Conditions: Alcohol Consumption
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: yes

Brief summary:
The main purpose of this study is to see whether heavy drinking will interfere with a specific pathway, called FXR signaling in the liver. The abnormality of this pathway may lead to liver injury in some patients who drink heavily.

Detailed description:

Arms:
arm 1: Heavy Drinkers on placebo arm 2: 10 mg Obeticholic Acid (OCA) Study medication will be administered orally, once daily for 4 weeks. arm 3: Non-drinking healthy controls

Interventions: intervention 1: Placebo intervention 2: 10 mg Obeticholic Acid (OCA)
Intervention descriptions: intervention 1: 1 tablet of placebo, taken orally daily with water, approximately 30 minutes prior to breakfast for 4 weeks. intervention 2: 10 mg Obeticholic Acid (OCA) Study medication will be administered orally, once daily, approximately 30 minutes prior to breakfast for 4 weeks.

Protocol document:
Prot_SAP_000.pdf: 
 
 
TREAT Protocol 005 
Obeticholic Acid (OCA) 
 
EFFECT OF HEAVY ALCOHOL CONSUMPTION ON FARNESOID X RECEPTOR 
(FXR) SIGNALING 
 
ClinicalTrials.Gov Identifier:  NCT02654236 
 
Version 3:  January 18, 2019 
 
 
 
 
Revised:  January 22, 2020 
 
 
 
 
Investigators: 
Indiana University:  Suthat Liangpunsakul, Naga Chalasani, David Crabb  
 
Disclosure 
This study is conducted the TREAT consortium which is funded by the National Institute of 
Alcohol Abuse and Alcoholism (NIAAA) to pursue translational investigations in alcoholic 
hepatitis.  TREAT Consortium contains Indiana University School of Medicine (Indianapolis, 
IN), Mayo Clinic (Rochester, MN) and Virginia Commonwealth University (Richmond, VA). 
Study drug and matching placebo are kindly provided by Intercept Pharmaceuticals, Inc.   
Some of the information contained herein is the property of Intercept Pharmaceuticals, Inc. 
and may not be reproduced, published, or disclosed to others without written authorization of 
Intercept Pharmaceuticals, Inc. 


 
 
 
 
Page 2 of 38 
 
SYNOPSIS 
Title of Trial 
Effect of alcohol consumption on farnesoid x receptor (FXR) signaling  
Name of Active Ingredient 
Obeticholic Acid (OCA; 6α-ethyl chenodeoxycholic acid; 6-ECDCA) also known as INT-747 
 
Investigational Site 
Indiana University Hospital, Indianapolis, Indiana 
 
Planned Number of Patients 
Approximately 45 subjects [healthy non-drinker controls (n=15) and heavy drinkers (n=30)].    
 
Hypotheses & Objectives 
 
1. To test the hypothesis that heavy alcohol consumption impairs farnesoid X receptor 
(FXR, the bile salt nuclear receptor) signaling which results in increased hepatocyte 
bile salt levels which cause liver injury.   
 
2. To test the hypothesis that impaired FXR signaling resulting from heavy alcohol 
consumption impairs gut integrity, promotes activation of Kupffer cells, enhances 
hepatic 
oxidative 
stress, 
and 
sensitizes 
hepatocytes 
to 
cytokine-induced 
necroapoptosis, and that these abnormalities can also be reversed with OCA.  
 
Design 
This study consists of two groups of participants – heavy drinking adults (n=30) and non-
drinking healthy controls (n=15).  There are two components to this study – initial cross-
sectional component followed by a 4 week longitudinal component.  We are seeking to 
increase the overall number of subjects allowed to be consented to 150 to ensure that 30 
heavy drinking adults can complete this study.   
 
In the cross-sectional component, both groups of participants will undergo testing for bile acid 
metabolism, markers of gut integrity, oxidative stress, and inflammatory cytokines. 
 
Both groups of participants will participate in the longitudinal component.  While healthy 
controls will not receive any specific intervention, participants in the heavy drinking group will 
be randomized to receive either OCA (10 mg/day) or placebo for 28 days.  At the end of 4 
weeks, both groups of participants will again undergo testing for bile acid metabolism, markers 
of gut integrity, oxidative stress, and inflammatory cytokines.  
 


 
 
 
 
Page 3 of 38 
 
Schematic Diagram  
 
Methodology 
Screening phase 
Subjects will be assessed for the eligibility criteria and a written informed consent will be 
obtained from the eligible subjects.  
 
Treatment phase,  
 
This investigation will consist of the following 2 study groups:   
Group A:  Healthy non-drinker controls (n = 15) 
Group B:  Heavy drinkers with no known history of liver disease  (n=30) 
 
 
Heavy alcohol drinking will be defined as ongoing consumption > 40 grams per day or >98 
grams in a week on average in women and > 60 grams per day or >196 grams in a week on 
average in men for a minimum of the past 6 months and within the 3 months prior to study 
enrolment.  Judgment regarding daily and yearly alcohol use will be made by the site 
investigator. During recruiting we will inform the patient that this level of drinking is harmful 
and will offer referral for treatment.  Absence of liver disease will be ascertained according to 
predefined criteria. Alcohol consumption will be quantified by interview and by a standard 
alcohol consumption questionnaire.  
 
 
Follow-up Phase: 
 
Heavy Drinker group will return to the clinic on Day 42 


 
 
 
 
Page 4 of 38 
 
 
Key Inclusion Criteria: 
 
(a)   Individuals ≥ 21 – 65 years old   
(b) Able to provide informed consent & negative urine pregnancy test where 
appropriate 
(c) Healthy controls must not have consumed any alcohol within 3 months prior to the 
screening visit 
(d) Healthy controls (non drinkers) must have normal ALT and AST values (<45 U/L) 
(e) Heavy drinkers must have ALT and AST lab values <100 U/L 
(f) Heavy alcohol drinking is defined as > 40 grams per day or >98 grams in a week 
on average in women and > 60 grams per day or >196 grams in a week on average 
in men for a minimum of 6 months and within the 3 months prior to study enrolment.  
Judgment regarding daily and yearly alcohol use will be made by the site 
investigator. 
 
