Conditions: NAFLD NASH
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 47
Healthy volunteers: no

Brief summary:
Double-blind, randomized, placebo-controlled study to explore the efficacy and safety of elobixibat compared to placebo in adults with NAFLD (nonalcoholic fatty liver disease) or NASH (nonalcoholic steatohepatitis)

Detailed description:
A total of 15 investigators at 15 sites received institutional review board (IRB)/ethics committee (EC) approval to participate in this study and enrolled at least 1 participant.

Arms:
arm 1: Elobixibat 5 mg once daily arm 2: Placebo

Interventions: intervention 1: Elobixibat intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: Elobixibat is a small molecule and a potent inhibitor of the ileal bile acid transporter (iBAT). intervention 2: Placebo identical in appearance to active drug

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL A3309-012 
A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to 
Explore the Efficacy and Safety of Elobixibat in Adults with 
Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic 
Steatohepatitis (NASH) 
 
IND number:  
141078 
Test product: 
Elobixibat 
Indication: 
Nonalcoholic Fatty Liver Disease or Nonalcoholic 
Steatohepatitis 
Sponsor: 
Elobix AB 
Development phase: 
Phase 2 
Sponsor medical monitor: 
 
Principal investigator: 
 
Date of the protocol: 
10 September 2019 
Version of the protocol:  
Version 3.0  
 
Version No. 
Previous Version Number 
Effective Date 
1.0 
N/A 
25 February 2019 
2.0 
1.0 
22 March 2019 
3.0 
2.0 
10 September 2019 
 
 
Confidential 
The information in this document contains trade secrets and commercial information that 
are privileged or confidential and may not be used, divulged, published, or otherwise 
disclosed without the written consent of Elobix AB. These restrictions on disclosure 
apply equally to all future information supplied to you or generated by you in 
connection with the study. 
 


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SPONSOR SIGNATURE PAGE 
PROTOCOL TITLE: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 
Study to Explore the Efficacy and Safety of Elobixibat in Adults with Nonalcoholic 
Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH)  
 
 
PROTOCOL NUMBER: A3309-012 
Elobix AB 


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INVESTIGATOR SIGNATURE PAGE 
PROTOCOL TITLE: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 
Study to Explore the Efficacy and Safety of Elobixibat in Adults with Nonalcoholic 
Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH)  
PROTOCOL NUMBER: A3309-012 
I have read this protocol and agree that it contains all necessary details for performing 
this study. I will conduct the study as outlined herein and will complete the study within 
the time designated, in accordance with all stipulations of the protocol and in accordance 
with Good Clinical Practice (GCP), local regulatory requirements, and the Declaration of 
Helsinki. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure that they are fully informed regarding the study drug and the conduct of 
the study. 
I will use only the informed consent approved by the Institutional Review Board (IRB) 
and will fulfill all responsibilities for submitting pertinent information to the IRB 
responsible for this study. 
I agree that the Sponsor (Elobix AB) shall have access to any source documents from 
which case report form (CRF) information may have been generated. 
I further agree not to originate or use the name of Elobix AB or elobixibat (A3309) in any 
publicity, news release, or other public announcement, written or oral, whether to the 
public, press, or otherwise, relating to this protocol, to any amendment to the protocol, or 
to the performance of this protocol without the prior written consent of Elobix AB. 
 
 
 
 
Name of Investigator 
 
 
 
 
Signature 
 
Date (day/month/year) 
 


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1. 
ADMINISTRATIVE INFORMATION 
Protocol no.: 
A3309-012 
Date of initial protocol: 
25 February 2019, Version 1.0 
Date and no. of amendments: 
22 March 2019, Version 2.0 
10 September 2019, Version 3.0 
Sponsor: 
Elobix AB 
Arvid Wallgrens backe 20 
413 46 Gӧteborg 
Sweden 
Clinical research organization: 
 
 
 
Sponsor Medical Monitor: 
 
 
 
 
Principal Investigator: 
 
 


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2. 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
Title of Study: 
A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Explore the Efficacy and Safety of 
Elobixibat in Adults with Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis 
(NASH) 
Principal Investigator: 
 
Study Centers: Up to 15 sites will be initiated for this study in the United States (US) 
Publication(s): Not applicable 
Planned Study Period: Q2 2019 to Q2 2020 
Development Phase: Phase 2 
Objectives: 
Primary Objective 
The primary objective is to evaluate the efficacy of repeated once-daily doses of 5 mg elobixibat on 
serum levels of low-density lipoprotein cholesterol (LDL-C) in patients with NAFLD or NASH. 
Secondary Objectives 
• 
To assess the safety and tolerability of elobixibat in patients with NAFLD or NASH 
• 
To evaluate the effect of elobixibat on liver steatosis as measured by magnetic resonance imaging 
(MRI) for (i) liver fat fraction (using proton density fat fraction [PDFF]) and (ii) total liver fat 
(using whole liver fat volume) 
• 
To evaluate the effect of elobixibat on liver function using alanine aminotransferase (ALT) 
• 
To evaluate the effect of elobixibat on lipids and total bile acids (BA) in patients with NAFLD or 
NASH 
Methodology: 
This is a double-blind, randomized, placebo-controlled, Phase 2 study to explore the efficacy and safety 
of elobixibat (oral dose of 5 mg) once daily for 16 weeks in patients with NAFLD or NASH. The study 
includes a 6-week Screening period, followed by a 16-week Treatment period, and a Follow-Up visit 
2 weeks after the last dose of study drug.  
After completing the Screening period, eligible patients will be randomized on Day 1 (Visit 2) in a 1:1 
fashion to either 5 mg/day elobixibat or matching placebo. There will be a total of 7 scheduled visits 
during the study. Additional unscheduled visits may be required for patients who need direct site 
assistance (e.g., due to adverse event [AE] monitoring, in order to fulfill screening requirements, and/or 
for safety maintenance).  Patients who screen fail may be rescreened if approved by Sponsor’s Medical 
Monitor. 
Number of Patients: Approximately 46 patients diagnosed with NAFLD/NASH and in accordance with 
the inclusion/exclusion criteria will be randomized.   
Inclusion Criteria: 
Patients must meet all of the following criteria to be included in the study: 
1. Be willing to participate in the study and provide written informed consent 
2. Be a man or woman ≥18 years of age 
3. Have a current biopsy-confirmed NASH within 6 months of screening or a suspected diagnosis 
of NAFLD/NASH based on the criteria outlined below: 
 


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a. 
Biopsy-confirmed NASH is defined as histological NASH diagnosis with fibrosis 
stage F1 through F3 and a NAFLD activity score (NAS) of ≥4 with a score of ≥1 in 
each of the NAS components below as assessed by a pathologist using the NASH 
Clinical Research Network criteria (Kleiner 2005): 
i. 
Steatosis (scored 0 to 3) 
ii. 
Ballooning degeneration (scored 0 to 2) 
iii. 
Lobular inflammation (scored 0 to 3) 
 
OR 
b. The suspected diagnosis of NAFLD/NASH is based on the diagnosis of metabolic 
syndrome as having any 3 of the following 5 risk factors at Screening: 
i. 
Fasting plasma glucose ≥100 mg/dL or undergoing drug treatment for 
elevated glucose 
ii. 
High-density lipoprotein-cholesterol (HDL-C) <40 mg/dL in males or 
<50 mg/dL in females or undergoing drug treatment for reduced HDL-C 
iii. 
Triglycerides ≥150 mg/dL or undergoing drug treatment for elevated 
triglycerides 
iv. 
Waist circumference >102 cm in males or >88 cm in females 
v. 
Systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg 
or undergoing drug treatment for hypertension, or antihypertensive drug 
treatment in a patient with a history of hypertension 
4. Screening MRI-PDFF with ≥10% liver steatosis 
5. Fasting serum LDL-C >100 mg/dL at screening 
6. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (beta 
human chorionic gonadotropin) at Screening and must agree to use highly effective birth 
control throughout the study and up to 30 days after the last dose of study drug. Highly 
effective contraception measures include combined estrogen- and progestogen-containing 
hormonal contraception (oral, intravaginal, and transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, and implantable), 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, 
vasectomized partner (only in the event that the vasectomized partner is the sole sexual partner 
of the WOCBP), and sexual abstinence (defined as refraining from heterosexual intercourse) 
only in the event that this is the preferred lifestyle of the patient.  
Childbearing potential is defined as being fertile following menarche and until becoming 
postmenopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) 
A postmenopausal state is defined as no menses for ≥12 consecutive months without an 
alternative medical cause. A follicle-stimulating hormone level in the postmenopausal range 
will be used to confirm a postmenopausal state in women ≤55 years of age 
Men with partners who are WOCBP must either be surgically sterile or agree to use a barrier 
contraceptive for the duration of the study and up to 30 days after the last dose of study drug 
7. Be willing to maintain a stable diet and physical activity throughout the course of the study 
 
Exclusion Criteria: 
1. Women who are pregnant, breastfeeding, or plan to become pregnant during the study 
2. Body mass index (BMI) <25 kg/m2 
3. Fibrosis-4 Index (Fib-4) >2.6 
4. Any of the following laboratory abnormalities: 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
a. 
ALT >5 × upper limit normal (ULN) or AST >5 × ULN 
b. International normalized ratio (INR) ≥1.3, unless on anticoagulant therapy 
c. 
Total bilirubin > ULN, except with an established diagnosis of Gilbert’s syndrome 
d. Platelet count less than the lower limit of normal (LLN) 
e. 
Creatinine clearance as calculated by the modification of diet in renal disease (MDRD) 
estimated glomerular filtration rate (eGFR) equation <60 mL/min 
NOTE: Unless otherwise specified, repeat testing may be performed in consultation with the 
Medical Monitor. 
5. Acute or chronic liver disease other than NAFLD/NASH including but not limited to the 
following: 
a. 
Hepatitis B (as defined by the presence of hepatitis B surface antigen at Screening) or 
hepatitis C (as defined by the presence of hepatitis C virus [HCV] antibody [anti-
HCV]. Patients with positive anti-HCV who test negative for HCV ribonucleic acid at 
Screening will be allowed to participate in the study as long as there is evidence of 
viral negativity for a minimum of 12 months prior to Screening) 
b. Evidence of autoimmune hepatitis 
c. 
History of primary biliary cholangitis, primary sclerosing cholangitis, Wilson’s 
disease, homozygous alpha-1-anti-trypsin deficiency, hemochromatosis or iron 
overload, drug-induced or alcoholic liver disease, or known bile duct obstruction 
d. Suspected or proven hepatocellular carcinoma 
6. Known history of human immunodeficiency virus 
7. Medical history of liver cirrhosis 
8. Clinical evidence of portal hypertension to include any history of ascites, hepatic 
encephalopathy, or presence of esophageal varices 
9. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for 
hormone replacement, anabolic steroids, or valproic acid) or other known hepatotoxins for 
>2 weeks in the year prior to Screening 
10. Use of the following medications: 
a. 
Glucagon-like peptide-1 (GLP-1) agonists unless on a stable dose 3 months prior to 
liver biopsy or Screening 
b. Ursodeoxycholic acid, thiazolidinediones, or obeticholic acid within 3 months prior to 
Screening 
c. 
Statins and other lipid-modifying therapies must have been stable for ≥3 months prior 
to Screening 
d. Oral antidiabetic drugs (other than those specifically excluded) must have been stable 
for ≥3 months prior to Screening 
e. 
Agents (including herbal over-the-counter weight loss preparations) or medications 
known to significantly impact body weight within 3 months prior to screening (e.g., 
sibutramine, phenetamine, and orlistat) 
11. History of significant alcohol consumption, defined as an average of >20 g/day in female 
patients and >30 g/day in male patients, for a period of >3 consecutive months within 1 year 
prior to Screening, hazardous alcohol use (Alcohol Use Disorders Identification Test score ≥8), 
or an inability to reliably quantify alcohol consumption based upon judgment of the 
Investigator 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
12. Weight change ≥10% within the 6 months prior to Screening or ≥5% within the 3 months prior 
to Screening 
13. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, sleeve 
gastrectomy and roux-en-Y gastric bypass) 
14. Type 1 diabetes by medical history 
15. Uncontrolled Type 2 diabetes defined as hemoglobin A1c (HbA1c) >9.5% at Screening 
(patients with HbA1c >9.5% may be rescreened) or requiring oral diabetic medication dose 
adjustment >10% within 2 months prior to Screening 
16. Clinical hyperthyroidism or hypothyroidism or Screening hormone results pointing to thyroid 
dysfunction. Patients receiving dose-stable thyroid replacement therapy for ≥3 months prior to 
Screening will be allowed to participate as long as thyroid tests (thyroid-stimulating 
hormone/triiodothyronine/thyroxine) show that the patient is euthyroid 
17. History of any condition causing malabsorption such as chronic pancreatitis, extensive 
bowel/small intestine surgery, celiac disease, or bile flow obstruction 
18. History of any condition associated with acute or chronic diarrhea such as inflammatory bowel 
disease (IBD), functional diarrhea, irritable bowel syndrome (IBS) with predominant diarrhea, 
IBS with mixed bowel habits, or unclassified IBS 
19. History of ischemic colitis 
20. Uncontrolled hypertension (either treated or untreated) defined as systolic blood pressure 
>160 mmHg or a diastolic blood pressure >100 mmHg at Screening. A retest of blood pressure, 
(after establishing good blood pressure control within a reasonable period of time and up to the 
Baseline visit) is permissible at the discretion of the Investigator 
21. History of New York Heart Association Class III or IV heart failure, or known left ventricular 
ejection fraction <30% 
22. History of myocardial infarction, unstable angina, percutaneous coronary intervention, 
coronary artery bypass graft, or stroke or major surgery within 6 months prior to Screening  
23. Active substance abuse, within 1 year prior to Screening  
24. Participation in an investigational new drug trial in the 30 days prior to Screening or within 
5 half-lives of an investigational agent, whichever is longer 
25. Malignancy within 5 years, except for basal- or squamous-cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated. Patients with a history of 
other malignancies that have been treated with curative intent and which have no recurrence 
within 5 years may also be eligible if approved by the Sponsor’s Medical Monitor. Patients 
under evaluation for malignancy are not eligible 
26. Patients with known intolerance to MRI or with conditions contraindicated for MRI procedures 
27. Any other condition which, in the opinion of the Investigator, would impede compliance, 
hinder completion of the study, compromise the well-being of the patient, or interfere with the 
study outcomes 
Test Product, Dose, and Mode of Administration: Elobixibat, 5 mg once a day, orally administered 
Reference Therapy, Dose and Duration of Administration: Matching placebo, orally administered 
Duration of Treatment: Up to 16 weeks 
Variables 
Efficacy:  
Primary Efficacy Endpoint 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
The primary efficacy endpoint is the change from baseline in serum LDL-C at Week 16. 
 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 
• 
Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured by MRI-PDFF 
• 
Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by MRI 
• 
Change from Baseline to Week 16, and Follow-Up in the following: 
o 
Serum ALT, AST, and gamma-glutamyl transferase 
o 
HDL-C, non-HDL-C, LDL-C/HDL-C ratio and triglycerides 
o 
Total bile acids 
 
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be assessed: 
• 
Change from Baseline (unless otherwise specified) to Week 4, Week 8, Week 12, Week 16, and 
Follow-Up in the following: 
o 
Fasting glucose, insulin, homeostatic model assessment-insulin resistance, HbA1c, 
free fatty acids 
o 
GLP-1, fibroblast growth factor-19 (FGF-19), and C4 levels 
o 
High-sensitivity C-reactive protein (CRP)  
o 
Lanosterol and beta-sitosterol 
o 
Body weight, BMI, waist circumference, and waist-to-hip ratio 
o 
Apolipoprotein A1 and Apolipoprotein B 
Safety:   
Safety criteria are as follows: 
• 
Occurrence of treatment-emergent adverse events categorized by causality, severity, and 
seriousness assessments made by Investigator by comparing study-drug exposure to placebo 
• 
Trends in safety evaluated for the following assessments:  
o 
Physical examinations 
o 
Concomitant medications 
o 
Vital signs 
o 
12-lead ECG 
o 
Laboratory test results (including clinical chemistry, hematology/coagulation, and 
urinalysis)  


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Statistical Methods 
Analysis Populations: 
• 
The intent-to-treat (ITT) population will include all patients who are randomized in the study 
and receive at least 1 dose of study drug. The ITT population will be used for all efficacy 
analyses based on the treatment randomized unless otherwise specified 
• 
The per protocol (PP) population will include all ITT patients who finish Visit 7/End of 
Treatment (EOT) with valid LDL-C measurements and do not have any major protocol 
deviations. Allocation of patients to the PP analysis set will be performed before unblinding of 
the study 
• 
The safety population will include all patients who are randomized and receive at least 1 dose 
of study drug and will be used for all safety analyses based on the treatment received 
• 
Summary statistics (number of patients, mean, standard deviation, median, minimum, and 
maximum) at all visits and change or percent change from Baseline will be provided for 
efficacy and safety continuous variables. Count and frequency will be used to tabulate 
categorical variables 
• 
Demographics, disposition, and study populations will be summarized descriptively 
 
Efficacy: 
• 
The primary efficacy endpoint is the change from Baseline in serum LDL-C at Week 16. 
Baseline is defined as the last non-missing LDL-C value prior to the first dose of study drug  
• 
An analysis of covariance (ANCOVA) will be used to analyze the primary efficacy endpoint. 
The model will include treatment arm and baseline LDL-C scores 
• 
Least square (LS) mean (SE), LS mean difference (SE), 95% confidence intervals, and 
P-values between elobixibat 5 mg and placebo will be provided. The model assumptions will 
be checked before the analysis. If there are concerns on model assumptions, i.e., normality and 
homogeneity of variances, a non-parametric ANCOVA based on the rank scores can be used as 
a sensitivity analysis 
• 
Exploratory comparisons between elobixibat 5 mg and placebo will be performed for the 
following secondary efficacy endpoints:  
o 
Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured by 
MRI-PDFF 
o 
Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by MRI 
• 
The analysis methods for the other secondary endpoints and exploratory endpoints will be 
detailed in the Statistical Analysis Plan for the study. 
 
Safety: 
• 
The safety endpoints for this study include clinical laboratory assessments, vital signs, AEs, 
ECGs, physical examinations, and concomitant medications 
• 
AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedRA). TEAEs will be defined as AEs that are new or worsening after the first dose of study 
drug. A general summary of patients with TEAEs and serious adverse events (SAEs)/adverse 
event of special interest (AESI) will be tabulated with numbers and percentages of patients and 
repeated for severity and relationship to study drug per treatment group. The number of AEs 
leading to withdrawal and SAEs leading to death will also be summarized. The incidence of 
TEAEs will be summarized by body system and treatment group 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
• 
The safety laboratory data will be summarized by visit and by treatment group, along with 
changes from Baseline. Values outside of the reference range will be flagged and laboratory 
abnormalities of special interest will be summarized 
 
Sample Size Determination: 
Due to the exploratory nature of this study, no formal power calculations were used to determine the 
sample size. The number of subjects (46 patients in total, 23 patients per treatment group) was chosen 
based on clinical experience with other similar proof-of-concept studies. 
Date of the Protocol: 10 September 2019 
 


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3. 
TABLE OF CONTENTS 
Sponsor Signature Page ...................................................................................................2 
Investigator Signature Page .............................................................................................3 
1. 
Administrative Information .....................................................................................4 
2. 
Study Synopsis .......................................................................................................5 
3. 
Table of Contents .................................................................................................. 12 
3.1 
List of Tables ................................................................................................. 14 
4. 
List of Abbreviations, Acronyms, and Definitions of Terms .................................. 15 
5. 
Introduction .......................................................................................................... 18 
5.1 
Investigational Medicinal Product .................................................................. 18 
5.2 
Background .................................................................................................... 18 
5.2.1 
Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic 
Steatohepatitis (NASH) ............................................................................ 18 
5.2.2 
Summary of Nonclinical Studies in NASH ............................................... 19 
5.3 
Rationale ........................................................................................................ 19 
5.4 
Risk/Benefit ................................................................................................... 20 
6. 
Study Objectives ................................................................................................... 21 
6.1 
Primary Objective .......................................................................................... 21 
6.2 
Secondary Objectives ..................................................................................... 21 
7. 
Investigational Plan ............................................................................................... 22 
7.1 
Overall Study Design and Plan ....................................................................... 22 
7.1.1 
Description .............................................................................................. 22 
7.1.2 
Schedule of Assessments ......................................................................... 23 
7.1.3 
Study Procedures and Assessments .......................................................... 27 
7.2 
Study Population ............................................................................................ 31 
7.2.1 
Inclusion Criteria ..................................................................................... 31 
7.2.2 
Exclusion Criteria .................................................................................... 33 
7.2.3 
Withdrawal of Patients ............................................................................. 36 
7.2.4 
Study Termination by Sponsor ................................................................. 37 
8. 
Treatment of Patients ............................................................................................ 39 
8.1 
Identity of Study Drug.................................................................................... 39 


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8.2 
Administration of Study Drug ........................................................................ 39 
8.3 
Study Treatment Packaging and Labeling ....................................................... 39 
8.3.1 
Packaging and Labeling ........................................................................... 39 
8.3.2 
Storage..................................................................................................... 39 
8.3.3 
Blinding and Randomization of Study Drug ............................................. 40 
8.4 
Procedure for Breaking the Randomization Code ........................................... 40 
8.5 
Patient Compliance ........................................................................................ 41 
8.6 
Study Drug Accountability ............................................................................. 41 
8.7 
Concomitant Therapy and Prohibited Medications ......................................... 42 
9. 
Assessment of Efficacy ......................................................................................... 43 
9.1 
Efficacy Endpoints ......................................................................................... 43 
9.1.1 
Primary Efficacy Endpoint ....................................................................... 43 
9.1.2 
Secondary Efficacy Endpoints.................................................................. 43 
9.1.3 
Exploratory Efficacy Endpoints ............................................................... 43 
9.2 
Efficacy Assessments ..................................................................................... 44 
9.2.1 
Lipid Profile............................................................................................. 44 
9.2.2 
Magnetic Resonance Imaging .................................................................. 44 
9.2.3 
Serum Bile Acids ..................................................................................... 44 
9.2.4 
Biomarkers and Blood Samples for Future Testing................................... 44 
10. 
Assessment of Safety ............................................................................................ 45 
10.1 
Adverse Events .............................................................................................. 45 
10.1.1 
Definitions and Investigator Assessments................................................. 45 
10.1.2 
Recording of Adverse Events ................................................................... 48 
10.1.3 
Recording and Reporting of Serious Adverse Events ................................ 49 
10.1.4 
Reporting of Suspected Unexpected Serious Adverse Reactions............... 50 
10.2 
Laboratory Values, Vital Signs, Physical Examinations, and Other 
Safety Assessments ........................................................................................ 51 
10.2.1 
Laboratory Assessments ........................................................................... 51 
10.2.2 
Individual Patient Safety Monitoring ........................................................ 54 
10.2.3 
Demographics/Medical and Surgical History ........................................... 55 
10.2.4 
Physical Examination ............................................................................... 55 


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10.2.5 
Vital Signs ............................................................................................... 55 
10.2.6 
12-Lead ECG ........................................................................................... 55 
10.2.7 
Overdose.................................................................................................. 56 
11. 
Statistical Evaluation ............................................................................................ 57 
11.1 
Sample Size and Power .................................................................................. 57 
11.2 
Statistical Methods ......................................................................................... 57 
11.2.1 
Statistical Analysis Populations ................................................................ 57 
11.2.2 
Methods of Statistical Analyses ............................................................... 58 
12. 
Direct Access to Source Data/Notes ...................................................................... 62 
13. 
Quality Control and Quality Assurance ................................................................. 63 
13.1 
Conduct of the Study ...................................................................................... 63 
13.2 
Study Monitoring ........................................................................................... 63 
14. 
Ethics .................................................................................................................... 65 
14.1 
Institutional Review Board ............................................................................. 65 
14.2 
Written Informed Consents ............................................................................ 65 
15. 
Data Handling and Recordkeeping ........................................................................ 66 
15.1 
Electronic Case Report Forms/Source Data Handling ..................................... 66 
15.2 
Retention of Essential Documents .................................................................. 66 
16. 
Financing and Insurance ....................................................................................... 67 
17. 
Publication Policy ................................................................................................. 68 
18. 
References List ..................................................................................................... 69 
 
3.1 
List of Tables 
Table 1 
Schedule of Assessments .............................................................................. 24 
Table 2: 
Laboratory Parameters ................................................................................. 52 
 


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4. 
LIST OF ABBREVIATIONS, ACRONYMS, AND DEFINITIONS OF 
TERMS 
Abbreviation 
Definition 
A3309 
elobixibat 
AE(s) 
adverse event(s) 
AESI(s) 
adverse event(s) of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
Anti-HCV 
hepatitis C antibody 
APRI 
AST to platelet ratio index 
ASBT 
apical sodium-dependent bile acid transporter (also known as IBAT) 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BA 
bile acid(s) 
BMI 
body mass index 
C4 
7α-hydroxy-4-cholesten-3-one  
CRA 
clinical research associate 
CRF 
case report form 
CRP 
C-reactive protein 
ECG(s) 
electrocardiogram(s) 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOT 
End of Treatment 
FDA 
US Food and Drug Administration 
FGF-19 
fibroblast growth factor-19  
Fib-4 
fibrosis-4 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP-1 
glucagon-like peptide-1 
H&E 
hematoxylin and eosin 


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Abbreviation 
Definition 
HbA1c 
hemoglobin A1c 
HCV 
hepatitis C virus 
HDL-C 
high-density lipoprotein-cholesterol 
IBAT 
ileal bile acid transporter (also known as ASBT) 
IBD 
inflammatory bowel disease 
IBS 
irritable bowel syndrome 
ICF(s) 
informed consent form(s) 
ICH 
International Council on Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent to treat 
IWRS 
Interactive Web Response System 
LDL 
low-density lipoprotein 
LDL-C 
low density lipoprotein-cholesterol 
LLN 
lower limit of normal 
LPLV 
last patient last visit 
LS 
least square 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging—proton density fat fraction 
N/A 
not applicable 
NAFLD 
nonalcoholic fatty liver disease  
NAS 
NAFLD activity score 
NASH 
nonalcoholic steatohepatitis 
ob/ob (mice) 
leptin-deficient mice 
PCS 
potentially clinically significant 
PDFF 
proton density fat fraction 
PP 
per protocol 
PVM 
pharmacovigilance manager 


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Abbreviation 
Definition 
RNA 
ribonucleic acid 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SE 
standard error 
SOC 
system organ class 
SOP(s) 
standard operating procedure(s) 
Sponsor 
Elobix AB 
SUSAR 
suspected unexpected serious adverse reaction(s) 
TEAE(s) 
treatment-emergent adverse event(s) 
ULN 
upper limit of normal 
US 
United States 
VLDL 
very low-density lipoprotein 
WHO 
World Health Organization 
WOCBP 
Women (woman) of childbearing potential 
α-SMA 
alpha-smooth muscle actin 
 


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5. 
INTRODUCTION 
5.1 
Investigational Medicinal Product 
Elobixibat is a potent inhibitor of the ileal bile acid transporter (IBAT; also known as the 
apical sodium bile acid transporter [ASBT]). The IBAT, expressed mainly in the distal 
ileum, is a key element in the enterohepatic circulation of bile acids because it facilitates 
the very efficient process of bile acid reabsorption. Elobixibat is orally administered and 
acts locally in the gut where it binds reversibly to the IBAT to decrease the reuptake of 
bile acids to the liver. Elobixibat has minimal systemic exposure at expected therapeutic 
dose ranges. 
5.2 
Background 
5.2.1 
Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic 
Steatohepatitis (NASH) 
Recent data suggest that bile acids may play an important role in NASH pathogenesis 
(Ferslew 2015; Aranha 2008; Puri 2018). Bile acids are signaling molecules involved in 
lipid, glucose, and energy homeostasis, which are metabolic pathways linked to 
NAFLD/NASH and comorbidities such as metabolic syndrome, obesity, and diabetes. 
Bile acids as well as free cholesterol, which is the precursor from which bile acids are 
synthesized, can act as lipotoxic agents that drive inflammation and fibrosis. Studies have 
shown that both serum and liver bile acids are increased in patients with NASH, and 
recent data have suggested that the presence and severity of NASH is associated with 
specific changes in circulating bile acids (Puri 2018). Thus, targeting of bile acid 
pathways has therapeutic potential in patients with NASH. 
The enterohepatic circulation of bile acids plays a crucial role in whole body sterol 
balance. Bile acids are secreted to the intestine via the bile duct and then reabsorbed, 
mainly by a specific bile acid transporter located in the ileum (IBAT or ASBT) and 
delivered back to the liver, completing the enterohepatic circulation (Prawitt 2011).  
Bile acid reabsorption from the intestine is a very efficient process where 95% of the 
secreted bile acids are reabsorbed and IBAT appears to be the major regulator of the bile 
acid pool in animals and humans. IBAT inhibitors reduce the reabsorption of bile acids 
from the ileum and prevent their return to the liver. The liver compensates for the 
decrease in bile acid levels by upregulating cholesterol 7α-hydroxylase, the rate-limiting 


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enzyme for bile acid synthesis. This results in lower hepatic cholesterol levels and an 
increased number of low-density lipoprotein (LDL) receptors in the liver leading to 
reduced plasma low-density lipoprotein cholesterol (LDL-C; [Bertolotti 2003; 
Naoumova 1999]). Bile acids also positively regulate glucagon-like peptide-1 (GLP-1) 
levels via activation of TGR5 (Prawitt 2011; Schaap 2014). GLP-1 is an insulinotropic 
hormone but has many other roles, e.g., slowing gastric emptying and increasing satiety 
signals leading to weight loss (Andersen 2018). 
Inhibition of bile acid absorption locally in the intestine has the potential to positively 
influence NASH, cardiovascular disease, and metabolic disease by targeting multiple 
mechanisms, as follows: lowering of LDL-C by increased bile acid synthesis; improving 
metabolic status and weight loss by increasing GLP-1 levels; and reducing hepatic cell 
damage by lowering toxic bile acid and free cholesterol in the liver. 
5.2.2 
Summary of Nonclinical Studies in NASH 
One nonclinical study with elobixibat in a NASH model has been completed. The study 
evaluated the effects of elobixibat in leptin-deficient ob/ob mice treated with a diet high 
in trans fats, fructose, and cholesterol. Although elobixibat did not reduce liver NAFLD 
activity score or fibrosis stage, there were indicators of relevant effects, including 
reduction in liver alpha-smooth muscle actin (α-SMA), which is a marker of stellate cell 
activation and thereby an indirect marker for fibrosis formation. Administration of 10 and 
30 mg/kg/day elobixibat decreased liver steatosis as quantified by lipid fractional area in 
hematoxylin and eosin (H&E)-stained liver sections in a dose-dependent fashion. This 
was further evident in animals treated with 30 mg/kg elobixibat that showed reduced liver 
triglycerides and liver total cholesterol as determined by biochemical analyses. Analysis 
of liver gene expression by next generation RNA sequencing revealed pronounced and 
dose-dependent effects of elobixibat. It affected the expression of genes in key pathways 
associated with NASH pathology. 
Additional nonclinical studies with elobixibat are summarized in the Investigator’s 
Brochure (M1.14.4.1). 
5.3 
Rationale 
Bile acids act as signaling molecules in lipid, glucose, and energy homeostasis. Studies 
have shown that both serum and liver bile acids are increased in patients with NASH 


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(Ferslew 2015), and recent data have suggested that the presence and severity of NASH 
is associated with specific changes in circulating bile acids (Puri 2018; Sanyal 2018). 
Inhibition of bile acid absorption from the intestine has the potential to improve the 
pathophysiology in NASH, including the related cardiovascular and metabolic disease 
due to impingement on multiple key metabolic feedback mechanisms, as follows: 
lowering of LDL-C by increased bile acid synthesis, and improving insulin sensitivity by 
increasing GLP-1 levels. A reduction of cardiovascular risk is particularly desirable for 
any pharmacological NASH treatment, because cardiovascular complications contribute 
to a significant amount of mortality in patients with NAFLD/NASH, with their annual 
risk being 2-fold increased (Mahfood Haddad 2017; Younossi 2018). IBAT inhibition 
reduces the levels of bile acid that circulate to the liver, and triggers increased hepatic 
bile acid synthesis from cholesterol. Thus, besides having a positive impact on 
cardiovascular health, IBAT inhibition might also reduce hepatic cell damage by 
lowering free cholesterol and changing the composition of toxic bile acids in the liver. 
5.4 
Risk/Benefit 
Elobixibat is orally administered and acts locally in the gut where it binds reversibly to 
the IBAT to decrease the reuptake of bile acids into the liver, thereby increasing the 
concentration of bile acids in the colon. Due to its mechanism of action, most adverse 
events (AEs) are gastrointestinal (GI) tract disorders, such as abdominal pain, diarrhea, 
abdominal distention, flatulence, and nausea; the incidence of these has increased with 
increasing dose levels. Diarrhea has been the most prominent dose-limiting side effect. 
No clinically significant findings in laboratory measures or electrocardiograms (ECGs) 
have been reported. Based on postmarketing case reporting, ischemic colitis will be 
monitored as an adverse event of special interest for elobixibat. 
There is no established benefit for subjects participating in this Phase 2 study. Based 
upon these data, the risk/benefit for subjects participating in this trial is acceptable. 
This study will be conducted in compliance with the protocol and with the International 
Council on Harmonisation (ICH) guidelines on GCP.  


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6. 
STUDY OBJECTIVES 
6.1 
Primary Objective 
The primary objective is to evaluate the efficacy of repeated once-daily doses of 5 mg 
elobixibat on serum levels of LDL-C in patients with NAFLD or NASH. 
6.2 
Secondary Objectives 
• To assess the safety and tolerability of elobixibat in patients with NAFLD or 
NASH 
• To evaluate the effect of elobixibat on liver steatosis as measured by magnetic 
resonance imaging (MRI) for (i) liver fat fraction (using proton density fat 
fraction [PDFF]) and (ii) total liver fat (using whole liver fat volume) 
• To evaluate the effect of elobixibat on liver function using alanine 
aminotransferase (ALT) 
• To evaluate the effect of elobixibat on lipids and total bile acids (BA) in patients 
with NAFLD or NASH 


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7. 
INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
7.1.1 
Description 
This is a double-blind, randomized, placebo-controlled, Phase 2 study to explore the 
efficacy and safety of elobixibat (oral dose of 5 mg) once daily for 16 weeks in patients 
with NAFLD or NASH. The study includes a 6-week Screening Period, followed by a 
16-week Treatment Period, and a Follow-Up Visit 2 weeks after the last dose of study 
drug.  
After completing the Screening Period, eligible patients will be randomized on Day 1 
(Visit 2) in a 1:1 fashion to either 5 mg/day elobixibat or matching placebo. Visit 
windows applicable to each visit are presented in the schedule of assessments (Table 1). 
There will be up to 7 clinic visits during the study, as follows: 
• Visit 1: Screening period (Week -6 through Day -1) 
• Visit 2: Day 1/Randomization visit 
• Visit 3: Week 4 
• Visit 4: Week 8 
• Visit 5: Week 12 
• Visit 6: Week 16/End of Treatment (EOT). Any patient that discontinues 
treatment prematurely should complete this visit at the time of discontinuation 
• Visit 7: Follow-Up period. The Follow-Up visit will occur 2 weeks after the last 
dose of study drug whether the patient completes the study or discontinues 
prematurely 
Additional unscheduled visits may be required for patients who need direct site assistance 
(due to AE monitoring, in order to fulfill screening requirements, and/or for safety 
maintenance).  
Patients who screen fail may be rescreened if approved by Sponsor’s Medical Monitor. 


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7.1.1.1 
Screening Period 
Informed consent must be obtained at Visit 1 prior to performing any study procedures. 
After signing the informed consent form (ICF), patients will be considered enrolled and 
evaluated for study eligibility. 
7.1.1.2 
Treatment Period 
Eligibility for randomization will be determined at Visit 2 using the assessment of 
eligibility in accordance to the inclusion/exclusion criteria.  
The patient will return to the clinic at Visits 3-6 for assessments. Patients will be 
requested to return study drug bottles as part of drug accountability during the Treatment 
period. 
7.1.1.3 
Follow-Up Period 
The patient will return to the clinic for Visit 7 approximately 2 weeks after the last dose 
of study drug. This visit will be completed for patients that discontinue treatment 
prematurely.  
7.1.1.4 
End of Study 
The end of the study is defined as last patient last visit (LPLV) and all sites are closed. 
7.1.2 
Schedule of Assessments 
The schedule of assessments is presented in Table 1. 


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Table 1 
Schedule of Assessments 
VISIT 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP 
PERIOD 
VISIT 1 
VISIT 2/ 
RANDOMIZA- 
TION 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6/ 
END OF 
TREATMENT 
VISIT 7 
STUDY WEEK 
WEEK -6 TO 
DAY -1 
DAY 1 
WEEK 4 
WEEK 8 
WEEK 12 
WEEK 16 
WEEK 18 
VISIT WINDOW 
 
 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Medical/surgical historyf 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Serologya 
X 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
X 
 
Physical examinationb 
X 
X 
 
 
 
X 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testd 
X 
X 
X 
X 
X 
X 
X 
MRIe 
X 
 
 
 
 
X 
 
Randomizationg 
 
X 
 
 
 
 
 
Clinical safety laboratory testsh 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
(Continued on next page) 


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VISIT 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP 
PERIOD 
VISIT 1 
VISIT 2/ 
RANDOMIZA- 
TION 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6/ 
END OF 
TREATMENT 
VISIT 7 
STUDY WEEK 
WEEK -6 TO 
DAY -1 
DAY 1 
WEEK 4 
WEEK 8 
WEEK 12 
WEEK 16 
WEEK 18 
VISIT WINDOW 
 
 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
Endocrinologyh 
X 
X 
X 
 
 
X 
 
GLP-1, FGF-19, C4h 
X 
X 
X 
X 
X 
X 
X 
Total bile acidsh 
X 
X 
X 
X 
X 
X 
X 
Lipid profileh 
X 
X 
X 
X 
X 
X 
X 
Fibrosis and inflammation markersh 
 
X 
X 
 
 
X 
 
High-sensitivity CRP 
X 
 
X 
 
 
X 
 
Stored blood sample for future testingi 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
X 
X 
X 
 
 
Review alcohol consumptionj 
X 
 
 
 
 
 
 
Review concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Review adverse events 
X 
X 
X 
X 
X 
X 
X 
a Includes hepatitis B virus surface antigen and hepatitis C virus antibody and RNA 
b Includes height (at Screening only), weight, waist circumference, and waist-to-hip ratio. Body mass index will be calculated based on height and weight. A full physical 
examination will be performed at Screening and at Visits 2 and 6.  
c Vital signs include blood pressure, heart rate, respiratory rate, and oral body temperature. 
(Continued on next page) 


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d For women of childbearing potential, a serum pregnancy test will be performed at Screening, and a urine pregnancy test will be performed at each visit at which study drug is 
dispensed. 
e Patients will have MRI to measure liver fat (PDFF), and total liver volume. Patients who discontinue before Visit 6 (Week 16) should have an MRI performed at End of 
Treatment if they completed at least 4 weeks of treatment. 
f Liver biopsy results for confirmed NASH within 6 months of Screening to confirm patient eligibility will be collected in the eCRF, if available. 
g Randomization will occur at Visit 2 to assign patients to either 5 mg/day elobixibat or placebo in 1:1 ratio. 
h See Table 2, Laboratory Parameters. Clinical safety laboratory tests include clinical chemistry, hematology/coagulation, and urinalysis 
i See Section 9.2.4. 
j History of alcohol consumption will be obtained at Screening. 
Abbreviations: C4: 7α-hydroxy-4-cholesten-3-one; CRF: case report form; CRP: C-reactive protein; ECG: electrocardiogram; EOT: End of Treatment; FGF-19: fibroblast growth 
factor-19; GLP-1: glucagon-like peptide-1; INR: international normalized ratio; MRI: magnetic resonance imaging; NASH: nonalcoholic steatohepatitis; PDFF: proton density fat 
fraction 
 


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7.1.3 
Study Procedures and Assessments 
7.1.3.1 
Screening Period (-6 Weeks to Day -1) 
7.1.3.1.1 
Visit 1 
Patients will undergo a Screening visit up to 6 weeks prior to the planned first day of 
study treatment. Screening procedures and assessments are as follows: 
• Obtain written informed consent 
• Assess inclusion/exclusion criteria (Sections 7.2.1 and 7.2.2, respectively) 
• Medical and surgical history (date of diagnosis of NAFLD/NASH including liver 
biopsy results for biopsy-confirmed NASH patients within 6 months of screening; 
any surgery performed; any other diagnosis) 
• Record demographics (age, full date of birth, gender, race, and ethnicity) 
• Serology 
• 12-lead ECG (Section 10.2.6) 
• Physical examination (Section 10.2.4) 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• MRI (Section 9.2.2) 
• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 
• Fibrosis and inflammation markers (Section 10.2.1) 


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• High-sensitivity CRP 
• Stored sample for future testing (Section 10.2.1) 
• Review of alcohol consumption 
• Document concomitant medications 
• AE monitoring  
7.1.3.2 
Treatment Period (Day 1 to Week 16) 
7.1.3.2.1 
Study Day 1/Visit 2 (Randomization) 
At the randomization visit, the following assessments will be conducted: 
• Review inclusion/exclusion criteria (Sections 7.2.1 and 7.2.2, respectively) 
• Physical examination (Section 10.2.4) 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 
• Fibrosis and inflammation markers (Section 10.2.1) 
• Stored sample for future testing (Section 10.2.1) 
• Study drug is dispensed and patients are instructed to administer daily from Day 1 
• Review of concomitant medications 
• AE monitoring 


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7.1.3.2.2 
Study Weeks 4-12/Visits 3-5  
The following procedures and assessments will be conducted: 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Visit 3 only; Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 
• Fibrosis and inflammation markers (Visit 3 only; Section 10.2.1) 
• High-sensitivity CRP (Visit 3 only; Section 10.2.1) 
• Stored sample for future testing (Section 10.2.1) 
• Study drug is dispensed; review of compliance  
• Review of concomitant medications 
• AE monitoring 
7.1.3.2.3 
Study Week 16/Visit 6/EOT 
The last dose of study drug will be taken in the morning the day before Visit 6 and the 
following procedures and assessments will be conducted (also conducted at the time a 
patient prematurely withdraws):  
• 12-lead ECG (Section 10.2.6) 
• Physical examination (Section 10.2.4) 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• MRI (Section 9.2.2) 


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• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 
• Fibrosis and inflammation markers (Section 10.2.1) 
• High-sensitivity CRP 
• Stored sample for future testing (Section 10.2.1) 
• Review of concomitant medications 
• AE monitoring 
7.1.3.3 
Follow-Up Period 
7.1.3.3.1 
Study Week 18/ Visit 7  
All patients will complete a Follow-Up visit approximately 2 weeks after the last dose of 
study drug for the following assessments: 
• Vital signs (Section 10.2.5) 
• Pregnancy test  
• Clinical safety laboratory tests (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total BA (Section 9.2.3) 
• Lipid profile (Section 10.2.1) 
• Stored sample for future testing (Section 10.2.1) 
• Review of concomitant medications 
• AE monitoring 


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7.2 
Study Population 
A total of approximately 46 patients with a clinical diagnosis of NAFLD/NASH (in 
accordance with the protocol definition) will be randomized.   
7.2.1 
Inclusion Criteria 
Patients must meet all the following criteria to be included in the study: 
1. Be willing to participate in the study and provide written informed consent 
2. Be a man or woman ≥18 years of age 
3. Have a current biopsy-confirmed NASH within 6 months of screening or a 
suspected diagnosis of NAFLD/NASH based on the criteria outlined below: 
a. Biopsy-confirmed NASH is defined as histological NASH diagnosis with 
fibrosis stage F1 through F3 and a NAFLD activity score (NAS) of 
≥4 with a score of ≥1 in each of the NAS components below as assessed 
by the central pathologist using the NASH Clinical Research Network 
criteria (Kleiner 2005) 
i. Steatosis (scored 0 to 3) 
ii. Ballooning degeneration (scored 0 to 2) 
iii. Lobular inflammation (scored 0 to 3) 
OR 
b. The suspected diagnosis of NAFLD/NASH is based on the diagnosis of 
metabolic syndrome as having any 3 of the following 5 risk factors at 
Screening: 
i. Fasting plasma glucose ≥100 mg/dL or undergoing drug treatment 
for elevated glucose 
ii. High-density lipoprotein-cholesterol (HDL-C) <40 mg/dL in males 
or <50 mg/dL in females or undergoing drug treatment for reduced 
HDL-C 


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iii. Triglycerides ≥150 mg/dL or undergoing drug treatment for 
elevated triglycerides 
iv. Waist circumference >102 cm in males or >88 cm in females 
v. Systolic blood pressure ≥130 mm Hg or diastolic blood pressure 
≥85 mm Hg or undergoing drug treatment for hypertension, or 
antihypertensive drug treatment in a patient with a history of 
hypertension 
4. Screening MRI-PDFF with ≥10% liver steatosis 
5. Fasting serum LDL-C >100 mg/dL at Screening 
6. Women of childbearing potential (WOCBP) must have a negative serum 
pregnancy test (beta human chorionic gonadotropin) at Screening and must agree 
to use highly effective birth control throughout the study and up to 30 days after 
the last dose of study drug. Highly effective contraception measures include 
combined estrogen- and progestogen-containing hormonal contraception (oral, 
intravaginal, and transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, and implantable), 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal 
occlusion, vasectomized partner (only in the event that the vasectomized partner 
is the sole sexual partner of the WOCBP), and sexual abstinence (defined as 
refraining from heterosexual intercourse) only in the event that this is the 
preferred lifestyle of the patient.  
Childbearing potential is defined as being fertile following menarche and until 
becoming postmenopausal unless permanently sterile (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy). 
A postmenopausal state is defined as no menses for ≥12 consecutive months 
without an alternative medical cause. A follicle-stimulating hormone level in the 
postmenopausal range will be used to confirm a postmenopausal state in women 
≤55 years of age. 


