 
relationship, severity, onset, and duration will be presented by treatment group within 
the Double-Blind Treatment Period. Liver-specific AEs also will be included. 
The number of subjects with AEs, as well as the number of AEs, also will be displayed.  
At the subject-level, each AE will be counted only once for a given subject within a 
specified system organ class, preferred term. If the same AE occurs on multiple 
occasions for a subject, the occurrence with the highest severity and relationship to 
study medication will be reported. Individual AE terms will be reported as separate 
events. 
Changes in vital signs, ECGs, and clinical laboratory parameters from Baseline to end 
of study will be examined and displayed using shift tables (low, normal, high). Shift 
tables for Week 18, or the last available study visit, will be presented relative to 
Baseline for all clinical laboratory parameters. 
9.2.6 
Sample Size 
An absolute change in LFC of 5% as measured by MRI-PDFF has been reported 
to be the minimal clinically relevant difference between active treatment and 
placebo that correlates with histological improvement in NASH (Loomba et al., 2015, 
Patel et al., 2015). Furthermore, Harrison and colleagues reported a pooled standard 
deviation of 6.3% for changes from Baseline in LFC (Harrison et al., 2018).  Based on 
this standard deviation, 35 subjects in each treatment group will provide 90% power to 
show a difference of 5 percentage points between any 2 treatment groups at the 5% 
level of significance. To allow for a dropout rate of 10%, 39 subjects will be 
randomized to each of the 3 treatment groups. 
9.2.7 
Interim Analysis 
An interim analysis will be conducted after a minimum of 51 subjects complete the 
assessment of the primary efficacy endpoint to assess sample size assumptions and 
futility through conditional power; the study will not be stopped for efficacy. The 
method of Cui and colleagues (Cui et al., 1999) will be used to compute the alpha spend 

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associated with the interim analysis to assess futility and to recompute sample size by 
evaluating the pooled standard deviation for the change from Baseline in LFC. 
Conditional power calculations will be performed for the difference between each of 
the 2 active treatment groups versus placebo for the primary endpoint. The following 
rules will be applied for the primary efficacy endpoint: 
1. If both conditional powers at the time of the interim analysis are <10%, then the 
study will be terminated for futility. 
2. If either conditional power is ≥10% but both are <36%, then the sample size will 
not be increased and the study will continue based on the original sample size. 
3. If either conditional power is ≥36% but both are <80%, then the sample size will 
be adjusted to retain the original power of 90% or a 50% increase in the sample 
size, whichever is the smallest. 
4. If either conditional power is ≥80%, then the study will continue as is. 
The Sponsor will be advised of either futility, no change, or of a specific sample size 
increase, but not about the degree of efficacy per treatment group. The analysis will be 
conducted by an independent statistician who is not otherwise involved in the 
operational aspects of this study. 
 

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10.0 
STUDY ADMINISTRATION 
10.1 
INFORMED 
CONSENT 
AND 
AUTHORIZATION 
FOR 
USE 
AND 
DISCLOSURE OF PROTECTED HEALTH INFORMATION  
Written informed consent and authorization of use and disclosure of protected health 
information must be obtained from each subject (or the subject’s legally acceptable 
representative) before performing any study-specific Screening or Baseline 
evaluations. One copy of the signed ICF and authorization for use and disclosure of 
protected health information form will be given to the subject, and the Investigator will 
retain the original. The ICF and authorization for use and disclosure of protected health 
information, which is prepared by the Investigator or the investigational site, must have 
been reviewed and approved by the Sponsor, the Study Monitor, and the Investigator’s 
IRB or IEC and privacy board (if separate from the IRB/IEC) before the initiation of 
the study. The ICF must contain the 20 elements of informed consent described in ICH 
E6, Section 4.8. The authorization for use and disclosure of protected health 
information must contain the elements required by Title 45 of the Code of Federal 
Regulations, Section 164.508(b), and any local regulations for valid authorizations. 
10.2 
STUDY DOCUMENTATION 
10.2.1 
Investigator Information 
Investigator information is included in the SPM (or other applicable instructions), 
which is updated as needed. 
10.2.2 
Investigator’s Study Files 
Documentation about the Investigator and his/her study staff, the IRB/IEC, and the 
institution is required before site initiation. Copies of these documents will be kept 
on-site in site-specific binders or electronic folders, along with the following 
supplemental information: a list of Investigator’s obligations; the Investigator’s 
Brochure; the clinical protocol and amendments; safety information; information about 
the investigational product, biological samples, and the applicable laboratory(ies); the 
SPM (or other applicable instructions) and study logs; eCRFs; records of monitoring 
activities; and correspondence between the Sponsor or Study Monitor and the 
Investigator. 