Exclusion Criteria: 
 
(a) Active infection as evidenced by positive urine culture, blood culture, or   
pneumonia, if necessary, after review of safety labs showing abnormalities, or 
determination by physical exam performed by PI/sub-I. 
(b) Serum creatinine > 1.5 mg/dL 
(c) Known co-existing infection with hepatitis C, hepatitis B, or HIV 
(d) Significant systemic or major illness including COPD, CHF and renal failure that 
in the opinion of the Investigator would preclude the patient from participating in 
and completing the study. 
(e) Participation in another investigational drug, biologic, or medical device trial within 
30 days prior to Screening 
(f)  Previous history of jaundice or signs of liver diseases such as spider angiomata, 
ascites, portal hypertension, or history of esophageal varices or hepatic 
encephalopathy 
(g) Total bilirubin > 2 mg/dl and INR > 1.5 
(h) Women who are pregnant or nursing 
(i)   Presence of any other disease or condition that is interfering with the absorption, 
distribution, metabolism, or excretion of drugs including bile salt metabolism in 
the intestine.  Patients who have undergone gastric bypass procedures will be 
excluded (gastric lap band is acceptable). 
(j)   Subjects who are taking warfarin  
 
    
Treatment Regimen 
1 tablet of placebo or 10 mg OCA as directed, taken daily with water, approximately 
30 minutes prior to breakfast  
 
Route of Administration 
Oral 


 
 
 
 
Page 5 of 38 
 
 
Duration of Treatment 
The duration of treatment will be 4 weeks.   
 
Study Measurements:   
The primary end points of interest are measures of FXR effect on bile salt metabolism (C4) 
and FGF19 levels.   
Secondary endpoints are measures of:  
(a) fasting serum bile salt 
(b) oxidative stress and CYP2E1 activity;  
(c)  gut permeability, bacterial translocation, and intestinal inflammation;  
(d) activation of innate immunity.    
 
Primary Objectives 
Variable 
Measuring surrogates of 
FXR activity 
Serum FGF19, C4 levels 
 
Secondary Objectives 
 
Clinical laboratory values:  
 
Fasting serum bile salt levels  
Adipocyte function (fasting NEFA, insulin, adiponectin), 
Oxidative stress (malondialdehyde, 8-isoprostane) 
CYP2E1 activity by chlorzoxazone clearance 
Gut permeability (lactulose/mannitol test) 
Bacterial translocation (plasma LPS, serum sCD14), Cytokine 
measurements (serum TNF-α, IL-1, IL-6, and IL-8) 
Intestinal inflammation (stool calprotectin). 
Any AE and SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Page 6 of 38 
 
 
 
 
 
 


 
 
 
 
Page 7 of 38 
 
TABLE OF CONTENTS 
SYNOPSIS ................................................................................................................ 2  
LIST OF PERSONNEL .............................................................................................. 8 
SPONSOR’S APPROVAL OF THE PROTOCOL ...................................................... 9 
INVESTIGATOR’S PROTOCOL APPROVAL PAGE ............................................... 10 
ABBREVIATIONS. ................................................................................................... 11 
1. INTRODUCTION AND RATIONALE .................................................................. 13 
1.1 Rationale .................................................................................................... 13 
1.2 Nonclinical Experience with Study Medication…………………………….....14  
1.3 Clinical Experience with Obeticholic Acid (OCA)..........................................15 
1.4 Rational for Trial Design and Dose for Study Medication…………………...15 
2. STUDY OBJECTIVES ........................................................................................ 16 
2.1 Primary Endpoints ...................................................................................... 16 
2.2 Secondary Endpoints ................................................................................. 16 
3. INVESTIGATIONAL PLAN ................................................................................. 17 
3.1 Overall Trial Design and Plan ..................................................................... 17 
3.2 Schedule of Study Procedures ................................................................... 18 
3.3 Duration of Trial by Phase .......................................................................... 18 
4. PATIENT SELECTION ....................................................................................... 19 
4.1 Patient Population ...................................................................................... 19 
4.2 Inclusion / Exclusion Criteria ...................................................................... 19 
4.3 Patient Withdrawal from the Trial ................................................................ 20 
5. INVESTIGATIONAL PRODUCT (IP) .................................................................. 20 
5.1 Description of IP ......................................................................................... 20 
5.2 Study Medication ........................................................................................ 21 
5.3 Packaging, Labelling and Storage .............................................................. 21 
5.4 Dose and Administration ............................................................................ 21 
5.5 Prior and Concomitant Medications or Procedures .................................... 22 
5.6 Treatment Compliance ............................................................................... 22 
5.7 Study Medication Accountability and Retention .......................................... 22 
5.8 Trial or Site Termination ............................................................................. 22 
6. TRIAL PROCEDURES ....................................................................................... 23 
6.1 Screening. .................................................................................................. 23 
6.2 Visit Procedures ......................................................................................... 23 
6.3   Physical Examination and Vital Signs...……..……………………………..….25 
6.4   Clinical Laboratory. ………………………………………..…………………….26 
6.5   Electrocardiogram………………………………………………………………..26 


 
 
 
 
Page 8 of 38 
 
7. ADVERSE EVENTS ........................................................................................... 26 
7.1 Definition and Reporting Period for Adverse Events ................................... 26 
7.2   Severity of AEs.…………………………………………………………………..27 
7.3   Relationship of AEs to Study Medication.……………………………………..27 
7.4   Definition of Serious Adverse Event..………………………………………….28 
7.5   Reporting SAEs. …………………………………………………………………29 
7.6   Notification of Post Trial SAE…………………………………….……………..30 
7.7   Follow Up of AEs …..…………………………………………………………….31 
8. DRUG INTERACTION…………………………………………………………………..32 
9. STASTICAL METHODS. ……………………………………………….....................32  
9.1 Cross-sectional Component ....................................................................... 32 
9.2 Longitudinal Component ............................................................................. 32 
9.3 Safety Analysis ........................................................................................... 33 
10. ADMINISTRATIVE AND REGULATORY CONSIDERATIONS .......................... 33 
10.1 Ethical Conduct of the Trial ........................................................................ 33 
10.2 Institutional Review Board (IRB) ................................................................. 34 
10.3 Patient Confidentiality and Data Protection ................................................ 34 
10.4 Access to Source Documents and Data ..................................................... 34 
11. 
References ................................................................................................. 36 
 