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Men with partners who are WOCBP must either be surgically sterile or agree to 
use a barrier contraceptive for the duration of the study and up to 30 days after the 
last dose of study drug. 
7. Be willing to maintain a stable diet and physical activity throughout the course of 
the study 
7.2.2 
Exclusion Criteria 
Patients who meet any of the following criteria will not be included in the study: 
1. Women who are pregnant, breastfeeding, or plan to become pregnant during the 
study 
2. Body mass index (BMI) <25 kg/m2 
3. Fibrosis-4 index (Fib-4) >2.6 
4. Any of the following laboratory abnormalities: 
a. ALT >5 × upper limit of normal (ULN) or AST >5 × ULN 
b. International normalized ratio (INR) ≥1.3, unless on anticoagulant therapy 
c. Total bilirubin >ULN, except with an established diagnosis of Gilbert’s 
syndrome 
d. Platelet count less than the lower limit of normal (LLN) 
e. Creatinine clearance as calculated by the modification of diet in renal 
disease (MDRD) estimated glomerular filtration rate (eGFR) equation 
<60 mL/min 
NOTE: Unless otherwise specified, repeat testing may be performed in 
consultation with the Medical Monitor. 
5. Acute or chronic liver disease other than NAFLD/NASH including but not limited 
to the following: 
a. Hepatitis B (as defined by the presence of hepatitis B surface antigen at 
screening) or hepatitis C (as defined by the presence of hepatitis C virus 
[HCV] antibody [anti-HCV]). Patients with positive anti-HCV who test 


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negative for HCV ribonucleic acid at screening will be allowed to 
participate in the study as long as there is evidence of viral negativity for a 
minimum of 12 months prior to screening) 
b. Evidence of autoimmune hepatitis 
c. History of primary biliary cholangitis, primary sclerosing cholangitis, 
Wilson’s disease, homozygous alpha-1-anti-trypsin deficiency, 
hemochromatosis or iron overload, drug-induced or alcoholic liver 
disease, or known bile duct obstruction 
d. Suspected or proven hepatocellular carcinoma 
6. Known history of human immunodeficiency virus 
7. Medical history of liver cirrhosis 
8. Clinical evidence of portal hypertension to include any history of ascites, hepatic 
encephalopathy, or presence of esophageal varices 
9. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, 
systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than 
those used for hormone replacement, anabolic steroids, or valproic acid) or other 
known hepatotoxins for >2 weeks in the year prior to screening 
10. Use of the following medications: 
a. GLP-1 agonists unless on a stable dose 3 months prior to liver biopsy or 
Screening 
b. Ursodeoxycholic acid, thiazolidinediones, or obeticholic acid within 
3 months prior to Screening  
c. Statins and other lipid-modifying therapies must have been stable for 
≥3 months prior to Screening 
d. Oral antidiabetic drugs (other than those specifically excluded) must have 
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e. Agents (including herbal over-the-counter weight-loss preparations) or 
medications known to significantly impact body weight within 3 months 
prior to Screening (e.g., sibutramine, phenetamine, and orlistat) 
11. History of significant alcohol consumption, defined as an average of >20 g/day in 
female patients and >30 g/day in male patients, for a period of >3 consecutive 
months within 1 year prior to Screening, hazardous alcohol use (Alcohol Use 
Disorders Identification Test score ≥8), or an inability to reliably quantify alcohol 
consumption based upon judgment of the Investigator 
12. Weight change ≥10% within the 6 months prior to Screening or ≥5% within the 
3 months prior to Screening 
13. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, 
sleeve gastrectomy and roux-en-Y gastric bypass) 
14. Type 1 diabetes by medical history 
15. Uncontrolled Type 2 diabetes defined as hemoglobin A1c (HbA1c) >9.5% at 
Screening (patients with HbA1c >9.5% may be rescreened) or requiring oral 
diabetes medication dose adjustment >10% within 2 months prior to Screening 
16. Clinical hyperthyroidism or hypothyroidism or screening hormone results 
pointing to thyroid dysfunction. Patients receiving dose-stable thyroid 
replacement therapy for ≥3 months prior to Screening will be allowed to 
participate as long as thyroid tests (thyroid-stimulating 
hormone/triiodothyronine/thyroxine) show that the patient is euthyroid 
17. History of any condition causing malabsorption such as chronic pancreatitis, 
extensive bowel/small intestine surgery, celiac disease, or bile flow obstruction 
18. History of any condition associated with acute or chronic diarrhea such as 
inflammatory bowel disease (IBD), functional diarrhea, irritable bowel syndrome 
(IBS) with predominant diarrhea, IBS with mixed bowel habits, or unclassified 
IBS 
19. History of ischemic colitis 


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20. Uncontrolled hypertension (either treated or untreated) defined as systolic blood 
pressure >160 mmHg or a diastolic blood pressure >100 mmHg at Screening. A 
retest of blood pressure, (after establishing good blood pressure control within a 
reasonable period of time and up to the Baseline visit) is permissible at the 
discretion of the Investigator 
21. History of New York Heart Association Class III or IV heart failure, or known 
left ventricular ejection fraction <30% 
22. History of myocardial infarction, unstable angina, percutaneous coronary 
intervention, coronary artery bypass graft, or stroke or major surgery within 
6 months prior to Screening  
23. Active substance abuse within 1 year prior to Screening 
24. Participation in an investigational new drug trial in the 30 days prior to Screening 
or within 5 half-lives of an investigational agent, whichever is longer 
25. Malignancy within 5 years, except for basal- or squamous-cell carcinoma of the 
skin or carcinoma in situ of the cervix that has been successfully treated. Patients 
with a history of other malignancies that have been treated with curative intent 
and which have no recurrence within 5 years may also be eligible if approved by 
the Sponsor’s Medical Monitor. Patients under evaluation for malignancy are not 
eligible 
26. Patients with known intolerance to MRI or with conditions contraindicated for 
MRI procedures 
27. Any other condition which, in the opinion of the Investigator, would impede 
compliance, hinder completion of the study, compromise the well-being of the 
patient, or interfere with the study outcomes 
7.2.3 
Withdrawal of Patients 
Patients will be informed that they have the right to withdraw from the study at any time, 
without prejudice to their medical care, and that they are not obliged to state their 
reasons. 


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Any withdrawal, and reasons for withdrawal, must be fully documented in the electronic 
case report form (eCRF) and source documents and the patient followed by the 
investigator/investigative staff. Even after the study is completed at the Follow-Up visit, 
the investigator/investigative staff will, regardless of reason for withdrawal, record any 
patient data they receive concerning serious adverse events (SAEs), and all drug-related 
non-serious AEs, and report these in the eCRF. Withdrawn patients will not be replaced. 
Patients will be withdrawn in the following circumstances: 
• A patient’s desire for withdrawal for any reason 
• Lost to follow-up (every effort must be made to contact the patient; a certified 
letter must be sent) 
• An AE that, in the opinion of the Investigator, necessitates withdrawal 
• Death 
• A patient’s substantial noncompliance (study drug compliance) or protocol 
violation 
• An Investigator’s opinion that continuing the patient in the study is not 
appropriate. The Investigator may withdraw a patient at any time if it is 
considered to be in the patient’s best interest 
A patient who withdraws from treatment prematurely will have EOT (Visit 6) 
assessments at the time of withdrawal and a Follow-Up assessment (Visit 7) 
approximately 2 weeks following the last dose of study drug, and the patient will be 
recorded as withdrawn. 
7.2.4 
Study Termination by Sponsor 
This study may be terminated at any time by the Sponsor if serious side effects should 
occur, if the Investigator does not adhere to the protocol, or if, in the Sponsor's judgment, 
there are no further benefits to be achieved from the study. In this event, the Sponsor or 
its designee will inform the study investigators, institutions, and all regulatory authorities. 
The Sponsor may temporarily or permanently discontinue the study at an investigative 
site at any time for safety, ethical, compliance, or other reasons. If this is necessary, the 
Sponsor will endeavor to provide advance notification to the site. If a site or the study is 


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suspended or discontinued, the Investigator/investigative staff will be responsible for 
promptly informing the IRB. If required by local regulations, the Sponsor or its designee 
will be responsible for informing the IRB and the regulatory authority of study or site 
discontinuation. In such an event, all study data and unused study drug must be returned 
to the Sponsor or its designee. 


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8. 
TREATMENT OF PATIENTS 
8.1 
Identity of Study Drug 
Elobixibat and placebo will be supplied as tablets for oral administration during the 
Treatment phase of the study. White tablets containing elobixibat or placebo will be 
provided.   
The elobixibat and placebo tablets will be identical in appearance. Tablet filling weight 
will also be identical for elobixibat and placebo. Bottles containing 34 tablets will be 
given to the patient at each visit. Refer to the study reference manual. 
8.2 
Administration of Study Drug 
Patients will be dosed with elobixibat at a dose of 5 mg or placebo once daily for 
16 weeks. Study drug will be dispensed to the patient at Visits 2-5 together with 
instructions on how to store and take the drug. Study drug compliance will be evaluated 
at each study visit.   
Elobixibat should be taken in the morning, prior to the first meal. On clinic visit days 
when laboratory assessments are conducted, study drug should be taken after the visit and 
after laboratory samples are taken.   
8.3 
Study Treatment Packaging and Labeling 
8.3.1 
Packaging and Labeling 
The tablets will be packed in high-density polyethylene bottles, with child-proof 
polypropylene caps. Packaging and labeling will be prepared to comply with applicable 
regulatory requirements. 
8.3.2 
Storage 
Treatment bottles containing elobixibat tablets should be stored and dispensed in 
accordance with regulations in their original containers. The storage facility at the 
investigative site should be locked and the storage temperature should be between 15°C 
and 25°C. 
Caregivers should be informed of appropriate storage conditions (i.e., room temperature, 
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Any deviations from the recommended storage conditions should be immediately 
reported to the Sponsor and the study drug should not be used until authorization has 
been given by the Sponsor. 
8.3.3 
Blinding and Randomization of Study Drug 
A double-blind design is employed so that both the investigators and the patients will be 
unaware of the treatment assignment during the study.  
After written informed consent is obtained from an eligible patient, a 6-digit patient 
number will be assigned. The first 3 digits will be the site number followed by a 3-digit 
patient sequence number. This number will be created and allocated by the site when the 
patient first enters at Screening. The randomization codes will be computer-generated by 
a statistician independent from the project team. The randomization will be done in 
blocks to ensure approximate balance between dose schemes (1:1). Randomization codes 
will be assigned sequentially as patients become eligible for randomization. 
Patients who are eligible for randomization will be assigned a unique 4-digit 
randomization number by the Interactive Web Response System (IWRS). This 
randomization number identifies which treatment will be allocated to the patient. Patients 
who withdraw from the study after randomization visit are not to be replaced and their 
randomization number will not be reused.   
To ensure blinding, the study drug and the matching placebo have the same shape and 
size. Labels on the treatment bottles will not identify the treatment to which a patient has 
been randomized. Traceability of the treatment is ensured by the bottle number. 
The 5-digit bottle number will identify the study-drug bottle and will be detailed on the 
study-drug label. Dispensing of the study drug will be coordinated by IWRS.  
The system will assign a study-drug number corresponding to the randomization arm. 
The randomization number will be used in the background only to ensure that there is no 
unblinding and will not be displayed to end-users in the IWRS.  
8.4 
Procedure for Breaking the Randomization Code 
Should a situation arise where unblinding is urgently required, i.e., only where 
knowledge of the study drug is required to adequately manage a life-threatening situation, 


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the Investigator at that study site may perform immediate unblinding through IWRS. The 
responsibility to break the treatment code in emergency situations resides solely with the 
Investigator. The Investigator should make every effort to discuss the rationale (status 
and outcome) for emergency unblinding with the Sponsor’s Medical Monitor as soon as 
possible to review the individual patient details. 
The study-site Investigator and appropriate project team members will be authorized to 
access the emergency unblinding functionality within the IWRS. Once the randomization 
code is broken for a patient, he/she must be withdrawn from the study and all assessments 
and procedures for Visit 6/EOT should be performed. Once a randomization code has 
been broken, the Investigator must inform the project team and Sponsor’s Medical 
Monitor in writing within 24 hours. In case of technical issues accessing the system 
online, please see the IWRS site user manual for contact telephone numbers for the help 
desk 24/7 system support. 
8.5 
Patient Compliance 
Patients will return all unused study drug at Visits 3 through 6. The study-site staff will 
count all returned drug, assess compliance, and record details in the eCRF. 
Any noncompliance will be documented and explained in the source documents. 
Treatment compliance = 100 × ([number of study drug dispensed—number of study drug 
returned]/number of study drug that should be taken) 
Treatment compliance between 80% and 120% is acceptable. 
8.6 
Study Drug Accountability 
Records shall be maintained of the delivery of study treatment(s) to the study site(s), of 
the inventory at the study site(s), of each use of the study treatment(s) for each patient 
and the return or destruction of used and unused study treatment(s). Local destruction of 
used/unused study treatment(s) will follow institution standard operating procedures 
(SOPs) and will require Sponsor pre-approval. 
These records shall include dates, quantities, batch numbers, expiry dates, and the unique 
code numbers assigned to the study drug and to the study patients. 


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The Investigator will be responsible for ensuring that the records adequately document 
that the patients were provided the quantities specified in the protocol and that all study 
drug received from the Sponsor or its designee is reconciled.  
8.7 
Concomitant Therapy and Prohibited Medications 
The Investigator will note all ongoing medication and any medication recently stopped 
(within 3 months prior to Visit 2) in the eCRF. At Visits 2 through 6, all changes in 
medication (stopping or starting new medication or changes in dose) will be recorded in 
the eCRF.   
All medications taken by a patient within 3 months prior to the first intake of study drug 
are regarded as prior medication. 
All medications taken by a patient on or after the first intake of study drug, and which 
continue to be taken during the study, are regarded as concomitant medication.  


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9. 
ASSESSMENT OF EFFICACY 
9.1 
Efficacy Endpoints 
9.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline in serum LDL-C at Week 16. 
9.1.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following:  
• Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured 
by MRI-PDFF 
• Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by 
MRI 
• Change from Baseline to Week 16, and Follow-Up in the following: 
o Serum ALT, AST, and gamma-glutamyl transferase 
o HDL-C, non-HDL-C, LDL-C/HDL-C ratio, and triglycerides 
o Total bile acids 
9.1.3 
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be assessed: 
• Change from Baseline (unless otherwise specified) to Week 4, Week 8, Week 12, 
Week 16, and Follow-Up in the following: 
o Fasting glucose, insulin, homeostatic model assessment-insulin resistance, 
HbA1c, free fatty acids 
o GLP-1, FGF-19, and C4 levels 
o High-sensitivity CRP 
o Lanosterol and beta-sitosterol 
o Body weight, BMI, waist circumference, and waist-to-hip ratio 


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o Apolipoprotein A1 and Apolipoprotein B 
9.2 
Efficacy Assessments 
9.2.1 
Lipid Profile 
Fasting blood samples for analysis of LDL-C will be drawn at all visits, according to the 
schedule of assessments (Table 1). Fasting should be for at least 8 hours prior to the 
collection of the blood sample. Samples will be processed and transported to a central 
laboratory per instructions in the study reference manual. 
9.2.2 
Magnetic Resonance Imaging 
Patients will have an MRI at Screening and EOT to assess liver fat by MRI-PDFF, and 
total liver volume. Details of the image acquisition and analysis can be found in the study 
reference manual. 
9.2.3 
Total Bile Acids 
Fasting blood samples for analysis of total BA will be drawn at all visits, according to the 
schedule of assessments (Table 1). Fasting should be for at least 8 hours prior to the 
collection of the blood sample. All BA results during the treatment period will be 
blinded. Samples will be processed and transported to a central laboratory per 
instructions in the study reference manual. 
9.2.4 
Biomarkers and Blood Samples for Future Testing 
Blood samples for analysis of additional markers of disease, fibrosis, inflammation, and 
cardiovascular risk factors, and other pharmacodynamic markers will be drawn at the 
appropriate visits, according to the schedule of assessments (Table 1). These include a 
bile acid profile, including primary and secondary bile acids, interleukin-6, Pro-C3, 
tumor necrosis factor alpha, and cytokeratine-18. Samples will be processed and 
transported to a central laboratory per instructions in the study reference manual. 


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10. 
ASSESSMENT OF SAFETY 
The timing and frequency of safety assessments are described in Section 7.1.3 and in 
Table 1. 
The primary safety analysis will include the occurrence of treatment emergent adverse 
events (TEAE) and TEAEs categorized by causality, severity, and seriousness 
assessments made by the Investigator by comparing study drug exposure to placebo. 
Trends in safety will also be evaluated for the following assessments: 
• AEs, including discontinuations due to AEs 
• Physical examinations 
• Concomitant medications 
• Vital signs 
• 12-lead ECG 
• Laboratory test results (including clinical chemistry, hematology/coagulation, and 
urinalysis) 
10.1 
Adverse Events 
10.1.1 
Definitions and Investigator Assessments 
An AE is defined as any untoward medical occurrence in an enrolled patient regardless of 
causal relationship with study drug. An AE can therefore be any clinically significant 
unfavorable and unintended sign, symptom, or disease that occurs once a patient is 
enrolled (ICF is signed) in the study until the patient is discharged from the study, 
whether or not related to the study drug. 
10.1.1.1 
Clinical Significance 
Clinical significance is defined as any abnormal finding that results in further clinical 
investigation(s), treatment(s), or the diagnosis of a new condition. Patient reported events 
and protocol mandated laboratory values, vital signs, and physical examination findings 
can be considered clinically significant (i.e., an AE) if there is a deterioration as 
compared to Baseline. Examples of clinically significant worsening from Baseline could 


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include, but is not limited to, events causing withdrawal from the study and events 
requiring medical intervention outside of the study causing apparent clinical 
manifestations or judged to be relevant by the Investigator.   
10.1.1.2 
Serious Adverse Events 
Serious criteria are applied by the investigator to each AE as specifically defined below. 
These criteria are used to determine whether an AE is serious or non-serious. The 
assessment is made independently of severity assessment (Section 10.1.1.3). For 
example, the development of a severe rash that occurs after signing of the ICF may not 
meet serious criteria as defined below and therefore would be considered a severe, 
non-serious AE. 
Any AE that meets any 1 of the following 6 criteria is considered to be an SAE: 
• The outcome of the AE is death 
• The AE is immediately life-threatening. Life-threatening means that the patient 
is, in the opinion of the Investigator, at immediate risk of death from the reaction 
as it occurred. This does not include an AE that, if more severe, might have 
caused death 
• The AE results in persistent or significant disability/incapacity. Disability means 
a substantial disruption of a person’s ability to conduct normal life functions 
• The AE requires or prolongs hospitalization  
• The AE results in a congenital anomaly/birth defect 
• The AE is an important medical event. Important medical events may meet 
serious criteria should the Investigator assess that they may significantly 
jeopardize the patient, represent a significant hazard, or require medical/surgical 
intervention to prevent one of the outcomes listed above. Examples of potential 
SAEs based on these criteria include, but are not limited to, allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions even if they do not result in inpatient 
hospitalization, or the development of drug dependency and drug abuse. 


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10.1.1.3 
Adverse Events of Special Interest 
An adverse event of special interest (AESI) should be recorded as an AE in the eCRF as 
outlined in Section 10.1.2 and reported using the SAE/AESI Report Form outlined in 
Section 10.1.3.  
For this study, any occurrence of ischemic colitis should be reported as an AESI.  
10.1.1.4 
Severity Assessment 
Severity assessments are based on the intensity of the event in relation to expectation. 
The Investigator will assess the intensity of AEs based on the following definitions: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
Severity is a measure of intensity where seriousness is defined by the criteria outlined in 
Section 10.1.1.2. An AE of severe intensity need not necessarily be considered serious. 
For example, nausea that persists for several hours may be considered severe nausea, but 
not meet serious criteria, and therefore would be assessed as a severe AE but not an SAE. 
10.1.1.5 
Causality Assessment 
The Investigator determines the causality of all AEs to the study drug using medical 
judgment and considering all relevant factors such as (but not limited to) the underlying 
study indication, coexisting disease, concomitant medication, relevant history, pattern of 
the AE, temporal relationship to the study drug, and de-challenge or re-challenge. The 
causality assessment of the AE/SAE is to be made as follows: 
Related to Study Drug (Possibly, Probably, or Definitely Related) 
Based on medical judgment, there is at least a reasonable possibility that the study drug 
caused the event; one or more of the following criteria apply: 
• The event follows a reasonable temporal sequence from administration of study 
drug 


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• The event could not be reasonably attributed to the known characteristics of the 
patient’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient 
• The event follows a known pattern of response to study drug 
• The event disappears or decreases on cessation or reduction in dose of the study 
drug. (It should be noted that in some situations an AE will not disappear or 
decrease in intensity upon discontinuation of study drug despite other clear 
indications of relatedness) 
• The event reappears or worsens when the study drug is re-administered 
Unrelated to Study Drug (Unlikely or Unrelated) 
Based on medical judgment there is no reasonable possibility that the study drug caused 
the event; one or more of the following criteria apply: 
• The event does not follow a reasonable temporal sequence from administration of 
study drug 
• The event could be reasonably attributed to the known characteristics of the 
patient’s clinical state, concurrent illness, environment or toxic factors, or other 
modes of therapy administered to the patient 
• The event does not follow a known pattern of response to study drug 
• The event does not disappear or decrease on cessation or reduction in dose of the 
study drug, and it does not reappear or worsen when the study drug is 
re-administered 
10.1.2 
Recording of Adverse Events 
It is the Investigator’s responsibility to assess whether each untoward event is a clinically 
significant worsening from Baseline, thereby considered an AE. For all AEs, the severity, 
seriousness, and causality to study drug for each AE as outlined in Section 10.1.1 will be 
assessed and recorded in the eCRF. 
All serious and non-serious AEs are collected once the patient has signed the ICF and 
until the post-treatment follow-up (Visit 7) or 14 days after the last dose of study drug. 


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Any AEs or SAEs that are unresolved at the patient’s last AE assessment are followed up 
by the Investigator until resolution or stabilization up to the database lock and recorded in 
the eCRF. The Sponsor retains the right to request additional information for any patient 
with ongoing AE(s) or SAE(s) at the end of the study. 
TEAEs are defined as any AE that occurs after first dose of study drug. All AEs that 
occur in the Screening period, i.e., after enrollment and prior to randomization, will be 
collected on the eCRF as non-TEAEs. 
If there is a clinically significant deterioration of a laboratory value/vital sign or other 
routine study assessment that is associated with a diagnosis, the clinical diagnosis will be 
reported as an AE and the associated signs and symptoms will be considered additional 
information unless the sign or symptom is more severe than expected given the diagnosis. 
For example, if an Investigator diagnoses a study patient with hepatitis during the study 
period, hepatitis would be considered the AE and the concomitant signs and symptoms of 
abdominal pain, vomiting, and elevated ALT and AST would not be reported separately 
unless, in the opinion of the Investigator, one of these signs or symptoms is more severe 
than expected and therefore a separate AE assessment is indicated. 
10.1.3 
Recording and Reporting of Serious Adverse Events and Adverse 
Events of Special Interest 
Every SAE/AESI (regardless of severity and causality) that occurs once the patient has 
signed the ICF and through 14 days after the final dose of study drug, should immediately 
and not later than within 24 hours of knowledge of the event, be reported by the 
Investigator or delegate using the SAE/AESI report form.  
Report of a SAE/AESI must include at least the following information: 
• Patient identification information (study number, site number, and date of birth 
[as per local country requirements for data protection]) 
• The last study drug administration date 
• The diagnosis of the event with the description (or a brief description of 
signs/symptoms/clinical course if the diagnosis is not available) and the date of 
onset 


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• The action used to treat the event (i.e., treatment medications, temporary 
discontinuation) 
• The reason(s) for considering the event serious 
• The relationship of the event to the study drug or to the study procedure (i.e., the 
Investigator’s assessment of causality) 
• A brief narrative of the SAE/AESI 
Follow-up reports including all new information obtained of the subsequent course of the 
SAE/AESI must be prepared and the information collected in the SAE/AESI report form 
submitted to the CRA, and 
 
 by e-mail within 24 hours of knowledge of the event. 
The pharmacovigilance manager (PVM) or the CRA may contact the Investigator to 
obtain further information on a reported SAE/AESI. The investigator/investigative staff 
must respond to any request for follow-up information or answers to questions regarding 
the SAE/AESI within the same timelines as for initial reports. 
The PVM reports the occurrence of the SAE/AESI and follow-up to the Sponsor’s 
Medical Monitor for medical assessment of the case. 
Should an outcome of death occur within the study period or within 14 days after the last 
administration of study drug, an SAE/AESI report form should be completed including 
the main and contributory causes of death. 
All SAE/AESI reports must be e-mailed to the following e-mail address within 24 hours: 
 
If email is unavailable, SAEs/AESIs may be transmitted via fax to the following number: 
 
10.1.4 
Notification of Suspected Unexpected Serious Adverse Reactions 
A suspected unexpected serious adverse reaction (SUSAR) is an SAE that occurs in a 
patient, the nature or severity of which is not expected per the applicable product 
information. The elobixibat Investigator’s Brochure will serve as the reference safety 
information for this study.  


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Reporting and tracking of SUSARs will be in accordance with all applicable competent 
authority regulations. The IRBs and all Investigators involved in this study will be 
informed according to local requirements. 
10.2 
Laboratory Values, Vital Signs, Physical Examinations, and Other Safety 
Assessments 
10.2.1 
Laboratory Assessments 
Samples will be collected for clinical chemistry, hematology, urinalysis, and other lab 
assessments at the time points specified in Table 1. The parameters assessed are 
presented in Table 2. All samples will be processed and transported to a central 
laboratory per instructions in the study reference manual. 
The observed values will be recorded and assessed as “normal” or “abnormal not 
clinically significant” or “abnormal clinically significant.” 
Additional blood samples may be needed due to follow-up of an abnormal value or 
analysis failure. The blood samples collected for safety laboratory analysis will be 
destroyed after the analyses have been completed.  
Stored blood samples for future testing are detailed in Section 9.2.4.  


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Table 2: 
Laboratory Parameters 
CLINICAL CHEMISTRY (FASTING) 
HEMATOLOGY/COAGULATION 
URINALYSIS 
• 
Albumin 
• 
ALT 
• 
Alkaline phosphatase  
• 
Amylase 
• 
AST 
• 
Bicarbonate 
• 
Blood urea nitrogen 
• 
Calcium 
• 
Chloride 
• 
Creatine kinase 
• 
eGFR by MDRD (screening only) 
• 
Gamma-glutamyl transferase 
• 
Glucose 
• 
Hemoglobin HbA1C 
• 
Inorganic phosphorus 
• 
Lactate dehydrogenase 
• 
Lipase 
• 
Potassium 
• 
Sodium 
• 
Total bilirubin 
• 
Total protein 
• 
Uric acid 
• 
Hematocrit 
• 
Hemoglobin 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count and differential 
(neutrophils, eosinophils, basophils, 
lymphocytes, and monocytes) 
Manual microscopic review is performed only if 
white blood cell count and/or differential values 
are out of reference range. 
• 
International normalized ratio (INR) 
• 
Prothrombin time (PT) 
• 
Bilirubin 
• 
Blood 
• 
Glucose 
• 
Ketones 
• 
Leukocyte esterase 
• 
Microscopy including leukocytes (performed 
only as needed based on positive dipstick test 
results) 
• 
Nitrites 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
 
 
 
 
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LIPID PROFILE (FASTING) 
OTHER TESTS 
ENDOCRINOLOGY 
• 
Apolipoprotein A1 
• 
Apolipoprotein B 
• 
Chylomicron cholesterol 
• 
Chylomicron triglycerides 
• 
High-density lipoprotein (HDL) cholesterol 
• 
Lipoprotein(a) cholesterol 
• 
Low-density lipoprotein (LDL) cholesterol1  
• 
LDL triglyceride 
• 
Non-high-density lipoprotein cholesterol 
• 
Total cholesterol 
• 
Triglycerides 
• 
Very low-density lipoprotein (VLDL) 
cholesterol 
• 
VLDL triglyceride 
• 
Lanosterol 
• 
Beta-sitosterol 
• 
High-sensitivity C-reactive protein (CRP) 
• 
C4 
• 
Fibroblast growth factor-19 (FGF-19) 
• 
Fibrosis and inflammation markers: FIB-4, 
APRI, and NAS  
• 
Glucagon-like peptide-1 (GLP-1) 
• 
Follicle-stimulating hormone2 
• 
Homeostatic model assessment-insulin 
resistance 
• 
Insulin 
• 
Thyroxine3 
• 
Triiodothyronine3 
• 
Thyroid-stimulating hormone3 
• 
Free fatty acids 
• 
Adipose tissue insulin resistance 
• 
Adiponectin 
BILE ACIDS (FASTING) 
PREGNANCY 
SEROLOGY 
• 
Total bile acids 
• 
Serum 
• 
Urine 
• 
Hepatitis B virus surface antigen 
• 
Hepatitis C virus antibody and ribonucleic 
acid  
1 
LDL-cholesterol will be determined by calculation when triglyceride levels are less than or equal to 400 mg/dL, LDL-C will be determined by preparative ultracentrifugation 
(PUC) when triglyceride levels are greater than 400 mg/dL. 
2 
A postmenopausal state is defined as no menses for ≥12 months without an alternative medical cause. A follicle-stimulating hormone level in the postmenopausal range will be 
used to confirm a postmenopausal state in women ≤55 years of age, performed at Screening visit only. 
3 
Thyroid function test will be performed during Screening visit only. 


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10.2.2 
Individual Patient Safety Monitoring 
10.2.2.1 
Liver Monitoring 
Strategies to monitor markers of liver disease throughout the study are outlined below 
where the ULN will be based on central laboratory reference values for age and gender. 
Patients will be monitored as described below for drug-induced liver injury from 
randomization to 2 weeks following the last administration of study drug. 
Elevated ALT  
• ALT >5 × ULN or >3 × Baseline (if ALT elevated at Baseline): repeat AST, 
ALT, total bilirubin, alkaline phosphatase (ALP), and INR within 72 hours of 
receipt of the result and closely monitor the patient. If liver enzyme elevation is 
confirmed, interrupt the study drug. The study drug can be restarted only if a 
competing etiology is identified or liver tests return to Baseline. 
Elevated AST  
• AST >5 × ULN or 3 × baseline (if AST elevated at baseline): repeat AST, ALT, 
total bilirubin, ALP, and INR within 72 hours of receipt of the result and closely 
monitor the patient. If liver enzyme elevation confirmed, interrupt the study drug. 
The study drug can be restarted only if a competing etiology is identified or liver 
tests return to Baseline. 
Elevated Total Bilirubin 
• Total bilirubin >2 × ULN or >1.5 × Baseline (if total bilirubin elevated at 
Baseline), regardless of ALT or AST levels: repeat AST, ALT, total bilirubin, 
ALP, and INR within 72 hours of receipt of the result and closely monitor the 
patient. If liver enzyme elevation confirmed, interrupt the study drug. The study 
drug can be restarted only if a competing etiology is identified or liver tests return 
to Baseline. 
Other Clinical Symptoms  
• Clinical signs of hepatitis or indicators of immunological reaction (e.g., nausea, 
vomiting, right upper quadrant pain, loss of appetite, dark urine, jaundice, rash, 


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eosinophilia >5% or symptoms/signs of hepatic decompensation): discontinue the 
study drug and repeat AST, ALT, total bilirubin, ALP, and INR within 72 hours 
and closely monitor. Other causes of hepatitis should be excluded.  
When close monitoring of a patient is not possible while the patient is on study drug, 
interrupt the study drug and closely monitor the patient. 
10.2.3 
Demographics/Medical and Surgical History 
Demographic information per country regulations (age, full date of birth, gender, race, 
and ethnicity), along with medical and surgical history, will be obtained and recorded in 
the eCRF at Visit 1. 
Medical and surgical history will be entered in the eCRF at Visit 1. This includes date of 
diagnosis of NASH/NAFLD including liver biopsy results for biopsy-confirmed NASH 
patients within 6 months of screening, ongoing medication, any surgery performed, and 
any other diagnoses.   
10.2.4 
Physical Examination 
A physician or suitably trained qualified assistant will perform a complete physical 
examination at Screening, at Visit 2, and at Visit 6. Height (Screening only), weight, 
waist circumference, and waist-to-hip ratio will also be collected. BMI will be calculated 
based on height and weight. 
A complete physical examination will include assessment of general appearance, eyes, 
ears, nose, throat, head/neck/thyroid, lymph nodes, cardiovascular, lungs/chest, abdomen, 
genitourinary, extremities, skin, musculoskeletal, neurologic, and other.  
10.2.5 
Vital Signs 
Evaluation of vital signs will be performed at all visits. This includes blood pressure 
(systolic and diastolic), pulse, respiratory rate, and oral temperature. 
10.2.6 
12-Lead ECG 
A 12-lead ECG will be performed at the Screening visit and the EOT visits.  


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10.2.7 
Overdose 
Elobixibat is minimally absorbed and has a very low systemic availability. It is not 
known whether elobixibat can be removed from the systemic circulation by dialysis. 
There are no known antidotes for elobixibat overdoses. If an overdose occurs, the patient 
should be carefully monitored and treated with supportive therapy. 
10.2.8 
Pregnancy 
If a pregnancy is discovered in a female patient enrolled in the study, the patient will be 
immediately discontinued from the study drug, if applicable, and will attend the same 
visits as a prematurely withdrawn patient. If the pregnancy is discovered after completion 
of the treatment period, the patient will continue in the study per protocol. If a pregnancy 
occurs in a male patient’s partner at any time during the study, the pregnancy should also 
be reported and followed. 
If the patient has been dosed with the study drug, the pregnancy must be recorded on the 
appropriate form and submitted to the PVM (Section 10.1.3) within 24 hours of learning 
of the pregnancy. 
The pregnancy should be followed to determine outcome, including spontaneous 
termination, details of birth and presence of any birth defects, congenital anomalies or 
newborn or maternal complication. While pregnancy itself is not considered to be an AE 
or SAE, any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE.  A spontaneous abortion (occurring at <22 
weeks gestational age) or still birth (occurring at >22 weeks gestational age) is always 
considered to be an SAE and will be reported as such.  
Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported as described in Section 10.1.3. While the 
investigator is not obligated to actively seek this information in former study participants, 
he or she may learn of an SAE through spontaneous reporting. 


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11. 
STATISTICAL EVALUATION 
All personnel involved with the analysis of the study will remain blinded until database 
lock for the double-blind treatment period and until major protocol violations have been 
identified. 
All statistical analyses will be performed using SAS version 9.3 or higher. 
11.1 
Sample Size and Power 
Due to the exploratory nature of this study, no formal power calculations were used to 
determine the sample size. The number of subjects (46 patients in total, 23 patients per 
treatment group) was chosen based on clinical experience with other similar proof-of- 
concept studies. 
11.2 
Statistical Methods 
11.2.1 
Statistical Analysis Populations 
ITT Population 
The intent-to-treat (ITT) population will include all patients who are randomized in the 
study and receive at least 1 dose of study drug. The ITT population will be used for all 
efficacy analyses based on the treatment randomized unless otherwise specified.  
Per Protocol Population 
The per protocol (PP) population will include all ITT patients who finish Visit 7/EOT 
with valid LDL-C measurements and do not have any major protocol deviations. 
Allocation of patients to the PP analysis set will be performed before unblinding of the 
study. 
Safety Population  
The safety population will include all patients who are randomized and receive at least 
1 dose of study drug and will be used for all safety analyses based on the treatment 
received.  


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11.2.2 
Methods of Statistical Analyses 
11.2.2.1 
General Principles 
Summary statistics (number of patients, mean, standard deviation, median, minimum, and 
maximum) at all visits and change or percent change from Baseline will be provided for 
efficacy and safety continuous variables. Count and frequency will be used to tabulate 
categorical variables. 
11.2.2.1.1 
Efficacy 
The primary efficacy endpoint is the change from Baseline in serum LDL-C at Week 16. 
Baseline is defined as the last non-missing LDL-C value prior to the first dose of study 
drug.  
Exploratory comparisons between elobixibat 5 mg and placebo will be performed for the 
following secondary efficacy endpoints:   
• Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured 
by MRI-PDFF 
• Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by 
MRI 
The analysis methods for the other secondary and exploratory endpoints will be detailed 
in the statistical analysis plan (SAP). 
11.2.2.1.2 
Safety 
The safety endpoints for this study include clinical laboratory assessments, vital signs, 
AEs, ECGs, physical examinations, and concomitant medications. 
AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedRA). TEAEs will be defined as AEs that are new or worsening after the 
first dose of study drug. A general summary of patients with TEAEs and serious adverse 
events (SAEs) will be tabulated with numbers and percentages of patients and repeated 
for severity and relationship to study drug per treatment group. The number of AEs 
leading to withdrawal and SAEs leading to death will also be summarized. The incidence 
of TEAEs will be summarized by body system and treatment group. 