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10.2.3 
Case Report Forms and Source Documentation 
The Investigator must make study data accessible to the Study Monitor, other 
authorized representatives of the Sponsor, and the appropriate regulatory authority 
inspectors. The eCRF for each subject will be checked against source documents at the 
investigational site by the Study Monitor, and a final copy of the eCRF will be signed 
by the Investigator with an electronic signature. A copy of the final eCRFs will be 
provided to the Investigator in PDF format on computer disc after study closure to be 
kept in the Investigator’s study files. 
10.2.4 
Retention of Study Documents 
According to ICH E6, Section 4.9, all eCRFs, as well as supporting paper and electronic 
source documentation and administrative records, must be retained by the Investigator 
until at least 2 years after the last approval of a marketing application and until there 
are no pending or contemplated marketing applications, or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period, however, if required 
by the applicable regulatory requirements or by an agreement with the Sponsor. The 
Sponsor is responsible for informing the Investigator and institution as to when these 
documents no longer need to be retained. No study documents will be destroyed or 
moved to a new location without prior written approval from the Sponsor. If the 
Investigator relocates, retires, or withdraws from the study for any reason, all records 
required to be maintained for the study should be transferred to an agreed-upon 
designee, such as another Investigator at the institution where the study was conducted. 
Audit trails for electronic documentation must be retained for a period at least as long 
as the period required for the subject’s electronic records to which they pertain. The 
Investigator must retain either the originals of the audit trails or a certified copy of the 
audit trails. 
10.3 
CONFIDENTIALITY 
10.3.1 
Data 
The Investigator must keep all information confidential about the nature of the 
proposed investigation provided by the Sponsor or Study Monitor to the Investigator 

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(with the exception of information required by law or regulations to be disclosed to the 
IRB/IEC, the subject, or the appropriate regulatory authority). 
10.3.2 
Subject Anonymity 
The anonymity of participating subjects must be maintained. Subjects will be identified 
by an assigned subject ID number (see Section 3.5) on eCRFs and other documents 
retrieved from the investigational site or sent to the Study Monitor, Sponsor, regulatory 
agencies, central laboratories, or blinded reviewers. Documents that identify the subject 
(e.g., the signed ICF) must be maintained in strict confidence by the Investigator, 
except to the extent necessary to allow auditing by the appropriate regulatory authority, 
the Study Monitor, or Sponsor representatives. 
10.4 
PROTOCOL COMPLIANCE 
Substantive changes in the protocol include changes that affect the safety of subjects 
or changes that alter the scope of the investigation, the scientific quality of the study, 
the experimental design, dosages, assessment variable(s), the number of subjects 
treated, or the subject-selection criteria. Such changes must be prepared as a protocol 
amendment by the Sponsor and implemented only upon joint approval of the Sponsor 
and the Investigator. A protocol amendment must receive IRB/IEC approval before 
implementation. In parallel with the IRB/IEC approval process, the protocol 
amendment will be submitted to the appropriate regulatory authority as an amendment 
to the regulatory submission under which the study is being conducted. If a protocol 
amendment requires changes in the ICF, the revised ICF prepared by the Investigator 
must also be approved by the Sponsor, Study Monitor, and the IRB/IEC before 
implementation. 
Departures from the protocol eligibility criteria (see Sections 3.3.1 and 3.3.2) are not 
permitted as these could jeopardize subject safety, study integrity, or regulatory 
acceptance of the results. 
Departures from other protocol procedures or requirements are allowed only in 
situations that eliminate an immediate risk to a subject and that are deemed crucial for 
the safety and well-being of that subject. The Investigator or the attending physician 
will also contact the Medical Monitor as soon as possible in the case of such a 
departure. These departures do not require pre-approval by the IRB/IEC; however, the 

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IRB/IEC and Medical Monitor must be notified in writing as soon as possible after the 
departure has been made.  In addition, the Investigator will document in the subject’s 
eCRF the reasons for the protocol deviation and the ensuing events. 
10.5 
STUDY MONITOR FUNCTIONS AND RESPONSIBILITY 
The Study Monitor, in accordance with the Sponsor’s requirements, will ensure that 
the study is conducted and documented properly by carrying out the activities outlined 
in ICH E6, Section 5.18.4. 
10.6 
GENERAL INFORMATION 
The Investigator should refer to the Investigator’s Brochure, SPM (or other applicable 
instructions), and any other information provided about the investigational product and 
details of the procedures to be followed during this study. 
 