 
LIST OF TABLES 
Table 1 
Schedule of Trial Procedures – .......................................................... 18 
Table 2 
Severity of AEs ................................................................................... 27 
Table 3 
Relationship of AEs to Study Medication ............................................ 28 
 
LIST OF FIGURES 
Figure 1 
Schematic Diagram of treatment protocol.............................................3   
 
 
 


 
 
 
 
Page 9 of 38 
 
LIST OF PERSONNEL 
Investigation Site  
 
Indiana University, Indianapolis, IN 
Site investigators 
Suthat Liangpunsakul, MD 
David W. Crabb, MD 
Naga P. Chalasani, MD 
 
Division of Gastroenterology and Hepatology 
Department of Medicine 
Indiana University School of Medicine 
702 Rotary Circle (Ste 225)  
Indianapolis, IN 46202 
 
Research Coordinators 
 
Jennifer Lehman, RN, CCRP 
 
Division of Gastroenterology and Hepatology 
Department of Medicine 
Indiana University School of Medicine 
702 Rotary Circle (Ste 225) 
Indianapolis, IN 46202 
 
SAE Reporting 
Contact: 
Samir Gawrieh, MD 
Telephone: 
1-317-278-1216 
Email: 
 sgawrieh@iu.edu 
SAE Email: 
 sgawrieh@iu.edu and sliangpu@iu.edu 
 


 
 
 
 
Page 10 of 38 
 
SPONSOR’S APPROVAL OF THE PROTOCOL 
 
 
Reviewed and Approved by: 
 
 
 
___________________________________ __5/23/2018___ 
Suthat Liangpunsakul, MD 
 
 
 
Date                           


 
 
 
 
Page 11 of 38 
 
INVESTIGATOR’S PROTOCOL APPROVAL PAGE 
 
I have received and read the current version of the Investigator’s Brochure (IB) for OCA and 
this Protocol TREAT-005.  Having fully considered all the information available, I agree that it 
is ethically justifiable to give OCA to selected subjects/patients according to this protocol. 
I understand that all information concerning OCA supplied to me by the Supporter, Intercept 
Pharmaceuticals, Inc., and/or its agents in connection with this trial and not previously 
published is confidential information. This includes the IB, and any other preclinical and clinical 
data provided by the Supporter. 
I understand that no data are to be made public or published without prior knowledge and 
written approval by the Supporter. 
By my signature below, I hereby attest that I have read, understood and agreed to abide by 
all the conditions, instructions and restrictions contained in Protocol TREAT-005 and in 
accordance with Good Clinical Practice (CPMP/ICH/135/95), 21CFR Part 312 and all 
applicable regulatory requirements. 
 
 
Suthat Liangpunsakul 
 
 
Investigator’s Name (Printed) 
 
 
 
 
 
5/23/2018 
Investigator’s Signature 
 
Date 
 


 
 
 
 
Page 12 of 38 
 
ABBREVIATIONS 


 
 
 
 
Page 13 of 38 
 
Abbreviation 
Definition 
AE(s) 
adverse event(s)  
ALT  
alanine aminotransferase 
ALP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
BA 
bile acid(s) 
BL 
Baseline 
BP 
blood pressure 
β-hCG 
beta human chorionic gonadotrophin 
BUN 
blood urea nitrogen 
CA 
cholic acid 
CDCA 
chenodeoxycholic acid 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organisations of Medical Sciences 
Cmax 
maximum concentration 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRP 
C-reactive protein 
DCA 
deoxycholic acid 
dL 
deciliter(s) 
DSMB 
Data and Safety Monitoring Board 
eCRF 
electronic case report form 
ECG 
Electrocardiogram 
ELISA 
enzyme linked immunosorbent assay 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor-19 
FXR 
farnesoid X receptor 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HbA1c 
hemoglobin A1c test 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
INR 
international normalized ratio 


 
 
 
 
Page 14 of 38 
 
Abbreviation 
Definition 
IRB 
Institutional Review Board 
IL-6 
Interleukin-6 
kg 
Kilogram 
LCA 
lithocholic acid 
LDL 
low-density lipoprotein 
MELD 
Model for End Stage Liver Disease 
mg 
milligram(s) 
mL 
milliliter(s) 
msec 
Millisecond 
NAFLD 
nonalcoholic fatty liver disease 
NASH 
nonalcoholic steatohepatitis 
OCA 
obeticholic acid 
PBC 
primary biliary cirrhosis 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PO 
Orally 
PSC 
primary sclerosing cholangitis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
Sponsor 
Intercept Pharmaceuticals, Inc. 
SUSAR 
suspected, unexpected serious adverse reaction 
TE 
transient elastography 
TNF-α 
tumor necrosis factor-alpha 
UDCA 
ursodeoxycholic acid 
VLDL 
very low density lipoprotein 
vs 
Versus 
WBC 
white blood cell 
WNL 
within normal limits 
 
 
 
 
 
 
 
 


 
 
 
 
Page 15 of 38 
 
1. INTRODUCTION AND RATIONALE 
1.1 
RATIONALE 
    
 
Alcoholic liver disease (ALD) is a complex disorder and its pathogenesis is a multi-step 
and multi-factorial process that progresses through a series of histopathological changes 1. 
More than 90% of drinkers develop alcoholic steatosis which is reversible upon abstinence. 
However, if alcohol abuse continues, the disease may progress to alcoholic hepatitis (AH), 
advanced fibrosis, and cirrhosis in up to 10-15% of heavy drinkers 2, 3. It is completely unknown 
why some heavy drinkers develop AH and what determines the severity of the condition. 
These questions can only be answered by studying sufficient numbers of patients with AH as 
well as heavy drinkers at risk for AH, and developing clinical studies testing basic 
pathophysiological mechanisms.   
   