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The safety laboratory data will be summarized by visit and by treatment group, along 
with changes from Baseline. Values outside of the reference range will be flagged and 
laboratory abnormalities of special interest will be summarized.  
11.2.2.2 
Missing Data 
Missing data handling for the primary efficacy endpoint will be specified in the SAP.  
11.2.2.3 
Demographic and Baseline Characteristics 
Descriptive summaries of demographics and other baseline characteristics (including 
medical and surgical history) will be presented by treatment group and overall using the 
ITT population.  
Prior medication will be summarized by treatment group and overall using the ITT 
population. 
11.2.2.4 
Subject Disposition 
The following will be summarized descriptively (by treatment group and overall where 
applicable): 
• Patients enrolled (who signed the informed consent) 
• Patients randomized 
• Patients treated 
• Patients completing the study 
• Patients withdrawing early (including withdrawal reason) 
11.2.2.5 
Evaluation of Primary Efficacy Endpoints 
 An analysis of covariance (ANCOVA) will be used to analyze the primary efficacy 
endpoint. The model will include treatment arm and Baseline LDL-C scores.  
Least square (LS) mean (SE), LS mean difference (SE), 95% confidence intervals, and 
P-values between elobixibat 5 mg and placebo will be provided. The model assumptions 
will be checked before the analysis. If there are concerns on model assumptions, i.e., 


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normality and homogeneity of variances, a non-parametric ANCOVA based on the rank 
scores can be used as a sensitivity analysis. 
Sensitivity analyses may be performed and will be detailed in the SAP. 
11.2.2.6 
Evaluation of Secondary and Exploratory Efficacy Endpoints 
Descriptive statistics will be provided for secondary and exploratory endpoints listed in 
Sections 9.1.2 and 9.1.3, respectively, unless otherwise specified. 
11.2.2.7 
Evaluation of Safety Endpoints 
Safety data will be analyzed using descriptive statistics and summaries by treatment 
group of SAEs, AEs, vital signs, clinical safety laboratory tests (hematology, coagulation, 
clinical chemistry, and urinalysis), and concomitant medication. Analyses will be 
performed using the safety analysis set.  
Summaries of AEs (coded according to the MedDRA system organ class [SOC] and 
MedDRA preferred term) will include the following:  
• Overview of the incidence of TEAEs (TEAEs, drug-related TEAEs, TEAEs 
leading to study discontinuation, and treatment-emergent SAEs) 
• TEAEs by SOC and preferred term 
• Intensity of TEAEs by SOC and preferred term 
• Drug-related TEAEs by SOC and preferred term 
• TEAEs leading to study discontinuation by SOC and preferred term 
• Treatment-emergent SAEs by SOC and preferred term 
Concomitant medication use during the treatment period will be summarized by 
Anatomical Therapeutic Chemical (ATC) class and World Health Organization (WHO) 
preferred name.  
Summaries of vital signs will be presented. For each visit, the actual results, the change 
from Baseline, and the observed post-baseline value will be presented. 
Summaries of clinical safety laboratory data will be presented. For each visit, the actual 
result, the change from Baseline, and the observed post-baseline value will be presented. 


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Data listings will be provided for each patient for all safety parameters. 
11.2.2.8 
Compliance and Exposure 
Exposure will be analyzed by calculating the number of days with exposure to study 
drug. Results will be presented by treatment group using the safety analysis set.  
The percentage compliance will be described by treatment group and the number of 
patients with a compliance <80%, between 80% and 120%, and >120% will be presented 
based on the safety analysis set. 


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12. 
DIRECT ACCESS TO SOURCE DATA/NOTES 
The Investigator/institution shall provide direct access to source data/documents for 
study-related monitoring, audits, IRB review, and regulatory inspection. 


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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Conduct of the Study 
The study team shall implement and maintain quality control and quality assurance 
procedures with written SOPs to ensure that the study is conducted, and data are 
generated, documented, and reported in compliance with the protocol, ICH GCP, and 
applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of 
Helsinki (October 1996) and all revisions thereof, and in accordance with US Food and 
Drug Administration (FDA) regulations (Code of Federal Regulations, Sections 312.50 
and 312.56) and with ICH GCP (CPMP 135/95). 
The Investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate competent authority and IRB, 
except when necessary to eliminate immediate hazards to the patient or when the 
change(s) involve(s) only logistical or administrative aspects of the study. Any deviations 
may result in the patient having to be withdrawn from the study and render that patient 
non-evaluable. 
13.2 
Study Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Sponsor 
representative or designee will review the protocol and eCRF with the Investigators and 
the investigative staff. During the study, the clinical monitor (the CRA) will visit the site 
regularly to check the completeness of patient records, the accuracy of entries on the 
eCRFs, the adherence to the protocol and to GCP, the progress of enrollment, and to 
ensure that study drug is being stored, dispensed, and accounted for according to 
specifications. 
The investigator must ensure that eCRFs are completed within a timely period of patient 
visits, as per individual site agreements, and must allow the CRA and the Sponsor 
representative or designee periodic access to patient records and all study-related 
materials, including relevant hospital or clinical records, to confirm their consistency 
with the eCRF entries. No information in these records about the identity of the patients 
will leave the study center. The Sponsor monitoring standards require full verification for 
the presence of the signed ICF, adherence to the inclusion/exclusion criteria, 


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documentation of SAEs, and recording of primary efficacy and safety variables. The 
CRA will review source data compared with the eCRFs and will verify source data 
according to the study-specific monitoring plan. The design of the study, the frequency of 
patient visits, and the site enrollment rate will determine the frequency of monitoring 
visits. Upon study completion, the CRA will visit the site to conduct a study termination 
visit, which will include collection of any outstanding documentation. 
It is recommended that the Investigator/investigative staff log into the eCRF system every 
working day or at minimum twice weekly in order to provide a prompt response to 
queries. The Investigator/investigative staff should respond to queries and make any 
relevant changes to the study data within 3 working days. 


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14. 
ETHICS 
14.1 
Institutional Review Board 
Prior to the start of the study, the Investigator is responsible for ensuring that the protocol 
and consent form have been reviewed and approved by a relevant IRB. The IRB shall be 
appropriately constituted and perform its functions in accordance with FDA, ICH, GCP, 
and local requirements as applicable. 
The IRB shall approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, patient recruitment 
procedures (e.g., advertisements), written information to be provided to the patients and 
caregivers, the Investigator’s Brochure, available safety information, information about 
payment and compensation available to patients, the Investigator’s curriculum vitae 
and/or other evidence of qualifications and any other documents requested by the IRB 
and regulatory authority (competent authority) as applicable. 
14.2 
Written Informed Consents 
The Investigator (physician) or investigative staff, in accordance with local regulations, 
will explain to each patient (or legally authorized representative) the nature of the study, 
its purpose, the procedures involved, the expected duration, alternative treatment, the 
potential risks and benefits involved, and any discomfort that may occur. Each patient 
will be informed that participation in the study is voluntary and that he/she may withdraw 
from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
If written consent is not possible, oral consent can be obtained if witnessed and followed 
by a signed statement from one or more persons not involved in the study, indicating why 
the patient was unable to sign the form. No patient can enter the study before his/her 
informed consent has been obtained, as required by country regulations. 
The ICF is part of the protocol and must be submitted by the Investigator/investigative 
staff with the protocol for IRB approval. The Sponsor will supply an ICF which complies 
with regulatory requirements and country laws and is considered appropriate for the 
study. Any changes to the ICF suggested by the Investigator must be agreed to by the 
Sponsor before submission to the IRB and a copy of the approved version must be 
provided to the clinical monitor after IRB approval. 


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15. 
DATA HANDLING AND RECORDKEEPING 
15.1 
Electronic Case Report Forms/Source Data Handling 
The investigator shall be provided with standardized eCRFs and shall ensure that all data 
from patient visits are promptly entered into the eCRFs in accordance with the specific 
instructions given. The Investigator must sign each eCRF to verify the integrity of the 
data recorded. 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to the start of the study. As a central laboratory has 
been selected to conduct any or all tests, it is essential that all samples be analyzed at that 
laboratory. 
The Investigator must maintain source documents such as laboratory reports, consultation 
reports, and complete medical history and physical examination reports. 
15.2 
Retention of Essential Documents 
Essential documents, as defined by ICH GCP, include the signed protocol and any 
amendment(s); copies of the completed eCRFs (for site archiving of eCRF data for 
specific patients will be provided); signed ICFs; hospital records and other source 
documents; IRB approvals and all related correspondence including approved documents; 
drug accountability records; study correspondence; and a list of patients’ names and 
addresses. 
The Investigator/investigative staff must retain copies of these essential documents for 
the period specified by ICH GCP and by applicable regulatory requirements. The 
Investigator/investigative staff will inform the Sponsor of the location where the essential 
documents are stored and must contact the Sponsor for approval before disposing of any 
essential documents. The Investigator/investigative staff should take measures to prevent 
accidental or premature destruction of these documents. 


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16. 
FINANCING AND INSURANCE 
Financing and insurance are addressed in a separate agreement. 


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17. 
PUBLICATION POLICY 
The Sponsor will retain ownership of all data. When the study is complete, the Sponsor 
will arrange the analysis, tabulation of data, and preparation of a clinical study report. 
The Sponsor may also use the data for publication, presentation at scientific meetings, 
and submission to regulatory authorities. All proposed publications based on this study 
must be subject to the Sponsor’s approval requirements. 


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18. 
REFERENCES LIST 
Andersen A, Lund A, Knop FK, Vilsbøll T. Glucagon-like peptide 1 in health and 
disease. Nature Rev. 2018;14(7):390-403. doi: 10.1038/s41574-018-0016-2. 
Aranha MM, Cortez-Pinto H, Costa A, et al. Bile acid levels are increased in the liver of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2008;20(6):519-525. 
doi: 10.1097/MEG.0b013e3282f4710a. 
Bertolotti M, Zambianci L, Carulli L, et al. Influence of newly synthesized cholesterol on 
bile acid synthesis during chronic inhibition of bile acid absorption. Hepatology. 
2003;38(4)939-946. 
Ferslew BC, Xie G, Johnston CK, et al. Altered bile acid metabolome in patients with 
non-alcoholic steatohepatitis. Dig Dis Sci. 2015;60(11):3318-3328. doi: 10.1007/s10620-
015-3776-8. 
Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological 
scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313-1321. 
doi: 10.1002/hep.20701. 
Mahfood Haddad T, Hamdeh S, Kanmanthareddy A, Alla VM. Nonalcoholic fatty liver 
disease and the risk of clinical cardiovascular events: a systematic review and meta-
analysis. Diabetes Metab Syndr. 2017;11(Suppl 1):S209-S216. 
doi: 10.1016/j.dsx.2016.12.033. 
Naoumova RP, O’Neill FH, Dunn S, et al. Effect of inhibiting HM-CoA reductase on 7α-
hydroxy-4-cholesten-3one, a marker of bile acid synthesis: contrasting findings in 
patients with and without prior up-regulation of the latter pathway. Eur J Clin Invest. 
1999;29(5):404-412.  
Prawitt J, Caron S, Staels B. Bile acid metabolism and the pathogenesis of type 2 
diabetes. Curr Diabetes Rep. 2011;11(3):160-166. doi: 10.1007/s11892-011-0187-x. 
Puri P, Daita K, Joyce A, et al. The presence and severity of nonalcoholic steatohepatitis 
is associated with specific changes in circulating bile acids. Hepatology. 
2018;67(2):534-548. doi: 10.1002/hep.29359. 


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Sanyal A, Harrison S, Charlton M, et al. Serum bile acids are markedly elevated in 
patients with compensated cirrhosis due to nonalcoholic steatohepatitis. J Hepatol. 
2018;68:S365-S604. doi: 10.1016/S0168-8278(18)31360-6. 
Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. 
Nat Rev Gastroenterol Hepatol. 2014;11(1):55-67. doi: 10.1038/nrgastro.2013.151. 
Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, 
predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 
2018;15(1):11-20. doi: 10.1038/nrgastro.2017.109. 
 


CLINICAL STUDY PROTOCOL A3309-012 
A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to 
Explore the Efficacy and Safety of Elobixibat in Adults with 
Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic 
Steatohepatitis (NASH) 
 
IND number:  
141078 
Test product: 
Elobixibat 
Indication: 
Nonalcoholic Fatty Liver Disease or Nonalcoholic 
Steatohepatitis 
Sponsor: 
Elobix AB 
Development phase: 
Phase 2 
Sponsor medical monitor: 
 
Principal investigator: 
 
Date of the protocol: 
22 March 2019 
Version of the protocol:  
Version 2.0  
 
Version No. 
Previous Version Number 
Effective Date 
1.0 
N/A 
25 February 2019 
2.0 
1.0 
22 March 2019 
 
 
Confidential 
The information in this document contains trade secrets and commercial information that 
are privileged or confidential and may not be used, divulged, published, or otherwise 
disclosed without the written consent of Elobix AB. These restrictions on disclosure 
apply equally to all future information supplied to you or generated by you in 
connection with the study. 
 


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SPONSOR SIGNATURE PAGE 
PROTOCOL TITLE: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 
Study to Explore the Efficacy and Safety of Elobixibat in Adults with Nonalcoholic 
Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH)  
 
 
PROTOCOL NUMBER: A3309-012 
Elobix AB 
 
 


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INVESTIGATOR SIGNATURE PAGE 
PROTOCOL TITLE: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 
Study to Explore the Efficacy and Safety of Elobixibat in Adults with Nonalcoholic 
Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH)  
PROTOCOL NUMBER: A3309-012 
I have read this protocol and agree that it contains all necessary details for performing 
this study. I will conduct the study as outlined herein and will complete the study within 
the time designated, in accordance with all stipulations of the protocol and in accordance 
with Good Clinical Practice (GCP), local regulatory requirements, and the Declaration of 
Helsinki. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure that they are fully informed regarding the study drug and the conduct of 
the study. 
I will use only the informed consent approved by the Institutional Review Board (IRB) 
and will fulfill all responsibilities for submitting pertinent information to the IRB 
responsible for this study. 
I agree that the Sponsor (Elobix AB) shall have access to any source documents from 
which case report form (CRF) information may have been generated. 
I further agree not to originate or use the name of Elobix AB or elobixibat (A3309) in any 
publicity, news release, or other public announcement, written or oral, whether to the 
public, press, or otherwise, relating to this protocol, to any amendment to the protocol, or 
to the performance of this protocol without the prior written consent of Elobix AB. 
 
 
 
 
Name of Investigator 
 
 
 
 
Signature 
 
Date (day/month/year) 
 


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1. 
ADMINISTRATIVE INFORMATION 
Protocol no.: 
A3309-012 
Date of initial protocol: 
25 February 2019, Version 1.0 
Date and no. of amendments: 
22 March 2019, Version 2.0 
Sponsor: 
Elobix AB 
Arvid Wallgrens backe 20 
413 46 Gӧteborg 
Sweden 
Clinical research organization: 
 
 
 
Sponsor Medical Monitor: 
 
 
 
 
Principal Investigator: 
 
 


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2. 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
Title of Study: 
A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Explore the Efficacy and Safety of 
Elobixibat in Adults with Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis 
(NASH) 
Principal Investigator: 
 
Study Centers: Up to 15 sites will be initiated for this study in the United States (US) 
Publication(s): Not applicable 
Planned Study Period: Q2 2019 to Q2 2020 
Development Phase: Phase 2 
Objectives: 
Primary Objective 
The primary objective is to evaluate the efficacy of repeated once-daily doses of 5 mg elobixibat on 
serum levels of low-density lipoprotein cholesterol (LDL-C) in patients with NAFLD or NASH. 
Secondary Objectives 
• 
To assess the safety and tolerability of elobixibat in patients with NAFLD or NASH 
• 
To evaluate the effect of elobixibat on liver steatosis as measured by magnetic resonance imaging 
(MRI) for (i) liver fat fraction (using proton density fat fraction [PDFF]) and (ii) total liver fat 
(using whole liver fat volume) 
• 
To evaluate the effect of elobixibat on liver function using alanine aminotransferase (ALT) 
• 
To evaluate the effect of elobixibat on lipids and serum bile acids (s-BA) in patients with NAFLD 
or NASH 
Methodology: 
This is a double-blind, randomized, placebo-controlled, Phase 2 study to explore the efficacy and safety 
of elobixibat (oral dose of 5 mg) once daily for 16 weeks in patients with NAFLD or NASH. The study 
includes a 6-week Screening period, followed by a 16-week Treatment period, and a Follow-Up visit 
2 weeks after the last dose of study drug. Continued collection of efficacy data for patients who 
discontinue treatment will be made for as long as possible per the schedule of assessments.  
After completing the Screening period, eligible patients will be randomized on Day 1 (Visit 2) in a 1:1 
fashion to either 5 mg/day elobixibat or matching placebo. There will be a total of 7 scheduled visits 
during the study. Additional unscheduled visits may be required for patients who need direct site 
assistance (e.g., due to adverse event [AE] monitoring, in order to fulfill screening requirements, and/or 
for safety maintenance).   
Number of Patients: Approximately 46 patients diagnosed with NAFLD/NASH and in accordance with 
the inclusion/exclusion criteria will be randomized.   
Inclusion Criteria: 
Patients must meet all of the following criteria to be included in the study: 
1. Be willing to participate in the study and provide written informed consent 
2. Be a man or woman ≥18 years of age 
3. Have a current biopsy-confirmed NASH within 6 months of screening or a suspected diagnosis 
of NAFLD/NASH based on the criteria outlined below: 
 


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a. 
Biopsy-confirmed NASH is defined as histological NASH diagnosis with fibrosis 
stage F1 through F3 and a NAFLD activity score (NAS) of ≥4 with a score of ≥1 in 
each of the NAS components below as assessed by a pathologist using the NASH 
Clinical Research Network criteria (Kleiner 2005): 
i. 
Steatosis (scored 0 to 3) 
ii. 
Ballooning degeneration (scored 0 to 2) 
iii. 
Lobular inflammation (scored 0 to 3) 
 
OR 
b. The suspected diagnosis of NAFLD/NASH is based on each of the following criteria 
being met: 
i. 
Serum AST ≥20 U/L and ALT ≥40 U/L 
ii. 
Diagnosis of metabolic syndrome as having any 3 of the following 5 risk 
factors at Screening: 
• 
Fasting plasma glucose ≥100 mg/dL or undergoing drug treatment 
for elevated glucose 
• 
High-density lipoprotein-cholesterol (HDL-C) <40 mg/dL in males 
or <50 mg/dL in females or undergoing drug treatment for reduced 
HDL-C 
• 
Triglycerides ≥150 mg/dL or undergoing drug treatment for elevated 
triglycerides 
• 
Waist circumference >102 cm in males or >88 cm in females 
• 
Systolic blood pressure ≥130 mm Hg or diastolic blood pressure 
≥85 mm Hg or undergoing drug treatment for hypertension, or 
antihypertensive drug treatment in a patient with a history of 
hypertension 
4. Screening MRI-PDFF with ≥10% liver steatosis 
5. Fasting serum LDL-C >130 mg/dL at screening, >110 mg/dL on lipid-lowering medications 
6. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (beta 
human chorionic gonadotropin) at Screening and must agree to use highly effective birth 
control throughout the study and up to 30 days after the last dose of study drug. Highly 
effective contraception measures include combined estrogen- and progestogen-containing 
hormonal contraception (oral, intravaginal, and transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, and implantable), 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, 
vasectomized partner (only in the event that the vasectomized partner is the sole sexual partner 
of the WOCBP), and sexual abstinence (defined as refraining from heterosexual intercourse) 
only in the event that this is the preferred lifestyle of the patient.  
Childbearing potential is defined as being fertile following menarche and until becoming 
postmenopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) 
A postmenopausal state is defined as no menses for ≥12 consecutive months without an 
alternative medical cause. A follicle-stimulating hormone level in the postmenopausal range 
will be used to confirm a postmenopausal state in women ≤55 years of age 
Men with partners who are WOCBP must either be surgically sterile or agree to use a barrier 
contraceptive for the duration of the study and up to 30 days after the last dose of study drug 
7. Be willing to maintain a stable diet and physical activity throughout the course of the study 
 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
Exclusion Criteria: 
1. Women who are pregnant, breastfeeding, or plan to become pregnant during the study 
2. Body mass index (BMI) <25 kg/m2 
3. Fibrosis-4 Index (Fib-4) >2.6 
4. Any of the following laboratory abnormalities: 
a. 
ALT >5 × upper limit normal (ULN) or AST >5 × ULN 
b. International normalized ratio (INR) ≥1.3, unless on anticoagulant therapy 
c. 
Total bilirubin > ULN, except with an established diagnosis of Gilbert’s syndrome 
d. Platelet count less than the lower limit of normal (LLN) 
e. 
Creatinine clearance as calculated by the modification of diet in renal disease (MDRD) 
estimated glomerular filtration rate (eGFR) equation <60 mL/min 
NOTE: Unless otherwise specified, repeat testing may be performed in consultation with the 
Medical Monitor. 
5. Acute or chronic liver disease other than NAFLD/NASH including but not limited to the 
following: 
a. 
Hepatitis B (as defined by the presence of hepatitis B surface antigen at Screening) or 
hepatitis C (as defined by the presence of hepatitis C virus [HCV] antibody [anti-
HCV]. Patients with positive anti-HCV who test negative for HCV ribonucleic acid at 
Screening will be allowed to participate in the study as long as there is evidence of 
viral negativity for a minimum of 12 months prior to Screening) 
b. Evidence of ongoing autoimmune hepatitis 
c. 
History of primary biliary cirrhosis, primary sclerosing cholangitis, Wilson’s disease, 
homozygous alpha-1-anti-trypsin deficiency, hemochromatosis or iron overload, 
drug-induced or alcoholic liver disease, or known bile duct obstruction 
d. Suspected or proven hepatocellular carcinoma 
6. Known history of human immunodeficiency virus 
7. Medical history of liver cirrhosis 
8. Clinical evidence of portal hypertension to include any history of ascites, hepatic 
encephalopathy, or presence of esophageal varices 
9. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for 
hormone replacement, anabolic steroids, or valproic acid) or other known hepatotoxins for 
>2 weeks in the year prior to Screening 
10. Use of the following medications: 
a. 
Glucagon-like peptide-1 (GLP-1) agonists unless on a stable dose 3 months prior to 
liver biopsy or Screening 
b. Ursodeoxycholic acid, thiazolidinediones, or obeticholic acid within 3 months prior to 
Screening 
c. 
Statins and other lipid-modifying therapies must have been stable for ≥3 months prior 
to Screening 
 
d. Oral antidiabetic drugs (other than those specifically excluded) must have been stable 
for ≥3 months prior to Screening 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
e. 
Agents (including herbal over-the-counter weight loss preparations) or medications 
known to significantly impact body weight within 3 months prior to screening (e.g., 
sibutramine, phenetamine, and orlistat) 
11. History of significant alcohol consumption, defined as an average of >20 g/day in female 
patients and >30 g/day in male patients, for a period of >3 consecutive months within 1 year 
prior to Screening, hazardous alcohol use (Alcohol Use Disorders Identification Test score ≥8), 
or an inability to reliably quantify alcohol consumption based upon judgment of the 
Investigator 
12. Weight change ≥10% within the 6 months prior to Screening or ≥5% within the 3 months prior 
to Screening 
13. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty and roux-en-Y 
gastric bypass) 
14. Type 1 diabetes by medical history 
15. Uncontrolled Type 2 diabetes defined as hemoglobin A1c (HbA1c) >9.5% at Screening 
(patients with HbA1c >9.5% may be rescreened) or requiring insulin dose adjustment >10% 
within 2 months prior to Screening 
16. Clinical hyperthyroidism or hypothyroidism or Screening hormone results pointing to thyroid 
dysfunction. Patients receiving dose-stable thyroid replacement therapy for ≥3 months prior to 
Screening will be allowed to participate as long as thyroid tests (thyroid-stimulating 
hormone/triiodothyronine/thyroxine) show that the patient is euthyroid 
17. History of any condition causing malabsorption such as chronic pancreatitis, extensive 
bowel/small intestine surgery, celiac disease, or bile flow obstruction 
18. History of any condition associated with acute or chronic diarrhea such as inflammatory bowel 
disease (IBD), functional diarrhea, irritable bowel syndrome (IBS) with predominant diarrhea, 
IBS with mixed bowel habits, or unclassified IBS 
19. History of ischemic colitis 
20. Uncontrolled hypertension (either treated or untreated) defined as systolic blood pressure 
>160 mmHg or a diastolic blood pressure >100 mmHg at Screening. A retest of blood pressure, 
(after establishing good blood pressure control within a reasonable period of time and up to the 
Baseline visit) is permissible at the discretion of the Investigator 
21. History of New York Heart Association Class III or IV heart failure, or known left ventricular 
ejection fraction <30% 
22. History of myocardial infarction, unstable angina, percutaneous coronary intervention, 
coronary artery bypass graft, or stroke or major surgery within 6 months prior to Screening  
23. Active substance abuse, within 1 year prior to Screening  
24. Participation in an investigational new drug trial in the 30 days prior to Screening or within 
5 half-lives of an investigational agent, whichever is longer 
25. Malignancy within 5 years, except for basal- or squamous-cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated. Patients with a history of 
other malignancies that have been treated with curative intent and which have no recurrence 
within 5 years may also be eligible if approved by the Sponsor’s Medical Monitor. Patients 
under evaluation for malignancy are not eligible 
26. Patients with known intolerance to MRI or with conditions contraindicated for MRI procedures 
27. Any other condition which, in the opinion of the Investigator, would impede compliance, 
hinder completion of the study, compromise the well-being of the patient, or interfere with the 
study outcomes 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
Test Product, Dose, and Mode of Administration: Elobixibat, 5 mg once a day, orally administered 
Reference Therapy, Dose and Duration of Administration: Matching placebo, orally administered 
Duration of Treatment: Up to 16 weeks 
Variables 
Efficacy:  
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in serum LDL-C at Week 16. 
 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 
• 
Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured by MRI-PDFF 
• 
Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by MRI 
• 
Change from Baseline to Week 16, and Follow-Up in the following: 
o 
Serum ALT, AST, and gamma-glutamyl transferase 
o 
HDL-C, non-HDL-C, LDL-C/HDL-C ratio and triglycerides 
o 
Serum total bile acids 
 
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be assessed: 
• 
Change from Baseline (unless otherwise specified) to Week 4, Week 8, Week 12, Week 16, and 
Follow-Up in the following: 
o 
Fasting glucose, insulin, homeostatic model assessment-insulin resistance, HbA1c, 
free fatty acids 
o 
GLP-1, fibroblast growth factor-19 (FGF-19), and C4 levels 
o 
High-sensitivity C-reactive protein (CRP)  
o 
Lanosterol and beta-sitosterol 
o 
Body weight, BMI, waist circumference, and waist-to-hip ratio 
o 
MRI-based measurement of pulse wave velocity to measure aortic stiffness 
o 
Apolipoprotein A1 and Apolipoprotein B 
Safety:   
Safety criteria are as follows: 
• 
Occurrence of treatment-emergent adverse events categorized by causality, severity, and 
seriousness assessments made by Investigator by comparing study-drug exposure to placebo 
• 
Trends in safety evaluated for the following assessments:  
o 
Physical examinations 
o 
Concomitant medications 
o 
Vital signs 
o 
12-lead ECG 
o 
Laboratory test results (including clinical chemistry, hematology/coagulation, and 
urinalysis)  


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Statistical Methods 
Analysis Populations: 
• 
The intent-to-treat (ITT) population will include all patients who are randomized in the study 
and receive at least 1 dose of study drug. The ITT population will be used for all efficacy 
analyses based on the treatment randomized unless otherwise specified 
• 
The per protocol (PP) population will include all ITT patients who finish Visit 7/End of 
Treatment (EOT) with valid LDL-C measurements and do not have any major protocol 
deviations. Allocation of patients to the PP analysis set will be performed before unblinding of 
the study 
• 
The safety population will include all patients who are randomized and receive at least 1 dose 
of study drug and will be used for all safety analyses based on the treatment received 
• 
Summary statistics (number of patients, mean, standard deviation, median, minimum, and 
maximum) at all visits and change or percent change from Baseline will be provided for 
efficacy and safety continuous variables. Count and frequency will be used to tabulate 
categorical variables 
• 
Demographics, disposition, and study populations will be summarized descriptively 
 
Efficacy: 
• 
The primary efficacy endpoint is the change from Baseline in serum LDL-C at Week 16. 
Baseline is defined as the last non-missing LDL-C value prior to the first dose of study drug  
• 
To address the potential missing data from patients who are lost to follow-up after treatment 
discontinuation, multiple imputation method will be used. Data from patients who discontinue 
the study drug but stay in the study with scheduled assessments collected will be used to impute 
missing values for patients lost to follow-up. This imputation will be done within each 
treatment group. Interim missing data will be handled as missing at random (predictable from 
observed data from subjects in the same treatment group) 
• 
After the imputation is performed, an analysis of covariance (ANCOVA) will be used to 
analyze the primary efficacy endpoint. The model will include treatment arm and Baseline 
LDL-C scores 
• 
Least square (LS) mean (SE), LS mean difference (SE), 95% confidence intervals, and 
P-values between elobixibat 5 mg and placebo will be provided. The model assumptions will 
be checked before the analysis. If there are concerns on model assumptions, i.e., normality and 
homogeneity of variances, a non-parametric ANCOVA based on the rank scores can be used as 
a sensitivity analysis 
• 
Exploratory comparisons between elobixibat 5 mg and placebo will be performed for the 
following secondary efficacy endpoints:  
o 
Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured by 
MRI-PDFF 
o 
Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by MRI 
• 
The analysis methods for the other secondary endpoints and exploratory endpoints will be 
detailed in the Statistical Analysis Plan for the study. 
 
Safety: 
• 
The safety endpoints for this study include clinical laboratory assessments, vital signs, AEs, 
ECGs, physical examinations, and concomitant medications 
• 
AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedRA). TEAEs will be defined as AEs that are new or worsening after the first dose of study 
drug. A general summary of patients with TEAEs and serious adverse events (SAEs)/adverse 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
event of special interest (AESI) will be tabulated with numbers and percentages of patients and 
repeated for severity and relationship to study drug per treatment group. The number of AEs 
leading to withdrawal and SAEs leading to death will also be summarized. The incidence of 
TEAEs will be summarized by body system and treatment group 
• 
The safety laboratory data will be summarized by visit and by treatment group, along with 
changes from Baseline. Values outside of the reference range will be flagged and laboratory 
abnormalities of special interest will be summarized 
 
Sample Size Determination: 
Due to the exploratory nature of this study, no formal power calculations were used to determine the 
sample size. The number of subjects (46 patients in total, 23 patients per treatment group) was chosen 
based on clinical experience with other similar proof-of-concept studies. 
Date of the Protocol: 22 March 2019 
 


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3. 
TABLE OF CONTENTS 
Sponsor Signature Page ...................................................................................................2 
Investigator Signature Page .............................................................................................3 
1. 
Administrative Information .....................................................................................4 
2. 
Study Synopsis .......................................................................................................5 
3. 
Table of Contents .................................................................................................. 12 
3.1 
List of Tables ................................................................................................. 14 
4. 
List of Abbreviations, Acronyms, and Definitions of Terms .................................. 15 
5. 
Introduction .......................................................................................................... 18 
5.1 
Investigational Medicinal Product .................................................................. 18 
5.2 
Background .................................................................................................... 18 
5.2.1 
Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic 
Steatohepatitis (NASH) ............................................................................ 18 
5.2.2 
Summary of Nonclinical Studies in NASH ............................................... 19 
5.3 
Rationale ........................................................................................................ 19 
5.4 
Risk/Benefit ................................................................................................... 20 
6. 
Study Objectives ................................................................................................... 21 
6.1 
Primary Objective .......................................................................................... 21 
6.2 
Secondary Objectives ..................................................................................... 21 
7. 
Investigational Plan ............................................................................................... 22 
7.1 
Overall Study Design and Plan ....................................................................... 22 
7.1.1 
Description .............................................................................................. 22 
7.1.2 
Schedule of Assessments ......................................................................... 23 
7.1.3 
Study Procedures and Assessments .......................................................... 27 
7.2 
Study Population ............................................................................................ 31 
7.2.1 
Inclusion Criteria ..................................................................................... 31 
7.2.2 
Exclusion Criteria .................................................................................... 33 
7.2.3 
Withdrawal of Patients ............................................................................. 37 
7.2.4 
Study Termination by Sponsor ................................................................. 37 
8. 
Treatment of Patients ............................................................................................ 39 
8.1 
Identity of Study Drug.................................................................................... 39 


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8.2 
Administration of Study Drug ........................................................................ 39 
8.3 
Study Treatment Packaging and Labeling ....................................................... 39 
8.3.1 
Packaging and Labeling ........................................................................... 39 
8.3.2 
Storage..................................................................................................... 39 
8.3.3 
Blinding and Randomization of Study Drug ............................................. 40 
8.4 
Procedure for Breaking the Randomization Code ........................................... 40 
8.5 
Patient Compliance ........................................................................................ 41 
8.6 
Study Drug Accountability ............................................................................. 41 
8.7 
Concomitant Therapy and Prohibited Medications ......................................... 42 
9. 
Assessment of Efficacy ......................................................................................... 43 
9.1 
Efficacy Endpoints ......................................................................................... 43 
9.1.1 
Primary Efficacy Endpoint ....................................................................... 43 
9.1.2 
Secondary Efficacy Endpoints.................................................................. 43 
9.1.3 
Exploratory Efficacy Endpoints ............................................................... 43 
9.2 
Efficacy Assessments ..................................................................................... 44 
9.2.1 
Lipid Profile............................................................................................. 44 
9.2.2 
Magnetic Resonance Imaging .................................................................. 44 
9.2.3 
Serum Bile Acids ..................................................................................... 44 
9.2.4 
Biomarkers and Blood Samples for Future Testing................................... 44 
10. 
Assessment of Safety ............................................................................................ 45 
10.1 
Adverse Events .............................................................................................. 45 
10.1.1 
Definitions and Investigator Assessments................................................. 45 
10.1.2 
Recording of Adverse Events ................................................................... 48 
10.1.3 
Recording and Reporting of Serious Adverse Events ................................ 49 
10.1.4 
Reporting of Suspected Unexpected Serious Adverse Reactions............... 51 
10.2 
Laboratory Values, Vital Signs, Physical Examinations, and Other 
Safety Assessments ........................................................................................ 51 
10.2.1 
Laboratory Assessments ........................................................................... 51 
10.2.2 
Individual Patient Safety Monitoring ........................................................ 54 
10.2.3 
Demographics/Medical and Surgical History ........................................... 55 
10.2.4 
Physical Examination ............................................................................... 55 


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10.2.5 
Vital Signs ............................................................................................... 55 
10.2.6 
12-Lead ECG ........................................................................................... 55 
10.2.7 
Overdose.................................................................................................. 55 
11. 
Statistical Evaluation ............................................................................................ 57 
11.1 
Sample Size and Power .................................................................................. 57 
11.2 
Statistical Methods ......................................................................................... 57 
11.2.1 
Statistical Analysis Populations ................................................................ 57 
11.2.2 
Methods of Statistical Analyses ............................................................... 58 
12. 
Direct Access to Source Data/Notes ...................................................................... 62 
13. 
Quality Control and Quality Assurance ................................................................. 63 
13.1 
Conduct of the Study ...................................................................................... 63 
13.2 
Study Monitoring ........................................................................................... 63 
14. 
Ethics .................................................................................................................... 65 
14.1 
Institutional Review Board ............................................................................. 65 
14.2 
Written Informed Consents ............................................................................ 65 
15. 
Data Handling and Recordkeeping ........................................................................ 66 
15.1 
Electronic Case Report Forms/Source Data Handling ..................................... 66 
15.2 
Retention of Essential Documents .................................................................. 66 
16. 
Financing and Insurance ....................................................................................... 67 
17. 
Publication Policy ................................................................................................. 68 
18. 
References List ..................................................................................................... 69 
 
3.1 
List of Tables 
Table 1 
Schedule of Assessments .............................................................................. 24 
Table 2: 
Laboratory Parameters ................................................................................. 52 
 


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4. 
LIST OF ABBREVIATIONS, ACRONYMS, AND DEFINITIONS OF 
TERMS 
Abbreviation 
Definition 
A3309 
elobixibat 
AE(s) 
adverse event(s) 
AESI(s) 
adverse event(s) of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
Anti-HCV 
hepatitis C antibody 
APRI 
AST to platelet ratio index 
ASBT 
apical sodium-dependent bile acid transporter (also known as IBAT) 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
C4 
7α-hydroxy-4-cholesten-3-one  
CRA 
clinical research associate 
CRF 
case report form 
CRP 
C-reactive protein 
ECG(s) 
electrocardiogram(s) 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOT 
End of Treatment 
FDA 
US Food and Drug Administration 
FGF-19 
fibroblast growth factor-19  
Fib-4 
fibrosis-4 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP-1 
glucagon-like peptide-1 
H&E 
hematoxylin and eosin 
HbA1c 
hemoglobin A1c 


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Abbreviation 
Definition 
HCV 
hepatitis C virus 
HDL-C 
high-density lipoprotein-cholesterol 
IBAT 
ileal bile acid transporter (also known as ASBT) 
IBD 
inflammatory bowel disease 
IBS 
irritable bowel syndrome 
ICF(s) 
informed consent form(s) 
ICH 
International Council on Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent to treat 
IWRS 
Interactive Web Response System 
LDL 
low-density lipoprotein 
LDL-C 
low density lipoprotein-cholesterol 
LLN 
lower limit of normal 
LPLV 
last patient last visit 
LS 
least square 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging—proton density fat fraction 
N/A 
not applicable 
NAFLD 
nonalcoholic fatty liver disease  
NAS 
NAFLD activity score 
NASH 
nonalcoholic steatohepatitis 
ob/ob (mice) 
leptin-deficient mice 
PCS 
potentially clinically significant 
PDFF 
proton density fat fraction 
PP 
per protocol 
PVM 
pharmacovigilance manager 
RNA 
ribonucleic acid 


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Abbreviation 
Definition 
s-BA 
serum bile acid(s) 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SE 
standard error 
SOC 
system organ class 
SOP(s) 
standard operating procedure(s) 
Sponsor 
Elobix AB 
SUSAR 
suspected unexpected serious adverse reaction(s) 
TEAE(s) 
treatment-emergent adverse event(s) 
ULN 
upper limit of normal 
US 
United States 
VLDL 
very low-density lipoprotein 
WHO 
World Health Organization 
WOCBP 
Women (woman) of childbearing potential 
α-SMA 
alpha-smooth muscle actin 
 


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5. 
INTRODUCTION 
5.1 
Investigational Medicinal Product 
Elobixibat is a potent inhibitor of the ileal bile acid transporter (IBAT; also known as the 
apical sodium bile acid transporter [ASBT]). The IBAT, expressed mainly in the distal 
ileum, is a key element in the enterohepatic circulation of bile acids because it facilitates 
the very efficient process of bile acid reabsorption. Elobixibat is orally administered and 
acts locally in the gut where it binds reversibly to the IBAT to decrease the reuptake of 
bile acids to the liver. Elobixibat has minimal systemic exposure at expected therapeutic 
dose ranges. 
5.2 
Background 
5.2.1 
Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic 
Steatohepatitis (NASH) 
Recent data suggest that bile acids may play an important role in NASH pathogenesis 
(Ferslew 2015; Aranha 2008; Puri 2018). Bile acids are signaling molecules involved in 
lipid, glucose, and energy homeostasis, which are metabolic pathways linked to 
NAFLD/NASH and comorbidities such as metabolic syndrome, obesity, and diabetes. 
Bile acids as well as free cholesterol, which is the precursor from which bile acids are 
synthesized, can act as lipotoxic agents that drive inflammation and fibrosis. Studies have 
shown that both serum and liver bile acids are increased in patients with NASH, and 
recent data have suggested that the presence and severity of NASH is associated with 
specific changes in circulating bile acids (Puri 2018). Thus, targeting of bile acid 
pathways has therapeutic potential in patients with NASH. 
The enterohepatic circulation of bile acids plays a crucial role in whole body sterol 
balance. Bile acids are secreted to the intestine via the bile duct and then reabsorbed, 
mainly by a specific bile acid transporter located in the ileum (IBAT or ASBT) and 
delivered back to the liver, completing the enterohepatic circulation (Prawitt 2011).  
Bile acid reabsorption from the intestine is a very efficient process where 95% of the 
secreted bile acids are reabsorbed and IBAT appears to be the major regulator of the bile 
acid pool in animals and humans. IBAT inhibitors reduce the reabsorption of bile acids 
from the ileum and prevent their return to the liver. The liver compensates for the 
decrease in bile acid levels by upregulating cholesterol 7α-hydroxylase, the rate-limiting 


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enzyme for bile acid synthesis. This results in lower hepatic cholesterol levels and an 
increased number of low-density lipoprotein (LDL) receptors in the liver leading to 
reduced plasma low-density lipoprotein cholesterol (LDL-C; [Bertolotti 2003; 
Naoumova 1999]). Bile acids also positively regulate glucagon-like peptide-1 (GLP-1) 
levels via activation of TGR5 (Prawitt 2011; Schaap 2014). GLP-1 is an insulinotropic 
hormone but has many other roles, e.g., slowing gastric emptying and increasing satiety 
signals leading to weight loss (Andersen 2018). 
Inhibition of bile acid absorption locally in the intestine has the potential to positively 
influence NASH, cardiovascular disease, and metabolic disease by targeting multiple 
mechanisms, as follows: lowering of LDL-C by increased bile acid synthesis; improving 
metabolic status and weight loss by increasing GLP-1 levels; and reducing hepatic cell 
damage by lowering toxic bile acid and free cholesterol in the liver. 
5.2.2 
Summary of Nonclinical Studies in NASH 
One nonclinical study with elobixibat in a NASH model has been completed. The study 
evaluated the effects of elobixibat in leptin-deficient ob/ob mice treated with a diet high 
in trans fats, fructose, and cholesterol. Although elobixibat did not reduce liver NAFLD 
activity score or fibrosis stage, there were indicators of relevant effects, including 
reduction in liver alpha-smooth muscle actin (α-SMA), which is a marker of stellate cell 
activation and thereby an indirect marker for fibrosis formation. Administration of 10 and 
30 mg/kg/day elobixibat decreased liver steatosis as quantified by lipid fractional area in 
hematoxylin and eosin (H&E)-stained liver sections in a dose-dependent fashion. This 
was further evident in animals treated with 30 mg/kg elobixibat that showed reduced liver 
triglycerides and liver total cholesterol as determined by biochemical analyses. Analysis 
of liver gene expression by next generation RNA sequencing revealed pronounced and 
dose-dependent effects of elobixibat. It affected the expression of genes in key pathways 
associated with NASH pathology. 
Additional nonclinical studies with elobixibat are summarized in the Investigator’s 
Brochure (M1.14.4.1). 
5.3 
Rationale 
Bile acids act as signaling molecules in lipid, glucose, and energy homeostasis. Studies 
have shown that both serum and liver bile acids are increased in patients with NASH 


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(Ferslew 2015), and recent data have suggested that the presence and severity of NASH 
is associated with specific changes in circulating bile acids (Puri 2018; Sanyal 2018). 
Inhibition of bile acid absorption from the intestine has the potential to improve the 
pathophysiology in NASH, including the related cardiovascular and metabolic disease 
due to impingement on multiple key metabolic feedback mechanisms, as follows: 
lowering of LDL-C by increased bile acid synthesis, and improving insulin sensitivity by 
increasing GLP-1 levels. A reduction of cardiovascular risk is particularly desirable for 
any pharmacological NASH treatment, because cardiovascular complications contribute 
to a significant amount of mortality in patients with NAFLD/NASH, with their annual 
risk being 2-fold increased (Mahfood Haddad 2017; Younossi 2018). IBAT inhibition 
reduces the levels of bile acid that circulate to the liver, and triggers increased hepatic 
bile acid synthesis from cholesterol. Thus, besides having a positive impact on 
cardiovascular health, IBAT inhibition might also reduce hepatic cell damage by 
lowering free cholesterol and changing the composition of toxic bile acids in the liver. 
5.4 
Risk/Benefit 
Elobixibat is orally administered and acts locally in the gut where it binds reversibly to 
the IBAT to decrease the reuptake of bile acids into the liver, thereby increasing the 
concentration of bile acids in the colon. Due to its mechanism of action, most adverse 
events (AEs) are gastrointestinal (GI) tract disorders, such as abdominal pain, diarrhea, 
abdominal distention, flatulence, and nausea; the incidence of these has increased with 
increasing dose levels. Diarrhea has been the most prominent dose-limiting side effect. 
No clinically significant findings in laboratory measures or electrocardiograms (ECGs) 
have been reported. Based on postmarketing case reporting, ischemic colitis will be 
monitored as an adverse event of special interest for elobixibat. 
There is no established benefit for subjects participating in this Phase 2 study. Based 
upon these data, the risk/benefit for subjects participating in this trial is acceptable. 
This study will be conducted in compliance with the protocol and with the International 
Council on Harmonisation (ICH) guidelines on GCP.  