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11.0 
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Swiss (CD-1) mice on gestational days 6 through 16. In: U.S. Department of Health 
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APPENDICES 

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APPENDIX A 
 
PROTECTION OF HUMAN SUBJECTS 
(International Conference on Harmonisation E6) 

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PROTECTION OF HUMAN SUBJECTS 
(International Conference on Harmonisation E6, Section 4.8) 
Informed consent must be obtained from every subject before he or she enters a study. It must be 
given freely and not under duress. Consent must be documented by the subject or the subject’s 
legally acceptable representative signing an IRB/IEC-approved ICF. When minors are involved, a 
parent or guardian should sign the ICF. If the minor is an adolescent (12 to 16-18 years of age, 
dependent on region, as specified in ICH E11, Clinical Investigation of Medicinal Products in the 
Pediatric Population), his or her signature should also be included. Subjects who do not speak 
English must be presented with an ICF written in a language that they understand. A copy of the 
signed ICF must be given and made available to Sponsor and representatives of the appropriate 
regulatory authority upon request. If, for any reason, subject risk is increased as the study 
progresses, a revised IRB/IEC-approved ICF must be signed by the subject. 
Nothing in these regulations is intended to limit the authority of a physician to provide emergency 
medical care to the extent the physician is permitted to do so under applicable federal, state, or 
local laws. Only in the case of a life-threatening incident may an investigational agent be used 
without prior signed consent. In such an emergency situation, separate certifications must be 
written by both a physician not participating in the study and the Investigator. The certifications, 
along with the protocol and ICF, must be sent to the IRB/IEC within 5 working days. In this 
situation, the Investigator may not administer any subsequent investigational product to that 
subject until informed consent and IRB/IEC approval are obtained. 
BASIC ELEMENTS OF INFORMED CONSENT 
Every ICF must include explanations of each of the following 22 elements: 
• The fact that the trial involves research 
• The purpose of the trial 
• The trial treatment(s) and the probability for random assignment to each treatment 
• The trial procedures to be followed, including all invasive procedures 
• The subject’s responsibilities 

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• Those aspects of the trial that are experimental 
• The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an 
embryo, fetus, or nursing infant 
• The reasonably expected benefits (When there is no intended clinical benefit to the subject, the 
subject should be made aware of this.) 
• The alternative procedure(s) or course(s) of treatment that may be available to the subject, as 
well as their important potential benefits and risks 
• The compensation or treatment available to the subject in the event of a trial-related injury 
• The anticipated prorated payment, if any, to the subject for participating in the trial 
• The anticipated expenses, if any, to the subject for participating in the trial 
• The fact that the subject’s participation in the trial is voluntary and that the subject may refuse 
to participate or withdraw from the trial, at any time, without penalty or loss of benefits to 
which the subject is otherwise entitled 
• That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be 
granted direct access to the subject’s original medical records for verification of study 
procedures or data, without violating the confidentiality of the subject, to the extent permitted 
by applicable laws and regulations and that, by signing a written ICF, the subject or the 
subject’s legally acceptable representative is authorizing such access 
• That the records identifying the subject will be kept confidential and, to the extent permitted 
by the applicable laws or regulations, will not be made publicly available; and if the results of 
the trial are published, the subject’s identity will remain confidential 
• That the subject or the subject’s legally acceptable representative will be informed in a timely 
manner if information becomes available that may be relevant to the subject’s willingness to 
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• The person(s) to contact for further information about the trial and the rights of trial subjects, 
and whom to contact in the event of a trial-related injury 
• The foreseeable circumstances or reasons under which the subject’s participation in the trial 
may be terminated 
• The expected duration of the subject’s participation in the trial 
• The approximate number of subjects involved in the trial 
• The consequences of a subject’s decision to withdraw from the research and the procedure for 
orderly termination of participation by the subject 
• That the trial will be included on ClinicalTrials.gov as required by United States law, and, if 
applicable, the appropriate study database of another regulatory agency (e.g., the Health 
Canada Clinical Trial Database, EudraCT). 
Nothing is intended to limit the authority of a physician to provide emergency medical care to the 
extent the physician is permitted to do so under applicable federal, state, or local laws. 
The informed consent requirements are not intended to preempt any applicable federal, state, or 
local laws that require additional information to be disclosed in order that informed consent be 
legally effective. Some states require further action on the Investigator’s part concerning subject 
consent. 
 