 
While alcoholic steatosis is a reversible condition, AH is associated with significant 
morbidity and mortality 4, 5.  In mild cases, patients may recover with conservative medical 
management and alcohol abstinence.  Those with more severe cases of AH; however, have 
a high mortality rate 6, 7.  Using the National Inpatient Sample data, we reported that AH 
accounted for 0.7% of all inpatient admissions in the United States.  The average length of 
stay (LOS) was 7 days and nearly 7% died during hospitalization.  Of importance, hospitalized 
AH patients result in significant healthcare cost and utilization 8.  The average total charges 
during hospitalization for AH were $37,769; which was higher than that from acute myocardial 
infarction (~$16,200), acute cerebrovascular disease (~$11,100), and acute pancreatitis 
($9,870).  Costs per hospitalization and cost adjusted for LOS were higher in those who died 
during the hospital stay, presumably from more severe forms of AH ($84,642 and 
$11,754/day, respectively) 8.  These data were obtained during a period of time when current 
best therapy (corticosteroids or pentoxifylline) was in broad use 9; thus, they confirm the 
disease burden of AH in the US and attest that better understanding of pathogenesis and 
treatment of AH are urgently needed to improve patients’ outcome.    
 
 
The study of alcoholic livery injury is complicated by the multiple abnormalities that 
heavy alcohol use elicits in the liver and the rest of the body. We have sought more 
fundamental pathophysiological abnormalities that could underlie multiple changes in liver 
function: these have included inhibition of PPARα 10 and AMPK 11, and activation of SREBP1c 
12 and acid sphingomyelinase 13.  We have demonstrated that pharmacological intervention 
aimed at these abnormalities with fibrates 14 or a sphingomyelinase inhibitor 15 improves 
alcohol-induced fatty liver (the phenotype we have studied most).  Others have shown that 
activation of AMPK and inhibition of SREBP1 with SIRT1 activators 16 reduces steatosis.   
 
 
 
FXR was originally cloned as a bile salt receptor, and activation of FXR affects genes 
that control bile salt synthesis and transport.  Activation of FXR reduces mRNA for 7-α 
hydroxylase (CYP7A1), the rate-limiting enzyme of bile salt synthesis, and the sinusoidal bile 
salt uptake pump, while inducing the bile salt export pump.  FXR induces the small 
heterodimerization partner (Shp).  This protein is a member of the nuclear receptor family of 
transcription factors, but Shp lacks a DNA binding domain, and as a result, its hetero-
dimerization with other nuclear receptors (in place of the typical dimerization partner RXR) 
inhibits transcriptional activity of the dimer.  Shp inhibition of liver receptor homologue-1 (LRH-
1) is responsible for the repression of CYP7A1.  Activation of FXR in the ileum leads to release 
of fibroblast growth factor 19 (FGF19) into the portal blood, which also represses CYP7A1 17, 
18. These FXR actions can be followed by measuring the bile salt intermediary 7α hydroxyl-3-
one-4-cholestene (C4).  FXR agonists have been studied particularly in primary biliary 


 
 
 
 
Page 16 of 38 
 
cirrhosis and in NASH, but not in heavy drinkers or in alcoholic liver disease. A second bile 
salt receptor, TGR5, is a seven transmembrane domain receptor linked to Gsα 19-22. FXR is 
expressed in hepatocytes, stellate cells, and endothelial cells (with ligand preference greatest 
for chenodeoxycholic acid), and TGR5 is also expressed on Kupffer cells (with a preference 
for lithocholic acid); the FXR agonist OCA used in this project activates FXR with an EC50 of 
100 nM, whereas the EC50 for TGR5 is 20 µM 23.    
 
 
Plasma bile salts are elevated in most patients with alcoholic hepatitis (with or 
without clinical cholestasis 24, 25. Intrahepatic cholestasis correlates with elevated bile salt 
levels, Maddrey Discriminant Function 7, histological severity, and survival 24. Many patients 
without histological cholestasis had elevated bile salt levels 25.  There is little information about 
the effect of heavy alcohol use on bile salt metabolism.   Vendemiale and Lieber reported that 
rats chronically fed a high alcohol diet had increased secretion of bile salts into the bile 
26.   Ackehed et al., measured fecal bile salts in 7 patients at admission for detoxification and 
9 days later.  They found that bile salt excretion was over twice that of normal controls, and 
slowly declined during abstention.  Since the rate of bile salt excretion in steady state must 
equal bile salt synthesis, this might reflect increased rates of synthesis of bile salts in heavy 
drinkers, consistent with our hypothesis regarding effects of alcohol on CYP7A1 expression 
27.  This elevation in bile salts ought to activate the FXR signaling pathway, with a return of 
bile salt levels toward normal: the fact that bile salt levels are nearly always increased in AH 
suggests that this homeostatic system is impaired. As shown in Figure 1, alcohol feeding of 
mice for 4 weeks reduces levels of Shp. We do not know how alcohol feeding reduced Shp 
levels.  We have previously shown that RXRα protein levels were reduced by alcohol feeding 
[18]; additional possibilities include direct effects on FXR and reduction in cis -retinoic acid, 
the ligand for RXR 28.  We suggest that a primary effect of heavy alcohol use in patients with 
alcoholic liver disease is inhibition of the ability of FXR to induce Shp. This would result in 
increased levels of CYP7A1 and sinusoidal bile salt uptake pump, and reduction in the bile 
salt export pump, resulting in elevated plasma and hepatocyte bile salt levels.    
 