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6. 
STUDY OBJECTIVES 
6.1 
Primary Objective 
The primary objective is to evaluate the efficacy of repeated once-daily doses of 5 mg 
elobixibat on serum levels of LDL-C in patients with NAFLD or NASH. 
6.2 
Secondary Objectives 
• To assess the safety and tolerability of elobixibat in patients with NAFLD or 
NASH 
• To evaluate the effect of elobixibat on liver steatosis as measured by magnetic 
resonance imaging (MRI) for (i) liver fat fraction (using proton density fat 
fraction [PDFF]) and (ii) total liver fat (using whole liver fat volume) 
• To evaluate the effect of elobixibat on liver function using alanine 
aminotransferase (ALT) 
• To evaluate the effect of elobixibat on lipids and serum bile acids (s-BA) in 
patients with NAFLD or NASH 


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7. 
INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
7.1.1 
Description 
This is a double-blind, randomized, placebo-controlled, Phase 2 study to explore the 
efficacy and safety of elobixibat (oral dose of 5 mg) once daily for 16 weeks in patients 
with NAFLD or NASH. The study includes a 6-week Screening Period, followed by a 
16-week Treatment Period, and a Follow-Up Visit 2 weeks after the last dose of study 
drug. Continued collection of efficacy data for patients who discontinue treatment will be 
made for as long as possible as per the schedule of assessments (Table 1).  
After completing the Screening Period, eligible patients will be randomized on Day 1 
(Visit 2) in a 1:1 fashion to either 5 mg/day elobixibat or matching placebo. Visit 
windows applicable to each visit are presented in the schedule of assessments (Table 1). 
There will be up to 7 clinic visits during the study, as follows: 
• Visit 1: Screening period (Week -6 through Day -1) 
• Visit 2: Day 1/Randomization visit 
• Visit 3: Week 4 
• Visit 4: Week 8 
• Visit 5: Week 12 
• Visit 6: Week 16/End of Treatment (EOT). Any patient that discontinues 
treatment prematurely should complete this visit at the time of discontinuation 
• Visit 7: Follow-Up period. The Follow-Up visit will occur 2 weeks after the last 
dose of study drug whether the patient completes the study or discontinues 
prematurely 
Additional unscheduled visits may be required for patients who need direct site assistance 
(due to AE monitoring, in order to fulfill screening requirements, and/or for safety 
maintenance).  


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7.1.1.1 
Screening Period 
Informed consent must be obtained at Visit 1 prior to performing any study procedures. 
After signing the informed consent form (ICF), patients will be considered enrolled and 
evaluated for study eligibility. 
7.1.1.2 
Treatment Period 
Eligibility for randomization will be determined at Visit 2 using the assessment of 
eligibility in accordance to the inclusion/exclusion criteria.  
The patient will return to the clinic at Visits 3-6 for assessments. Patients will be 
requested to return study drug bottles as part of drug accountability during the Treatment 
period. 
7.1.1.3 
Follow-Up Period 
The patient will return to the clinic for Visit 7 approximately 2 weeks after the last dose 
of study drug. This visit will be completed for patients that may discontinue the study 
prematurely.  
7.1.1.4 
End of Study 
The end of the study is defined as last patient last visit (LPLV) and all sites are closed. 
7.1.2 
Schedule of Assessments 
The schedule of assessments is presented in Table 1. 


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Table 1 
Schedule of Assessments 
VISIT 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP 
PERIOD 
VISIT 1 
VISIT 2/ 
RANDOMIZA- 
TION 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6/ 
END OF 
TREATMENT 
VISIT 7 
STUDY WEEK 
WEEK -6 TO 
DAY -1 
DAY 1 
WEEK 4 
WEEK 8 
WEEK 12 
WEEK 16 
WEEK 18 
VISIT WINDOW 
 
 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Serologya 
X 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
X 
 
Physical examinationb 
X 
X 
 
 
 
X 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testd 
X 
X 
X 
X 
X 
X 
X 
MRIe 
X 
 
 
 
 
X 
 
Liver biopsyf 
X 
 
 
 
 
 
 
Randomizationg 
 
X 
 
 
 
 
 
Clinical safety laboratory testsh 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
(Continued on next page) 


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VISIT 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP 
PERIOD 
VISIT 1 
VISIT 2/ 
RANDOMIZA- 
TION 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6/ 
END OF 
TREATMENT 
VISIT 7 
STUDY WEEK 
WEEK -6 TO 
DAY -1 
DAY 1 
WEEK 4 
WEEK 8 
WEEK 12 
WEEK 16 
WEEK 18 
VISIT WINDOW 
 
 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
Endocrinologyh 
X 
X 
X 
 
 
X 
 
GLP-1, FGF-19, C4h 
X 
X 
X 
X 
X 
X 
X 
Total serum bile acidsh 
X 
X 
X 
X 
X 
X 
X 
Lipid profileh 
X 
X 
X 
X 
X 
X 
X 
Fibrosis and inflammation markersh 
 
X 
X 
 
 
X 
 
High-sensitivity CRP 
X 
 
X 
 
 
X 
 
Stored blood sample for future testingi 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
X 
X 
X 
 
 
Review alcohol consumptionj 
X 
 
 
 
 
 
 
Review concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Review adverse events 
X 
X 
X 
X 
X 
X 
X 
a Includes hepatitis B virus surface antigen and hepatitis C virus antibody and RNA 
b Includes height (at Screening only), weight, waist circumference, and waist-to-hip ratio. Body mass index will be calculated based on height and weight. A full physical 
examination will be performed at Screening and at Visits 2 and 6.  
c Vital signs include blood pressure, heart rate, respiratory rate, and oral body temperature. 
(Continued on next page) 


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d For women of childbearing potential, a serum pregnancy test will be performed at Screening, and a urine pregnancy test will be performed at each visit at which study drug is 
dispensed. 
e Patients will have MRI to measure liver fat (PDFF), total liver volume, and pulse wave velocity. Patients who discontinue before Visit 6 (Week 16) should have an MRI 
performed at End of Treatment if they completed at least 4 weeks of treatment. 
f Liver biopsy results for confirmed NASH within 6 months of Screening to confirm patient eligibility will be collected in the eCRF, if available. 
g Randomization will occur at Visit 2 to assign patients to either 5 mg/day elobixibat or placebo in 1:1 ratio. 
h See Table 2, Laboratory Parameters. Clinical safety laboratory tests include clinical chemistry, hematology/coagulation, and urinalysis 
i See Section 9.2.4. 
j History of alcohol consumption will be obtained at Screening. 
Abbreviations: C4: 7α-hydroxy-4-cholesten-3-one; CRF: case report form; CRP: C-reactive protein; ECG: electrocardiogram; EOT: End of Treatment; FGF-19: fibroblast growth 
factor-19; GLP-1: glucagon-like peptide-1; INR: international normalized ratio; MRI: magnetic resonance imaging; NASH: nonalcoholic steatohepatitis; PDFF: proton density fat 
fraction 
 


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7.1.3 
Study Procedures and Assessments 
7.1.3.1 
Screening Period (-6 Weeks to Day -1) 
7.1.3.1.1 
Visit 1 
Patients will undergo a Screening visit up to 6 weeks prior to the planned first day of 
study treatment. Screening procedures and assessments are as follows: 
• Obtain written informed consent 
• Assess inclusion/exclusion criteria (Sections 7.2.1 and 7.2.2, respectively) 
• Medical and surgical history (date of diagnosis of NAFLD/NASH; any surgery 
performed; any other diagnosis) 
• Record demographics (age, full date of birth, gender, race, and ethnicity) 
• Serology 
• 12-lead ECG (Section 10.2.6) 
• Physical examination (Section 10.2.4) 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• MRI (Section 9.2.2) 
• Liver biopsy (applicable for patients’ biopsy-confirmed NASH within 6 months 
of Screening) 
• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total s-BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 


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• Fibrosis and inflammation markers (Section 10.2.1) 
• High-sensitivity CRP 
• Stored sample for future testing (Section 10.2.1) 
• Review of alcohol consumption 
• Document concomitant medications 
• AE monitoring  
7.1.3.2 
Treatment Period (Day 1 to Week 16) 
7.1.3.2.1 
Study Day 1/Visit 2 (Randomization) 
At the randomization visit, the following assessments will be conducted: 
• Review inclusion/exclusion criteria (Sections 7.2.1 and 7.2.2, respectively) 
• Physical examination (Section 10.2.4) 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total s-BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 
• Fibrosis and inflammation markers (Section 10.2.1) 
• Stored sample for future testing (Section 10.2.1) 
• Study drug is dispensed and patients are instructed to administer daily from Day 1 
• Review of concomitant medications 
• AE monitoring 


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7.1.3.2.2 
Study Weeks 4-12/Visits 3-5  
The following procedures and assessments will be conducted: 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Visit 3 only; Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total s-BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 
• Fibrosis and inflammation markers (Visit 3 only; Section 10.2.1) 
• High-sensitivity CRP (Visit 3 only; Section 10.2.1) 
• Stored sample for future testing (Section 10.2.1) 
• Study drug is dispensed; review of compliance  
• Review of concomitant medications 
• AE monitoring 
7.1.3.2.3 
Study Week 16/Visit 6/EOT 
The last dose of study drug will be taken in the morning the day before Visit 6 and the 
following procedures and assessments will be conducted (also conducted at the time a 
patient prematurely withdraws):  
• 12-lead ECG (Section 10.2.6) 
• Physical examination (Section 10.2.4) 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• MRI (Section 9.2.2) 


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• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total s-BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 
• Fibrosis and inflammation markers (Section 10.2.1) 
• High-sensitivity CRP 
• Stored sample for future testing (Section 10.2.1) 
• Review of concomitant medications 
• AE monitoring 
7.1.3.3 
Follow-Up Period 
7.1.3.3.1 
Study Week 18/ Visit 7  
All patients will complete a Follow-Up visit approximately 2 weeks after the last dose of 
study drug for the following assessments: 
• Vital signs (Section 10.2.5) 
• Pregnancy test  
• Clinical safety laboratory tests (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total s-BA (Section 9.2.3) 
• Lipid profile (Section 10.2.1) 
• Stored sample for future testing (Section 10.2.1) 
• Review of concomitant medications 
• AE monitoring 


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7.2 
Study Population 
A total of approximately 46 patients with a clinical diagnosis of NAFLD/NASH (in 
accordance with the protocol definition) will be randomized.   
7.2.1 
Inclusion Criteria 
Patients must meet all the following criteria to be included in the study: 
1. Be willing to participate in the study and provide written informed consent 
2. Be a man or woman ≥18 years of age 
3. Have a current biopsy-confirmed NASH within 6 months of screening or a 
suspected diagnosis of NAFLD/NASH based on the criteria outlined below: 
a. Biopsy-confirmed NASH is defined as histological NASH diagnosis with 
fibrosis stage F1 through F3 and a NAFLD activity score (NAS) of 
≥4 with a score of ≥1 in each of the NAS components below as assessed 
by the central pathologist using the NASH Clinical Research Network 
criteria (Kleiner 2005) 
i. Steatosis (scored 0 to 3) 
ii. Ballooning degeneration (scored 0 to 2) 
iii. Lobular inflammation (scored 0 to 3) 
OR 
b. The suspected diagnosis of NAFLD/NASH is based on each of the 
following criteria being met: 
i. Serum aspartate aminotransferase (AST) ≥20 U/L and ALT 
≥40 U/L 
ii. Diagnosis of metabolic syndrome as having any 3 of the following 
5 risk factors at Screening: 
o Fasting plasma glucose ≥100 mg/dL or undergoing drug 
treatment for elevated glucose 


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o High-density lipoprotein-cholesterol (HDL-C) <40 mg/dL 
in males or <50 mg/dL in females or undergoing drug 
treatment for reduced HDL-C 
o Triglycerides ≥150 mg/dL or undergoing drug treatment for 
elevated triglycerides 
o Waist circumference >102 cm in males or >88 cm in 
females 
o Systolic blood pressure ≥130 mm Hg or diastolic blood 
pressure ≥85 mm Hg or undergoing drug treatment for 
hypertension, or antihypertensive drug treatment in a 
patient with a history of hypertension 
4. Screening MRI-PDFF with ≥10% liver steatosis 
5. Fasting serum LDL-C >130 mg/dL at Screening, >110 mg/dL on lipid-lowering 
medications 
6. Women of childbearing potential (WOCBP) must have a negative serum 
pregnancy test (beta human chorionic gonadotropin) at Screening and must agree 
to use highly effective birth control throughout the study and up to 30 days after 
the last dose of study drug. Highly effective contraception measures include 
combined estrogen- and progestogen-containing hormonal contraception (oral, 
intravaginal, and transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, and implantable), 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal 
occlusion, vasectomized partner (only in the event that the vasectomized partner 
is the sole sexual partner of the WOCBP), and sexual abstinence (defined as 
refraining from heterosexual intercourse) only in the event that this is the 
preferred lifestyle of the patient.  
Childbearing potential is defined as being fertile following menarche and until 
becoming postmenopausal unless permanently sterile (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy). 


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A postmenopausal state is defined as no menses for ≥12 consecutive months 
without an alternative medical cause. A follicle-stimulating hormone level in the 
postmenopausal range will be used to confirm a postmenopausal state in women 
≤55 years of age. 
Men with partners who are WOCBP must either be surgically sterile or agree to 
use a barrier contraceptive for the duration of the study and up to 30 days after the 
last dose of study drug. 
7. Be willing to maintain a stable diet and physical activity throughout the course of 
the study 
7.2.2 
Exclusion Criteria 
Patients who meet any of the following criteria will not be included in the study: 
1. Women who are pregnant, breastfeeding, or plan to become pregnant during the 
study 
2. Body mass index (BMI) <25 kg/m2 
3. Fibrosis-4 index (Fib-4) >2.6 
4. Any of the following laboratory abnormalities: 
a. ALT >5 × upper limit of normal (ULN) or AST >5 × ULN 
b. International normalized ratio (INR) ≥1.3, unless on anticoagulant therapy 
c. Total bilirubin >ULN, except with an established diagnosis of Gilbert’s 
syndrome 
d. Platelet count less than the lower limit of normal (LLN) 
e. Creatinine clearance as calculated by the modification of diet in renal 
disease (MDRD) estimated glomerular filtration rate (eGFR) equation 
<60 mL/min 
NOTE: Unless otherwise specified, repeat testing may be performed in 
consultation with the Medical Monitor. 


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5. Acute or chronic liver disease other than NAFLD/NASH including but not limited 
to the following: 
a. Hepatitis B (as defined by the presence of hepatitis B surface antigen at 
screening) or hepatitis C (as defined by the presence of hepatitis C virus 
[HCV] antibody [anti-HCV]). Patients with positive anti-HCV who test 
negative for HCV ribonucleic acid at screening will be allowed to 
participate in the study as long as there is evidence of viral negativity for a 
minimum of 12 months prior to screening) 
b. Evidence of ongoing autoimmune hepatitis 
c. History of primary biliary cirrhosis, primary sclerosing cholangitis, 
Wilson’s disease, homozygous alpha-1-anti-trypsin deficiency, 
hemochromatosis or iron overload, drug-induced or alcoholic liver 
disease, or known bile duct obstruction 
d. Suspected or proven hepatocellular carcinoma 
6. Known history of human immunodeficiency virus 
7. Medical history of liver cirrhosis 
8. Clinical evidence of portal hypertension to include any history of ascites, hepatic 
encephalopathy, or presence of esophageal varices 
9. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, 
systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than 
those used for hormone replacement, anabolic steroids, or valproic acid) or other 
known hepatotoxins for >2 weeks in the year prior to screening 
10. Use of the following medications: 
a. GLP-1 agonists unless on a stable dose 3 months prior to liver biopsy or 
Screening 
b. Ursodeoxycholic acid, thiazolidinediones, or obeticholic acid within 
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c. Statins and other lipid-modifying therapies must have been stable for 
≥3 months prior to Screening 
d. Oral antidiabetic drugs (other than those specifically excluded) must have 
been stable for ≥3 months prior to Screening 
e. Agents (including herbal over-the-counter weight-loss preparations) or 
medications known to significantly impact body weight within 3 months 
prior to Screening (e.g., sibutramine, phenetamine, and orlistat) 
11. History of significant alcohol consumption, defined as an average of >20 g/day in 
female patients and >30 g/day in male patients, for a period of >3 consecutive 
months within 1 year prior to Screening, hazardous alcohol use (Alcohol Use 
Disorders Identification Test score ≥8), or an inability to reliably quantify alcohol 
consumption based upon judgment of the Investigator 
12. Weight change ≥10% within the 6 months prior to Screening or ≥5% within the 
3 months prior to Screening 
13. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty and 
roux-en-Y gastric bypass) 
14. Type 1 diabetes by medical history 
15. Uncontrolled Type 2 diabetes defined as hemoglobin A1c (HbA1c) >9.5% at 
Screening (patients with HbA1c >9.5% may be rescreened) or requiring insulin 
dose adjustment >10% within 2 months prior to Screening 
16. Clinical hyperthyroidism or hypothyroidism or screening hormone results 
pointing to thyroid dysfunction. Patients receiving dose-stable thyroid 
replacement therapy for ≥3 months prior to Screening will be allowed to 
participate as long as thyroid tests (thyroid-stimulating 
hormone/triiodothyronine/thyroxine) show that the patient is euthyroid 
17. History of any condition causing malabsorption such as chronic pancreatitis, 
extensive bowel/small intestine surgery, celiac disease, or bile flow obstruction 
18. History of any condition associated with acute or chronic diarrhea such as 
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(IBS) with predominant diarrhea, IBS with mixed bowel habits, or unclassified 
IBS 
19. History of ischemic colitis 
20. Uncontrolled hypertension (either treated or untreated) defined as systolic blood 
pressure >160 mmHg or a diastolic blood pressure >100 mmHg at Screening. A 
retest of blood pressure, (after establishing good blood pressure control within a 
reasonable period of time and up to the Baseline visit) is permissible at the 
discretion of the Investigator 
21. History of New York Heart Association Class III or IV heart failure, or known 
left ventricular ejection fraction <30% 
22. History of myocardial infarction, unstable angina, percutaneous coronary 
intervention, coronary artery bypass graft, or stroke or major surgery within 
6 months prior to Screening  
23. Active substance abuse within 1 year prior to Screening 
24. Participation in an investigational new drug trial in the 30 days prior to Screening 
or within 5 half-lives of an investigational agent, whichever is longer 
25. Malignancy within 5 years, except for basal- or squamous-cell carcinoma of the 
skin or carcinoma in situ of the cervix that has been successfully treated. Patients 
with a history of other malignancies that have been treated with curative intent 
and which have no recurrence within 5 years may also be eligible if approved by 
the Sponsor’s Medical Monitor. Patients under evaluation for malignancy are not 
eligible 
26. Patients with known intolerance to MRI or with conditions contraindicated for 
MRI procedures 
27. Any other condition which, in the opinion of the Investigator, would impede 
compliance, hinder completion of the study, compromise the well-being of the 
patient, or interfere with the study outcomes 


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7.2.3 
Withdrawal of Patients 
Patients will be informed that they have the right to withdraw from the study at any time, 
without prejudice to their medical care, and that they are not obliged to state their 
reasons. 
Any withdrawal, and reasons for withdrawal, must be fully documented in the electronic 
case report form (eCRF) and source documents and the patient followed by the 
investigator/investigative staff. Even after the study is completed at the Follow-Up visit, 
the investigator/investigative staff will, regardless of reason for withdrawal, record any 
patient data they receive concerning serious adverse events (SAEs), and all drug-related 
non-serious AEs, and report these in the eCRF. Withdrawn patients will not be replaced. 
Patients will be withdrawn in the following circumstances: 
• A patient’s desire for withdrawal for any reason 
• Lost to follow-up (every effort must be made to contact the patient; a certified 
letter must be sent) 
• An AE that, in the opinion of the Investigator, necessitates withdrawal 
• Death 
• A patient’s substantial noncompliance (study drug compliance) or protocol 
violation 
• An Investigator’s opinion that continuing the patient in the study is not 
appropriate. The Investigator may withdraw a patient at any time if it is 
considered to be in the patient’s best interest 
A patient who withdraws from treatment prematurely will have EOT (Visit 6) 
assessments at the time of withdrawal and a Follow-Up assessment (Visit 7) 
approximately 2 weeks following the last dose of study drug, and the patient will be 
recorded as withdrawn. 
7.2.4 
Study Termination by Sponsor 
This study may be terminated at any time by the Sponsor if serious side effects should 
occur, if the Investigator does not adhere to the protocol, or if, in the Sponsor's judgment, 


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there are no further benefits to be achieved from the study. In this event, the Sponsor or 
its designee will inform the study investigators, institutions, and all regulatory authorities. 
The Sponsor may temporarily or permanently discontinue the study at an investigative 
site at any time for safety, ethical, compliance, or other reasons. If this is necessary, the 
Sponsor will endeavor to provide advance notification to the site. If a site or the study is 
suspended or discontinued, the Investigator/investigative staff will be responsible for 
promptly informing the IRB. If required by local regulations, the Sponsor or its designee 
will be responsible for informing the IRB and the regulatory authority of study or site 
discontinuation. In such an event, all study data and unused study drug must be returned 
to the Sponsor or its designee. 


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8. 
TREATMENT OF PATIENTS 
8.1 
Identity of Study Drug 
Elobixibat and placebo will be supplied as tablets for oral administration during the 
Treatment phase of the study. White tablets containing elobixibat or placebo will be 
provided.   
The elobixibat and placebo tablets will be identical in appearance. Tablet filling weight 
will also be identical for elobixibat and placebo. Bottles containing 34 tablets will be 
given to the patient at each visit. Refer to the study reference manual. 
8.2 
Administration of Study Drug 
Patients will be dosed with elobixibat at a dose of 5 mg or placebo once daily for 
16 weeks. Study drug will be dispensed to the patient at Visits 2-5 together with 
instructions on how to store and take the drug. Study drug compliance will be evaluated 
at each study visit.   
Elobixibat should be taken in the morning, prior to the first meal. On clinic visit days 
when laboratory assessments are conducted, study drug should be taken after the visit and 
after laboratory samples are taken.   
8.3 
Study Treatment Packaging and Labeling 
8.3.1 
Packaging and Labeling 
The tablets will be packed in high-density polyethylene bottles, with child-proof 
polypropylene caps. Packaging and labeling will be prepared to comply with applicable 
regulatory requirements. 
8.3.2 
Storage 
Treatment bottles containing elobixibat tablets should be stored and dispensed in 
accordance with regulations in their original containers. The storage facility at the 
investigative site should be locked and the storage temperature should be between 15°C 
and 25°C. 
Caregivers should be informed of appropriate storage conditions (i.e., room temperature, 
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Any deviations from the recommended storage conditions should be immediately 
reported to the Sponsor and the study drug should not be used until authorization has 
been given by the Sponsor. 
8.3.3 
Blinding and Randomization of Study Drug 
A double-blind design is employed so that both the investigators and the patients will be 
unaware of the treatment assignment during the study.  
After written informed consent is obtained from an eligible patient, a 6-digit patient 
number will be assigned. The first 3 digits will be the site number followed by a 3-digit 
patient sequence number. This number will be created and allocated by the Interactive 
Web Response System (IWRS), when the patient first enters the system at Screening. The 
randomization codes will be computer-generated by a statistician independent from the 
project team. The randomization will be done in blocks to ensure approximate balance 
between dose schemes (1:1). Randomization codes will be assigned sequentially as 
patients become eligible for randomization. 
Patients who are eligible for randomization will be assigned a unique 4-digit 
randomization number by IWRS. This randomization number identifies which treatment 
will be allocated to the patient. Patients who withdraw from the study after randomization 
visit are not to be replaced and their randomization number will not be reused.   
To ensure blinding, the study drug and the matching placebo have the same shape and 
size. Labels on the treatment bottles will not identify the treatment to which a patient has 
been randomized. Traceability of the treatment is ensured by the bottle number. 
The 5-digit bottle number will identify the study-drug bottle and will be detailed on the 
study-drug label. Dispensing of the study drug will be coordinated by IWRS.  
The system will assign a study-drug number corresponding to the randomization arm. 
The randomization number will be used in the background only to ensure that there is no 
unblinding and will not be displayed to end-users in the IWRS.  
8.4 
Procedure for Breaking the Randomization Code 
Should a situation arise where unblinding is urgently required, i.e., only where 
knowledge of the study drug is required to adequately manage a life-threatening situation, 


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the Investigator at that study site may perform immediate unblinding through IWRS. The 
responsibility to break the treatment code in emergency situations resides solely with the 
Investigator. The Investigator should make every effort to discuss the rationale (status 
and outcome) for emergency unblinding with the Sponsor’s Medical Monitor as soon as 
possible to review the individual patient details. 
The study-site Investigator and appropriate project team members will be authorized to 
access the emergency unblinding functionality within the IWRS. Once the randomization 
code is broken for a patient, he/she must be withdrawn from the study and all assessments 
and procedures for Visit 6/EOT should be performed. Once a randomization code has 
been broken, the Investigator must inform the project team and Sponsor’s Medical 
Monitor in writing within 24 hours. In case of technical issues accessing the system 
online, please see the IWRS site user manual for contact telephone numbers for the help 
desk 24/7 system support. 
8.5 
Patient Compliance 
Patients will return all unused study drug at Visits 3 through 6. The study-site staff will 
count all returned drug, assess compliance, and record details in the eCRF. 
Any noncompliance will be documented and explained in the source documents. 
Treatment compliance = 100 × ([number of study drug dispensed—number of study drug 
returned]/number of study drug that should be taken) 
Treatment compliance between 80% and 120% is acceptable. 
8.6 
Study Drug Accountability 
Records shall be maintained of the delivery of study treatment(s) to the study site(s), of 
the inventory at the study site(s), of each use of the study treatment(s) for each patient 
and the return or destruction of used and unused study treatment(s). Local destruction of 
used/unused study treatment(s) will follow institution standard operating procedures 
(SOPs) and will require Sponsor pre-approval. 
These records shall include dates, quantities, batch numbers, expiry dates, and the unique 
code numbers assigned to the study drug and to the study patients. 


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The Investigator will be responsible for ensuring that the records adequately document 
that the patients were provided the quantities specified in the protocol and that all study 
drug received from the Sponsor or its designee is reconciled.  
8.7 
Concomitant Therapy and Prohibited Medications 
The Investigator will note all ongoing medication and any medication recently stopped 
(within 3 months prior to Visit 2) in the eCRF. At Visits 2 through 6, all changes in 
medication (stopping or starting new medication or changes in dose) will be recorded in 
the eCRF.   
All medications taken by a patient within 3 months prior to the first intake of study drug 
are regarded as prior medication. 
All medications taken by a patient on or after the first intake of study drug, and which 
continue to be taken during the study, are regarded as concomitant medication.  


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9. 
ASSESSMENT OF EFFICACY 
9.1 
Efficacy Endpoints 
9.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline in serum LDL-C at Week 16. 
9.1.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following:  
• Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured 
by MRI-PDFF 
• Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by 
MRI 
• Change from Baseline to Week 16, and Follow-Up in the following: 
o Serum ALT, AST, and gamma-glutamyl transferase 
o HDL-C, non-HDL-C, LDL-C/HDL-C ratio, and triglycerides 
o Serum total bile acids 
9.1.3 
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be assessed: 
• Change from Baseline (unless otherwise specified) to Week 4, Week 8, Week 12, 
Week 16, and Follow-Up in the following: 
o Fasting glucose, insulin, homeostatic model assessment-insulin resistance, 
HbA1c, free fatty acids 
o GLP-1, FGF-19, and C4 levels 
o High-sensitivity CRP 
o Lanosterol and beta-sitosterol 
o Body weight, BMI, waist circumference, and waist-to-hip ratio 


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o MRI-based measurement of pulse wave velocity to measure aortic 
stiffness 
o Apolipoprotein A1 and Apolipoprotein B 
9.2 
Efficacy Assessments 
9.2.1 
Lipid Profile 
Fasting blood samples for analysis of LDL-C will be drawn at all visits, according to the 
schedule of assessments (Table 1). Fasting should be for at least 8 hours prior to the 
collection of the blood sample. Samples will be processed and transported to a central 
laboratory per instructions in the study reference manual. 
9.2.2 
Magnetic Resonance Imaging 
Patients will have an MRI at Screening and EOT to assess liver fat by MRI-PDFF, total 
liver volume, and aortic pulse wave velocity. Details of the image acquisition and 
analysis can be found in the study reference manual. 
9.2.3 
Serum Bile Acids 
Fasting blood samples for analysis of total s-BA will be drawn at all visits, according to 
the schedule of assessments (Table 1). Fasting should be for at least 8 hours prior to the 
collection of the blood sample. All s-BA results during the treatment period will be 
blinded. Samples will be processed and transported to a central laboratory per 
instructions in the study reference manual. 
9.2.4 
Biomarkers and Blood Samples for Future Testing 
Blood samples for analysis of additional markers of disease, fibrosis, inflammation, and 
cardiovascular risk factors, and other pharmacodynamic markers will be drawn at the 
appropriate visits, according to the schedule of assessments (Table 1). These include a 
bile acid profile, including primary and secondary bile acids, interleukin-6, Pro-C3, 
tumor necrosis factor alpha, and cytokeratine-18. Samples will be processed and 
transported to a central laboratory per instructions in the study reference manual. 


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10. 
ASSESSMENT OF SAFETY 
The timing and frequency of safety assessments are described in Section 7.1.3 and in 
Table 1. 
The primary safety analysis will include the occurrence of treatment-emergent adverse 
events (TEAE) and TEAEs categorized by causality, severity, and seriousness 
assessments made by the Investigator by comparing study drug exposure to placebo. 
Trends in safety will also be evaluated for the following assessments: 
• AEs, including discontinuations due to AEs 
• Physical examinations 
• Concomitant medications 
• Vital signs 
• 12-lead ECG 
• Laboratory test results (including clinical chemistry, hematology/coagulation, and 
urinalysis) 
10.1 
Adverse Events 
10.1.1 
Definitions and Investigator Assessments 
An AE is defined as any untoward medical occurrence in an enrolled patient regardless of 
causal relationship with study drug. An AE can therefore be any clinically significant 
unfavorable and unintended sign, symptom, or disease that occurs once a patient is 
enrolled (ICF is signed) in the study until the patient is discharged from the study, 
whether or not related to the study drug. 
10.1.1.1 
Clinical Significance 
Clinical significance is defined as any abnormal finding that results in further clinical 
investigation(s), treatment(s), or the diagnosis of a new condition. Patient-reported events 
and protocol-mandated laboratory values, vital signs, and physical examination findings 
can be considered clinically significant (i.e., an AE) if there is a deterioration as 
compared to Baseline. Examples of clinically significant worsening from Baseline could 


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include, but is not limited to, events causing withdrawal from the study and events 
requiring medical intervention outside of the study causing apparent clinical 
manifestations or judged to be relevant by the Investigator.   
10.1.1.2 
Serious Adverse Events 
Serious criteria are applied by the investigator to each AE as specifically defined below. 
These criteria are used to determine whether an AE is serious or non-serious. The 
assessment is made independently of severity assessment (Section 10.1.1.3). For 
example, the development of a severe rash that occurs after signing of the ICF may not 
meet serious criteria as defined below and therefore would be considered a severe, 
non-serious AE. 
Any AE that meets any 1 of the following 6 criteria is considered to be an SAE: 
• The outcome of the AE is death 
• The AE is immediately life-threatening. Life-threatening means that the patient 
is, in the opinion of the Investigator, at immediate risk of death from the reaction 
as it occurred. This does not include an AE that, if more severe, might have 
caused death 
• The AE results in persistent or significant disability/incapacity. Disability means 
a substantial disruption of a person’s ability to conduct normal life functions 
• The AE requires or prolongs hospitalization  
• The AE results in a congenital anomaly/birth defect 
• The AE is an important medical event. Important medical events may meet 
serious criteria should the Investigator assess that they may significantly 
jeopardize the patient, represent a significant hazard, or require medical/surgical 
intervention to prevent one of the outcomes listed above. Examples of potential 
SAEs based on these criteria include, but are not limited to, allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions even if they do not result in inpatient 
hospitalization, or the development of drug dependency and drug abuse. 


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10.1.1.3 
Adverse Events of Special Interest 
An adverse event of special interest (AESI) should be recorded as an AE in the eCRF as 
outlined in Section 10.1.2 and reported using the SAE/AESI Report Form outlined in 
Section 10.1.3.  
For this study, any occurrence of ischemic colitis should be reported as an AESI.  
10.1.1.4 
Severity Assessment 
Severity assessments are based on the intensity of the event in relation to expectation. 
The Investigator will assess the intensity of AEs based on the following definitions: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
Severity is a measure of intensity where seriousness is defined by the criteria outlined in 
Section 10.1.1.2. An AE of severe intensity need not necessarily be considered serious. 
For example, nausea that persists for several hours may be considered severe nausea, but 
not meet serious criteria, and therefore would be assessed as a severe AE but not an SAE. 
10.1.1.5 
Causality Assessment 
The Investigator determines the causality of all AEs to the study drug using medical 
judgment and considering all relevant factors such as (but not limited to) the underlying 
study indication, coexisting disease, concomitant medication, relevant history, pattern of 
the AE, temporal relationship to the study drug, and de-challenge or re-challenge. The 
causality assessment of the AE/SAE is to be made as follows: 
Related to Study Drug (Possibly, Probably, or Definitely Related) 
Based on medical judgment, there is at least a reasonable possibility that the study drug 
caused the event; one or more of the following criteria apply: 
• The event follows a reasonable temporal sequence from administration of study 
drug 


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• The event could not be reasonably attributed to the known characteristics of the 
patient’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient 
• The event follows a known pattern of response to study drug 
• The event disappears or decreases on cessation or reduction in dose of the study 
drug. (It should be noted that in some situations an AE will not disappear or 
decrease in intensity upon discontinuation of study drug despite other clear 
indications of relatedness) 
• The event reappears or worsens when the study drug is re-administered 
Unrelated to Study Drug (Unlikely or Unrelated) 
Based on medical judgment there is no reasonable possibility that the study drug caused 
the event; one or more of the following criteria apply: 
• The event does not follow a reasonable temporal sequence from administration of 
study drug 
• The event could be reasonably attributed to the known characteristics of the 
patient’s clinical state, concurrent illness, environment or toxic factors, or other 
modes of therapy administered to the patient 
• The event does not follow a known pattern of response to study drug 
• The event does not disappear or decrease on cessation or reduction in dose of the 
study drug, and it does not reappear or worsen when the study drug is 
re-administered 
10.1.2 
Recording of Adverse Events 
It is the Investigator’s responsibility to assess whether each untoward event is a clinically 
significant worsening from Baseline, thereby considered an AE. For all AEs, the severity, 
seriousness, and causality to study drug for each AE as outlined in Section 10.1.1 will be 
assessed and recorded in the eCRF. 


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All serious and non-serious AEs are collected once the caregiver/patient has signed the 
ICF and until the post-treatment follow-up (Visit 7) or 14 days after the last dose of study 
drug. 
Any AEs or SAEs that are unresolved at the patient’s last AE assessment are followed up 
by the Investigator until resolution or stabilization up to the database lock and recorded in 
the eCRF. The Sponsor retains the right to request additional information for any patient 
with ongoing AE(s) or SAE(s) at the end of the study. 
TEAEs are defined as any AE that occurs after randomization (Day 1). All AEs that 
occur in the Screening period, i.e., after enrollment and prior to randomization, will be 
collected on the eCRF as non-TEAEs. 
If there is a clinically significant deterioration of a laboratory value/vital sign or other 
routine study assessment that is associated with a diagnosis, the clinical diagnosis will be 
reported as an AE and the associated signs and symptoms will be considered additional 
information unless the sign or symptom is more severe than expected given the diagnosis. 
For example, if an Investigator diagnoses a study patient with hepatitis during the study 
period, hepatitis would be considered the AE and the concomitant signs and symptoms of 
abdominal pain, vomiting, and elevated ALT and AST would not be reported separately 
unless, in the opinion of the Investigator, one of these signs or symptoms is more severe 
than expected and therefore a separate AE assessment is indicated. 
10.1.3 
Recording and Reporting of Serious Adverse Events and Adverse 
Events of Special Interest 
Every SAE/AESI (regardless of severity and causality) that occurs once the patient has 
signed the ICF and through 14 days after the final dose of study drug, should immediately 
and not later than within 24 hours of knowledge of the event, be reported by the 
Investigator or delegate in the SAE/AESI report form.  
Report of a SAE/AESI must include at least the following information: 
• Patient identification information (study number, site number, and date of birth 
[as per local country requirements for data protection]) 
• The last study drug administration date 


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• The diagnosis of the event with the description (or a brief description of 
signs/symptoms/clinical course if the diagnosis is not available) and the date of 
onset 
• The action used to treat the event (i.e., treatment medications, temporary 
discontinuation) 
• The reason(s) for considering the event serious 
• The relationship of the event to the study drug or to the study procedure (i.e., the 
Investigator’s assessment of causality) 
• A brief narrative of the SAE/AESI 
Follow-up reports including all new information obtained of the subsequent course of the 
SAE/AESI must be prepared and the information collected in the SAE/AESI report form 
submitted to the CRA, 
 
 by e-mail within 24 hours of knowledge of the event. 
The pharmacovigilance manager (PVM) of the CRA may contact the Investigator to 
obtain further information on a reported SAE/AESI. The investigator/investigative staff 
must respond to any request for follow-up information or answers to questions regarding 
the SAE/AESI within the same timelines as for initial reports. 
The PVM reports the occurrence of the SAE/AESI and follow-up to the Sponsor’s 
Medical Monitor for medical assessment of the case. 
Should an outcome of death occur within the study period or within 14 days after the last 
administration of study drug, an SAE/AESI report form should be completed including 
the main and contributory causes of death. 
All SAE/AESI reports must be e-mailed to the following e-mail address within 24 hours: 
 
If email is unavailable, SAEs/AESIs may be transmitted via fax to the following number: 
 


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10.1.4 
Reporting of Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reaction (SUSAR) is an SAE that occurs in a 
patient, the nature or severity of which is not expected per the applicable product 
information (e.g., the Investigator’s Brochure for an unauthorized investigational product 
or summary of product characteristics for an authorized product).  
Reporting and tracking of SUSARs will be in accordance with all applicable competent 
authority regulations. The IRBs and all Investigators involved in this study will be 
informed according to local requirements. 
10.2 
Laboratory Values, Vital Signs, Physical Examinations, and Other Safety 
Assessments 
10.2.1 
Laboratory Assessments 
Samples will be collected for clinical chemistry, hematology, urinalysis, and other lab 
assessments at the time points specified in Table 1. The parameters assessed are 
presented in Table 2. All samples will be processed and transported to a central 
laboratory per instructions in the study reference manual. 
The observed values will be recorded and assessed as “normal” or “abnormal not 
clinically significant” or “abnormal clinically significant.” 
Additional blood samples may be needed due to follow-up of an abnormal value or 
analysis failure. The blood samples collected for safety laboratory analysis will be 
destroyed after the analyses have been completed.  
Stored blood sample for future testing are detailed in Section 9.2.4.  