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APPENDIX B 
 
REQUISITE DOCUMENTS FOR APPROVAL OF STUDY SITE 

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REQUISITE DOCUMENTS FOR APPROVAL OF STUDY SITE 
Investigational product will be provided to the investigators after they have submitted the 
following documents to the Sponsor or Study Monitor (if applicable): 
• Signed statement of Investigator (if required by the regulatory agency) 
• Institutional review board or IEC composition 
• Document indicating IRB or IEC approval of the final protocol and amendment(s) if applicable 
(to include name, address, and chairperson of the IRB or IEC) 
• Document indicating IRB or IEC approval of the final and revised ICF if applicable (to include 
name, address, and chairperson of the IRB or IEC) 
• Blank copy of the IRB or IEC-approved final and revised ICF 
• Signed Investigator’s study agreement and confidentiality disclosure agreement 
• Laboratory certification or accreditation and normal ranges for tests that are performed in the 
laboratory for study assessments 
• Curricula vitae for the Investigator and subinvestigator(s) listed on the Form FDA 1572 of the 
study. 
• Financial disclosure for the Investigator and subinvestigator(s) listed on the Form FDA 1572 
of the study. 
 

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APPENDIX C 
 
RESPONSIBILITIES AND OBLIGATIONS  
OF INVESTIGATORS AND SPONSORS 

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RESPONSIBILITIES AND OBLIGATIONS OF INVESTIGATORS AND SPONSORS 
For non-treatment protocols (e.g., separate follow-up protocol, observational protocol), some of 
the following may not be applicable. 
1.0 
SPONSOR 
The following sections describe the responsibilities and obligation of the Sponsor or 
designee. 
1.1 
Conduct a site selection visit or study initiation visit to: 
1.1.1 
Establish the acceptability of the facility and record the visit in a written report (i.e., 
memorandum or form). 
1.1.2 
Discuss with the Investigator the proposed study and supply him or her with draft eCRFs, 
the Investigator’s Brochure, and the draft protocol for his or her review and approval. 
1.1.3 
Discuss with the Investigator the regulatory requirements with respect to informed 
consent, IRB/IEC approval of the trial, the protocol, protocol amendments, and changes 
to the ICF. 
1.1.4 
Discuss with the Investigator the timing of interim and final reports to the Study Monitor 
and his or her obligation to supply the Study Monitor with copies of all study-related 
documents (including IRB or IEC approval, IRB or IEC charter or equivalent, 
membership and qualifications, protocol amendments, ICFs, and consent changes), 
eCRFs, eCRF changes, and all pertinent correspondence to and from the IRB or IEC. 
1.2 
Conduct periodic on-site visit(s) to: 
1.2.1 
Ensure adherence to the protocol. 
1.2.2 
Review eCRFs and source documents for accuracy and completeness of information. 

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1.2.3 
Examine pharmacy records for documentation of quantity and date of receipt of 
investigational drug, dispensation and accountability data for product administration to 
each subject, loss of materials, contamination, and unused supplies. 
1.2.4 
Record and report (summarize) observations on the progress of the trial and continued 
acceptability of the facilities, and prepare an on-site visit report. 
1.2.5 
Review Investigator files for required documents (e.g., protocols; protocol amendments; 
Investigator’s Brochure; SPM; IRB or IEC approval of protocols, amendments, and ICF; 
IRB or IEC charter and membership; and communications to and from the IRB/IEC and 
the Study Monitor). 
2.0 
INVESTIGATOR 
2.1 
Institutional review board or independent ethics committee 
The Investigator must assure the Study Monitor that the IRB or IEC: 
2.1.1 
Meets ICH guidelines as defined in ICH E6 Section 3, IRB/IEC 
2.1.2 
Has the authority delegated by the parent institution and found in the IRB or IEC by-laws, 
operation guidelines, or charter to approve or disapprove clinical studies and protocols, 
including the ICF and other documents (e.g., protocol amendments and information to 
be supplied to subjects concerning informed consent) 
2.1.3 
Complies with proper personnel make-up of the board 
2.1.4 
Convenes meetings using acceptable rules of order for making decisions, recording such 
decisions, and implementing them 
2.1.5 
Maintains files that contain (a) documentation of its decisions, such as are found in IRB 
or IEC minutes and correspondence, (b) written guidelines or by-laws governing IRB or 
IEC functions, (c) protocol, (d) protocol amendments, (e) approved informed consent 
document and information to be supplied to the subject, and (f) correspondence between 
the IRB or IEC and Investigator (e.g., consent changes, protocol amendments) 