 
We hypothesize that alcohol-induced impairment of signaling via farnesoid X receptor 
(FXR, the bile salt nuclear receptor) results in increased hepatocyte bile salt levels and that 
this contributes to liver injury.  To address this hypothesis, we will conduct a study in healthy 
non-drinker controls (n=15) and heavy drinkers (n=30) We expect that (a) heavy drinking is 
associated with impaired FXR signaling, resulting in increased bile salt synthesis (reflected by 
increased levels of the bile acid C4) and reduced synthesis of FGF19 (reflected by decreased 
plasma levels); and (b) an FXR agonist, obeticholic acid (OCA), will reverse these 
abnormalities.  As a secondary hypothesis, we propose that impaired FXR signaling impairs 
gut integrity, promotes activation of Kupffer cells, enhances hepatic oxidative stress, and 
sensitizes hepatocytes to cytokine-induced necroapoptosis, and that these abnormalities can 
also be reversed with OCA.   
 
1.2 Nonclinical Experience with Study medication 
 
Data from long term safety and reproductive toxicology studies conducted according to 
International Conference on Harmonisation (ICH) Guidelines support the use of OCA for 
longer term administration and in women of child bearing potential.  Administration of OCA 
to rats (for 6 months) and dogs (for 9 months) in repeat dose toxicity studies resulted 
primarily in adverse effects on the liver and gastrointestinal (GI) tract at only the highest 
dose levels.  OCA was not genotoxic in a battery of 3 genotoxicity studies.  Reproductive 
and developmental toxicity studies in rats and rabbits demonstrated no adverse effects on 
fertility and embryo/fetal development at doses where OCA caused maternal toxicity. 


 
 
 
 
Page 17 of 38 
 
 
1.3 Clinical Experience with Obeticholic Acid (OCA) 
 
OCA has been extensively evaluated in human studies ranging from patients with primary 
biliary cirrhosis to non-alcoholic steatohepatitis.  Please refer to the investigator brochure 
(IB) Section 5 pages 50-116 for full detail. 
 
As for the 10 mg dose of OCA that we proposed in this study, in Study 747-105 (see IB 
Page 55, oral administration of single doses of OCA (5 mg, 10 mg, and 25 mg) resulted in 
rapid absorption with plasma OCA concentrations measurable as early as 15 minutes post 
dose. Mean Cmax values ranged from 19 ng/mL at the 5 mg dose to 79 ng/mL for the 25 mg 
dose. Median time to achieve peak plasma OCA concentration (Tmax) occurred between 
0.5 hours and 1.8 hours post dose across all 3 dose levels. Secondary absorption peaks 
were observed, generally occurring following a meal, which is suggestive of enterohepatic 
recirculation as expected for a bile acid and thus leading to prolonged exposure. 
 
 
1.4 Rationale for Trial Design and Dose for Study Medication 
 
This proposed trial will evaluate the endpoints of interest between controls (n=15) and heavy 
drinkers (n=30).  To determine the effect of OCA on FXR signaling, we will randomize heavy 
drinker subjects into placebo (n=15) and OCA (dose 10 mg orally once a day for 28 days, n= 
15).   
 
Rationale for Doses 
 
Inherently, there is an element of arbitrariness in choosing dose of and duration of treatment 
in early phase clinical trials. Twenty-eight day treatment is consistent with the treatment 
duration for prednisolone and pentoxifylline 9, two pharmacological agents with some 
efficacy in patients with acute AH.    
 
We chose 10 mg dose to investigate because (a) it is the dose that is being used in the 
ongoing PBC and NASH clinical trials, (b) it is the dosage that is being investigated to treat 
portal hypertension in subjects with alcoholic cirrhosis in the United Kingdom 
(http://www.controlled-trials.com/ISRCTN22662520), and (c) in one study, although OCA 
and FGF19 levels increased in a dose-dependent fashion, OCA administered at a 10 mg 
dose had similar effect on serum C4 levels as OCA 50 mg (reduction in C4 concentration, 
reflecting inhibition of bile salt synthesis of - 6.8 ng/ml vs. -6.5 ng/ml, p=ns).  
 
Rationale for Duration 
 
The duration of treatment has been chosen based on the similar duration of treatment of 
currently available therapy for AH (i.e., prednisone or pentoxyphylline).    
 
Summary of known potential risks with study medication  
 
Please refer to the IB section 5.3 for the reported safety across all the studies conducted with 
OCA.  One major issue is pruritus in patients taking OCA.  The dose of 10 mg in this study is 
similar to that was used in the longer-term, Phase 3 PBC study (747-301).  In this study, 
lower doses of OCA and a titration strategy (titrating from 5 mg daily to 10 mg daily after 


 
 
 
 
Page 18 of 38 
 
6 months of treatment) were tested. These changes appeared to result in improved safety 
and tolerability, and the majority of subjects (198 [92%]) completed the 1-year, double-
blind phase. A total of 16 OCA-treated subjects (11%) discontinued from the study, 8 of 
whom were due to pruritus. An overwhelming majority of subjects who discontinued due 
to pruritus were randomized to initiate treatment at the 10-mg OCA dose level (7 of 8 
subjects). Conversely, in subjects who initiated treatment at the 5 mg dose level (titration 
arm) only 1 subject discontinued due to pruritus. No placebo-treated subjects 
discontinued due to pruritus in any of the PBC studies.  Please note that in this proposed 
study, the duration of treatment is much shorter (only 4 weeks), thus we expect that this 
potential side effect would be minimal.   
 