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Table 2: 
Laboratory Parameters 
CLINICAL CHEMISTRY (FASTING) 
HEMATOLOGY/COAGULATION 
URINALYSIS 
• 
Albumin 
• 
ALT 
• 
Alkaline phosphatase  
• 
Amylase 
• 
AST 
• 
Bicarbonate 
• 
Blood urea nitrogen 
• 
Calcium 
• 
Chloride 
• 
Creatine kinase 
• 
eGFR by MMRD (screening only) 
• 
Gamma-glutamyl transferase 
• 
Glucose 
• 
Hemoglobin HbA1C 
• 
Inorganic phosphorus 
• 
Lactate dehydrogenase 
• 
Lipase 
• 
Potassium 
• 
Sodium 
• 
Total bilirubin 
• 
Total protein 
• 
Uric acid 
• 
Hematocrit 
• 
Hemoglobin 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count and differential 
(neutrophils, eosinophils, basophils, 
lymphocytes, and monocytes) 
Manual microscopic review is performed only if 
white blood cell count and/or differential values 
are out of reference range. 
• 
International normalized ratio (INR) 
• 
Prothrombin time (PT) 
• 
Bilirubin 
• 
Blood 
• 
Glucose 
• 
Ketones 
• 
Leukocytes esterase 
• 
Microscopy including leukocytes (performed 
only as needed based on positive dipstick test 
results) 
• 
Nitrites 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
 
 
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LIPID PROFILE (FASTING) 
OTHER TESTS 
ENDOCRINOLOGY 
• 
Apolipoprotein A1 
• 
Apolipoprotein B 
• 
Chylomicron cholesterol 
• 
Chylomicron triglycerides 
• 
High-density lipoprotein (HDL) cholesterol 
• 
Lipoprotein(a) cholesterol 
• 
Low-density lipoprotein (LDL) cholesterol by 
calculation 
• 
LDL triglyceride 
• 
Non-high-density lipoprotein cholesterol 
• 
Total cholesterol 
• 
Triglycerides 
• 
Very low-density lipoprotein (VLDL) 
cholesterol 
• 
VLDL triglyceride 
• 
Lanosterol 
• 
Beta-sitosterol 
• 
High-sensitivity C-reactive protein (CRP) 
• 
C4 
• 
Fibroblast growth factor-19 (FGF-19) 
• 
Fibrosis and inflammation markers: FIB-4, 
APRI, and NAS  
• 
Glucagon-like peptide-1 (GLP-1) 
• 
Follicle-stimulating hormone1 
• 
Homeostatic model assessment-insulin 
resistance 
• 
Insulin 
• 
Thyroxine2 
• 
Triiodothyronine2 
• 
Thyroid-stimulating hormone2 
• 
Free fatty acids 
• 
Adipose tissue insulin resistance 
• 
Adiponectin 
BILE ACIDS (FASTING) 
PREGNANCY 
SEROLOGY 
• 
Total serum bile acids 
• 
Serum 
• 
Urine 
• 
Hepatitis B virus surface antigen 
• 
Hepatitis C virus antibody and ribonucleic 
acid  
1 
A postmenopausal state is defined as no menses for ≥12 months without an alternative medical cause. A follicle-stimulating hormone level in the postmenopausal range will be 
used to confirm a postmenopausal state in women ≤55 years of age, performed at Screening visit only. 
2 
Thyroid function test will be performed during Screening visit only. 
 


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10.2.2 
Individual Patient Safety Monitoring 
10.2.2.1 
Liver Monitoring 
Strategies to monitor markers of liver disease throughout the study are outlined below 
where the ULN will be based on central laboratory reference values for age and gender. 
Patients will be monitored as described below for drug-induced liver injury from 
randomization to 2 weeks following the last administration of study drug. 
Elevated ALT  
• ALT >5 × ULN or >3 × Baseline (if ALT elevated at Baseline): repeat AST, 
ALT, total bilirubin, alkaline phosphatase (ALP), and INR within 72 hours and 
closely monitor the patient. If liver enzyme elevation is confirmed, interrupt the 
study drug. The study drug can be restarted only if a competing etiology is 
identified or liver tests return to Baseline. 
Elevated AST  
• AST >5 × ULN or 3 × baseline (if AST elevated at baseline): repeat AST, ALT, 
total bilirubin, ALP, and INR within 72 hours and closely monitor the patient. If 
liver enzyme elevation confirmed, interrupt the study drug. The study drug can be 
restarted only if a competing etiology is identified or liver tests return to Baseline. 
Elevated Total Bilirubin 
• Total bilirubin >2 × ULN or >1.5 × Baseline (if total bilirubin elevated at 
Baseline), regardless of ALT or AST levels: repeat AST, ALT, total bilirubin, 
ALP, and INR within 72 hours and closely monitor the patient. If liver enzyme 
elevation confirmed, interrupt the study drug. The study drug can be restarted 
only if a competing etiology is identified or liver tests return to Baseline. 
Other Clinical Symptoms  
• Clinical signs of hepatitis or indicators of immunological reaction (e.g., nausea, 
vomiting, right upper quadrant pain, loss of appetite, dark urine, jaundice, rash, 
eosinophilia >5% or symptoms/signs of hepatic decompensation): discontinue the 


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study drug and repeat AST, ALT, total bilirubin, ALP, and INR within 72 hours 
and closely monitor. Other causes of hepatitis should be excluded.  
When close monitoring of a patient is not possible while the patient is on study drug, 
interrupt the study drug and closely monitor the patient. 
10.2.3 
Demographics/Medical and Surgical History 
Demographic information per country regulations (age, full date of birth, gender, race, 
and ethnicity), along with medical and surgical history, will be obtained and recorded in 
the eCRF at Visit 1. 
Medical and surgical history will be entered in the eCRF at Visit 1. This includes date of 
diagnosis of NASH/NAFLD, ongoing medication, any surgery performed, and any other 
diagnoses.   
10.2.4 
Physical Examination 
A physician or suitably trained qualified assistant will perform a complete physical 
examination at Screening, at Visit 2, and at Visit 6. Height (Screening only), weight, 
waist circumference, and waist-to-hip ratio will also be collected. BMI will be calculated 
based on height and weight. 
A complete physical examination will include assessment of general appearance, eyes, 
ears, nose, throat, head/neck/thyroid, lymph nodes, cardiovascular, lungs/chest, abdomen, 
genitourinary, extremities, skin, musculoskeletal, neurologic, and other.  
10.2.5 
Vital Signs 
Evaluation of vital signs will be performed at all visits. This includes blood pressure 
(systolic and diastolic), pulse, respiratory rate, and oral temperature. 
10.2.6 
12-Lead ECG 
A 12-lead ECG will be performed at the Screening visit and the EOT visits.  
10.2.7 
Overdose 
Elobixibat is minimally absorbed and has a very low systemic availability. It is not 
known whether elobixibat can be removed from the systemic circulation by dialysis. 


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There are no known antidotes for elobixibat overdoses. If an overdose occurs, the patient 
should be carefully monitored and treated with supportive therapy. 
10.2.8 
Pregnancy 
If a pregnancy is discovered in a female patient enrolled in the study, the patient will be 
immediately discontinued from the study drug, if applicable, and will attend the same 
visits as a prematurely withdrawn patient. If the pregnancy is discovered after completion 
of the treatment period, the patient will continue in the study per protocol. If a pregnancy 
occurs in a male patient’s partner at any time during the study, the pregnancy should also 
be reported and followed. 
If the patient has been dosed with the study drug, the pregnancy must be recorded on the 
appropriate form and submitted to the PVM (Section 10.1.3) within 24 hours of learning 
of the pregnancy. 
The pregnancy should be followed to determine outcome, including spontaneous 
termination, details of birth and presence of any birth defects, congenital anomalies or 
newborn or maternal complication. While pregnancy itself is not considered to be an AE 
or SAE, any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE.  A spontaneous abortion (occurring at <22 
weeks gestational age) or still birth (occurring at >22 weeks gestational age) is always 
considered to be an SAE and will be reported as such.  
Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported as described in Section 10.1.3. While the 
investigator is not obligated to actively seek this information in former study participants, 
he or she may learn of an SAE through spontaneous reporting. 


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11. 
STATISTICAL EVALUATION 
All personnel involved with the analysis of the study will remain blinded until database 
lock for the double-blind treatment period and until major protocol violations have been 
identified. 
All statistical analyses will be performed using SAS version 9.3 or higher. 
11.1 
Sample Size and Power 
Due to the exploratory nature of this study, no formal power calculations were used to 
determine the sample size. The number of subjects (46 patients in total, 23 patients per 
treatment group) was chosen based on clinical experience with other similar proof-of- 
concept studies. 
11.2 
Statistical Methods 
11.2.1 
Statistical Analysis Populations 
ITT Population 
The intent-to-treat (ITT) population will include all patients who are randomized in the 
study and receive at least 1 dose of study drug. The ITT population will be used for all 
efficacy analyses based on the treatment randomized unless otherwise specified.  
Per Protocol Population 
The per protocol (PP) population will include all ITT patients who finish Visit 7/EOT 
with valid LDL-C measurements and do not have any major protocol deviations. 
Allocation of patients to the PP analysis set will be performed before unblinding of the 
study. 
Safety Population  
The safety population will include all patients who are randomized and receive at least 
1 dose of study drug and will be used for all safety analyses based on the treatment 
received.  


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11.2.2 
Methods of Statistical Analyses 
11.2.2.1 
General Principles 
Summary statistics (number of patients, mean, standard deviation, median, minimum, and 
maximum) at all visits and change or percent change from Baseline will be provided for 
efficacy and safety continuous variables. Count and frequency will be used to tabulate 
categorical variables. 
11.2.2.1.1 
Efficacy 
The primary efficacy endpoint is the change from Baseline in serum LDL-C at Week 16. 
Baseline is defined as the last non-missing LDL-C value prior to the first dose of study 
drug.  
Exploratory comparisons between elobixibat 5 mg and placebo will be performed for the 
following secondary efficacy endpoints:   
• Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured 
by MRI-PDFF 
• Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by 
MRI 
The analysis methods for the other secondary and exploratory endpoints will be detailed 
in the statistical analysis plan (SAP). 
11.2.2.1.2 
Safety 
The safety endpoints for this study include clinical laboratory assessments, vital signs, 
AEs, ECGs, physical examinations, and concomitant medications. 
AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedRA). TEAEs will be defined as AEs that are new or worsening after the 
first dose of study drug. A general summary of patients with TEAEs and serious adverse 
events (SAEs) will be tabulated with numbers and percentages of patients and repeated 
for severity and relationship to study drug per treatment group. The number of AEs 
leading to withdrawal and SAEs leading to death will also be summarized. The incidence 
of TEAEs will be summarized by body system and treatment group. 


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The safety laboratory data will be summarized by visit and by treatment group, along 
with changes from Baseline. Values outside of the reference range will be flagged and 
laboratory abnormalities of special interest will be summarized.  
11.2.2.2 
Missing Data 
Continued collection of efficacy data for patients who discontinue treatment will be made 
for as long as possible as per the schedule of assessments (Table 1). Missing data 
handling for the primary efficacy endpoint is specified under Section 11.2.2.6. Details on 
missing data handling for secondary and exploratory endpoints will be specified in the 
SAP.  
11.2.2.3 
Demographic and Baseline Characteristics 
Descriptive summaries of demographics and other baseline characteristics (including 
medical and surgical history) will be presented by treatment group and overall using the 
ITT population.  
Prior medication will be summarized by treatment group and overall using the ITT 
population. 
11.2.2.4 
Subject Disposition 
The following will be summarized descriptively (by treatment group and overall where 
applicable): 
• Patients enrolled (who signed the informed consent) 
• Patients randomized 
• Patients treated 
• Patients completing the study 
• Patients withdrawing early (including withdrawal reason) 
11.2.2.5 
Evaluation of Primary Efficacy Endpoints 
To address the potential missing data from patients who are lost to follow-up after 
treatment discontinuation, multiple imputation method will be used. Data from patients 
who discontinue the study drug but stay in the study with scheduled assessments 


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collected will be used to impute missing values for patients lost to follow-up. This 
imputation will be done within each treatment group. Interim missing data will be 
handled as missing at random (predictable from observed data from subjects in the same 
treatment group).  
After the imputation is performed, an analysis of covariance (ANCOVA) will be used to 
analyze the primary efficacy endpoint. The model will include treatment arm and 
Baseline LDL-C scores.  
Least square (LS) mean (SE), LS mean difference (SE), 95% confidence intervals, and 
P-values between elobixibat 5 mg and placebo will be provided. The model assumptions 
will be checked before the analysis. If there are concerns on model assumptions, i.e., 
normality and homogeneity of variances, a non-parametric ANCOVA based on the rank 
scores can be used as a sensitivity analysis. 
Sensitivity analyses may be performed and will be detailed in the SAP. 
11.2.2.6 
Evaluation of Secondary and Exploratory Efficacy Endpoints 
Descriptive statistics will be provided for secondary and exploratory endpoints listed in 
Sections 9.1.2 and 9.1.3, respectively, unless otherwise specified. 
11.2.2.7 
Evaluation of Safety Endpoints 
Safety data will be analyzed using descriptive statistics and summaries by treatment 
group of SAEs, AEs, vital signs, clinical safety laboratory tests (hematology, coagulation, 
clinical chemistry, and urinalysis), and concomitant medication. Analyses will be 
performed using the safety analysis set.  
Summaries of AEs (coded according to the MedDRA system organ class [SOC] and 
MedDRA preferred term) will include the following:  


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• Overview of the incidence of TEAEs (TEAEs, drug-related TEAEs, TEAEs 
leading to study discontinuation, and treatment-emergent SAEs) 
• TEAEs by SOC and preferred term 
• Intensity of TEAEs by SOC and preferred term 
• Drug-related TEAEs by SOC and preferred term 
• TEAEs leading to study discontinuation by SOC and preferred term 
• Treatment-emergent SAEs by SOC and preferred term 
Concomitant medication use during the treatment period will be summarized by 
Anatomical Therapeutic Chemical (ATC) class and World Health Organization (WHO) 
preferred name.  
Summaries of vital signs will be presented. For each visit, the actual results and the 
change from Baseline, and the number and percentage of patients with potentially 
clinically significant (PCS) values as defined in the SAP, observed post-baseline will be 
presented. 
Summaries of clinical safety laboratory data will be presented. For each visit, the actual 
result and the change from Baseline, and the number and percentage of patients with PCS 
values as defined in the SAP, observed post-baseline will be presented. 
Data listings will be provided for each patient for all safety parameters. 
11.2.2.8 
Compliance and Exposure 
Exposure will be analyzed by calculating the number of days with exposure to study 
drug. Results will be presented by treatment group using the safety analysis set.  
The percentage compliance will be described by treatment group and the number of 
patients with a compliance <80%, between 80% and 120%, and >120% will be presented 
based on the safety analysis set. 


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12. 
DIRECT ACCESS TO SOURCE DATA/NOTES 
The Investigator/institution shall provide direct access to source data/documents for 
study-related monitoring, audits, IRB review, and regulatory inspection. 


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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Conduct of the Study 
The study team shall implement and maintain quality control and quality assurance 
procedures with written SOPs to ensure that the study is conducted, and data are 
generated, documented, and reported in compliance with the protocol, ICH GCP, and 
applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of 
Helsinki (October 1996) and all revisions thereof, and in accordance with US Food and 
Drug Administration (FDA) regulations (Code of Federal Regulations, Sections 312.50 
and 312.56) and with ICH GCP (CPMP 135/95). 
The Investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate competent authority and IRB, 
except when necessary to eliminate immediate hazards to the patient or when the 
change(s) involve(s) only logistical or administrative aspects of the study. Any deviations 
may result in the patient having to be withdrawn from the study and render that patient 
non-evaluable. 
13.2 
Study Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Sponsor 
representative or designee will review the protocol and eCRF with the Investigators and 
the investigative staff. During the study, the clinical monitor (the CRA) will visit the site 
regularly to check the completeness of patient records, the accuracy of entries on the 
eCRFs, the adherence to the protocol and to GCP, the progress of enrollment, and to 
ensure that study drug is being stored, dispensed, and accounted for according to 
specifications. 
The investigator must ensure that eCRFs are completed within a timely period of patient 
visits, as per individual site agreements, and must allow the CRA and the Sponsor 
representative or designee periodic access to patient records and all study-related 
materials, including relevant hospital or clinical records, to confirm their consistency 
with the eCRF entries. No information in these records about the identity of the patients 
will leave the study center. The Sponsor monitoring standards require full verification for 
the presence of the signed ICF, adherence to the inclusion/exclusion criteria, 


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documentation of SAEs, and recording of primary efficacy and safety variables. The 
CRA will review source data compared with the eCRFs and will verify source data 
according to the study-specific monitoring plan. The design of the study, the frequency of 
patient visits, and the site enrollment rate will determine the frequency of monitoring 
visits. Upon study completion, the CRA will visit the site to conduct a study termination 
visit, which will include collection of any outstanding documentation. 
It is recommended that the Investigator/investigative staff log into the eCRF system every 
working day or at minimum twice weekly in order to provide a prompt response to 
queries. The Investigator/investigative staff should respond to queries and make any 
relevant changes to the study data within 3 working days. 


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14. 
ETHICS 
14.1 
Institutional Review Board 
Prior to the start of the study, the Investigator is responsible for ensuring that the protocol 
and consent form have been reviewed and approved by a relevant IRB. The IRB shall be 
appropriately constituted and perform its functions in accordance with FDA, ICH, GCP, 
and local requirements as applicable. 
The IRB shall approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, patient recruitment 
procedures (e.g., advertisements), written information to be provided to the patients and 
caregivers, the Investigator’s Brochure, available safety information, information about 
payment and compensation available to patients, the Investigator’s curriculum vitae 
and/or other evidence of qualifications and any other documents requested by the IRB 
and regulatory authority (competent authority) as applicable. 
14.2 
Written Informed Consents 
The Investigator (physician) or investigative staff, in accordance with local regulations, 
will explain to each patient (or legally authorized representative) the nature of the study, 
its purpose, the procedures involved, the expected duration, alternative treatment, the 
potential risks and benefits involved, and any discomfort that may occur. Each patient 
will be informed that participation in the study is voluntary and that he/she may withdraw 
from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
If written consent is not possible, oral consent can be obtained if witnessed and followed 
by a signed statement from one or more persons not involved in the study, indicating why 
the patient was unable to sign the form. No patient can enter the study before his/her 
informed consent has been obtained, as required by country regulations. 
The ICF is part of the protocol and must be submitted by the Investigator/investigative 
staff with the protocol for IRB approval. The Sponsor will supply an ICF which complies 
with regulatory requirements and country laws and is considered appropriate for the 
study. Any changes to the ICF suggested by the Investigator must be agreed to by the 
Sponsor before submission to the IRB and a copy of the approved version must be 
provided to the clinical monitor after IRB approval. 


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15. 
DATA HANDLING AND RECORDKEEPING 
15.1 
Electronic Case Report Forms/Source Data Handling 
The investigator shall be provided with standardized eCRFs and shall ensure that all data 
from patient visits are promptly entered into the eCRFs in accordance with the specific 
instructions given. The Investigator must sign each eCRF to verify the integrity of the 
data recorded. 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to the start of the study. As a central laboratory has 
been selected to conduct any or all tests, it is essential that all samples be analyzed at that 
laboratory. 
The Investigator must maintain source documents such as laboratory reports, consultation 
reports, and complete medical history and physical examination reports. 
15.2 
Retention of Essential Documents 
Essential documents, as defined by ICH GCP, include the signed protocol and any 
amendment(s); copies of the completed eCRFs (for site archiving of eCRF data for 
specific patients will be provided); signed ICFs; hospital records and other source 
documents; IRB approvals and all related correspondence including approved documents; 
drug accountability records; study correspondence; and a list of patients’ names and 
addresses. 
The Investigator/investigative staff must retain copies of these essential documents for 
the period specified by ICH GCP and by applicable regulatory requirements. The 
Investigator/investigative staff will inform the Sponsor of the location where the essential 
documents are stored and must contact the Sponsor for approval before disposing of any 
essential documents. The Investigator/investigative staff should take measures to prevent 
accidental or premature destruction of these documents. 


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16. 
FINANCING AND INSURANCE 
Financing and insurance are addressed in a separate agreement. 


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17. 
PUBLICATION POLICY 
The Sponsor will retain ownership of all data. When the study is complete, the Sponsor 
will arrange the analysis, tabulation of data, and preparation of a clinical study report. 
The Sponsor may also use the data for publication, presentation at scientific meetings, 
and submission to regulatory authorities. All proposed publications based on this study 
must be subject to the Sponsor’s approval requirements. 


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18. 
REFERENCES LIST 
Andersen A, Lund A, Knop FK, Vilsbøll T. Glucagon-like peptide 1 in health and 
disease. Nature Rev. 2018;14(7):390-403. doi: 10.1038/s41574-018-0016-2. 
Aranha MM, Cortez-Pinto H, Costa A, et al. Bile acid levels are increased in the liver of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2008;20(6):519-525. 
doi: 10.1097/MEG.0b013e3282f4710a. 
Bertolotti M, Zambianci L, Carulli L, et al. Influence of newly synthesized cholesterol on 
bile acid synthesis during chronic inhibition of bile acid absorption. Hepatology. 
2003;38(4)939-946. 
Ferslew BC, Xie G, Johnston CK, et al. Altered bile acid metabolome in patients with 
non-alcoholic steatohepatitis. Dig Dis Sci. 2015;60(11):3318-3328. doi: 10.1007/s10620-
015-3776-8. 
Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological 
scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313-1321. 
doi: 10.1002/hep.20701. 
Mahfood Haddad T, Hamdeh S, Kanmanthareddy A, Alla VM. Nonalcoholic fatty liver 
disease and the risk of clinical cardiovascular events: a systematic review and meta-
analysis. Diabetes Metab Syndr. 2017;11(Suppl 1):S209-S216. 
doi: 10.1016/j.dsx.2016.12.033. 
Naoumova RP, O’Neill FH, Dunn S, et al. Effect of inhibiting HM-CoA reductase on 7α-
hydroxy-4-cholesten-3one, a marker of bile acid synthesis: contrasting findings in 
patients with and without prior up-regulation of the latter pathway. Eur J Clin Invest. 
1999;29(5):404-412.  
Prawitt J, Caron S, Staels B. Bile acid metabolism and the pathogenesis of type 2 
diabetes. Curr Diabetes Rep. 2011;11(3):160-166. doi: 10.1007/s11892-011-0187-x. 
Puri P, Daita K, Joyce A, et al. The presence and severity of nonalcoholic steatohepatitis 
is associated with specific changes in circulating bile acids. Hepatology. 
2018;67(2):534-548. doi: 10.1002/hep.29359. 


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Sanyal A, Harrison S, Charlron M, et al. Serum bile acids are markedly elevated in 
patients with compensated cirrhosis due to nonalcoholic steatohepatitis. J Hepatol. 
2018;68:S365-S604. doi: 10.1016/S0168-8278(18)31360-6. 
Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. 
Nat Rev Gastroenterol Hepatol. 2014;11(1):55-67. doi: 10.1038/nrgastro.2013.151. 
Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, 
predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 
2018;15(1):11-20. doi: 10.1038/nrgastro.2017.109. 
 


CLINICAL STUDY PROTOCOL A3309-012 
A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to 
Explore the Efficacy and Safety of Elobixibat in Adults with 
Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic 
Steatohepatitis (NASH) 
 
IND number:  
141078 
Test product: 
Elobixibat 
Indication: 
Nonalcoholic Fatty Liver Disease or Nonalcoholic 
Steatohepatitis 
Sponsor: 
Elobix AB 
Development phase: 
Phase 2 
Sponsor medical monitor: 
 
Principal investigator: 
 
Date of the protocol: 
25 February 2019 
Version of the protocol:  
Version 1.0 (Original) 
 
Version No. 
Previous Version Number 
Effective Date 
1.0 
N/A 
25 February 2019 
 
 
Confidential 
The information in this document contains trade secrets and commercial information that 
are privileged or confidential and may not be used, divulged, published, or otherwise 
disclosed without the written consent of Elobix AB. These restrictions on disclosure 
apply equally to all future information supplied to you or generated by you in 
connection with the study. 
 


Elobix AB
43309 - 141078
Module 5: Clinical Study Reports
M5.3.5.1- Protocol
SPONSOR SIGNATURE PAGE
PROTOCOL TITLE: A Double-Blindo Randomized, Placebo-Controlled, Phase 2
Study to Explore the Eflicacy and Safety of Elobixibat in Adults with Nonalcoholic
Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASÐ
PROTOCOL NUMBER: 43309-0 12
Elobix AB
Confidential
Version 1.0 (Original)/25 Feb 2019
Page 2 ofTI


Elobix AB 
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INVESTIGATOR SIGNATURE PAGE 
PROTOCOL TITLE: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 
Study to Explore the Efficacy and Safety of Elobixibat in Adults with Nonalcoholic 
Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH)  
PROTOCOL NUMBER: A3309-012 
I have read this protocol and agree that it contains all necessary details for performing 
this study. I will conduct the study as outlined herein and will complete the study within 
the time designated, in accordance with all stipulations of the protocol and in accordance 
with Good Clinical Practice (GCP), local regulatory requirements, and the Declaration of 
Helsinki. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure that they are fully informed regarding the study drug and the conduct of 
the study. 
I will use only the informed consent approved by the Institutional Review Board (IRB) 
and will fulfill all responsibilities for submitting pertinent information to the IRB 
responsible for this study. 
I agree that the Sponsor (Elobix AB) shall have access to any source documents from 
which case report form (CRF) information may have been generated. 
I further agree not to originate or use the name of Elobix AB or elobixibat (A3309) in any 
publicity, news release, or other public announcement, written or oral, whether to the 
public, press, or otherwise, relating to this protocol, to any amendment to the protocol, or 
to the performance of this protocol without the prior written consent of Elobix AB. 
 
 
 
 
Name of Investigator 
 
 
 
 
Signature 
 
Date (day/month/year) 
 


Elobix AB 
A3309 – 141078 
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1. 
ADMINISTRATIVE INFORMATION 
Protocol no.: 
A3309-012 
Date of initial protocol: 
25 February 2019 
Date and no. of amendments: 
N/A 
Sponsor: 
Elobix AB 
Arvid Wallgrens backe 20 
413 46 Gӧteborg 
Sweden 
Clinical research organization: 
 
 
 
Sponsor Medical Monitor: 
 
 
 
 
Principal Investigator: 
 
 


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2. 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
Title of Study: 
A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Explore the Efficacy and Safety of 
Elobixibat in Adults with Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis 
(NASH) 
Principal Investigator: 
 
Study Centers: Up to 15 sites will be initiated for this study in the United States (US) 
Publication(s): Not applicable 
Planned Study Period: Q2 2019 to Q2 2020 
Development Phase: Phase 2 
Objectives: 
Primary Objective 
The primary objective is to evaluate the efficacy of repeated once-daily doses of 5 mg elobixibat on serum 
levels of low-density lipoprotein cholesterol (LDL-C) in patients with NAFLD or NASH. 
Secondary Objectives 
• 
To assess the safety and tolerability of elobixibat in patients with NAFLD or NASH 
• 
To evaluate the effect of elobixibat on liver steatosis as measured by magnetic resonance imaging 
(MRI) for (i) liver fat fraction (using proton density fat fraction [PDFF]) and (ii) total liver fat (using 
whole liver fat volume) 
• 
To evaluate the effect of elobixibat on liver function using alanine aminotransferase (ALT) 
• 
To evaluate the effect of elobixibat on lipids and serum bile acids (s-BA) in patients with NAFLD or 
NASH 
Methodology: 
This is a double-blind, randomized, placebo-controlled, Phase 2 study to explore the efficacy and safety of 
elobixibat (oral dose of 5 mg) once daily for 16 weeks in patients with NAFLD or NASH. The study 
includes a 6-week Screening period, followed by a 16-week Treatment period, and a Follow-Up visit 
2 weeks after the last dose of study drug. Continued collection of efficacy data for patients who discontinue 
treatment will be made for as long as possible per the schedule of assessments.  
After completing the Screening period, eligible patients will be randomized on Day 1 (Visit 2) in a 1:1 
fashion to either 5 mg/day elobixibat or matching placebo. There will be a total of 7 scheduled visits during 
the study. Additional unscheduled visits may be required for patients who need direct site assistance (e.g., 
due to adverse event [AE] monitoring, in order to fulfill screening requirements, and/or for safety 
maintenance).   
Number of Patients: Approximately 46 patients diagnosed with NAFLD/NASH and in accordance with 
the inclusion/exclusion criteria will be randomized.   
Inclusion Criteria: 
Patients must meet all of the following criteria to be included in the study: 
1. Be willing to participate in the study and provide written informed consent 
2. Be a man or woman ≥18 years of age 
3. Have a current biopsy-confirmed NASH within 6 months of screening or a suspected diagnosis of 
NAFLD/NASH based on the criteria outlined below: 
 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
a. 
Biopsy-confirmed NASH is defined as histological NASH diagnosis with fibrosis stage 
F1 through F3 and a NAFLD activity score (NAS) of ≥4 with a score of ≥1 in each of the 
NAS components below as assessed by a pathologist using the NASH Clinical Research 
Network criteria (Kleiner 2005): 
i. 
Steatosis (scored 0 to 3) 
ii. 
Ballooning degeneration (scored 0 to 2) 
iii. 
Lobular inflammation (scored 0 to 3) 
 
OR 
b. The suspected diagnosis of NAFLD/NASH is based on each of the following criteria 
being met: 
i. 
Serum AST ≥20 U/L and ALT ≥40 U/L 
ii. 
Diagnosis of metabolic syndrome as having any 3 of the following 5 risk factors 
at Screening: 
• 
Fasting plasma glucose ≥100 mg/dL or undergoing drug treatment for 
elevated glucose 
• 
High-density lipoprotein-cholesterol (HDL-C) <40 mg/dL in males or 
<50 mg/dL in females or undergoing drug treatment for reduced 
HDL-C 
• 
Triglycerides ≥150 mg/dL or undergoing drug treatment for elevated 
triglycerides 
• 
Waist circumference >102 cm in males or >88 cm in females 
• 
Systolic blood pressure ≥130 mm Hg or diastolic blood pressure 
≥85 mm Hg or undergoing drug treatment for hypertension, or 
antihypertensive drug treatment in a patient with a history of 
hypertension 
4. Screening MRI-PDFF with ≥10% liver steatosis 
5. Fasting serum LDL-C >130 mg/dL at screening, >110 mg/dL on lipid-lowering medications 
6. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (beta 
human chorionic gonadotropin) at Screening and must agree to use highly effective birth control 
throughout the study and up to 30 days after the last dose of study drug. Highly effective 
contraception measures include combined estrogen- and progestogen-containing hormonal 
contraception (oral, intravaginal, and transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, and implantable), intrauterine device, 
intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner (only in the 
event that the vasectomized partner is the sole sexual partner of the WOCBP), and sexual 
abstinence (defined as refraining from heterosexual intercourse) only in the event that this is the 
preferred lifestyle of the patient.  
Childbearing potential is defined as being fertile following menarche and until becoming 
postmenopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) 
A postmenopausal state is defined as no menses for ≥12 consecutive months without an alternative 
medical cause. A follicle-stimulating hormone level in the postmenopausal range will be used to 
confirm a postmenopausal state in women ≤55 years of age 
Men with partners who are WOCBP must either be surgically sterile or agree to use a barrier 
contraceptive for the duration of the study and up to 30 days after the last dose of study drug 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
7. Be willing to maintain a stable diet and physical activity throughout the course of the study 
 
Exclusion Criteria: 
1. Women who are pregnant, breastfeeding, or plan to become pregnant during the study 
2. Body mass index (BMI) <25 kg/m2 
3. Fibrosis-4 Index (Fib-4) >2.6 
4. Any of the following laboratory abnormalities: 
a. 
ALT >5 × upper limit normal (ULN) or AST >5 × ULN 
b. International normalized ratio (INR) ≥1.3, unless on anticoagulant therapy 
c. 
Total bilirubin > ULN, except with an established diagnosis of Gilbert’s syndrome 
d. Platelet count less than the lower limit of normal (LLN) 
e. 
Creatinine clearance as calculated by the modification of diet in renal disease (MDRD) 
estimated glomerular filtration rate (eGFR) equation <60 mL/min 
NOTE: Unless otherwise specified, repeat testing may be performed in consultation with the 
Medical Monitor. 
5. Acute or chronic liver disease other than NAFLD/NASH including but not limited to the 
following: 
a. 
Hepatitis B (as defined by the presence of hepatitis B surface antigen at Screening) or 
hepatitis C (as defined by the presence of hepatitis C virus [HCV] antibody [anti-HCV]. 
Patients with positive anti-HCV who test negative for HCV ribonucleic acid at Screening 
will be allowed to participate in the study as long as there is evidence of viral negativity 
for a minimum of 12 months prior to Screening) 
b. Evidence of ongoing autoimmune hepatitis 
c. 
History of primary biliary cirrhosis, primary sclerosing cholangitis, Wilson’s disease, 
homozygous alpha-1-anti-trypsin deficiency, hemochromatosis or iron overload, 
drug-induced or alcoholic liver disease, or known bile duct obstruction 
d. Suspected or proven hepatocellular carcinoma 
6. Known history of human immunodeficiency virus 
7. Medical history of liver cirrhosis 
8. Clinical evidence of portal hypertension to include any history of ascites, hepatic encephalopathy, 
or presence of esophageal varices 
9. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone 
replacement, anabolic steroids, or valproic acid) or other known hepatotoxins for >2 weeks in the 
year prior to Screening 
10. Use of the following medications: 
a. 
Glucagon-like peptide-1 (GLP-1) agonists unless on a stable dose 3 months prior to liver 
biopsy or Screening 
b. Ursodeoxycholic acid, thiazolidinediones, or obeticholic acid within 3 months prior to 
Screening 
c. 
Statins and other lipid-modifying therapies must have been stable for ≥3 months prior to 
Screening 
 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
d. Oral antidiabetic drugs (other than those specifically excluded) must have been stable for 
≥3 months prior to Screening 
e. 
Agents (including herbal over-the-counter weight loss preparations) or medications 
known to significantly impact body weight within 3 months prior to screening (e.g., 
sibutramine, phenetamine, and orlistat) 
11. History of significant alcohol consumption, defined as an average of >20 g/day in female patients 
and >30 g/day in male patients, for a period of >3 consecutive months within 1 year prior to 
Screening, hazardous alcohol use (Alcohol Use Disorders Identification Test score ≥8), or an 
inability to reliably quantify alcohol consumption based upon judgment of the Investigator 
12. Weight change ≥10% within the 6 months prior to Screening or ≥5% within the 3 months prior to 
Screening 
13. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty and roux-en-Y 
gastric bypass) 
14. Type 1 diabetes by medical history 
15. Uncontrolled Type 2 diabetes defined as hemoglobin A1c (HbA1c) >9.5% at Screening (patients 
with HbA1c >9.5% may be rescreened) or requiring insulin dose adjustment >10% within 
2 months prior to Screening 
16. Clinical hyperthyroidism or hypothyroidism or Screening hormone results pointing to thyroid 
dysfunction. Patients receiving dose-stable thyroid replacement therapy for ≥3 months prior to 
Screening will be allowed to participate as long as thyroid tests (thyroid-stimulating 
hormone/triiodothyronine/thyroxine) show that the patient is euthyroid 
17. History of any condition causing malabsorption such as chronic pancreatitis, extensive 
bowel/small intestine surgery, celiac disease, or bile flow obstruction 
18. History of any condition associated with acute or chronic diarrhea such as inflammatory bowel 
disease (IBD), functional diarrhea, irritable bowel syndrome (IBS) with predominant diarrhea, IBS 
with mixed bowel habits, or unclassified IBS 
19. Uncontrolled hypertension (either treated or untreated) defined as systolic blood pressure 
>160 mmHg or a diastolic blood pressure >100 mmHg at Screening. A retest of blood pressure, 
(after establishing good blood pressure control within a reasonable period of time and up to the 
Baseline visit) is permissible at the discretion of the Investigator 
20. History of New York Heart Association Class III or IV heart failure, or known left ventricular 
ejection fraction <30% 
21. History of myocardial infarction, unstable angina, percutaneous coronary intervention, coronary 
artery bypass graft, or stroke or major surgery within 6 months prior to Screening  
22. Active substance abuse, within 1 year prior to Screening  
23. Participation in an investigational new drug trial in the 30 days prior to Screening or within 
5 half-lives of an investigational agent, whichever is longer 
24. Malignancy within 5 years, except for basal- or squamous-cell carcinoma of the skin or carcinoma 
in situ of the cervix that has been successfully treated. Patients with a history of other 
malignancies that have been treated with curative intent and which have no recurrence within 
5 years may also be eligible if approved by the Sponsor’s Medical Monitor. Patients under 
evaluation for malignancy are not eligible 
25. Patients with known intolerance to MRI or with conditions contraindicated for MRI procedures 
26. Any other condition which, in the opinion of the Investigator, would impede compliance, hinder 
completion of the study, compromise the well-being of the patient, or interfere with the study 
outcomes 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
Test Product, Dose, and Mode of Administration: Elobixibat, 5 mg once a day, orally administered 
Reference Therapy, Dose and Duration of Administration: Matching placebo, orally administered 
Duration of Treatment: Up to 16 weeks 
Variables 
Efficacy:  
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in serum LDL-C at Week 16. 
 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 
• 
Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured by MRI-PDFF 
• 
Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by MRI 
• 
Change from Baseline to Week 16, and Follow-Up in the following: 
o 
Serum ALT, AST, and gamma-glutamyl transferase 
o 
HDL-C, non-HDL-C, LDL-C/HDL-C ratio and triglycerides 
o 
Serum total bile acids 
 
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be assessed: 
• 
Change from Baseline (unless otherwise specified) to Week 4, Week 8, Week 12, Week 16, and 
Follow-Up in the following: 
o 
Fasting glucose, insulin, homeostatic model assessment-insulin resistance, HbA1c, free 
fatty acids 
o 
GLP-1, fibroblast growth factor-19 (FGF-19), and C4 levels 
o 
High-sensitivity C-reactive protein (CRP)  
o 
Lanosterol and beta-sitosterol 
o 
Body weight, BMI, waist circumference, and waist-to-hip ratio 
o 
MRI-based measurement of pulse wave velocity to measure aortic stiffness 
o 
Apolipoprotein A1 and Apolipoprotein B 
Safety:   
Safety criteria are as follows: 
• 
Occurrence of treatment-emergent adverse events categorized by causality, severity, and 
seriousness assessments made by Investigator by comparing study-drug exposure to placebo 
• 
Trends in safety evaluated for the following assessments:  
o 
Physical examinations 
o 
Concomitant medications 
o 
Vital signs 
o 
12-lead ECG 
o 
Laboratory test results (including clinical chemistry, hematology/coagulation, and 
urinalysis)  


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
Statistical Methods 
Analysis Populations: 
• 
The intent-to-treat (ITT) population will include all patients who are randomized in the study and 
receive at least 1 dose of study drug. The ITT population will be used for all efficacy analyses 
based on the treatment randomized unless otherwise specified 
• 
The per protocol (PP) population will include all ITT patients who finish Visit 7/End of Treatment 
(EOT) with valid LDL-C measurements and do not have any major protocol deviations. 
Allocation of patients to the PP analysis set will be performed before unblinding of the study 
• 
The safety population will include all patients who are randomized and receive at least 1 dose of 
study drug and will be used for all safety analyses based on the treatment received 
• 
Summary statistics (number of patients, mean, standard deviation, median, minimum, and 
maximum) at all visits and change or percent change from Baseline will be provided for efficacy 
and safety continuous variables. Count and frequency will be used to tabulate categorical variables 
• 
Demographics, disposition, and study populations will be summarized descriptively 
 
Efficacy: 
• 
The primary efficacy endpoint is the change from Baseline in serum LDL-C at Week 16. Baseline 
is defined as the last non-missing LDL-C value prior to the first dose of study drug  
• 
To address the potential missing data from patients who are lost to follow-up after treatment 
discontinuation, multiple imputation method will be used. Data from patients who discontinue the 
study drug but stay in the study with scheduled assessments collected will be used to impute 
missing values for patients lost to follow-up. This imputation will be done within each treatment 
group. Interim missing data will be handled as missing at random (predictable from observed data 
from subjects in the same treatment group) 
• 
After the imputation is performed, an analysis of covariance (ANCOVA) will be used to analyze 
the primary efficacy endpoint. The model will include treatment arm and Baseline LDL-C scores 
• 
Least square (LS) mean (SE), LS mean difference (SE), 95% confidence intervals, and P-values 
between elobixibat 5 mg and placebo will be provided. The model assumptions will be checked 
before the analysis. If there are concerns on model assumptions, i.e., normality and homogeneity 
of variances, a non-parametric ANCOVA based on the rank scores can be used as a sensitivity 
analysis 
• 
Exploratory comparisons between elobixibat 5 mg and placebo will be performed for the 
following secondary efficacy endpoints:  
o 
Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured by 
MRI-PDFF 
o 
Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by MRI 
• 
The analysis methods for the other secondary endpoints and exploratory endpoints will be detailed 
in the Statistical Analysis Plan for the study. 
 