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2.2 
Informed consent of human subjects 
The Investigator must assure the Study Monitor that the ICF for a subject: 
2.2.1 
Meets ICH guidelines as defined in ICH E6, Section 4.8, Informed Consent of Trial 
subjects 
2.2.2 
Has been approved by the IRB or IEC, including (when required) information to be given 
to the subject about the trial in which he or she is enrolled 
2.2.3 
Includes the basic elements and any additional elements of informed consent that are 
appropriate 
2.2.4 
Has been signed by both the subject (or the subject’s legally acceptable representative), 
the Investigator, and a witness, and a copy has been given to the subject 
2.2.5 
Is provided, if necessary, to the subject in the “short form” ICF (presented orally to the 
subject or the subject's legally acceptable representative, with a witness listening) with 
written information as an alternative 
2.2.6 
Allows for assent to be obtained for minor children as required by the IRB or IEC 
2.3 
Storage and dispensing of product supplies 
The Investigator (or the Investigator’s pharmacist) must assure the Study Monitor that: 
2.3.1 
Adequate and accurate written records show receipt and disposition of all product 
supplies, including dates, serial or lot numbers, quantities received, and each quantity 
dispensed, administered, or used, with identification of each subject.  
2.3.2 
Purpose and reasons are given in written records for product disposal (e.g., the amount 
contaminated, broken, or lost) and the quantity that was returned to the Sponsor. 
 
 

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2.4 
Case report forms 
The Investigator must assure the Study Monitor that: 
2.4.1 
The completed eCRF accurately reflects the hospital records for each subject. 
2.4.2 
The eCRFs and hospital records will be accessible to the Study Monitor during on-site 
visits. 
2.5 
Files and records 
The Investigator must ensure the quality, integrity, and content of his or her files, which 
will be subject to audit by the Study Monitor and the appropriate regulatory authority 
inspectors. The files must contain, as minimum the following: 
• 
Investigator’s Brochure 
• 
Investigator’s obligations, including the following: 
1. 21 Code of Federal Regulations (CFR) Part 312.50, General Responsibilities 
of Sponsors  
2. 21 CFR Part 312.60, General Responsibilities of Investigators 
3. 21 CFR Part 50, Protection of Human Subjects 
4. 21 CFR Part 56, Institutional Review Boards 
− ICH, E6, Guideline for Good Clinical Practice 
• 
IRB or IEC-approved protocol and protocol amendments 
• 
Blank eCRFs (and amendments to eCRF) 
• 
Study procedures manual and amended pages 
• 
Statement of Investigator forms (copy of signed Form FDA 1572 and a copy of 
each revised form if required by the regulatory agency) as well as current 
curricula vitae and bibliography for each Investigator and subinvestigator 

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• 
IRB or IEC document, including the following: 
1. IRB or IEC charter membership and qualifications of each member 
2. IRB or IEC letter of approval of protocol and amendments 
3. IRB or IEC letter of approval of ICF and amendments 
4. Investigator’s annual report to the IRB or IEC 
5. IRB or IEC annual re-approval of protocol  
6. Reports to IRB or IEC of deaths and serious adverse events (SAEs) 
7. Notification to IRB of study completion and Investigator’s final report 
8. IRB approval of advertisements for subject recruitment (if applicable) 
− All additional correspondence with the IRB/IEC 
• 
IRB/IEC - approved informed consent document (all versions) and information 
to be supplied to the subject 
• 
Study staff signature log 
• 
Subject accountability records, including the following: 
1. Subject screening log 
2. Medical exceptions log 
3. Site status report 
4. Subject identification code list 
5. Original signed ICF 
6. A note stating the location of the eCRFs and data clarification requests 
− Copies of completed eCRF transmittal logs  

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• 
Investigation product records, including the following: 
1. Receipt, date and quantity, and batch or lot number  
2. Disposition dates and quantity administered to each subject 
3. Inventory records 
− All correspondence related to the investigational product 
• 
SAE/safety reports 
1. Copies of signed SAE reports 
2. All SAE correspondence, including MedWatch and Form FDA 3500A 
• 
Biological sample inventory forms and correspondence with the analytical 
laboratory 
• 
Monitoring activities 
1. Monitoring log (should include all visits [i.e., site initiation, periodic, and 
termination visits]) 
2. Telephone contact reports 
3. Site initiation visit reports 
• 
General Correspondence 
1. All correspondence between the Study Monitor, Sponsor, and the site 
2. All correspondence between site staff about the protocol 
Documents and records must be retained by the Investigator for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or for at least 2 years after the 
formal discontinuation of clinical development of the investigational product.