2. STUDY OBJECTIVES 
The objectives of our study is to test the hypothesis that heavy alcohol consumption leads to 
the alteration of FXR signaling and such effect of alcohol on FXR can be reversed with the 
treatment of OCA.  The endpoints of this study are  
2.1 The primary end points of interest are measures of FXR effect on bile salt metabolism 
(C4) and FGF19 levels 
 
2.2 Secondary endpoints are measures of: (a) fasting serum bile salt levels, oxidative 
stress and CYP2E1 activity; (c) gut permeability, bacterial translocation, and intestinal 
inflammation; and (d) activation of innate immunity 


 
 
 
 
Page 19 of 38 
 
3. INVESTIGATIONAL PLAN 
3.1 
OVERALL TRIAL DESIGN AND PLAN 
 
Design 
 
Schematic Diagram  
 
 
 


 
Page 20 of 38 
 
3.2 SCHEDULE OF STUDY PROCEDURES 
Table 1 
Schedule of Study Procedures  
 
 
Screening 
D0 
D7 
D28 
D42 
Informed Consent 
x 
 
 
 
 
Confirmation of Eligibility Criteria 
x 
x 
 
 
 
History and physical 
x 
x 
 
x 
 
Vitals (Day 42- Heavy Drinker group only) 
x 
x 
 
x 
x 
Randomization (Heavy Drinker group only) 
 
x 
 
 
 
Telephone Visit (Heavy Drinker group only) 
 
 
x 
 
 
Alcohol consumption history  
x 
x 
 
x 
 
Concomitant medications Assessment  
(Day7 & 42 -Heavy Drinker group only) 
x 
x 
x 
x 
x 
Adverse Event Assessment  
(Day7 & 42 -Heavy Drinker group only) 
 
x 
x 
x 
x 
Electrocardiogram (Heavy Drinker group only) 
x 
 
 
x 
 
Dispense Study Medication (Heavy Drinker group only) 
 
x 
 
 
 
Evaluation of study drug compliance (Heavy Drinker 
group only) 
 
 
x 
x 
 
CBC with Diff, CMP, PT/ INR Safety labs  
(Day 28 & 42– Heavy Drinker group only) 
x 
x 
 
x 
x 
Urinalysis 
x 
 
 
 
 
Urine Pregnancy test (if applicable) 
x 
x 
 
x 
 
Hepatic CYP2E1 measurement study 
 
x 
 
x 
 
Gut Permeability Test  
 
x 
 
x 
 
Collection of Research Blood Samples for special 
investigations1 
 
x 
 
x 
 
Collection of stool specimen (optional)1 
 
x 
 
x 
 
1Special Investigation Research samples collected for this protocol consist of FGF19, C4, fasting bile acid pool, 
adipocyte function (fasting NEFA, insulin, adiponectin), oxidative stress (malondialdehyde, 8-isoprostane), 
bacterial translocation (plasma LPS, serum sCD14), cytokine measurements (serum TNF-α, IL-1, IL-6 and IL-8) 
and stool for calprotectin 
3.3 Duration of Trial by Phase 
Time expected for all patients to be 
enrolled: 
4. 4 years  
Duration of individual patient participation: 
Approximately 2.5 months 
Up to 30 days for the screening 
phase 
30 Days for the treatment phase 
(includes 28 day intervention for 
Heavy Drinker group) 
14 days for the follow-up phase    


 
Page 21 of 38 
 
5. PATIENT SELECTION  
5.1 
PATIENT POPULATION  
Prospective patients will be identified primarily from the hospitals including Fairbanks Drug 
and Alcohol Rehabilitation Hospital, outpatient clinics, self-referrals or may be referred by 
physicians from other hospitals and clinics.  Throughout this protocol, the terms ‘Principal 
Investigator (PI)’, ‘investigator’ and ‘investigator or designee’ are used synonymously.  
Irrespective of the term used, the intention remains the same:  that the overall trial 
responsibility remains with the PI who has agreed to personally conduct or supervise the 
trial and who may delegate aspects of the trial conduct, to appropriate, qualified trial site 
staff who have been informed about their obligations in meeting the above commitments. 
 
5.2 
INCLUSION/ EXCLUSION CRITERIA  
 
If used, the term ‘baseline’ (BL) within this protocol, unless otherwise specified, is intended to 
mean, ‘pre-study’ or ‘pre-treatment’ (of study medication).  It refers to values obtained during 
the Screening or Day 0 visits, prior to the patient’s first dose of study medication. The statistical 
or calculated definition(s) of ‘baseline’ to be used in the analyses of the data may be different 
and will be further defined in the statistical analysis plan (SAP) for this trial. 
Patients must meet all of the following criteria to enter the trial.   
 
Inclusion Criteria:   
 
(a) Individuals ≥ 21 to 65 years old   
(b) Able to provide informed consent & negative urine pregnancy test where 
appropriate 
(c) Healthy controls must have not consumed any alcohol within 3 months prior to the 
screening visit 
(d) Healthy controls (non drinkers) must have normal ALT and AST values (<45 U/L) 
(e) Heavy drinkers must have ALT and AST lab values <100 U/L 
(f) Heavy alcohol drinking is defined as > 40 grams per day or 98 grams in a week on 
average in women and > 60 grams per day or 196 grams in a week on average in 
men for a minimum of 6 months and within the 3 months prior to study enrolment.  
Judgment regarding daily and yearly alcohol use will be made by the site 
investigator. 
(e) Women of child bearing potential should be willing to practice contraception 
throughout the treatment period  
 
 
Exclusion Criteria: 
 
(a) Active infection as evidenced by positive urine culture, blood culture, or   
pneumonia, if necessary, after review of safety labs showing abnormalities, or 
determination by physical exam performed by PI/sub-I. 
(b) Serum creatinine > 1.5 mg/dL 
(c) Known co-existing infection with hepatitis C, hepatitis B, or HIV 


 
Page 22 of 38 
 
(d) Significant systemic or major illness including COPD, CHF and renal failure that 
in the opinion of the Investigator would preclude the patient from participating in 
and completing the study. 
(e) Participation in another investigational drug, biologic, or medical device trial within 
30 days prior to Screening 
(f)  Previous history of jaundice or signs of liver diseases such as spider angiomata, 
ascites, portal hypertension, or history of esophageal varices or hepatic 
encephalopathy 
(g) Total bilirubin > 2 mg/dl and INR > 1.5 
(h) Women who are pregnant or nursing 
(i)   Presence of any other disease or condition that is interfering with the absorption, 
distribution, metabolism, or excretion of drugs including bile salt metabolism in 
the intestine.  Patients who have undergone gastric bypass procedures will be 
excluded (gastric lap band is acceptable). 
(j)   Subjects who are taking warfarin  
5.3 
PATIENT WITHDRAWAL FROM THE TRIAL  
 