Safety: 
• 
The safety endpoints for this study include clinical laboratory assessments, vital signs, AEs, 
ECGs, physical examinations, and concomitant medications 
• 
AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedRA). TEAEs will be defined as AEs that are new or worsening after the first dose of study 
drug. A general summary of patients with TEAEs and serious adverse events (SAEs) will be 


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Name of Sponsor/Company: 
Elobix AB 
Name of Product: 
Elobixibat 
Name of Active Ingredient: 
Elobixibat 
tabulated with numbers and percentages of patients and repeated for severity and relationship to 
study drug per treatment group. The number of AEs leading to withdrawal and SAEs leading to 
death will also be summarized. The incidence of TEAEs will be summarized by body system and 
treatment group 
• 
The safety laboratory data will be summarized by visit and by treatment group, along with changes 
from Baseline. Values outside of the reference range will be flagged and laboratory abnormalities 
of special interest will be summarized 
 
Sample Size Determination: 
Due to the exploratory nature of this study, no formal power calculations were used to determine the 
sample size. The number of subjects (46 patients in total, 23 patients per treatment group) was chosen 
based on clinical experience with other similar proof-of-concept studies. 
Date of the Protocol: 25 February 2019 
 


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3. 
TABLE OF CONTENTS 
Sponsor Signature Page ...................................................................................................... 2 
Investigator Signature Page ................................................................................................ 3 
1. 
Administrative Information ....................................................................................... 4 
2. 
Study Synopsis ........................................................................................................... 5 
3. 
Table of Contents ..................................................................................................... 12 
3.1 
List of Tables .................................................................................................... 14 
4. 
List of Abbreviations, Acronyms, and Definitions of Terms .................................. 15 
5. 
Introduction .............................................................................................................. 18 
5.1 
Investigational Medicinal Product .................................................................... 18 
5.2 
Background ....................................................................................................... 18 
5.2.1 
Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic 
Steatohepatitis (NASH) .............................................................................. 18 
5.2.2 
Summary of Nonclinical Studies in NASH ................................................ 19 
5.3 
Rationale ........................................................................................................... 20 
5.4 
Risk/Benefit ...................................................................................................... 20 
6. 
Study Objectives ...................................................................................................... 21 
6.1 
Primary Objective ............................................................................................. 21 
6.2 
Secondary Objectives ....................................................................................... 21 
7. 
Investigational Plan .................................................................................................. 22 
7.1 
Overall Study Design and Plan ......................................................................... 22 
7.1.1 
Description ................................................................................................. 22 
7.1.2 
Schedule of Assessments ............................................................................ 23 
7.1.3 
Study Procedures and Assessments ............................................................ 27 
7.2 
Study Population ............................................................................................... 31 
7.2.1 
Inclusion Criteria ........................................................................................ 31 
7.2.2 
Exclusion Criteria ....................................................................................... 33 
7.2.3 
Withdrawal of Patients ............................................................................... 37 
7.2.4 
Study Termination by Sponsor ................................................................... 37 
8. 
Treatment of Patients ............................................................................................... 39 


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8.1 
Identity of Study Drug ...................................................................................... 39 
8.2 
Administration of Study Drug .......................................................................... 39 
8.3 
Study Treatment Packaging and Labeling ........................................................ 39 
8.3.1 
Packaging and Labeling ............................................................................. 39 
8.3.2 
Storage ........................................................................................................ 39 
8.3.3 
Blinding and Randomization of Study Drug .............................................. 40 
8.4 
Procedure for Breaking the Randomization Code ............................................ 40 
8.5 
Patient Compliance ........................................................................................... 41 
8.6 
Study Drug Accountability ............................................................................... 41 
8.7 
Concomitant Therapy and Prohibited Medications .......................................... 42 
9. 
Assessment of Efficacy ............................................................................................ 43 
9.1 
Efficacy Endpoints ............................................................................................ 43 
9.1.1 
Primary Efficacy Endpoint ......................................................................... 43 
9.1.2 
Secondary Efficacy Endpoints ................................................................... 43 
9.1.3 
Exploratory Efficacy Endpoints ................................................................. 43 
9.2 
Efficacy Assessments ....................................................................................... 44 
9.2.1 
Lipid Profile ............................................................................................... 44 
9.2.2 
Magnetic Resonance Imaging .................................................................... 44 
9.2.3 
Serum Bile Acids ........................................................................................ 44 
9.2.4 
Biomarkers and Blood Samples for Future Testing ................................... 44 
10. Assessment of Safety ............................................................................................... 45 
10.1 
Adverse Events ................................................................................................. 45 
10.1.1 
Definitions and Investigator Assessments .................................................. 45 
10.1.2 
Recording of Adverse Events ..................................................................... 48 
10.1.3 
Recording and Reporting of Serious Adverse Events ................................ 49 
10.1.4 
Reporting of Suspected Unexpected Serious Adverse Reactions .............. 50 
10.2 
Laboratory Values, Vital Signs, Physical Examinations, and Other 
Safety Assessments ........................................................................................... 51 
10.2.1 
Laboratory Assessments ............................................................................. 51 
10.2.2 
Individual Patient Safety Monitoring ......................................................... 54 
10.2.3 
Demographics/Medical and Surgical History ............................................ 55 


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10.2.4 
Physical Examination ................................................................................. 55 
10.2.5 
Vital Signs .................................................................................................. 55 
10.2.6 
12-Lead ECG .............................................................................................. 55 
10.2.7 
Overdose ..................................................................................................... 55 
11. Statistical Evaluation ............................................................................................... 57 
11.1 
Sample Size and Power ..................................................................................... 57 
11.2 
Statistical Methods ............................................................................................ 57 
11.2.1 
Statistical Analysis Populations ................................................................. 57 
11.2.2 
Methods of Statistical Analyses ................................................................. 58 
12. Direct Access to Source Data/Notes ........................................................................ 62 
13. Quality Control and Quality Assurance ................................................................... 63 
13.1 
Conduct of the Study ........................................................................................ 63 
13.2 
Study Monitoring .............................................................................................. 63 
14. Ethics........................................................................................................................ 65 
14.1 
Institutional Review Board ............................................................................... 65 
14.2 
Written Informed Consents ............................................................................... 65 
15. Data Handling and Recordkeeping .......................................................................... 67 
15.1 
Electronic Case Report Forms/Source Data Handling ..................................... 67 
15.2 
Retention of Essential Documents .................................................................... 67 
16. Financing and Insurance .......................................................................................... 68 
17. Publication Policy .................................................................................................... 69 
18. References List......................................................................................................... 70 
 
3.1 
List of Tables 
Table 1 
Schedule of Assessments .................................................................................24 
Table 2: 
Laboratory Parameters .....................................................................................52 
 


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4. 
LIST OF ABBREVIATIONS, ACRONYMS, AND DEFINITIONS OF 
TERMS 
Abbreviation 
Definition 
A3309 
elobixibat 
AE(s) 
adverse event(s) 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
Anti-HCV 
hepatitis C antibody 
APRI 
AST to platelet ratio index 
ASBT 
apical sodium-dependent bile acid transporter (also known as IBAT) 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
C4 
7α-hydroxy-4-cholesten-3-one  
CRA 
clinical research associate 
CRF 
case report form 
CRP 
C-reactive protein 
ECG(s) 
electrocardiogram(s) 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOT 
End of Treatment 
FDA 
US Food and Drug Administration 
FGF-19 
fibroblast growth factor-19  
Fib-4 
fibrosis-4 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP-1 
glucagon-like peptide-1 
H&E 
hematoxylin and eosin 
HbA1c 
hemoglobin A1c 
HCV 
hepatitis C virus 


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Abbreviation 
Definition 
HDL-C 
high-density lipoprotein-cholesterol 
IBAT 
ileal bile acid transporter (also known as ASBT) 
IBD 
inflammatory bowel disease 
IBS 
irritable bowel syndrome 
ICF(s) 
informed consent form(s) 
ICH 
International Council on Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent to treat 
IWRS 
Interactive Web Response System 
LDL 
low-density lipoprotein 
LDL-C 
low density lipoprotein-cholesterol 
LLN 
lower limit of normal 
LPLV 
last patient last visit 
LS 
least square 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging—proton density fat fraction 
N/A 
not applicable 
NAFLD 
nonalcoholic fatty liver disease  
NAS 
NAFLD activity score 
NASH 
nonalcoholic steatohepatitis 
ob/ob (mice) 
leptin-deficient mice 
PCS 
potentially clinically significant 
PDFF 
proton density fat fraction 
PP 
per protocol 
PVM 
pharmacovigilance manager 
RNA 
ribonucleic acid 
s-BA 
serum bile acid(s) 


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Abbreviation 
Definition 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SE 
standard error 
SOC 
system organ class 
SOP(s) 
standard operating procedure(s) 
Sponsor 
Elobix AB 
SUSAR 
suspected unexpected serious adverse reaction(s) 
TEAE(s) 
treatment-emergent adverse event(s) 
ULN 
upper limit of normal 
US 
United States 
VLDL 
very low-density lipoprotein 
WHO 
World Health Organization 
WOCBP 
Women (woman) of childbearing potential 
α-SMA 
alpha-smooth muscle actin 
 


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5. 
INTRODUCTION 
5.1 
Investigational Medicinal Product 
Elobixibat is a potent inhibitor of the ileal bile acid transporter (IBAT; also known as the 
apical sodium bile acid transporter [ASBT]). The IBAT, expressed mainly in the distal 
ileum, is a key element in the enterohepatic circulation of bile acids because it facilitates 
the very efficient process of bile acid reabsorption. Elobixibat is orally administered and 
acts locally in the gut where it binds reversibly to the IBAT to decrease the reuptake of 
bile acids to the liver. Elobixibat has minimal systemic exposure at expected therapeutic 
dose ranges. 
5.2 
Background 
5.2.1 
Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic 
Steatohepatitis (NASH) 
Recent data suggest that bile acids may play an important role in NASH pathogenesis 
(Ferslew 2015; Aranha 2008; Puri 2018). Bile acids are signaling molecules involved in 
lipid, glucose, and energy homeostasis, which are metabolic pathways linked to 
NAFLD/NASH and comorbidities such as metabolic syndrome, obesity, and diabetes. 
Bile acids as well as free cholesterol, which is the precursor from which bile acids are 
synthesized, can act as lipotoxic agents that drive inflammation and fibrosis. Studies have 
shown that both serum and liver bile acids are increased in patients with NASH, and 
recent data have suggested that the presence and severity of NASH is associated with 
specific changes in circulating bile acids (Puri 2018). Thus, targeting of bile acid 
pathways has therapeutic potential in patients with NASH. 
The enterohepatic circulation of bile acids plays a crucial role in whole body sterol 
balance. Bile acids are secreted to the intestine via the bile duct and then reabsorbed, 
mainly by a specific bile acid transporter located in the ileum (IBAT or ASBT) and 
delivered back to the liver, completing the enterohepatic circulation (Prawitt 2011).  
Bile acid reabsorption from the intestine is a very efficient process where 95% of the 
secreted bile acids are reabsorbed and IBAT appears to be the major regulator of the bile 
acid pool in animals and humans. IBAT inhibitors reduce the reabsorption of bile acids 
from the ileum and prevent their return to the liver. The liver compensates for the 


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decrease in bile acid levels by upregulating cholesterol 7α-hydroxylase, the rate-limiting 
enzyme for bile acid synthesis. This results in lower hepatic cholesterol levels and an 
increased number of low-density lipoprotein (LDL) receptors in the liver leading to 
reduced plasma low-density lipoprotein cholesterol (LDL-C; [Bertolotti 2003; 
Naoumova 1999]). Bile acids also positively regulate glucagon-like peptide-1 (GLP-1) 
levels via activation of TGR5 (Prawitt 2011; Schaap 2014). GLP-1 is an insulinotropic 
hormone but has many other roles, e.g., slowing gastric emptying and increasing satiety 
signals leading to weight loss (Andersen 2018). 
Inhibition of bile acid absorption locally in the intestine has the potential to positively 
influence NASH, cardiovascular disease, and metabolic disease by targeting multiple 
mechanisms, as follows: lowering of LDL-C by increased bile acid synthesis; improving 
metabolic status and weight loss by increasing GLP-1 levels; and reducing hepatic cell 
damage by lowering toxic bile acid and free cholesterol in the liver. 
5.2.2 
Summary of Nonclinical Studies in NASH 
One nonclinical study with elobixibat in a NASH model has been completed. The study 
evaluated the effects of elobixibat in leptin-deficient ob/ob mice treated with a diet high 
in trans fats, fructose, and cholesterol. Although elobixibat did not reduce liver NAFLD 
activity score or fibrosis stage, there were indicators of relevant effects, including 
reduction in liver alpha-smooth muscle actin (α-SMA), which is a marker of stellate cell 
activation and thereby an indirect marker for fibrosis formation. Administration of 10 and 
30 mg/kg/day elobixibat decreased liver steatosis as quantified by lipid fractional area in 
hematoxylin and eosin (H&E)-stained liver sections in a dose-dependent fashion. This 
was further evident in animals treated with 30 mg/kg elobixibat that showed reduced liver 
triglycerides and liver total cholesterol as determined by biochemical analyses. Analysis 
of liver gene expression by next generation RNA sequencing revealed pronounced and 
dose-dependent effects of elobixibat. It affected the expression of genes in key pathways 
associated with NASH pathology. 
Additional nonclinical studies with elobixibat are summarized in the Investigator’s 
Brochure (M1.14.4.1). 


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5.3 
Rationale 
Bile acids act as signaling molecules in lipid, glucose, and energy homeostasis. Studies 
have shown that both serum and liver bile acids are increased in patients with NASH 
(Ferslew 2015), and recent data have suggested that the presence and severity of NASH 
is associated with specific changes in circulating bile acids (Puri 2018; Sanyal 2018). 
Inhibition of bile acid absorption from the intestine has the potential to improve the 
pathophysiology in NASH, including the related cardiovascular and metabolic disease 
due to impingement on multiple key metabolic feedback mechanisms, as follows: 
lowering of LDL-C by increased bile acid synthesis, and improving insulin sensitivity by 
increasing GLP-1 levels. A reduction of cardiovascular risk is particularly desirable for 
any pharmacological NASH treatment, because cardiovascular complications contribute 
to a significant amount of mortality in patients with NAFLD/NASH, with their annual 
risk being 2-fold increased (Mahfood Haddad 2017; Younossi 2018). IBAT inhibition 
reduces the levels of bile acid that circulate to the liver, and triggers increased hepatic 
bile acid synthesis from cholesterol. Thus, besides having a positive impact on 
cardiovascular health, IBAT inhibition might also reduce hepatic cell damage by 
lowering free cholesterol and changing the composition of toxic bile acids in the liver. 
5.4 
Risk/Benefit 
Elobixibat is orally administered and acts locally in the gut where it binds reversibly to 
the IBAT to decrease the reuptake of bile acids into the liver, thereby increasing the 
concentration of bile acids in the colon. Due to its mechanism of action, most adverse 
events (AEs) are gastrointestinal (GI) tract disorders, such as abdominal pain, diarrhea, 
abdominal distention, flatulence, and nausea; the incidence of these has increased with 
increasing dose levels. Diarrhea has been the most prominent dose-limiting side effect. 
No clinically significant findings in laboratory measures or electrocardiograms (ECGs) 
have been reported.  
There is no established benefit for subjects participating in this Phase 2 study. Based 
upon these data, the risk/benefit for subjects participating in this trial is acceptable. 
This study will be conducted in compliance with the protocol and with the International 
Council on Harmonisation (ICH) guidelines on GCP.  


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6. 
STUDY OBJECTIVES 
6.1 
Primary Objective 
The primary objective is to evaluate the efficacy of repeated once-daily doses of 5 mg 
elobixibat on serum levels of LDL-C in patients with NAFLD or NASH. 
6.2 
Secondary Objectives 
• To assess the safety and tolerability of elobixibat in patients with NAFLD or 
NASH 
• To evaluate the effect of elobixibat on liver steatosis as measured by magnetic 
resonance imaging (MRI) for (i) liver fat fraction (using proton density fat 
fraction [PDFF]) and (ii) total liver fat (using whole liver fat volume) 
• To evaluate the effect of elobixibat on liver function using alanine 
aminotransferase (ALT) 
• To evaluate the effect of elobixibat on lipids and serum bile acids (s-BA) in 
patients with NAFLD or NASH 


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7. 
INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan 
7.1.1 
Description 
This is a double-blind, randomized, placebo-controlled, Phase 2 study to explore the 
efficacy and safety of elobixibat (oral dose of 5 mg) once daily for 16 weeks in patients 
with NAFLD or NASH. The study includes a 6-week Screening Period, followed by a 
16-week Treatment Period, and a Follow-Up Visit 2 weeks after the last dose of study 
drug. Continued collection of efficacy data for patients who discontinue treatment will be 
made for as long as possible as per the schedule of assessments (Table 1).  
After completing the Screening Period, eligible patients will be randomized on Day 1 
(Visit 2) in a 1:1 fashion to either 5 mg/day elobixibat or matching placebo. Visit 
windows applicable to each visit are presented in the schedule of assessments (Table 1). 
There will be up to 7 clinic visits during the study, as follows: 
• Visit 1: Screening period (Week -6 through Day -1) 
• Visit 2: Day 1/Randomization visit 
• Visit 3: Week 4 
• Visit 4: Week 8 
• Visit 5: Week 12 
• Visit 6: Week 16/End of Treatment (EOT). Any patient that discontinues 
treatment prematurely should complete this visit at the time of discontinuation 
• Visit 7: Follow-Up period. The Follow-Up visit will occur 2 weeks after the last 
dose of study drug whether the patient completes the study or discontinues 
prematurely 
Additional unscheduled visits may be required for patients who need direct site assistance 
(due to AE monitoring, in order to fulfill screening requirements, and/or for safety 
maintenance).  


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7.1.1.1 
Screening Period 
Informed consent must be obtained at Visit 1 prior to performing any study procedures. 
After signing the informed consent form (ICF), patients will be considered enrolled and 
evaluated for study eligibility. 
7.1.1.2 
Treatment Period 
Eligibility for randomization will be determined at Visit 2 using the assessment of 
eligibility in accordance to the inclusion/exclusion criteria.  
The patient will return to the clinic at Visits 3-6 for assessments. Patients will be 
requested to return study drug bottles as part of drug accountability during the Treatment 
period. 
7.1.1.3 
Follow-Up Period 
The patient will return to the clinic for Visit 7 approximately 2 weeks after the last dose 
of study drug. This visit will be completed for patients that may discontinue the study 
prematurely.  
7.1.1.4 
End of Study 
The end of the study is defined as last patient last visit (LPLV) and all sites are closed. 
7.1.2 
Schedule of Assessments 
The schedule of assessments is presented in Table 1. 


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Table 1 
Schedule of Assessments 
VISIT 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP 
PERIOD 
VISIT 1 
VISIT 2/ 
RANDOMIZA- 
TION 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6/ 
END OF 
TREATMENT 
VISIT 7 
STUDY WEEK 
WEEK -6 TO 
DAY -1 
DAY 1 
WEEK 4 
WEEK 8 
WEEK 12 
WEEK 16 
WEEK 18 
VISIT WINDOW 
 
 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Serologya 
X 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
X 
 
Physical examinationb 
X 
X 
 
 
 
X 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testd 
X 
X 
X 
X 
X 
X 
X 
MRIe 
X 
 
 
 
 
X 
 
Liver biopsyf 
X 
 
 
 
 
 
 
Randomizationg 
 
X 
 
 
 
 
 
Clinical safety laboratory testsh 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
(Continued on next page) 


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VISIT 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP 
PERIOD 
VISIT 1 
VISIT 2/ 
RANDOMIZA- 
TION 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6/ 
END OF 
TREATMENT 
VISIT 7 
STUDY WEEK 
WEEK -6 TO 
DAY -1 
DAY 1 
WEEK 4 
WEEK 8 
WEEK 12 
WEEK 16 
WEEK 18 
VISIT WINDOW 
 
 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
±3 DAYS 
Endocrinology8 
X 
X 
X 
 
 
X 
 
GLP-1, FGF-19, C4h 
X 
X 
X 
X 
X 
X 
X 
Total serum bile acidsh 
X 
X 
X 
X 
X 
X 
X 
Lipid profileh 
X 
X 
X 
X 
X 
X 
X 
Fibrosis and inflammation markersh 
 
X 
X 
 
 
X 
 
High-sensitivity CRP 
X 
 
X 
 
 
X 
 
Stored blood sample for future testingi 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
X 
X 
X 
 
 
Review alcohol consumptionj 
X 
 
 
 
 
 
 
Review concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Review adverse events 
X 
X 
X 
X 
X 
X 
X 
a Includes hepatitis B virus surface antigen and hepatitis C virus antibody and RNA 
b Includes height (at Screening only), weight, waist circumference, and waist-to-hip ratio. Body mass index will be calculated based on height and weight. A full physical 
examination will be performed at Screening and at Visits 6 and 7.  
c Vital signs include blood pressure, heart rate, respiratory rate, and oral body temperature. 
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d For women of childbearing potential, a serum pregnancy test will be performed at Screening, and a urine pregnancy test will be performed at each visit at which study drug is 
dispensed. 
e Patients will have MRI to measure liver fat (PDFF), total liver volume, and pulse wave velocity. Patients who discontinue before Visit 6 (Week 16) should have an MRI 
performed at End of Treatment if they completed at least 4 weeks of treatment. 
f Liver biopsy results for confirmed NASH within 6 months of Screening to confirm patient eligibility will be collected in the eCRF, if available. 
g Randomization will occur at Visit 2 to assign patients to either 5 mg/day elobixibat or placebo in 1:1 ratio. 
h See Table 2, Laboratory Parameters. Clinical safety laboratory tests include clinical chemistry, hematology/coagulation, and urinalysis 
i See Section 9.2.4. 
j History of alcohol consumption will be obtained at Screening. 
Abbreviations: C4: 7α-hydroxy-4-cholesten-3-one; CRF: case report form; CRP: C-reactive protein; ECG: electrocardiogram; EOT: End of Treatment; FGF-19: fibroblast growth 
factor-19; GLP-1: glucagon-like peptide-1; INR: international normalized ratio; MRI: magnetic resonance imaging; NASH: nonalcoholic steatohepatitis; PDFF: proton density fat 
fraction 
 


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7.1.3 
Study Procedures and Assessments 
7.1.3.1 
Screening Period (-6 Weeks to Day -1) 
7.1.3.1.1 
Visit 1 
Patients will undergo a Screening visit up to 6 weeks prior to the planned first day of 
study treatment. Screening procedures and assessments are as follows: 
• Obtain written informed consent 
• Assess inclusion/exclusion criteria (Sections 7.2.1 and 7.2.2, respectively) 
• Medical and surgical history (date of diagnosis of NAFLD/NASH; any surgery 
performed; any other diagnosis) 
• Record demographics (age, full date of birth, gender, race, and ethnicity) 
• Serology 
• 12-lead ECG (Section 10.2.6) 
• Physical examination (Section 10.2.4) 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• MRI (Section 9.2.2) 
• Liver biopsy (applicable for patients’ biopsy-confirmed NASH within 6 months 
of Screening) 
• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total s-BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 


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• Fibrosis and inflammation markers (Section 10.2.1) 
• High-sensitivity CRP 
• Stored sample for future testing (Section 10.2.1) 
• Review of alcohol consumption 
• Document concomitant medications 
• AE monitoring  
7.1.3.2 
Treatment Period (Day 1 to Week 16) 
7.1.3.2.1 
Study Day 1/Visit 2 (Randomization) 
At the randomization visit, the following assessments will be conducted: 
• Review inclusion/exclusion criteria (Sections 7.2.1 and 7.2.2, respectively) 
• Physical examination (Section 10.2.4) 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total s-BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 
• Fibrosis and inflammation markers (Section 10.2.1) 
• Stored sample for future testing (Section 10.2.1) 
• Study drug is dispensed and patients are instructed to administer daily from Day 1 
• Review of concomitant medications 
• AE monitoring 


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7.1.3.2.2 
Study Weeks 4-12/Visits 3-5  
The following procedures and assessments will be conducted: 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Visit 3 only; Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total s-BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 
• Fibrosis and inflammation markers (Visit 3 only; Section 10.2.1) 
• High-sensitivity CRP (Visit 3 only; Section 10.2.1) 
• Stored sample for future testing (Section 10.2.1) 
• Study drug is dispensed; review of compliance  
• Review of concomitant medications 
• AE monitoring 
7.1.3.2.3 
Study Week 16/Visit 6/EOT 
The last dose of study drug will be taken in the morning the day before Visit 6 and the 
following procedures and assessments will be conducted (also conducted at the time a 
patient prematurely withdraws):  
• 12-lead ECG (Section 10.2.6) 
• Physical examination (Section 10.2.4) 
• Vital signs (Section 10.2.5) 
• Pregnancy test 
• MRI (Section 9.2.2) 


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• Clinical safety laboratory tests (Section 10.2.1) 
• Endocrinology (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total s-BA (Section 9.2.3) 
• Lipid profile (Section 9.2.1) 
• Fibrosis and inflammation markers (Section 10.2.1) 
• High-sensitivity CRP 
• Stored sample for future testing (Section 10.2.1) 
• Review of concomitant medications 
• AE monitoring 
7.1.3.3 
Follow-Up Period 
7.1.3.3.1 
Study Week 18/ Visit 7  
All patients will complete a Follow-Up visit approximately 2 weeks after the last dose of 
study drug for the following assessments: 
• Vital signs (Section 10.2.5) 
• Pregnancy test  
• Clinical safety laboratory tests (Section 10.2.1) 
• GLP-1, FGF-19, C4 (Section 10.2.1) 
• Total s-BA (Section 9.2.3) 
• Lipid profile (Section 10.2.1) 
• Stored sample for future testing (Section 10.2.1) 
• Review of concomitant medications 
• AE monitoring 


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7.2 
Study Population 
A total of approximately 46 patients with a clinical diagnosis of NAFLD/NASH (in 
accordance with the protocol definition) will be randomized.   
7.2.1 
Inclusion Criteria 
Patients must meet all the following criteria to be included in the study: 
1. Be willing to participate in the study and provide written informed consent 
2. Be a man or woman ≥18 years of age 
3. Have a current biopsy-confirmed NASH within 6 months of screening or a 
suspected diagnosis of NAFLD/NASH based on the criteria outlined below: 
a. Biopsy-confirmed NASH is defined as histological NASH diagnosis with 
fibrosis stage F1 through F3 and a NAFLD activity score (NAS) of 
≥4 with a score of ≥1 in each of the NAS components below as assessed 
by the central pathologist using the NASH Clinical Research Network 
criteria (Kleiner 2005) 
i. Steatosis (scored 0 to 3) 
ii. Ballooning degeneration (scored 0 to 2) 
iii. Lobular inflammation (scored 0 to 3) 
OR 
b. The suspected diagnosis of NAFLD/NASH is based on each of the 
following criteria being met: 
i. Serum aspartate aminotransferase (AST) ≥20 U/L and ALT 
≥40 U/L 
ii. Diagnosis of metabolic syndrome as having any 3 of the following 
5 risk factors at Screening: 
o Fasting plasma glucose ≥100 mg/dL or undergoing drug 
treatment for elevated glucose 


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o High-density lipoprotein-cholesterol (HDL-C) <40 mg/dL 
in males or <50 mg/dL in females or undergoing drug 
treatment for reduced HDL-C 
o Triglycerides ≥150 mg/dL or undergoing drug treatment for 
elevated triglycerides 
o Waist circumference >102 cm in males or >88 cm in 
females 
o Systolic blood pressure ≥130 mm Hg or diastolic blood 
pressure ≥85 mm Hg or undergoing drug treatment for 
hypertension, or antihypertensive drug treatment in a 
patient with a history of hypertension 
4. Screening MRI-PDFF with ≥10% liver steatosis 
5. Fasting serum LDL-C >130 mg/dL at Screening, >110 mg/dL on lipid-lowering 
medications 
6. Women of childbearing potential (WOCBP) must have a negative serum 
pregnancy test (beta human chorionic gonadotropin) at Screening and must agree 
to use highly effective birth control throughout the study and up to 30 days after 
the last dose of study drug. Highly effective contraception measures include 
combined estrogen- and progestogen-containing hormonal contraception (oral, 
intravaginal, and transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, and implantable), 
intrauterine device, intrauterine hormone-releasing system, bilateral tubal 
occlusion, vasectomized partner (only in the event that the vasectomized partner 
is the sole sexual partner of the WOCBP), and sexual abstinence (defined as 
refraining from heterosexual intercourse) only in the event that this is the 
preferred lifestyle of the patient.  
Childbearing potential is defined as being fertile following menarche and until 
becoming postmenopausal unless permanently sterile (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy). 


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A postmenopausal state is defined as no menses for ≥12 consecutive months 
without an alternative medical cause. A follicle-stimulating hormone level in the 
postmenopausal range will be used to confirm a postmenopausal state in women 
≤55 years of age. 
Men with partners who are WOCBP must either be surgically sterile or agree to 
use a barrier contraceptive for the duration of the study and up to 30 days after the 
last dose of study drug. 
7. Be willing to maintain a stable diet and physical activity throughout the course of 
the study 
7.2.2 
Exclusion Criteria 
Patients who meet any of the following criteria will not be included in the study: 
1. Women who are pregnant, breastfeeding, or plan to become pregnant during the 
study 
2. Body mass index (BMI) <25 kg/m2 
3. Fibrosis-4 index (Fib-4) >2.6 
4. Any of the following laboratory abnormalities: 
a. ALT >5 × upper limit of normal (ULN) or AST >5 × ULN 
b. International normalized ratio (INR) ≥1.3, unless on anticoagulant therapy 
c. Total bilirubin >ULN, except with an established diagnosis of Gilbert’s 
syndrome 
d. Platelet count less than the lower limit of normal (LLN) 
e. Creatinine clearance as calculated by the modification of diet in renal 
disease (MDRD) estimated glomerular filtration rate (eGFR) equation 
<60 mL/min 
NOTE: Unless otherwise specified, repeat testing may be performed in 
consultation with the Medical Monitor. 


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5. Acute or chronic liver disease other than NAFLD/NASH including but not limited 
to the following: 
a. Hepatitis B (as defined by the presence of hepatitis B surface antigen at 
screening) or hepatitis C (as defined by the presence of hepatitis C virus 
[HCV] antibody [anti-HCV]). Patients with positive anti-HCV who test 
negative for HCV ribonucleic acid at screening will be allowed to 
participate in the study as long as there is evidence of viral negativity for a 
minimum of 12 months prior to screening) 
b. Evidence of ongoing autoimmune hepatitis 
c. History of primary biliary cirrhosis, primary sclerosing cholangitis, 
Wilson’s disease, homozygous alpha-1-anti-trypsin deficiency, 
hemochromatosis or iron overload, drug-induced or alcoholic liver 
disease, or known bile duct obstruction 
d. Suspected or proven hepatocellular carcinoma 
6. Known history of human immunodeficiency virus 
7. Medical history of liver cirrhosis 
8. Clinical evidence of portal hypertension to include any history of ascites, hepatic 
encephalopathy, or presence of esophageal varices 
9. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, 
systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than 
those used for hormone replacement, anabolic steroids, or valproic acid) or other 
known hepatotoxins for >2 weeks in the year prior to screening 
10. Use of the following medications: 
a. GLP-1 agonists unless on a stable dose 3 months prior to liver biopsy or 
Screening 
b. Ursodeoxycholic acid, thiazolidinediones, or obeticholic acid within 
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c. Statins and other lipid-modifying therapies must have been stable for 
≥3 months prior to Screening 
d. Oral antidiabetic drugs (other than those specifically excluded) must have 
been stable for ≥3 months prior to Screening 
e. Agents (including herbal over-the-counter weight-loss preparations) or 
medications known to significantly impact body weight within 3 months 
prior to Screening (e.g., sibutramine, phenetamine, and orlistat) 
11. History of significant alcohol consumption, defined as an average of >20 g/day in 
female patients and >30 g/day in male patients, for a period of >3 consecutive 
months within 1 year prior to Screening, hazardous alcohol use (Alcohol Use 
Disorders Identification Test score ≥8), or an inability to reliably quantify alcohol 
consumption based upon judgment of the Investigator 
12. Weight change ≥10% within the 6 months prior to Screening or ≥5% within the 
3 months prior to Screening 
13. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty and 
roux-en-Y gastric bypass) 
14. Type 1 diabetes by medical history 
15. Uncontrolled Type 2 diabetes defined as hemoglobin A1c (HbA1c) >9.5% at 
Screening (patients with HbA1c >9.5% may be rescreened) or requiring insulin 
dose adjustment >10% within 2 months prior to Screening 
16. Clinical hyperthyroidism or hypothyroidism or screening hormone results 
pointing to thyroid dysfunction. Patients receiving dose-stable thyroid 
replacement therapy for ≥3 months prior to Screening will be allowed to 
participate as long as thyroid tests (thyroid-stimulating 
hormone/triiodothyronine/thyroxine) show that the patient is euthyroid 
17. History of any condition causing malabsorption such as chronic pancreatitis, 
extensive bowel/small intestine surgery, celiac disease, or bile flow obstruction 
18. History of any condition associated with acute or chronic diarrhea such as 
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(IBS) with predominant diarrhea, IBS with mixed bowel habits, or unclassified 
IBS 
19. Uncontrolled hypertension (either treated or untreated) defined as systolic blood 
pressure >160 mmHg or a diastolic blood pressure >100 mmHg at Screening. A 
retest of blood pressure, (after establishing good blood pressure control within a 
reasonable period of time and up to the Baseline visit) is permissible at the 
discretion of the Investigator 
20. History of New York Heart Association Class III or IV heart failure, or known 
left ventricular ejection fraction <30% 
21. History of myocardial infarction, unstable angina, percutaneous coronary 
intervention, coronary artery bypass graft, or stroke or major surgery within 
6 months prior to Screening  
22. Active substance abuse within 1 year prior to Screening 
23. Participation in an investigational new drug trial in the 30 days prior to Screening 
or within 5 half-lives of an investigational agent, whichever is longer 
24. Malignancy within 5 years, except for basal- or squamous-cell carcinoma of the 
skin or carcinoma in situ of the cervix that has been successfully treated. Patients 
with a history of other malignancies that have been treated with curative intent 
and which have no recurrence within 5 years may also be eligible if approved by 
the Sponsor’s Medical Monitor. Patients under evaluation for malignancy are not 
eligible 
25. Patients with known intolerance to MRI or with conditions contraindicated for 
MRI procedures 
26. Any other condition which, in the opinion of the Investigator, would impede 
compliance, hinder completion of the study, compromise the well-being of the 
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7.2.3 
Withdrawal of Patients 
Patients will be informed that they have the right to withdraw from the study at any time, 
without prejudice to their medical care, and that they are not obliged to state their 
reasons. 
Any withdrawal, and reasons for withdrawal, must be fully documented in the electronic 
case report form (eCRF) and source documents and the patient followed by the 
investigator/investigative staff. Even after the study is completed at the Follow-Up visit, 
the investigator/investigative staff will, regardless of reason for withdrawal, record any 
patient data they receive concerning serious adverse events (SAEs), and all drug-related 
non-serious AEs, and report these in the eCRF. Withdrawn patients will not be replaced. 
Patients will be withdrawn in the following circumstances: 
• A patient’s desire for withdrawal for any reason 
• Lost to follow-up (every effort must be made to contact the patient; a certified 
letter must be sent) 
• An AE that, in the opinion of the Investigator, necessitates withdrawal 
• Death 
• A patient’s substantial noncompliance (study drug compliance) or protocol 
violation 
• An Investigator’s opinion that continuing the patient in the study is not 
appropriate. The Investigator may withdraw a patient at any time if it is 
considered to be in the patient’s best interest 
A patient who withdraws from treatment prematurely will have EOT (Visit 6) 
assessments at the time of withdrawal and a Follow-Up assessment (Visit 7) 
approximately 2 weeks following the last dose of study drug, and the patient will be 
recorded as withdrawn. 
7.2.4 
Study Termination by Sponsor 
This study may be terminated at any time by the Sponsor if serious side effects should 
occur, if the Investigator does not adhere to the protocol, or if, in the Sponsor's judgment, 


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there are no further benefits to be achieved from the study. In this event, the Sponsor or 
its designee will inform the study investigators, institutions, and all regulatory authorities. 
The Sponsor may temporarily or permanently discontinue the study at an investigative 
site at any time for safety, ethical, compliance, or other reasons. If this is necessary, the 
Sponsor will endeavor to provide advance notification to the site. If a site or the study is 
suspended or discontinued, the Investigator/investigative staff will be responsible for 
promptly informing the IRB. If required by local regulations, the Sponsor or its designee 
will be responsible for informing the IRB and the regulatory authority of study or site 
discontinuation. In such an event, all study data and unused study drug must be returned 
to the Sponsor or its designee. 


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8. 
TREATMENT OF PATIENTS 
8.1 
Identity of Study Drug 
Elobixibat and placebo will be supplied as tablets for oral administration during the 
Treatment phase of the study. White tablets containing elobixibat or placebo will be 
provided.   
The elobixibat and placebo tablets will be identical in appearance. Tablet filling weight 
will also be identical for elobixibat and placebo. Bottles containing 34 tablets will be 
given to the patient at each visit. Refer to the study reference manual. 
8.2 
Administration of Study Drug 
Patients will be dosed with elobixibat at a dose of 5 mg or placebo once daily for 
16 weeks. Study drug will be dispensed to the patient at Visits 2-5 together with 
instructions on how to store and take the drug. Study drug compliance will be evaluated 
at each study visit.   
Elobixibat should be taken in the morning, prior to the first meal. On clinic visit days 
when laboratory assessments are conducted, study drug should be taken after the visit and 
after laboratory samples are taken.   
8.3 
Study Treatment Packaging and Labeling 
8.3.1 
Packaging and Labeling 
The tablets will be packed in high-density polyethylene bottles, with child-proof 
polypropylene caps. Packaging and labeling will be prepared to comply with applicable 
regulatory requirements. 
8.3.2 
Storage 
Treatment bottles containing elobixibat tablets should be stored and dispensed in 
accordance with regulations in their original containers. The storage facility at the 
investigative site should be locked and the storage temperature should be between 15°C 
and 25°C. 
Caregivers should be informed of appropriate storage conditions (i.e., room temperature, 
between 15°C and 25°C). 


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Any deviations from the recommended storage conditions should be immediately 
reported to the Sponsor and the study drug should not be used until authorization has 
been given by the Sponsor. 
8.3.3 
Blinding and Randomization of Study Drug 
A double-blind design is employed so that both the investigators and the patients will be 
unaware of the treatment assignment during the study.  
After written informed consent is obtained from an eligible patient, a 6-digit patient 
number will be assigned. The first 3 digits will be the site number followed by a 3-digit 
patient sequence number. This number will be created and allocated by the Interactive 
Web Response System (IWRS), when the patient first enters the system at Screening. The 
randomization codes will be computer-generated by a statistician independent from the 
project team. The randomization will be done in blocks to ensure approximate balance 
between dose schemes (1:1). Randomization codes will be assigned sequentially as 
patients become eligible for randomization. 
Patients who are eligible for randomization will be assigned a unique 4-digit 
randomization number by IWRS. This randomization number identifies which treatment 
will be allocated to the patient. Patients who withdraw from the study after randomization 
visit are not to be replaced and their randomization number will not be reused.   
To ensure blinding, the study drug and the matching placebo have the same shape and 
size. Labels on the treatment bottles will not identify the treatment to which a patient has 
been randomized. Traceability of the treatment is ensured by the bottle number. 
The 5-digit bottle number will identify the study-drug bottle and will be detailed on the 
study-drug label. Dispensing of the study drug will be coordinated by IWRS.  
The system will assign a study-drug number corresponding to the randomization arm. 
The randomization number will be used in the background only to ensure that there is no 
unblinding and will not be displayed to end-users in the IWRS.  
8.4 
Procedure for Breaking the Randomization Code 
Should a situation arise where unblinding is urgently required, i.e., only where 
knowledge of the study drug is required to adequately manage a life-threatening situation, 


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the Investigator at that study site may perform immediate unblinding through IWRS. The 
responsibility to break the treatment code in emergency situations resides solely with the 
Investigator. The Investigator should make every effort to discuss the rationale (status 
and outcome) for emergency unblinding with the Sponsor’s Medical Monitor as soon as 
possible to review the individual patient details. 
The study-site Investigator and appropriate project team members will be authorized to 
access the emergency unblinding functionality within the IWRS. Once the randomization 
code is broken for a patient, he/she must be withdrawn from the study and all assessments 
and procedures for Visit 6/EOT should be performed. Once a randomization code has 
been broken, the Investigator must inform the project team and Sponsor’s Medical 
Monitor in writing within 24 hours. In case of technical issues accessing the system 
online, please see the IWRS site user manual for contact telephone numbers for the help 
desk 24/7 system support. 
8.5 
Patient Compliance 
Patients will return all unused study drug at Visits 3 through 6. The study-site staff will 
count all returned drug, assess compliance, and record details in the eCRF. 
Any noncompliance will be documented and explained in the source documents. 
Treatment compliance = 100 × ([number of study drug dispensed—number of study drug 
returned]/number of study drug that should be taken) 
Treatment compliance between 80% and 120% is acceptable. 
8.6 
Study Drug Accountability 
Records shall be maintained of the delivery of study treatment(s) to the study site(s), of 
the inventory at the study site(s), of each use of the study treatment(s) for each patient 
and the return or destruction of used and unused study treatment(s). Local destruction of 
used/unused study treatment(s) will follow institution standard operating procedures 
(SOPs) and will require Sponsor pre-approval. 
These records shall include dates, quantities, batch numbers, expiry dates, and the unique 
code numbers assigned to the study drug and to the study patients. 