Reasons for Mandatory Trial Discontinuation 
If a female patient becomes pregnant, she must stop taking study medication and must be 
withdrawn from the trial. The patient must be followed by the investigator through pregnancy 
outcome. The mother (and infant) will be followed as considered appropriate by the 
investigator and study physician (Dr. Liangpunsakul or designee). For reporting purposes 
pregnancy is not considered a serious adverse event (SAE). 
Other Reasons for Trial or Treatment Discontinuation 
The following events are considered appropriate reasons for a patient to discontinue from the 
trial: 
• 
The patient withdraws consent or requests to be withdrawn from the trial.  It is fully 
understood that all patients volunteer for the trial and that they may withdraw their 
consent to continue trial participation at any time. 
• 
The patient experiences an adverse event (such as AE grade 3) that in the opinion of 
the investigator or Safety Monitor is caused by or exacerbated by any of the trial 
procedures or study medication, of sufficient intensity to warrant discontinuation. 
• 
The patient refuses to comply with the requirements for trial participation. 
• 
Investigator’s decision. 
When possible, the investigator should discuss the potential discontinuation of a patient with 
the study physician (Dr. Liangpunsakul or designee) in advance.   
Patient Discontinuation Notification 
The investigator must notify the study designated physician (Dr. Liangpunsakul  or his 
designee) as soon as possible if any patient prematurely discontinues from the trial. The date 
when the patient is withdrawn and the primary reason(s) for discontinuation must be recorded 
in the CRF; additional information may be requested to complete a discontinuation narrative.  
Patients will be considered “lost to follow up” only after reasonable, documented attempts to 
reach the patient prove unsuccessful.  In all cases, a reasonable effort must be made to 


 
Page 23 of 38 
 
determine the reason(s) that a patient fails to return for required trial visits or discontinues 
from the trial. If a patient is withdrawn from the trial early during the treatment phase 
(regardless of the cause), all of the Day 28 evaluations should be performed at the time of 
withdrawal, to the extent possible.   
6. INVESTIGATIONAL PRODUCT (IP) 
5.1 
DESCRIPTION OF IP 
For the purpose of this protocol, the term ‘investigational product (IP)’ is interchangeable 
with the term ‘study medication’. 
 
5.2  
Study Medication 
OCA is a white, round tablet with “INT” engraved on one side and “3547” engraved on 
the other side. All study medication will be provided as a tablet for oral administration and 
provided in high density polyethylene (HDPE) bottles with an induction seal and child proof 
caps. 
All study medication (OCA and matching placebo) will be provided by Intercept 
Pharmaceutical and manufactured according to Good Manufacturing Practice (GMP). 
6.3 
PACKAGING, LABELLING, AND STORAGE 
The packaging and labeling of study medication supplies will be performed according to GMP 
standards by a designated qualified vendor and in accordance to 21 CFR 312.6.  It will be 
Limited by Federal Law to Investigational Use Only. 
The designated drug packaging/distribution vendor will also be responsible for the distribution 
of the study medication to the investigator and, where applicable, providing the Qualified 
Person (QP) release of study medication.  Study medication should be stored in the containers 
in which they are received from the Sponsor’s supplier, at controlled room temperature, and 
protected from excess humidity.  
Study medication will be packaged for the trial as described below.  Study medication for the 
trial will be packaged and labeled as single bottles containing 30 tablets and should be 
dispensed to the patient as received.   The investigative pharmacist at the site will prepare the 
study medication for appropriate dispensing to the subjects according to standard operating 
procedures. 
6.4 
DOSE AND ADMINISTRATION 
Heavy drinker subjects will be randomized to placebo or OCA (10 mg). Study medication will 
be administered orally, once daily for 28 days during the study.  Patients will be instructed to 
begin dosing on the day after the Day 0 visit and after the baseline endpoint measurements 
are obtained (i.e., on Day 1) and to take study medication with water, approximately 30 
minutes prior to breakfast.  Patients must be instructed to swallow the tablet whole; they 
must not chew, divide, or crush the tablet. 
 
Missed Doses 
Patients who miss a dose of study medication should be instructed to take it later the same 
day, as soon as they remember.  ‘Missed’ doses should not be taken on a subsequent day 
(i.e., the patient should not take more than the prescribed daily dose) 


 
Page 24 of 38 
 
Overdosage 
The maximum dose of OCA that has been given to humans is 500 mg as a single dose and 
250 mg as a multiple dose.  Reversible increases in aminotransferases were seen in most of 
the healthy volunteers who took 250 mg OCA.  There is no specific information available 
regarding the treatment of possible overdose with OCA.  If overdose occurs in a patient 
enrolled in the trial, general medical supportive measures should be provided, including 
observation and follow up (e.g., serum chemistry) as appropriate.  Due to the extensive 
enterohepatic recirculation of the drug it is likely that it will take several days before blood (and 
organ) concentrations of the drug will decrease.  Treatment with cholestyramine (Questran™), 
colesevelam (Welcol™) and other bile acid sequestrants is both logical and recommended 
given that they should bind and eliminate the drug in feces.  Although there is no experience 
with OCA, plasmapheresis might be expected to reduce circulating levels of the drug.  The 
study physician (Dr. Liangpunsakul or designee) should be notified immediately in the event 
of a significant overdose. 
6.5 
PRIOR AND CONCOMITANT MEDICATIONS OR PROCEDURES 
Relevant information about all concomitant drugs (including prescribed, over the counter, or 
herbal preparations) taken prior to and during the trial must be recorded in the source 
documents and CRF, as well as any dose or dose regimen changes that occur during the trial. 
6.6 
TREATMENT COMPLIANCE 
The investigator should assess the patient’s compliance with dosing of study medication on 
an ongoing basis.   
Patients should be instructed to retain all bottles of study medication, even if empty, and to 
return them to the investigator at the subsequent visit.  The investigator or designee should 
perform drug accountability and, if applicable, follow up with the patient to retrieve any study 
medication bottles that have not been returned.  
If the investigator has concerns about a patient’s dosing compliance s/he should discuss this 
with the patient, assess the reasons for noncompliance and the likelihood that the patient will 
remain noncompliant, and notify the Sponsor accordingly.  Continued trial eligibility should be 
assessed based on the patient’s compliance with study medication dosing and clinic visits. 
6.7 
STUDY MEDICATION ACCOUNTABILITY AND RETENTION 
Intercept Pharmaceutical, Inc’s representative will send study medication to the trial site under 
appropriate storage conditions.  All shipments of study medication should be unpacked and 
the contents reviewed immediately upon receipt.  If it is not possible to verify the contents 
immediately, they must be stored under the appropriate storage conditions until verification of 
the contents is possible (ideally, within 1 business day from receipt).  The pharmacist or 
designee should verify the study medication against the shipment documentation. The 
pharmacist or designee should contact Intercept Pharmaceuticals immediately to report any 
concerns regarding the shipment.  
All study medication will be provided for use only in this trial and is not to be used for any other 
purpose.  The investigator or designee will maintain a full record of study medication 
accountability, including records of individual patient dispensing and final return or disposition 
(as directed by the Sponsor).  