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The Investigator will be responsible for ensuring that the records adequately document 
that the patients were provided the quantities specified in the protocol and that all study 
drug received from the Sponsor or its designee is reconciled.  
8.7 
Concomitant Therapy and Prohibited Medications 
The Investigator will note all ongoing medication and any medication recently stopped 
(within 3 months prior to Visit 2) in the eCRF. At Visits 2 through 6, all changes in 
medication (stopping or starting new medication or changes in dose) will be recorded in 
the eCRF.   
All medications taken by a patient within 3 months prior to the first intake of study drug 
are regarded as prior medication. 
All medications taken by a patient on or after the first intake of study drug, and which 
continue to be taken during the study, are regarded as concomitant medication.  


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9. 
ASSESSMENT OF EFFICACY 
9.1 
Efficacy Endpoints 
9.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline in serum LDL-C at Week 16. 
9.1.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following:  
• Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured 
by MRI-PDFF 
• Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by 
MRI 
• Change from Baseline to Week 16, and Follow-Up in the following: 
o Serum ALT, AST, and gamma-glutamyl transferase 
o HDL-C, non-HDL-C, LDL-C/HDL-C ratio, and triglycerides 
o Serum total bile acids 
9.1.3 
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be assessed: 
• Change from Baseline (unless otherwise specified) to Week 4, Week 8, Week 12, 
Week 16, and Follow-Up in the following: 
o Fasting glucose, insulin, homeostatic model assessment-insulin resistance, 
HbA1c, free fatty acids 
o GLP-1, FGF-19, and C4 levels 
o High-sensitivity CRP 
o Lanosterol and beta-sitosterol 
o Body weight, BMI, waist circumference, and waist-to-hip ratio 


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o MRI-based measurement of pulse wave velocity to measure aortic 
stiffness 
o Apolipoprotein A1 and Apolipoprotein B 
9.2 
Efficacy Assessments 
9.2.1 
Lipid Profile 
Fasting blood samples for analysis of LDL-C will be drawn at all visits, according to the 
schedule of assessments (Table 1). Fasting should be for at least 8 hours prior to the 
collection of the blood sample. Samples will be processed and transported to a central 
laboratory per instructions in the study reference manual. 
9.2.2 
Magnetic Resonance Imaging 
Patients will have an MRI at Screening and EOT to assess liver fat by MRI-PDFF, total 
liver volume, and aortic pulse wave velocity. Details of the image acquisition and 
analysis can be found in the study reference manual. 
9.2.3 
Serum Bile Acids 
Fasting blood samples for analysis of total s-BA will be drawn at all visits, according to 
the schedule of assessments (Table 1). Fasting should be for at least 8 hours prior to the 
collection of the blood sample. All s-BA results during the treatment period will be 
blinded. Samples will be processed and transported to a central laboratory per 
instructions in the study reference manual. 
9.2.4 
Biomarkers and Blood Samples for Future Testing 
Blood samples for analysis of additional markers of disease, fibrosis, inflammation, and 
cardiovascular risk factors, and other pharmacodynamic markers will be drawn at the 
appropriate visits, according to the schedule of assessments (Table 1). These include a 
bile acid profile, including primary and secondary bile acids, interleukin-6, Pro-C3, 
tumor necrosis factor alpha, and cytokeratine-18. Samples will be processed and 
transported to a central laboratory per instructions in the study reference manual. 


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10. 
ASSESSMENT OF SAFETY 
The timing and frequency of safety assessments are described in Section 7.1.3 and in 
Table 1. 
The primary safety analysis will include the occurrence of treatment-emergent adverse 
events (TEAE) and TEAEs categorized by causality, severity, and seriousness 
assessments made by the Investigator by comparing study drug exposure to placebo. 
Trends in safety will also be evaluated for the following assessments: 
• AEs, including discontinuations due to AEs 
• Physical examinations 
• Concomitant medications 
• Vital signs 
• 12-lead ECG 
• Laboratory test results (including clinical chemistry, hematology/coagulation, and 
urinalysis) 
10.1 
Adverse Events 
10.1.1 
Definitions and Investigator Assessments 
An AE is defined as any untoward medical occurrence in an enrolled patient regardless of 
causal relationship with study drug. An AE can therefore be any clinically significant 
unfavorable and unintended sign, symptom, or disease that occurs once a patient is 
enrolled (ICF is signed) in the study until the patient is discharged from the study, 
whether or not related to the study drug. 
10.1.1.1 
Clinical Significance 
Clinical significance is defined as any abnormal finding that results in further clinical 
investigation(s), treatment(s), or the diagnosis of a new condition. Patient-reported events 
and protocol-mandated laboratory values, vital signs, and physical examination findings 
can be considered clinically significant (i.e., an AE) if there is a deterioration as 
compared to Baseline. Examples of clinically significant worsening from Baseline could 


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include, but is not limited to, events causing withdrawal from the study and events 
requiring medical intervention outside of the study causing apparent clinical 
manifestations or judged to be relevant by the Investigator.   
10.1.1.2 
Serious Adverse Events 
Serious criteria are applied by the investigator to each AE as specifically defined below. 
These criteria are used to determine whether an AE is serious or non-serious. The 
assessment is made independently of severity assessment (Section 10.1.1.3). For 
example, the development of a severe rash that occurs after signing of the ICF may not 
meet serious criteria as defined below and therefore would be considered a severe, 
non-serious AE. 
Any AE that meets any 1 of the following 6 criteria is considered to be an SAE: 
• The outcome of the AE is death 
• The AE is immediately life-threatening. Life-threatening means that the patient 
is, in the opinion of the Investigator, at immediate risk of death from the reaction 
as it occurred. This does not include an AE that, if more severe, might have 
caused death 
• The AE results in persistent or significant disability/incapacity. Disability means 
a substantial disruption of a person’s ability to conduct normal life functions 
• The AE requires or prolongs hospitalization  
• The AE results in a congenital anomaly/birth defect 
• The AE is an important medical event. Important medical events may meet 
serious criteria should the Investigator assess that they may significantly 
jeopardize the patient, represent a significant hazard, or require medical/surgical 
intervention to prevent one of the outcomes listed above. Examples of potential 
SAEs based on these criteria include, but are not limited to, allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions even if they do not result in inpatient 
hospitalization, or the development of drug dependency and drug abuse. 


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10.1.1.3 
Severity Assessment 
Severity assessments are based on the intensity of the event in relation to expectation. 
The Investigator will assess the intensity of AEs based on the following definitions: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
Severity is a measure of intensity where seriousness is defined by the criteria outlined in 
Section 10.1.1.2. An AE of severe intensity need not necessarily be considered serious. 
For example, nausea that persists for several hours may be considered severe nausea, but 
not meet serious criteria, and therefore would be assessed as a severe AE but not an SAE. 
10.1.1.4 
Causality Assessment 
The Investigator determines the causality of all AEs to the study drug using medical 
judgment and considering all relevant factors such as (but not limited to) the underlying 
study indication, coexisting disease, concomitant medication, relevant history, pattern of 
the AE, temporal relationship to the study drug, and de-challenge or re-challenge. The 
causality assessment of the AE/SAE is to be made as follows: 
Related to Study Drug (Possibly, Probably, or Definitely Related) 
Based on medical judgment, there is at least a reasonable possibility that the study drug 
caused the event; one or more of the following criteria apply: 
• The event follows a reasonable temporal sequence from administration of study 
drug 
• The event could not be reasonably attributed to the known characteristics of the 
patient’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient 
• The event follows a known pattern of response to study drug 
• The event disappears or decreases on cessation or reduction in dose of the study 
drug. (It should be noted that in some situations an AE will not disappear or 


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decrease in intensity upon discontinuation of study drug despite other clear 
indications of relatedness) 
• The event reappears or worsens when the study drug is re-administered 
Unrelated to Study Drug (Unlikely or Unrelated) 
Based on medical judgment there is no reasonable possibility that the study drug caused 
the event; one or more of the following criteria apply: 
• The event does not follow a reasonable temporal sequence from administration of 
study drug 
• The event could be reasonably attributed to the known characteristics of the 
patient’s clinical state, concurrent illness, environment or toxic factors, or other 
modes of therapy administered to the patient 
• The event does not follow a known pattern of response to study drug 
• The event does not disappear or decrease on cessation or reduction in dose of the 
study drug, and it does not reappear or worsen when the study drug is 
re-administered 
10.1.2 
Recording of Adverse Events 
It is the Investigator’s responsibility to assess whether each untoward event is a clinically 
significant worsening from Baseline, thereby considered an AE. For all AEs, the severity, 
seriousness, and causality to study drug for each AE as outlined in Section 10.1.1 will be 
assessed and recorded in the eCRF. 
All serious and non-serious AEs are collected once the caregiver/patient has signed the 
ICF and until the post-treatment follow-up (Visit 7) or 14 days after the last dose of study 
drug. 
Any AEs or SAEs that are unresolved at the patient’s last AE assessment are followed up 
by the Investigator until resolution or stabilization up to the database lock and recorded in 
the eCRF. The Sponsor retains the right to request additional information for any patient 
with ongoing AE(s) or SAE(s) at the end of the study. 


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TEAEs are defined as any AE that occurs after randomization (Day 1). All AEs that 
occur in the Screening period, i.e., after enrollment and prior to randomization, will be 
collected on the eCRF as non-TEAEs. 
If there is a clinically significant deterioration of a laboratory value/vital sign or other 
routine study assessment that is associated with a diagnosis, the clinical diagnosis will be 
reported as an AE and the associated signs and symptoms will be considered additional 
information unless the sign or symptom is more severe than expected given the diagnosis. 
For example, if an Investigator diagnoses a study patient with hepatitis during the study 
period, hepatitis would be considered the AE and the concomitant signs and symptoms of 
abdominal pain, vomiting, and elevated ALT and AST would not be reported separately 
unless, in the opinion of the Investigator, one of these signs or symptoms is more severe 
than expected and therefore a separate AE assessment is indicated. 
10.1.3 
Recording and Reporting of Serious Adverse Events 
Every SAE (regardless of severity and causality) that occurs once the patient has signed 
the ICF and through 14 days after the final dose of study drug, should immediately and 
not later than within 24 hours of knowledge of the event, be reported by the Investigator 
or delegate in the SAE report form.  
Report of a SAE must include at least the following information: 
• Patient identification information (study number, site number, and date of birth 
[as per local country requirements for data protection]) 
• The last study drug administration date 
• The diagnosis of the event with the description (or a brief description of 
signs/symptoms/clinical course if the diagnosis is not available) and the date of 
onset 
• The action used to treat the event (i.e., treatment medications, temporary 
discontinuation) 
• The reason(s) for considering the event serious 
• The relationship of the event to the study drug or to the study procedure (i.e., the 
Investigator’s assessment of causality) 


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• A brief narrative of the SAE 
Follow-up reports including all new information obtained of the subsequent course of the 
SAE must be prepared and the information collected in the SAE report form submitted to 
the CRA, 
 
 by e-mail within 24 hours of knowledge of the event. 
The pharmacovigilance manager (PVM) of the CRA may contact the Investigator to 
obtain further information on a reported SAE. The investigator/investigative staff must 
respond to any request for follow-up information or answers to questions regarding the 
SAE within the same timelines as for initial reports. 
The PVM reports the occurrence of the SAE and follow-up to the Sponsor’s Medical 
Monitor for medical assessment of the case. 
Should an outcome of death occur within the study period or within 14 days after the last 
administration of study drug, an SAE form should be completed including the main and 
contributory causes of death. 
All SAE reports must be e-mailed to the following e-mail address within 24 hours: 
 
If email is unavailable, SAEs may be transmitted via fax to the following number: 
 
10.1.4 
Reporting of Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reaction (SUSAR) is an SAE that occurs in a 
patient, the nature or severity of which is not expected per the applicable product 
information (e.g., the Investigator’s Brochure for an unauthorized investigational product 
or summary of product characteristics for an authorized product).  
Reporting and tracking of SUSARs will be in accordance with all applicable competent 
authority regulations. The IRBs and all Investigators involved in this study will be 
informed according to local requirements. 


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10.2 
Laboratory Values, Vital Signs, Physical Examinations, and Other Safety 
Assessments 
10.2.1 
Laboratory Assessments 
Samples will be collected for clinical chemistry, hematology, urinalysis, and other lab 
assessments at the time points specified in Table 1. The parameters assessed are 
presented in Table 2. All samples will be processed and transported to a central 
laboratory per instructions in the study reference manual. 
The observed values will be recorded and assessed as “normal” or “abnormal not 
clinically significant” or “abnormal clinically significant.” 
Additional blood samples may be needed due to follow-up of an abnormal value or 
analysis failure. The blood samples collected for safety laboratory analysis will be 
destroyed after the analyses have been completed.  
Stored blood sample for future testing are detailed in Section 9.2.4.  


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Table 2: 
Laboratory Parameters 
CLINICAL CHEMISTRY (FASTING) 
HEMATOLOGY/COAGULATION 
URINALYSIS 
• 
Albumin 
• 
ALT 
• 
Alkaline phosphatase  
• 
Amylase 
• 
AST 
• 
Bicarbonate 
• 
Blood urea nitrogen 
• 
Calcium 
• 
Chloride 
• 
Creatine kinase 
• 
eGFR by MMRD (screening only) 
• 
Gamma-glutamyl transferase 
• 
Glucose 
• 
Hemoglobin HbA1C 
• 
Inorganic phosphorus 
• 
Lactate dehydrogenase 
• 
Lipase 
• 
Potassium 
• 
Sodium 
• 
Total bilirubin 
• 
Total protein 
• 
Uric acid 
• 
Hematocrit 
• 
Hemoglobin 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count and differential 
(neutrophils, eosinophils, basophils, 
lymphocytes, and monocytes) 
Manual microscopic review is performed only if 
white blood cell count and/or differential values are 
out of reference range. 
• 
International normalized ratio (INR) 
• 
Prothrombin time (PT) 
• 
Bilirubin 
• 
Blood 
• 
Glucose 
• 
Ketones 
• 
Leukocytes esterase 
• 
Microscopy including leukocytes (performed 
only as needed based on positive dipstick test 
results) 
• 
Nitrites 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
 
 
(Continued on next page) 


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LIPID PROFILE (FASTING) 
OTHER TESTS 
ENDOCRINOLOGY 
• 
Apolipoprotein A1 
• 
Apolipoprotein B 
• 
Chylomicron cholesterol 
• 
Chylomicron triglycerides 
• 
High-density lipoprotein (HDL) cholesterol 
• 
Lipoprotein(a) cholesterol 
• 
Low-density lipoprotein (LDL) cholesterol by 
calculation 
• 
LDL triglyceride 
• 
Non-high-density lipoprotein cholesterol 
• 
Total cholesterol 
• 
Triglycerides 
• 
Very low-density lipoprotein (VLDL) 
cholesterol 
• 
VLDL triglyceride 
• 
Lanosterol 
• 
Beta-sitosterol 
• 
High-sensitivity C-reactive protein (CRP) 
• 
C4 
• 
Fibroblast growth factor-19 (FGF-19) 
• 
Fibrosis and inflammation markers: FIB-4, 
APRI, and NAS  
• 
Glucagon-like peptide-1 (GLP-1) 
• 
Follicle-stimulating hormone1 
• 
Homeostatic model assessment-insulin 
resistance 
• 
Insulin 
• 
Thyroxine2 
• 
Triiodothyronine2 
• 
Thyroid-stimulating hormone2 
• 
Free fatty acids 
• 
Adipose tissue insulin resistance 
• 
Adiponectin 
BILE ACIDS (FASTING) 
PREGNANCY 
SEROLOGY 
• 
Total serum bile acids 
• 
Serum 
• 
Urine 
• 
Hepatitis B virus surface antigen 
• 
Hepatitis C virus antibody and ribonucleic acid  
1 
A postmenopausal state is defined as no menses for ≥12 months without an alternative medical cause. A follicle-stimulating hormone level in the postmenopausal range will be 
used to confirm a postmenopausal state in women ≤55 years of age, performed at Screening visit only. 
2 
Thyroid function test will be performed during Screening visit only. 
 


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10.2.2 
Individual Patient Safety Monitoring 
10.2.2.1 
Liver Monitoring 
Strategies to monitor markers of liver disease throughout the study are outlined below 
where the ULN will be based on central laboratory reference values for age and gender. 
Patients will be monitored as described below for drug-induced liver injury from 
randomization to 2 weeks following the last administration of study drug. 
Elevated ALT  
• ALT >5 × ULN or >3 × Baseline (if ALT elevated at Baseline): repeat AST, 
ALT, total bilirubin, alkaline phosphatase (ALP), and INR within 72 hours and 
closely monitor the patient. If liver enzyme elevation is confirmed, interrupt the 
study drug. The study drug can be restarted only if a competing etiology is 
identified or liver tests return to Baseline. 
Elevated AST  
• AST >5 × ULN or 3 × baseline (if AST elevated at baseline): repeat AST, ALT, 
total bilirubin, ALP, and INR within 72 hours and closely monitor the patient. If 
liver enzyme elevation confirmed, interrupt the study drug. The study drug can be 
restarted only if a competing etiology is identified or liver tests return to Baseline. 
Elevated Total Bilirubin 
• Total bilirubin >2 × ULN or >1.5 × Baseline (if total bilirubin elevated at 
Baseline), regardless of ALT or AST levels: repeat AST, ALT, total bilirubin, 
ALP, and INR within 72 hours and closely monitor the patient. If liver enzyme 
elevation confirmed, interrupt the study drug. The study drug can be restarted 
only if a competing etiology is identified or liver tests return to Baseline. 
Other Clinical Symptoms  
• Clinical signs of hepatitis or indicators of immunological reaction (e.g., nausea, 
vomiting, right upper quadrant pain, loss of appetite, dark urine, jaundice, rash, 
eosinophilia >5% or symptoms/signs of hepatic decompensation): discontinue the 


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study drug and repeat AST, ALT, total bilirubin, ALP, and INR within 72 hours 
and closely monitor. Other causes of hepatitis should be excluded.  
When close monitoring of a patient is not possible while the patient is on study drug, 
interrupt the study drug and closely monitor the patient. 
10.2.3 
Demographics/Medical and Surgical History 
Demographic information per country regulations (age, full date of birth, gender, race, 
and ethnicity), along with medical and surgical history, will be obtained and recorded in 
the eCRF at Visit 1. 
Medical and surgical history will be entered in the eCRF at Visit 1. This includes date of 
diagnosis of NASH/NAFLD, ongoing medication, any surgery performed, and any other 
diagnoses.   
10.2.4 
Physical Examination 
A physician or suitably trained qualified assistant will perform a complete physical 
examination at Screening, at Visit 2, and at Visit 6. Height (Screening only), weight, 
waist circumference, and waist-to-hip ratio will also be collected. BMI will be calculated 
based on height and weight. 
A complete physical examination will include assessment of general appearance, eyes, 
ears, nose, throat, head/neck/thyroid, lymph nodes, cardiovascular, lungs/chest, abdomen, 
genitourinary, extremities, skin, musculoskeletal, neurologic, and other.  
10.2.5 
Vital Signs 
Evaluation of vital signs will be performed at all visits. This includes blood pressure 
(systolic and diastolic), pulse, respiratory rate, and oral temperature. 
10.2.6 
12-Lead ECG 
A 12-lead ECG will be performed at the Screening visit and the EOT visits.  
10.2.7 
Overdose 
Elobixibat is minimally absorbed and has a very low systemic availability. It is not 
known whether elobixibat can be removed from the systemic circulation by dialysis. 


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There are no known antidotes for elobixibat overdoses. If an overdose occurs, the patient 
should be carefully monitored and treated with supportive therapy. 


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11. 
STATISTICAL EVALUATION 
All personnel involved with the analysis of the study will remain blinded until database 
lock for the double-blind treatment period and until major protocol violations have been 
identified. 
All statistical analyses will be performed using SAS version 9.3 or higher. 
11.1 
Sample Size and Power 
Due to the exploratory nature of this study, no formal power calculations were used to 
determine the sample size. The number of subjects (46 patients in total, 23 patients per 
treatment group) was chosen based on clinical experience with other similar proof-of- 
concept studies. 
11.2 
Statistical Methods 
11.2.1 
Statistical Analysis Populations 
ITT Population 
The intent-to-treat (ITT) population will include all patients who are randomized in the 
study and receive at least 1 dose of study drug. The ITT population will be used for all 
efficacy analyses based on the treatment randomized unless otherwise specified.  
Per Protocol Population 
The per protocol (PP) population will include all ITT patients who finish Visit 7/EOT 
with valid LDL-C measurements and do not have any major protocol deviations. 
Allocation of patients to the PP analysis set will be performed before unblinding of the 
study. 
Safety Population  
The safety population will include all patients who are randomized and receive at least 
1 dose of study drug and will be used for all safety analyses based on the treatment 
received.  


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11.2.2 
Methods of Statistical Analyses 
11.2.2.1 
General Principles 
Summary statistics (number of patients, mean, standard deviation, median, minimum, and 
maximum) at all visits and change or percent change from Baseline will be provided for 
efficacy and safety continuous variables. Count and frequency will be used to tabulate 
categorical variables. 
11.2.2.1.1 
Efficacy 
The primary efficacy endpoint is the change from Baseline in serum LDL-C at Week 16. 
Baseline is defined as the last non-missing LDL-C value prior to the first dose of study 
drug.  
Exploratory comparisons between elobixibat 5 mg and placebo will be performed for the 
following secondary efficacy endpoints:   
• Absolute change from Baseline to Week 16 in liver fat fraction (%) as measured 
by MRI-PDFF 
• Absolute change from Baseline to Week 16 in total liver fat (mL) as measured by 
MRI 
The analysis methods for the other secondary and exploratory endpoints will be detailed 
in the statistical analysis plan (SAP). 
11.2.2.1.2 
Safety 
The safety endpoints for this study include clinical laboratory assessments, vital signs, 
AEs, ECGs, physical examinations, and concomitant medications. 
AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedRA). TEAEs will be defined as AEs that are new or worsening after the 
first dose of study drug. A general summary of patients with TEAEs and serious adverse 
events (SAEs) will be tabulated with numbers and percentages of patients and repeated 
for severity and relationship to study drug per treatment group. The number of AEs 
leading to withdrawal and SAEs leading to death will also be summarized. The incidence 
of TEAEs will be summarized by body system and treatment group. 


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The safety laboratory data will be summarized by visit and by treatment group, along 
with changes from Baseline. Values outside of the reference range will be flagged and 
laboratory abnormalities of special interest will be summarized.  
11.2.2.2 
Missing Data 
Continued collection of efficacy data for patients who discontinue treatment will be made 
for as long as possible as per the schedule of assessments (Table 1). Missing data 
handling for the primary efficacy endpoint is specified under Section 11.2.2.6. Details on 
missing data handling for secondary and exploratory endpoints will be specified in the 
SAP.  
11.2.2.3 
Demographic and Baseline Characteristics 
Descriptive summaries of demographics and other baseline characteristics (including 
medical and surgical history) will be presented by treatment group and overall using the 
ITT population.  
Prior medication will be summarized by treatment group and overall using the ITT 
population. 
11.2.2.4 
Subject Disposition 
The following will be summarized descriptively (by treatment group and overall where 
applicable): 
• Patients enrolled (who signed the informed consent) 
• Patients randomized 
• Patients treated 
• Patients completing the study 
• Patients withdrawing early (including withdrawal reason) 
11.2.2.5 
Evaluation of Primary Efficacy Endpoints 
To address the potential missing data from patients who are lost to follow-up after 
treatment discontinuation, multiple imputation method will be used. Data from patients 
who discontinue the study drug but stay in the study with scheduled assessments 


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collected will be used to impute missing values for patients lost to follow-up. This 
imputation will be done within each treatment group. Interim missing data will be 
handled as missing at random (predictable from observed data from subjects in the same 
treatment group).  
After the imputation is performed, an analysis of covariance (ANCOVA) will be used to 
analyze the primary efficacy endpoint. The model will include treatment arm and 
Baseline LDL-C scores.  
Least square (LS) mean (SE), LS mean difference (SE), 95% confidence intervals, and 
P-values between elobixibat 5 mg and placebo will be provided. The model assumptions 
will be checked before the analysis. If there are concerns on model assumptions, i.e., 
normality and homogeneity of variances, a non-parametric ANCOVA based on the rank 
scores can be used as a sensitivity analysis. 
Sensitivity analyses may be performed and will be detailed in the SAP. 
11.2.2.6 
Evaluation of Secondary and Exploratory Efficacy Endpoints 
Descriptive statistics will be provided for secondary and exploratory endpoints listed in 
Sections 9.1.2 and 9.1.3, respectively, unless otherwise specified. 
11.2.2.7 
Evaluation of Safety Endpoints 
Safety data will be analyzed using descriptive statistics and summaries by treatment 
group of SAEs, AEs, vital signs, clinical safety laboratory tests (hematology, coagulation, 
clinical chemistry, and urinalysis), and concomitant medication. Analyses will be 
performed using the safety analysis set.  
Summaries of AEs (coded according to the MedDRA system organ class [SOC] and 
MedDRA preferred term) will include the following:  


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• Overview of the incidence of TEAEs (TEAEs, drug-related TEAEs, TEAEs 
leading to study discontinuation, and treatment-emergent SAEs) 
• TEAEs by SOC and preferred term 
• Intensity of TEAEs by SOC and preferred term 
• Drug-related TEAEs by SOC and preferred term 
• TEAEs leading to study discontinuation by SOC and preferred term 
• Treatment-emergent SAEs by SOC and preferred term 
Concomitant medication use during the treatment period will be summarized by 
Anatomical Therapeutic Chemical (ATC) class and World Health Organization (WHO) 
preferred name.  
Summaries of vital signs will be presented. For each visit, the actual results and the 
change from Baseline, and the number and percentage of patients with potentially 
clinically significant (PCS) values as defined in the SAP, observed post-baseline will be 
presented. 
Summaries of clinical safety laboratory data will be presented. For each visit, the actual 
result and the change from Baseline, and the number and percentage of patients with PCS 
values as defined in the SAP, observed post-baseline will be presented. 
Data listings will be provided for each patient for all safety parameters. 
11.2.2.8 
Compliance and Exposure 
Exposure will be analyzed by calculating the number of days with exposure to study 
drug. Results will be presented by treatment group using the safety analysis set.  
The percentage compliance will be described by treatment group and the number of 
patients with a compliance <80%, between 80% and 120%, and >120% will be presented 
based on the safety analysis set. 


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12. 
DIRECT ACCESS TO SOURCE DATA/NOTES 
The Investigator/institution shall provide direct access to source data/documents for 
study-related monitoring, audits, IRB review, and regulatory inspection. 


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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Conduct of the Study 
The study team shall implement and maintain quality control and quality assurance 
procedures with written SOPs to ensure that the study is conducted, and data are 
generated, documented, and reported in compliance with the protocol, ICH GCP, and 
applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of 
Helsinki (October 1996) and all revisions thereof, and in accordance with US Food and 
Drug Administration (FDA) regulations (Code of Federal Regulations, Sections 312.50 
and 312.56) and with ICH GCP (CPMP 135/95). 
The Investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate competent authority and IRB, 
except when necessary to eliminate immediate hazards to the patient or when the 
change(s) involve(s) only logistical or administrative aspects of the study. Any deviations 
may result in the patient having to be withdrawn from the study and render that patient 
non-evaluable. 
13.2 
Study Monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Sponsor 
representative or designee will review the protocol and eCRF with the Investigators and 
the investigative staff. During the study, the clinical monitor (the CRA) will visit the site 
regularly to check the completeness of patient records, the accuracy of entries on the 
eCRFs, the adherence to the protocol and to GCP, the progress of enrollment, and to 
ensure that study drug is being stored, dispensed, and accounted for according to 
specifications. 
The investigator must ensure that eCRFs are completed within a timely period of patient 
visits, as per individual site agreements, and must allow the CRA and the Sponsor 
representative or designee periodic access to patient records and all study-related 
materials, including relevant hospital or clinical records, to confirm their consistency 
with the eCRF entries. No information in these records about the identity of the patients 
will leave the study center. The Sponsor monitoring standards require full verification for 


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the presence of the signed ICF, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and recording of primary efficacy and safety variables. The 
CRA will review source data compared with the eCRFs and will verify source data 
according to the study-specific monitoring plan. The design of the study, the frequency of 
patient visits, and the site enrollment rate will determine the frequency of monitoring 
visits. Upon study completion, the CRA will visit the site to conduct a study termination 
visit, which will include collection of any outstanding documentation. 
It is recommended that the Investigator/investigative staff log into the eCRF system every 
working day or at minimum twice weekly in order to provide a prompt response to 
queries. The Investigator/investigative staff should respond to queries and make any 
relevant changes to the study data within 3 working days. 


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14. 
ETHICS 
14.1 
Institutional Review Board 
Prior to the start of the study, the Investigator is responsible for ensuring that the protocol 
and consent form have been reviewed and approved by a relevant IRB. The IRB shall be 
appropriately constituted and perform its functions in accordance with FDA, ICH, GCP, 
and local requirements as applicable. 
The IRB shall approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, patient recruitment 
procedures (e.g., advertisements), written information to be provided to the patients and 
caregivers, the Investigator’s Brochure, available safety information, information about 
payment and compensation available to patients, the Investigator’s curriculum vitae 
and/or other evidence of qualifications and any other documents requested by the IRB 
and regulatory authority (competent authority) as applicable. 
14.2 
Written Informed Consents 
The Investigator (physician) or investigative staff, in accordance with local regulations, 
will explain to each patient (or legally authorized representative) the nature of the study, 
its purpose, the procedures involved, the expected duration, alternative treatment, the 
potential risks and benefits involved, and any discomfort that may occur. Each patient 
will be informed that participation in the study is voluntary and that he/she may withdraw 
from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
If written consent is not possible, oral consent can be obtained if witnessed and followed 
by a signed statement from one or more persons not involved in the study, indicating why 
the patient was unable to sign the form. No patient can enter the study before his/her 
informed consent has been obtained, as required by country regulations. 
The ICF is part of the protocol and must be submitted by the Investigator/investigative 
staff with the protocol for IRB approval. The Sponsor will supply an ICF which complies 
with regulatory requirements and country laws and is considered appropriate for the 
study. Any changes to the ICF suggested by the Investigator must be agreed to by the 


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Sponsor before submission to the IRB and a copy of the approved version must be 
provided to the clinical monitor after IRB approval. 


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15. 
DATA HANDLING AND RECORDKEEPING 
15.1 
Electronic Case Report Forms/Source Data Handling 
The investigator shall be provided with standardized eCRFs and shall ensure that all data 
from patient visits are promptly entered into the eCRFs in accordance with the specific 
instructions given. The Investigator must sign each eCRF to verify the integrity of the 
data recorded. 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to the start of the study. As a central laboratory has 
been selected to conduct any or all tests, it is essential that all samples be analyzed at that 
laboratory. 
The Investigator must maintain source documents such as laboratory reports, consultation 
reports, and complete medical history and physical examination reports. 
15.2 
Retention of Essential Documents 
Essential documents, as defined by ICH GCP, include the signed protocol and any 
amendment(s); copies of the completed eCRFs (for site archiving of eCRF data for 
specific patients will be provided); signed ICFs; hospital records and other source 
documents; IRB approvals and all related correspondence including approved documents; 
drug accountability records; study correspondence; and a list of patients’ names and 
addresses. 
The Investigator/investigative staff must retain copies of these essential documents for 
the period specified by ICH GCP and by applicable regulatory requirements. The 
Investigator/investigative staff will inform the Sponsor of the location where the essential 
documents are stored and must contact the Sponsor for approval before disposing of any 
essential documents. The Investigator/investigative staff should take measures to prevent 
accidental or premature destruction of these documents. 


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16. 
FINANCING AND INSURANCE 
Financing and insurance are addressed in a separate agreement. 


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17. 
PUBLICATION POLICY 
The Sponsor will retain ownership of all data. When the study is complete, the Sponsor 
will arrange the analysis, tabulation of data, and preparation of a clinical study report. 
The Sponsor may also use the data for publication, presentation at scientific meetings, 
and submission to regulatory authorities. All proposed publications based on this study 
must be subject to the Sponsor’s approval requirements. 


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18. 
REFERENCES LIST 
Andersen A, Lund A, Knop FK, Vilsbøll T. Glucagon-like peptide 1 in health and 
disease. Nature Rev. 2018;14(7):390-403. doi: 10.1038/s41574-018-0016-2. 
Aranha MM, Cortez-Pinto H, Costa A, et al. Bile acid levels are increased in the liver of 
patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2008;20(6):519-525. 
doi: 10.1097/MEG.0b013e3282f4710a. 
Bertolotti M, Zambianci L, Carulli L, et al. Influence of newly synthesized cholesterol on 
bile acid synthesis during chronic inhibition of bile acid absorption. Hepatology. 
2003;38(4)939-946. 
Ferslew BC, Xie G, Johnston CK, et al. Altered bile acid metabolome in patients with 
non-alcoholic steatohepatitis. Dig Dis Sci. 2015;60(11):3318-3328. doi: 10.1007/s10620-
015-3776-8. 
Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological 
scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313-1321. 
doi: 10.1002/hep.20701. 
Mahfood Haddad T, Hamdeh S, Kanmanthareddy A, Alla VM. Nonalcoholic fatty liver 
disease and the risk of clinical cardiovascular events: a systematic review and meta-
analysis. Diabetes Metab Syndr. 2017;11(Suppl 1):S209-S216. 
doi: 10.1016/j.dsx.2016.12.033. 
Naoumova RP, O’Neill FH, Dunn S, et al. Effect of inhibiting HM-CoA reductase on 7α-
hydroxy-4-cholesten-3one, a marker of bile acid synthesis: contrasting findings in 
patients with and without prior up-regulation of the latter pathway. Eur J Clin Invest. 
1999;29(5):404-412.  
Prawitt J, Caron S, Staels B. Bile acid metabolism and the pathogenesis of type 2 
diabetes. Curr Diabetes Rep. 2011;11(3):160-166. doi: 10.1007/s11892-011-0187-x. 
Puri P, Daita K, Joyce A, et al. The presence and severity of nonalcoholic steatohepatitis 
is associated with specific changes in circulating bile acids. Hepatology. 
2018;67(2):534-548. doi: 10.1002/hep.29359. 


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Sanyal A, Harrison S, Charlron M, et al. Serum bile acids are markedly elevated in 
patients with compensated cirrhosis due to nonalcoholic steatohepatitis. J Hepatol. 
2018;68:S365-S604. doi: 10.1016/S0168-8278(18)31360-6. 
Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. 
Nat Rev Gastroenterol Hepatol. 2014;11(1):55-67. doi: 10.1038/nrgastro.2013.151. 
Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, 
predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 
2018;15(1):11-20. doi: 10.1038/nrgastro.2017.109. 
 

SAP_001.pdf: 
Sponsor: Elobix AB 
Protocol No: A3309-012 
Statistical Analysis Plan 1.0 
06July2020 
Confidential 
Page 1 of 29 
 
 
 
 
 
 
Statistical Analysis Plan 
 
A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Explore 
the Efficacy and Safety of Elobixibat in Adults with Nonalcoholic Fatty Liver 
Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH) 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL NO. 
A3309-012 
Sponsor 
Elobix AB 
CRO 
 
Version 
1.0 
Date 
06-July-2020 


Sponsor: Elobix AB 
Protocol No: A3309-012 
Statistical Analysis Plan 1.0 
06July2020 
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SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 
Signature 
Date 
 


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DOCUMENT REVISON HISTORY 
VERSION 
DATE 
AUTHOR/ 
UPDATED BY 
COMMENTS 
1.0 
07/06/2020 
NA 
NA 


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TABLE OF CONTENTS 
1 
INTRODUCTION .............................................................................................................................................. 8 
1.1 
STUDY OBJECTIVES .......................................................................................................................................................................... 8 
Primary Objective ................................................................................................................................................ 8 
Secondary Objectives ........................................................................................................................................... 8 
1.2 
STUDY ENDPOINTS ............................................................................................................................................................................ 8 
Primary Efficacy Endpoint ................................................................................................................................... 8 
Secondary Efficacy Endpoints .............................................................................................................................. 8 
Exploratory Efficacy Endpoints ........................................................................................................................... 8 
Safety Endpoints ................................................................................................................................................... 9 
1.3 
STUDY DESIGN ................................................................................................................................................................................... 9 
General Study Design and Plan ........................................................................................................................... 9 
Randomization and Blinding .............................................................................................................................. 10 
Sample Size ........................................................................................................................................................ 10 
2 
STATISTICAL CONSIDERATIONS ............................................................................................................ 10 
2.1 
GENERAL CONSIDERATIONS ....................................................................................................................................................... 10 
2.2 
DEFINITIONS OF ANALYSIS SETS .............................................................................................................................................. 11 
ITT Population .................................................................................................................................................. 11 
Per Protocol Population ................................................................................................................................... 11 
2.3 
CONVENTIONS FOR DATA HANDLING ..................................................................................................................................... 11 
Baseline ............................................................................................................................................................. 11 
Study Day .......................................................................................................................................................... 11 
Analysis Visit ...................................................................................................................................................... 12 
Missing and Partial Date ................................................................................................................................... 12 
2.4 
CHANGES TO THE STATISTICAL ANALYSIS FROM THE PROTOCOL .................................................................................. 13 
2.5 
IMPACT OF COVID-19 ON THE CLINICAL TRIAL.................................................................................................................. 13 
3 
STATISTICAL ANALYSES ........................................................................................................................... 13 
3.1 
SUBJECT INFORMATION ................................................................................................................................................................ 13 
Disposition of Subjects ....................................................................................................................................... 13 
Protocol Deviations and Violation of Inclusion/Exclusion Criteria .................................................................. 14 
Demographics and Baseline Characteristics ..................................................................................................... 14 
Medical and Surgical History ............................................................................................................................ 14 
Prior and Concomitant Medications .................................................................................................................. 15 
3.2 
EFFICACY ANALYSES .................................................................................................................................................................... 15 
Primary Endpoint ............................................................................................................................................... 15 
Multiple Imputation for Primary Endpoint Variable ......................................................................................... 15 
Sensitivity Analysis for primary endpoint ........................................................................................................... 17 
Secondary Efficacy Endpoints ............................................................................................................................ 17 
Exploratory Efficacy Endpoints ......................................................................................................................... 18 
3.3 
STUDY DRUG EXPOSURE AND TREATMENT COMPLIANCE ................................................................................................ 18 
3.4 
SAFETY ANALYSIS ......................................................................................................................................................................... 19 
Adverse Events ................................................................................................................................................... 19 
Vital Signs .......................................................................................................................................................... 20 
12-Lead ECG ..................................................................................................................................................... 20 
Laboratory Tests ................................................................................................................................................ 20 
Pregnancy Test ................................................................................................................................................... 21 
4 
MINIMIZING RISK TO TRIAL INTEGRITY DURING THE COVID-19 PANDEMIC ........................ 21 
REFERENCES .......................................................................................................................................................... 22 
5 
STERLING RK, LISSEN E, CLUMECK N, ET. AL. (2006), “DEVELOPMENT OF A SIMPLE 


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NONINVASIVE INDEX TO PREDICT SIGNIFICANT FIBROSIS PATIENTS WITH HIV/HCV CO- 
INFECTION,” HEPATOLOGY, 43, 1317-1325.APPENDIX ................................................................................ 23 
Schedule of Assessments ..................................................................................................................................... 23 
Laboratory Parameters ...................................................................................................................................... 25 
SAS sample code for multiple imputation ........................................................................................................... 27 
SAS sample code for MMRM ............................................................................................................................. 29 


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ABBREVIATIONS 
 
Abbreviation 
Term 
A3309 
Elobixibat 
AE(s) 
adverse event(s) 
AESI(s) 
adverse event(s) of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
Anti-HCV 
hepatitis C antibody 
APRI 
AST to platelet ratio index 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Class 
BMI 
body mass index 
C4 
7α-hydroxy-4-cholesten-3-one 
CI 
confidence interval 
CM 
concomitant medication 
CRF 
case report form 
CRP 
C-reactive protein 
ECG(s) 
electrocardiogram(s) 
eGFR 
estimated glomerular filtration rate 
EOT 
End of Treatment 
EOS 
End of Study 
FGF-19 
fibroblast growth factor-19 
FIB-4 
fibrosis-4 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
HbA1c 
hemoglobin A1c 
HDL-C 
high-density lipoprotein-cholesterol 
ICF(s) 
Informed Consent Form(s) 
ICH 
International Council on Harmonisation 
INR 
international normalized ratio 
IPD 
important protocol deviation(s) 
IRB 
institutional review board 


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Abbreviation 
Term 
ITT 
intent to treat 
IWRS 
Interactive Web Response System 
LDL 
low-density lipoprotein 
LDL-C 
low density lipoprotein-cholesterol 
LS 
least squares 
lsmean 
least squares mean 
MCMC 
Markov chain Monte-Carlo 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed models repeated measures 
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging-proton density fat fraction 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
NALFD activity score 
NASH 
nonalcoholic Steatohepatitis 
NFS 
NALFD fibrosis score 
PCS 
potentially clinically significant 
PDFF 
proton density fat fraction 
PP 
per protocol 
PT 
preferred term 
QQ Plot 
quantile-quantile plot 
EM 
expectation – maximization 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TEAE(s) 
treatment-emergent adverse event(s) 
VLDL 
very low-density lipoprotein 
WHO 
World Health Organization 


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1 INTRODUCTION 
 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report efficacy and safety data for study A3309-012 based 
on protocol dated on 10 September 2019 (version 3.0). 
1.1 STUDY OBJECTIVES 
Primary Objective 
• To evaluate the efficacy of repeated once-daily doses of 5 mg elobixibat on serum levels 
of low-density lipoprotein cholesterol (LDL-C) in patients with NAFLD or NASH. 
 
Secondary Objectives 
• To assess the safety and tolerability of elobixibat in patients with NAFLD or NASH 
• To evaluate the effect of elobixibat on liver steatosis as measured by magnetic resonance 
imaging (MRI) for (i) liver fat fraction (using proton density fat fraction [PDFF]) and (ii) 
total liver fat (using whole liver fat volume) 
• To evaluate the effect of elobixibat on liver function using alanine aminotransferase (ALT) 
• To evaluate the effect of elobixibat on lipids and total bile acids in patients with NAFLD 
or NASH 
1.2 STUDY 
ENDPOINTS 
Primary Efficacy Endpoint 
• Change from baseline in serum LDL-C at week 16. 
 
Secondary Efficacy Endpoints 
• Absolute change from baseline to week 16 in liver fat fraction (%) as measured by MRI- 
PDFF 
• Absolute change from baseline to week 16 in total liver fat (mL) as measured by MRI 
• Change from baseline to week 16, and follow-up in the following: 
o Serum ALT, AST, and gamma-glutamyl transferase 
o HDL-C, non-HDL-C, LDL-C/HDL-C ratio, and triglycerides 
o Total bile acids 
Exploratory Efficacy Endpoints 
• Change from baseline (unless otherwise specified) to week 4, week 8, week 12, week 16, 
and follow-up in the following: 


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o Fasting glucose, insulin, homeostatic model assessment-insulin resistance, HbA1c, 
free fatty acids 
o GLP-1, FGF-19, and C4 levels 
o High-sensitivity C-reactive protein (CRP) 
o Lanosterol and beta-sitosterol 
o Body weight, BMI, waist circumference, and waist-to-hip ratio 
o Apolipoprotein A1 and Apolipoprotein B 
o Fibrosis and inflammation markers: FIB-4, APRI, and NFS 
Safety Endpoints 
The safety endpoints for this study include clinical laboratory assessments, vital signs, AEs, 
ECGs, and concomitant medications. 
 
1.3 STUDY DESIGN 
General Study Design and Plan 
This is a double-blind, randomized, placebo-controlled, Phase 2 study to explore the efficacy and 
safety of elobixibat (oral dose of 5 mg) once daily for 16 weeks in patients with NAFLD or NASH. 
The study includes a 6-week Screening Period, followed by a 16-week Treatment Period, and a 
follow-up visit 2 weeks after the last dose of study drug. 
After completing the Screening period, eligible patients will be randomized on Day 1 (Visit 2) in 
a 1:1 fashion to either 5 mg/day elobixibat or matching placebo. There will be a total of 7 
scheduled visits during the study, as follows: 
• Visit 1: Screening period (week -6 through Day -1) 
• Visit 2: Day 1/Randomization visit 
• Visit 3: Week 4 
• Visit 4: Week 8 
• Visit 5: Week 12 
• Visit 6: Week 16/End of Treatment (EOT). Any patient that discontinues treatment 
prematurely should complete this visit at the time of discontinuation 
• Visit 7: Follow-Up period. The follow-up visit will occur 2 weeks after the last dose of 
study drug whether the patient completes the study or discontinues prematurely 
 
Additional unscheduled visits may be required for patients who need direct site assistance (e.g., 
due to AE monitoring, in order to fulfill screening requirements, and/or for safety maintenance). 


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Randomization and Blinding 
A double-blind design is employed so that both the investigators and the patients will be unaware 
of the treatment assignment during the study. Eligible patients will be randomly assigned in a 1:1 
ratio to the study drug or the matching placebo by the Interactive Web Response System (IWRS). 
Patients who withdraw from the study after the randomization visit are not to be replaced and their 
randomization number will not be reused. 
To ensure blinding, the study drug and the matching placebo have the same shape and size. Labels 
on the treatment bottles will not identify the treatment to which a patient has been randomized. 
Traceability of the treatment is ensured by the bottle number. Other than designated randomization 
personnel, all study conduct persons, investigators, and patients are blinded to study drug 
assignment. 
 
Per the protocol, total bile acids results are blinded. Operationally, blinding was implemented by 
not having total bile acids, FGF-19, C4, and lanosterol and beta-sitosterol results available until 
after database lock. The same blinding approach was applied to the imaging results for the post- 
baseline imaging results. 
 
Sample Size 
Due to the exploratory nature of this study, no formal power calculations were used to determine 
the sample size. The number of subjects (46 patients in total, 23 patients per treatment group) was 
chosen based on clinical experience with other similar proof-of- concept studies. 
 
2 STATISTICAL CONSIDERATIONS 
2.1 GENERAL CONSIDERATIONS 
General principles will be followed: 
• Population summaries (e.g., disposition, demographics and baseline characteristics, 
medical/surgical history, prior and concomitant medications) and efficacy tables will 
summarize data by the randomized treatment group. Safety tables will be summarized by 
the actual treatment subject received. 
• All continuous variables will be summarized using descriptive statistics including the 
number of patients with data to be summarized (n), mean, standard deviation (SD), median, 
minimum (min) and maximum (max). Minimum and maximum will be displayed with a 
maximum of 2 decimal places. Mean and median will be rounded to 1 additional decimal 
place, SD will be rounded to 2 additional decimal places, compared to the displayed 
minimum and maximum. 
• Categorical variables will be summarized with count and percent; the denominator will be 
based on the number of subjects in the treatment group, unless otherwise stated. 
• In general, efficacy analysis will be performed using the intent-to-treat (ITT) population 
and safety analyses will be performed using the safety population. Per-protocol population 
will be used for the primary endpoint sensitivity analysis. 


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• The default significance level will be (5%); confidence intervals (CIs) will be 95% and all 
tests will be two-sided, unless otherwise specified in the description of the analyses. 
• P-values will be rounded to three decimal places. If a p-value is less than 0.001, it will be 
reported as “<0.001.” If a p-value is greater than 0.999 it will be reported as “>0.999”. 
 
All analyses will be performed using SAS®, Version 9.4 or higher. 
2.2 DEFINITIONS OF ANALYSIS SETS 
ITT Population 
The intent-to-treat (ITT) population will include all patients who are randomized in the study and 
receive at least 1 dose of study drug. The ITT population will be used for all efficacy analyses 
based on the treatment randomized unless otherwise specified. 
 
Per Protocol Population 
The per-protocol (PP) population will include all ITT patients who finish Visit 6/EOT with valid 
LDL-C measurements and do not have any important protocol deviations that may impact the 
analysis of efficacy. The important protocol deviations are: 
 
• Failure to meet the Inclusion criteria 
• Failure to meet the Exclusion criteria 
• Compliance rate of <80% or >120% with study drug administration 
• Took disallowed meds over 50% time of treatment period 
• Others (mis-randomized, took the wrong drug, etc.) 
Safety Population 
The safety population will include all patients who are randomized and receive at least 1 dose of 
study drug and will be used for all safety analyses based on the treatment received. The Safety 
and ITT Populations are the same, as there were no subjects that did not receive the treatment to 
which they were randomized. 
2.3 CONVENTIONS FOR DATA HANDLING 
Baseline 
Baseline for a particular variable will be defined as the last available assessment for that variable 
prior to the initiation of first dose of study drug. 
 
Study Day 
Study Day will be calculated from the reference start date and will be used to show start/stop day 
of assessments and events. 


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Reference start date (Study Day 1) is defined as the day of first dose for efficacy and safety analysis. 
Note: A few patients were randomized but not treated until the next day. 
For assessments or events after the reference start date 
Study day = date of assessment or event – reference start date + 1 
For assessments or events prior to the reference start date 
Study day = date of assessment or event – reference start date 
 
Analysis Visit 
Visit-based data summaries will be presented by analysis visits. A window assessment will be 
performed according to the below table for any subject that missed a planned visit (on both efficacy 
and safety endpoints). The purpose of using this analysis window is to include potential 
unscheduled visits when a subject missed the planned visit. If a subject’s planned visit assessment 
is out of the defined visit window and there is no unscheduled assessment within the same window, 
then this CRF collected planned visit assessment will be used for the analysis. 
 
 
Period 
Analysis Visit 
Protocol 
Defined 
Window 
Scheduled 
Study Day 
Windows 
Screening 
Visit 1 (Screening) 
-6 Weeks to Day -1 
-41 to -1 
<= -1 
Treatment 
Visit 2/ 
Randomization (Day 1) 
Day 1 
1 
1 
Visit 3 (Week 4) 
Week 4 (±3 days) 
28 
2, 42 
Visit 4 (Week 8) 
Week 8 (±3 days) 
56 
43, 70 
Visit 5 (Week 12) 
Week 12 (±3 days) 
84 
71, 98 
Visit 6/EOT (Week 16) 
Week 16 (±3 days) 
112 
99, 119 
Follow-up 
Visit 7 (Follow-up) 
Week 18 (±3 days) 
126 
>=120 
If multiple records in the same analysis visit, the scheduled visit is preferred to the unscheduled 
visits, otherwise the one closest to the scheduled visit study day will be selected for the analysis 
and summaries. The later one is preferred if there are more than one record have the same distance 
to the scheduled study day. 
In the derivation of post baseline extreme values (e.g., minimum, maximum, worst, last), all post 
baseline assessments will be included. 
 
All data including additional unscheduled visits required for patients who need direct site 
assistance (due to AE monitoring, in order to fulfill screening requirements, and/or for safety 
maintenance) will be presented in subject listings unless otherwise specified. 
 
Missing and Partial Date 
No imputations will be done for study visit dates, birth dates, informed consent date, and 
assessment dates. 


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Partial concomitant medication, and AE start dates will be imputed as following: 
• If missing day, use the later of (01 of the month, the first dose date) if the first dose is 
at the same year and month of AE/CM, otherwise use the 01 of the month. 
• If missing day and month, use the later of (01JAN of the year, first dose date) if the 
first dose year is at the same year of AE/CM, otherwise use the 01JAN of the year. 
• If completely missing, no imputation will be applied 
Partial concomitant medication and AE end dates will be imputed as the following: 
• If missing day, use the last day of the month 
• If missing day and month, use 31st December 
• If completely missing, no imputation will be applied 
Partial initial diagnostic dates will be imputed as: if day and/or month are missing use 01 and/or 
Jan. If year is missing, then no imputation, treat the date as missing. Any other imputation will 
be based on evidence from additional data, and will be noted for each case, should it occur. 
 
2.4 CHANGES TO THE STATISTICAL ANALYSIS FROM THE PROTOCOL 
Fibrosis and inflammation markers (FIB-4, APRI, and NALFD fibrosis score (NFS)) have 
been added as exploratory endpoints. Additional analyses may include analyses of subjects 
stratifying by baseline Fib-4 at 1.3. Pro-C3 results, indicating fibrosis, may also be available for 
analysis. 
Physical examination (including general appearance, eyes, nose, throat, head/neck/thyroid, lymph 
nodes, cardiovascular, lungs/chest, abdomen, genitourinary, extremities, skin, musculoskeletal, 
neurologic, and other) as listed in protocol section 10.2.4 are not collected. 
 
2.5 IMPACT OF COVID-19 ON THE CLINICAL TRIAL 
During the data review meeting in which major protocol violations are identified, violations of the 
protocol that were the result of the COVID-19 pandemic will be noted. 
 
3 STATISTICAL ANALYSES 
3.1 SUBJECT INFORMATION 
Disposition of Subjects 
The number and percentage of subjects for the following will be summarized by randomized 
treatment group and overall where applicable: 
• Patients enrolled (who signed the informed consent) 
• Patients included in each analysis set 


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• Patients completed the study 
• Patients discontinued treatment early (including EOT reason) 
• Patients discontinued study early (including EOS reason) 
The disposition listing will include information such as: included in an analysis set, first dose date, 
end of treatment (EOT) status, end of study (EOS) status, and with EOT/EOS reasons. 
Subjects that were screen failures and the reason for screen fail will be provided in a listing. 
 
Per Version 3.0 of the protocol, subjects that are screen failures, may be rescreened if approved by 
the Medical Monitor. Subjects that have been rescreened will be noted. 
 
Protocol Deviations and Violation of Inclusion/Exclusion Criteria 
All personnel involved with the analysis of the study will remain blinded until database lock for 
the double-blind treatment period and until major protocol violations have been identified. 
Subjects who received study drug but violated any inclusion or exclusion criteria will be listed. 
Protocol deviations will be captured for each site and reviewed by the medical monitor to identify 
major protocol deviations from the list. If noted stated elsewhere, a major protocol violation is a 
deviation that has an impact on patient safety, may substantially alter risks to patients, may have 
an effect on the integrity of the study data, or may affect the patient's willingness to participate in 
the study. 
All major protocol deviations will be presented in a listing. 
 
Demographics and Baseline Characteristics 
Descriptive summaries of demographics and other baseline characteristics will be presented by 
treatment group and overall using the Safety/ITT population. These summaries will include age, 
gender, childbearing potential, race, ethnicity, height, weight and body mass index (BMI). 
Conversion factors and calculations for height and weight are: 
• Height (in cm) = height (in inches) * 2.54 
• Weight (in kg) = weight (in lbs) * 0.4536 
By subject listings for demography and baseline characteristics will be provided. 
 
Medical and Surgical History 
NASH/NAFLD history variables characteristics will be summarized by randomized treatment 
group and total on ITT. 
Medical histories include type of disease under study (NASH or NAFLD), duration of disease 
under study, NASH confirmed by live biopsy (Yes or No), and whether patients have any other 
relevant medical or surgical history. The duration of disease under study is calculated as (the date 
of randomization – date of initial diagnosis + 1)/365.25. Imputed date of initial diagnosis date will 
be used if the collected date is partial. 


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If applicable, the other relevant medical and surgical history will be coded by latest MedDRA 
version. The number (percent) of subjects reporting a history of any other relevant medical or 
surgical history, will be summarized for each randomized treatment group and overall. 
A subject data listing of medical and surgical history will be provided. 
 
Prior and Concomitant Medications 
All medications with a stop date prior to and within 3 months (92 days) of the date of first dose 
are regarded as prior medication. All medications with a start date or stop date on or after the first 
dose date are regarded as concomitant medication. Medications where start date and end date are 
both completely missing (both dates cannot be imputed) will be treated as concomitant medications. 
The number (percent) of subjects who took prior and concomitant medications will be summarized 
respectively by Anatomic Therapeutic Chemical (ATC) level and preferred term for each 
randomized treatment group and overall on ITT. Subjects taking the same medication multiple 
times will only be counted once for that ATC class and preferred term. A subject level listing will 
also be presented. 
All investigator terms for medications recorded on the CRF will be coded using the World Health 
Organization (WHO) Drug Dictionary B3, March 2019 version. 
3.2 EFFICACY ANALYSES 
Primary Endpoint 
The primary efficacy endpoint for this study is the change from baseline in serum LDL-C at week 
16. 
Change from baseline in serum LDL-C will be analyzed by using an analysis of covariance 
(ANCOVA) after the missing data imputation. The ANCOVA model will include treatment group 
as a factor, baseline LDL-C and baseline LDL-C by treatment interaction values, and baseline lipid 
lowering medications (Yes or No) as covariates. 
Serum LDL-C results and the change from baseline at each scheduled time point, along with the 
minimum and maximum post baseline value, will be summarized using descriptive statistics. 
Box plots for serum LDL-C results absolute value and change from baseline overtime will be 
provided. 
Multiple Imputation for Primary Endpoint Variable 
If a subject terminates the study prematurely, the subject’s LDL-C values may not be collected 
after termination. Since the estimand of this study is treatment difference at week 16 in the ITT 
population, a multiple imputation procedure ( 
Angulo, J. M. et al. (2007), “The NAFLD fibrosis score: A noninvasive system that identifies liver 
fibrosis in patients with NAFLD,” Hepatology, 45, 846-854. 
utilizing the regression method will be used to impute each missing data point up to week 16 with 
a set of plausible values that represent the uncertainty about the values to be imputed. The LDL- 


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C data from completers in the placebo arm will be used to impute the missing data in early 
terminators. The imputed values should have an LDL-C value that is greater than minimum of all 
observed values minus 15% or less than maximum of all observed values plus 15%. The following 
options in SAS Proc MI statement will be used to limit the minimum and maximum imputed 
values: Minimum=x and Maximum=y, where x and y are the minimum and maximum values stated 
above. With this option, when the imputed value is outside of this limit, the MI procedure redraws 
another value until the imputed value is within the limits. 
The steps below will be followed in the imputation: 
• Step 1: Non-monotone missing data at intermediate visits will be imputed for 200 times to 
generate 200 imputed datasets, so the data will have a monotone missing pattern. SAS® 
procedure PROC MI will be used for the multiple imputation. The monotone Markov Chain 
Monte Carlo (MCMC) method will be used at this step. Non-convergence may occur at this 
step. If the MCMC imputation does not converge, additional imputations will be repeated. 
The first 200 convergent MCMC imputations will be used in the analysis. 
In the SAS MI procedure at this step, the following options will be used: nimpute = 200 and 
seed = 396858. The following options will be used in the MCMC statement: impute = 
monotone, chain = multiple, initial = EM, prior = Jeffreys. In the EM statement, the option 
maxiter=200 will be used. The var statement will include treatment arm, baseline LDL-C value, 
baseline lipid lowering medications, and the change from baseline in LDL-C value at each 
scheduled post-randomization visit up to week 16. Sample SAS codes for multiple imputations 
are provided in the Appendix. 
• Step 2:    After the intermediate missing values have been imputed, subjects are categorized 
to 3 groups: 1) Completers (defined as subjects who completed the study treatment) in the 
control arm with non-missing value at week 16. 2) Subjects with a missing value at week 16 
in both arms. Missing values in these subjects will be imputed using subjects in group 1. 3) 
Completers in the active arm with non-missing value at week 16 (based on the analysis visit 
window in section 2.3). These subjects will not be used to impute missing values in the next 
step. 
• Step 3:   At this point, each subject in the 200 data sets generated at step 1 either has 
complete data or has monotone missing data. Subjects in group 1 in Step 2 will be used to 
impute missing values in subjects in group 2. Missing data in group 2 will be imputed as the 
predicted value from a regression model with treatment arm, LDL-C baseline, baseline lipid 
lowering medications, and the change from baseline of all previous scheduled visits included 
in the model. Since the dataset has a monotone missing data pattern, the imputation process 
will start from the earliest visit with missing data (e.g. week 4) through week 16 in a sequential 
order. SAS Proc MI with option Monotone Reg, nimpute=1, and seed = 25380 will be applied. 
The imputation will be done for each one of the 200 data sets generated at step 1. 
• Step 4:    After imputation for monotone missing values at Step 3, subjects in all 3 groups 
will be pooled and sorted by imputation sequence (variable name _Imputation_ from Step 1). 
• Step 5: Each imputed complete dataset will be analyzed using the analysis of covariance 
(ANCOVA) model with the randomized treatment group as a factor and baseline LDL-C values 


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as a covariate. The estimates of least-square means (lsmeans), least-square mean differences 
95% CI, and p-value will be generated for each one of the 200 imputed complete datasets. 
• Step 6: The results from the 200 complete datasets, including lsmeans and lsmean 
difference with their corresponding 95% confidence intervals, and the p-value between 
elobixibat 5 mg and placebo will be combined using SAS® procedure PROC MIANALYZE 
for statistical inference. 
The above primary efficacy analysis will be repeated using the PP population. 
 
Sensitivity Analysis for primary endpoint 
Mixed models repeated measures (MMRM) analysis based on both imputed data and observed 
data will be used as sensitivity analysis. The explanatory variables will include treatment, week, 
baseline value, baseline lipid lowering medications, treatment-by-week interaction, and treatment- 
by-baseline interaction, with unstructured covariance model across week. The average treatment 
effect at Week 16 (lsmeans with 95% CI for each treatment group and lsmean difference with 95% 
CI) will be provided as both tables and figures. Additional MMRM analyses may include the 
addition of other model covariates such as age at baseline, sex, and baseline FIB-4 (dichotomized 
at ≥1.3). An additional series of models may include percent change from baseline as the 
dependent variable. 
A plot of fitted values versus residuals and the residual QQ Plot will be used to check the ANCOVA 
model assumptions. If there are concerns about the model assumptions, i.e., normality and 
homogeneity of variances, a non-parametric ANCOVA based on the rank scores will be used as a 
sensitivity analysis as well. 
 
Secondary Efficacy Endpoints 
A summary of descriptive statistics of the absolute change from baseline to week 16 in liver fat 
fraction (%) as measured by MRI-PDFF and total liver fat (mL) as measured by MRI will be 
provided. 
The test results and changes from baseline at each scheduled time point, including week 16 and 
Follow-up, will be summarized for the following variables: 
• Serum ALT, AST, and gamma-glutamyl transferase 
• HDL-C, non-HDL-C, LDL-C/HDL-C ratio, and triglycerides 
• Total bile acids 
The minimum and maximum post baseline value for each above lab test will be included in the 
visit summaries. 
The change from baseline at week 16 will be analyzed using the analysis of covariance (ANCOVA) 
with the treatment group as a factor and the corresponding baseline value as a covariate. The model 
assumptions for each secondary efficacy endpoint will be evaluated before the analysis. If there 
are concerns about the model assumptions, i.e., normality and homogeneity of variances, non- 


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parametric ANCOVA based on the rank scores will be used. No missing data imputation for 
secondary efficacy endpoints. 
MMRM figures of change from baseline by study arm and the difference between study arms will 
be generated for all secondary endpoints. 
 
Exploratory Efficacy Endpoints 
The test results and change from baseline (unless otherwise specified) to week 4, week 8, week 12, 
week 16, and follow-up, will be summarized for the following variables: 
• Fasting glucose, insulin, homeostatic model assessment-insulin resistance, HbA1c, free 
fatty acids 
• GLP-1, FGF-19, and C4 levels 
• High-sensitivity CRP 
• Lanosterol and beta-sitosterol 
• Body weight, BMI, waist circumference, and waist-to-hip ratio (Physical examination) 
• Apolipoprotein A1 and Apolipoprotein B 
• Fibrosis and inflammation markers: FIB-4, APRI and NFS 
By patient figures (spaghetti plots) plots for the absolute value and change from baseline over time 
will be provided for each efficacy endpoint. An MMRM of change from baseline will be provided 
for all efficacy endpoints. Two plots for each MMRM analysis will be provided, one figure by 
treatment arm, and a second figure for the contrast between treatment arms. Correlation matrices 
will be provided for efficacy endpoints overall, by treatment, and by treatment by study visit. 
FIB-4 = [Age (years) × AST (U/l)]/[Platelet(×109/l) × (ALT(U/l))0.5] 
APRI = [[AST (IU/l)/AST (ULN)]/ Platelet(×109/l)] × 100 
NAFLD fibrosis score = −1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × 
IFG/diabetes (yes = 1, no = 0) + 0.99 × AST/ALT ratio − 0.013 × platelet (×109/l) − 0.66 × 
albumin (g/dl) 
Additional analyses may be performed to identify differences in treatment effect by baseline 
characteristics, such as dichotomized subjects by FIB-4 <1.3, and ≥1.3, BMI (<30/≥30), type 2 
diabetes (Y/N), cardiovascular co-morbidities (Y/N), lipid lowering concomitant medications 
(Y/N), and LDL-C (by < /≥ median value). 
 
3.3 STUDY DRUG EXPOSURE AND TREATMENT COMPLIANCE 
Exposure will be analyzed by calculating the number of days with exposure to study drug. 
Descriptive summary statistics will be provided using the safety population. 


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The treatment compliance will be calculated as (the actual total dose / the expected total dose) 
×100, where: 
• The actual total dose = (total number tablets of dispensed – total number of tablets 
returned) × 5 (Note: If tablets were not returned, the data will be considered missing.) 
• The expected total dose = (last dose date – first dose date +1) × 5 
The number of patients with an overall study treatment compliance <80%, between 80% and 120%, 
and >120% will be presented based on the safety population. 
Treatment compliance for below time periods will be calculated and presented as the same 
categories as overall compliance: 
• Day 1 to Week 4 [study day 1 to study day 28] 
• Week 4 to Week 8 [study day 29 to study day 56] 
• Week 8 to Week 12 [study day 57 to study day 84] 
• Week 12 to Week16 [study day 85 to study day 112] 
A subject level listing for study drug exposure (the first dose date, last dose date, duration of 
treatment) and compliance (including overall compliance and compliance by each time period 
defined above) will be presented. 
Study drug dispensing and accountability will be listed as well. 
 
3.4 SAFETY ANALYSIS 
All safety analyses will be performed on the safety population. No inferential statistics will be 
performed; only summary statistics will be provided unless otherwise noted. Safety data will be 
presented by actual treatment group. 
Safety variables include AEs, vital signs, 12-lead ECG, and clinical laboratory results. 
 
Adverse Events 
Adverse events will be coded to primary System Organ Class (SOC) and preferred term (PT) using 
MedDRA Version (Version 22.0). 
TEAEs will be defined as AEs that are new or worsening after the first dose of study drug AEs 
with missing onset and end date will be considered as a TEAE. . Serious adverse events (SAEs) 
are captured in the CRF and are determined by the investigator based on protocol section 10.1.1.2. 
Adverse events of special interest (AESIs) are recorded in the CRF and are defined in protocol 
section 10.1.1.3. 
A general summary or patients with TEAEs, SAEs and AESIs will be tabulated with numbers and 
percentages of patients per treatment group. The number of AEs leading to withdrawal and SAEs 
leading to death will also be summarized. 
The incidence of TEAEs will be reported as the number (percent) of subjects with TEAEs within 
SOC and PT. Subjects will be counted only once within a SOC and PT, even if the subject 


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experienced more than one TEAE within a specific SOC and PT. The number (percent) of subjects 
with TEAEs will also be summarized by severity (mild, moderate, or severe) and relationship 
(unrelated, unlikely related, possibly related, probably related, or definitely related) as captured in 
the CRF. The relationship of each AE to the study drug will be grouped as related (unlikely related, 
possibly related, probably related, or definitely related, missing) or unrelated. 
The following incidence summary tables will be provided: 
• All TEAEs 
• All TEAEs by severity 
• All TEAEs by relationship 
• AEs with outcome of death 
• Serious TEAEs 
• Serious TEAEs related to study drug 
• AEs leading to discontinuation of treatment 
• All treatment emergent AESI 
By subject listings for all AEs (including TEAE and non-TEAE), serious TEAE, treatment 
emergent AESI, related TEAE, AEs leading to study drug discontinuation, and AEs with an 
outcome of death will be provided. 
 
Vital Signs 
Evaluation of vital signs (systolic and diastolic blood pressure, pulse, respiratory rate and body 
temperature) will be performed at all visits. Vital signs will be summarized as actual value and 
change from baseline for each treatment group at each scheduled assessment. 
A listing of all vital sign assessments will be presented. 
 
12-Lead ECG 
ECG assessments are performed at the Screening visit and the EOT visits. Descriptive statistics 
for ECG parameters (Heart rate, PR Interval, QRS Interval, QT Interval and QTC Interval) and 
changes from baseline at each scheduled timepoint will be presented by treatment group. 
A subject data listing will present changes from baseline in ECG results captured in the CRF 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically significant) 
to end of treatment. 
 
Laboratory Tests 
Descriptive summaries of laboratory data (for clinical chemistry, hematology/coagulation, 
urinalysis, lipid profile, endocrinology, bile acids, serology, and other tests as listed in the 
Appendix) will be presented for the safety analysis set along with listings of lab data collected. 
Laboratory results at each scheduled visit will be summarized by actual treatment group, along 


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with changes from baseline to each post-baseline visit. Values outside of the reference range will 
be flagged in the listings. 
Shift tables for the shift from baseline with respect to the reference normal range will be provided. 
Laboratory abnormalities of special interest will be summarized. 
Pregnancy Test 
For all females of child-bearing potential, a listing of pregnancy test including test date, test result 
and reason if test not taken will be presented. 
 
4 
MINIMIZING RISK TO TRIAL INTEGRITY DURING THE COVID-19 
PANDEMIC 
Missed or delayed study visits as a result of the COVID-19 pandemic have occurred. A listing of 
missed study visits and procedures will be provided. Should the MRI not occur on schedule, that 
is at the last visit on treatment, the validity of the liver fat quantification (measured by MRI PDFF) 
results may be compromised, as the potential effects of study drug on liver fat are expected to 
decrease once study treatment is stopped, although the speed of this loss of potential response is 
unknown. This loss of documented benefit may also be seen with other efficacy-based laboratory 
tests. For this reason, these endpoints may be tested in the per protocol population, in addition to 
the ITT population. 


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REFERENCES 
 
Angulo, J. M. et al. (2007), “The NAFLD fibrosis score: A noninvasive system that identifies liver 
fibrosis in patients with NAFLD,” Hepatology, 45, 846-854. 
 
Barnard, J. and Rubin, D.B. (1999), “Small-Sample Degrees of Freedom with Multiple Imputation,” 
Biometrika, 86, 948–955. 
 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency Guidance for Industry, Investigators, and Institutional Review Boards March 2020 
Updated on May 14, 2020. 
 
Lin ZH, Xin YN, Dong QJ, et al. (2011), “Performance of the aspartate aminotransferase-to- 
platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. 
Hepatology,” 53, 726-36. 
 
Rubin, D.B. (1987). Multiple Imputation for Nonresponse in Surveys, John Wiley & Sons, Inc. 


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5 
STERLING RK, LISSEN E, CLUMECK N, ET. AL. (2006), “DEVELOPMENT 
OF A SIMPLE NONINVASIVE INDEX TO PREDICT SIGNIFICANT 
FIBROSIS PATIENTS WITH HIV/HCV CO-INFECTION,” HEPATOLOGY, 43, 
1317-1325.APPENDIX 
Schedule of Assessments 
 
VISIT 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP 
PERIOD 
VISIT 1 
VISIT 2/ 
RANDOMIZA- 
TION 
VISIT 
3 
VISIT 
4 
VISIT 
5 
VISIT 6/ 
END OF 
TREATMENT 
VISIT 7 
STUDY WEEK 
WEEK -6 
TO DAY -1 
DAY 1 
WEEK 
4 
WEEK 
8 
WEEK 
12 
WEEK 16 
WEEK 18 
VISIT WINDOW 
±3 
DAYS 
±3 
DAYS 
±3 
DAYS 
±3 DAYS 
±3 DAYS 
Informed consent 
Medical/surgical historyf 
Demographics 
Serologya 
Review alcohol 
consumptionj 
X 
Inclusion/exclusion criteria 
X 
X 
Randomizationg 
X 
12-lead ECG 
X 
X 
Physical examinationb 
X 
X 
X 
Vital signsc 
Pregnancy testd 
Clinical safety laboratory 
testsh 
GLP-1, FGF-19, C4h 
Total bile acidsh 
Lipid profileh 
Store blood samplesi 
X 
X 
X 
X 
X 
X 
X 
MRIe 
X 
X 
Endocrinologyh 
X 
X 
X 
X 
Fibrosis and inflammation 
markersh 
X 
X 
X 
High-sensitivity CRP 
X 
X 
X 
Dispense study drug 
X 
X 
X 
X 


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Review concomitant 
medications and adverse 
events 
X 
X 
X 
X 
X 
X 
X 
 
a Includes hepatitis B virus surface antigen and hepatitis C virus antibody and RNA 
b Includes height (at Screening only), weight, waist circumference, and waist-to-hip ratio. Body mass index will be calculated 
based on height and weight. A full physical examination will be performed at Screening and at Visits 2 and 6. 
c Vital signs include blood pressure, heart rate, respiratory rate, and oral body temperature. 
d For women of childbearing potential, a serum pregnancy test will be performed at Screening, and a urine pregnancy test will 
be performed at each visit at which study drug is dispensed. 
e Patients will have MRI to measure liver fat (PDFF), and total liver volume. Patients who discontinue before Visit 6 (Week 16) 
should have an MRI performed at End of Treatment if they completed at least 4 weeks of treatment. 
f    Liver biopsy results for confirmed NASH within 6 months of Screening to confirm patient eligibility will be collected in the 
eCRF, if available. g Randomization will occur at Visit 2 to assign patients to either 5 mg/day elobixibat or placebo in 1:1 ratio. 
h Laboratory Parameters. Clinical safety laboratory tests include clinical chemistry, hematology/coagulation, and urinalysis i 
j History of alcohol consumption will be obtained at Screening. 
 
Abbreviations: C4: 7α-hydroxy-4-cholesten-3-one; CRF: case report form; CRP: C-reactive protein; ECG: electrocardiogram; 
EOT: End of Treatment; FGF-19: fibroblast growth factor-19; GLP-1: glucagon-like peptide-1; INR: international normalized ratio; 
MRI: magnetic resonance imaging; NASH: nonalcoholic steatohepatitis; PDFF: proton density fat fraction 


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Laboratory Parameters 
 
CLINICAL CHEMISTRY 
(FASTING) 
HEMATOLOGY/ 
COAGULATION 
URINALYSIS 
Albumin 
Hematocrit 
Bilirubin 
ALT [b] 
Hemoglobin 
Blood 
Alkaline phosphatase 
Platelet count 
Glucose 
Amylase 
Red blood cell count 
Ketones 
AST [b] 
White blood cell count 
Leukocytes esterase 
Bicarbonate 
Neutrophils 
Nitrites 
Blood urea nitrogen 
Eosinophils 
Microscopy including leukocytes (if 
applicable) 
Calcium 
Basophils 
pH 
Chloride 
Lymphocytes 
Protein 
Creatine kinase 
monocytes 
Specific gravity 
eGFR by MDRD (screening only) 
International normalized ratio (INR) 
Urobilinogen 
Gamma-glutamyl transferase [b] 
Prothrombin time 
Glucose [c] 
Hemoglobin HbA1c [c] 
Inorganic phosphorus 
Lactate dehydrogenase 
Lipase 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
LIPID PROFILE (FASTING) 
OTHER TESTS 
ENDOCRINOLOGY 
Apolipoprotein A1 [c] 
High-sensitivity C-reactive protein 
(CRP) [c] 
Follicle-stimulating hormone2 
Apolipoprotein B [c] 
C4 [c] 
Homeostatic model assessment-insulin 
resistance [c] 
Chylomicron cholesterol 
Fibroblast growth factor-19 (FGF-19) 
[c] 
Insulin [c] 
Chylomicron triglycerides [b] 
FIB-4 
Thyroxine3 
High-density lipoprotein (HDL) 
cholesterol [b] 
APRI 
Triiodothyronine3 
Lipoprotein(a) cholesterol [b] 
NAS 
Thyroid-stimulating hormone3 
Low-density lipoprotein (LDL) 
cholesterol 1[a] 
Glucagon-like peptide-1 (GLP-1) [c] 
Free fatty acids [c] 
LDL triglyceride [b] 
Adipose tissue insulin resistance 


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Non-high-density lipoprotein 
cholesterol [b] 
Adiponectin 
Total cholesterol 
Triglycerides [b] 
Very low-density lipoprotein (VLDL) 
cholesterol 
VLDL triglyceride 
Lanosterol [c] 
Beta-sitosterol [c] 
BILE ACIDS (FASTING) 
PREGNANCY 
SEROLOGY 
Total bile acids [b] 
Serum 
Hepatitis B virus surface antigen 
Urine 
Hepatitis C virus antibody and 
ribonucleic acid 
1. LDL-cholesterol will be determined by calculation when triglyceride levels are less than or equal to 400 mg/dL, LDL-C will be 
determined by preparative ultracentrifugation when triglyceride levels are greater than 400 mg/dL. 
2. A postmenopausal state is defined as no menses for ≥12 months without an alternative medical cause. A follicle-stimulating 
hormone level in the postmenopausal range will be used to confirm a postmenopausal state in women ≤55 years of age, performed 
at Screening visit only. 
3. Thyroid function test will be performed during Screening visit only. 
[a] Primary efficacy endpoint. 
[b] Secondary efficacy endpoints. 
[c] Exploratory efficacy endpoints. 


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SAS sample code for multiple imputation 
• For subjects terminated the study prematurely: 
/*Step 1 Non-monotone missing data at intermediate visits will be imputed to generate 
imputed dataset using MCMC method. */ 
PROC MI data=LDL-C out=Mono round=0.1 
seed=396858 nimpute=200; 
MCMC IMPUTE=monotone; 
VAR trtp base lipid_low chg1 chg2 chg3 chg_eot; 
RUN; 
Where chg1- chg3 represents the change from baseline at week 4, week 8, and week 
12; chg_eot represents the change from baseline at week 16. 
 
/*Step 2: subjects are categorized to the following groups**/ 
data Mono_1 grp3; 
set Mono; 
if trtp='Placebo' and chg_eot^=. then do; group=1; output 
Mono_1; end; 
if chg_eot=. and not (trtp=’Drug’ and completer=’Y’) then do; 
group=2; output Mono_1; end; 
if trtp='Drug' and chg_eot^=. then do; group=3; output grp3; end; 
if trtp=’Drug’ and completer=’Y’ and chg_eot=. then do; 
group=4; output grp3; end; 
run; 
 
/*Step3 use group1 and group2 to do imputation*/ 
PROC MI data=Mono_1 out=imputed_1 seed=25380 nimpute=1; 
By _imputation_; 
CLASS group; 
VAR trtp base lipid_low chg1 chg2 chg3 chg_eot; 
MONOTONE reg(chg1=base lipid_low); 
MNAR model (chg1/modelobs = (group=’1’)); 
MONOTONE reg(chg2=base lipid_low chg1); 
MNAR model (chg2/modelobs = (group=’1’)); 
MONOTONE reg(chg3=base lipid_low chg1 chg2); 
MNAR model (chg3/modelobs = (group=’1’)); 
MONOTONE reg(chg_eot=base lipid_low chg1 chg2 chg3); 
MNAR model (chg_eot/modelobs = (group=’1’)); 
RUN; 
 
/*Step 4 After imputation for monotone missing values at Step 3, subjects in all 3 groups 
will be pooled and sorted */ 
data imputed; 
set imputed_1 grp3; 


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proc sort; 
by _Imputation_; 
run; 
 
/*Step 5: perform ANCOVA for 200 times using imputed datasets*/ 
PROC MIXED data=imputed plots(maxpoints=none); 
by _Imputation_; 
CLASS trtp; 
MODEL chg_eot=trtp base trtp*base; 
LSMEANS trtp/diff cl; 
ODS OUTPUT diffs=diffs lsmeans=lsmeans; 
RUN; 
 
proc sort data=lsmeans; 
by trtp _Imputation_; 
run; 
 
/*Step 6: Sample code for combining lsmeans and diffs is as below*/ 
PROC mianalyze data=lsmeans; 
BY trtp; 
MODELEFFECTS estimate; 
STDERR stderr; 
RUN; 
 
PROC mianalyze data=diffs; 
MODELEFFECTS estimate; 
STDERR stderr; 
RUN; 
 
 
• In case there is any missing week-16 serum LDL-C for on-treatment subjects in the active arm, 
the same imputation method will be performed using the completers’ data in the active arm. 
Note that placebo completers with a missing week-16 LDL-C will be imputed by subjects with 
non-missing week-16 value in the same arm in steps 2 and 3 above. 
 
 
/* Step 3.2: Execute the following code there is any missing week-16 serum LDL-C for 
on-treatment subjects in the active arm. Then, continue to step 4 above. */ 
 
PROC MI data=grp3 out=grp3 seed=25380 nimpute=1; 
By _imputation; 
CLASS group; 
VAR base lipid_low chg1 chg2 chg3 chg_eot; 
MONOTONE reg(chg1= base lipid_low); 
MNAR model (chg1/modelobs = (group=' '3')); 


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MONOTONE reg(chg2= base lipid_low chg1 ); 
MNAR model (chg2/modelobs = (group= ' '3')); 
MONOTONE reg(chg3= base lipid_low chg1 chg2); 
MNAR model (chg3/modelobs = (group= '3')); 
MONOTONE reg(chg_eot= base lipid_low chg1 chg2 chg3); 
MNAR model (chg_eot/modelobs = (group= '3')); 
RUN; 
 
 
SAS sample code for MMRM 
proc mixed data=mmrm method=reml; 
class trtp usubjid week lipid_low; 
model chg= trtp base lipid_low trtp*base week trtp*week; 
repeated week/ type = un subject=subnum; 
lsmeans week /pdiff cl; 
ods output lsmeans = lsmeans ; 
run; 
 
Note: variables included in the model and class statement varies for different endpoints;