 
Page 25 of 38 
 
6.8 
TRIAL OR SITE TERMINATION 
The Sponsor reserves the right to terminate the trial at any time.  It is normal procedure to 
review the emerging clinical and safety data.  As a result of such a review or a 
recommendation by the DSMB, it may be necessary to stop the trial before all patients have 
completed the trial.   
The investigator must notify the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) of discontinuation of the trial and the reason for doing so. 
7. TRIAL PROCEDURES 
7.1 
SCREENING 
Informed Consent 
The investigator or designee will explain the nature, purpose and risks of the trial to the patient 
and will provide him/her with a copy of the written information and informed consent form 
(ICF).  The patient will be given sufficient time to consider the trial before deciding whether or 
not to participate.  The patient will be informed that participation is voluntary and that her/his 
future medical treatment will not be compromised by participation in the trial and that s/he can 
withdraw from the trial at any time.  The patient must be willing and able to provide written 
informed consent before entering the trial.  The investigator or a medically qualified designee 
is responsible for administering and documenting the written informed consent of the patient.  
Screening Numbers 
At the Screening Visit, after the patient has provided written informed consent, the patient will 
be assigned a 5 digit subject participant (screening) number.  This number will be recorded in 
the CRF.   
Patient Identification Assignment 
After the patient has met eligibility criteria and enrolls into the study, the patient will be 
assigned a unique 5 digit study ID number. This 5 digit number will be used to identify the 
participant throughout the trial and during the data analysis. 
 
7.2   VISIT PROCEDURES  
Patients should be instructed to fast overnight (at least 8 hours) immediately prior to all at-
clinic visits, including the Screening Visit.  While fasting, water is permitted.  
Screening Procedures (≤30 days) 
The Screening Visit assessments must be performed within 30 days prior to Day 0 to 
determine whether the patient meets all the inclusion criteria and none of the exclusion criteria.  
Patients who do not fulfill all eligibility criteria will not be enrolled in the trial.   
Screening Visit procedures are as follows: 
• 
The patient is to review and sign the informed consent document. Informed consent must 
be obtained from the patient before performing any trial related procedures, including 
Screening procedures 


 
Page 26 of 38 
 
• 
Collect medical and disease history 
• 
Collect alcohol use history   
• 
Verify inclusion and exclusion criteria for eligibility 
• 
Perform a physical examination, including height (Screening only) and weight 
• 
Record vital signs 
• 
Perform a standard 12-lead electrocardiogram (ECG)  –Heavy Drinker Group Only 
• 
Record prior (within 30 days of screening visit) and current concomitant medications.   
• 
Obtain blood samples for serum chemistry and hematology tests 
• 
Obtain urine sample for dipstick urinalysis 
• 
Perform a urine based beta human chorionic gonadotrophin (β-hCG) pregnancy test in 
females of childbearing potential 
         
Day 0 Procedures (Randomization and Baseline Study Day)  
• 
Review inclusion and exclusion criteria for eligibility 
• 
Record vital signs 
• 
Perform a Physical Examination 
• 
Assess and record any pretreatment emergent events 
• 
Record prior (within 30 days of Day 0) and current concomitant medications 
• 
Assess Alcohol Consumption  
• 
Perform an urine pregnancy test in females of childbearing potential  
• 
Perform Hepatic CYP2E1 Measurement Study  
• 
Perform Gut Permeability Test (Lactulose/ Mannitol test)   
• 
Obtain safety labs (CMP, CBC and PT/INR) 
• 
Obtain Research Blood samples as outlined in Table 1: Schedule of Study Procedures 
• 
Obtain Stool Specimen (optional) 
• 
Randomization to study drug (Heavy drinker group only) 
• 
Dispense study drug (Heavy drinker group only) and instruct patient to begin dosing on 
the day after Day 0 visit and to take the study medication with water approximately 30 
minutes prior to breakfast.  
 
Day 7 Procedures (+/- 2 days)- Heavy Drinker Group Only 
• 
This consists of a telephone visit where the study staff will inquire with the subject on 
his/her wellbeing, compliance with study medication, adverse events and concomitant 
medication use. 


 
Page 27 of 38 
 
 
Day 28 Procedures (+/- 2 days) 
Healthy non-drinkers controls will have repeated procedures at D0 performed.  The same 
procedures will also be done in heavy drinkers when they complete the study drug for 28-day.  
• 
Record vital signs 
• 
Perform a Physical Examination 
• 
Assess and record any Adverse Events 
• 
Assess concomitant medications 
• 
Perform a standard 12 Lead Electrocardiogram (Heavy Drinker Group only) 
• 
Obtain Safety Labs (CBC, CMP and PT/ INR) (Heavy Drinker group only) 
• 
Evaluation of Study Drug Compliance (Heavy Drinker Group only) 
• 
Collection of all study medication and bottles (Heavy Drinker Group only)  
• 
Assess Alcohol Consumption  
• 
Perform Hepatic CYP2E1 Measurement Study 
• 
Perform Gut Permeability Test (Lactulose/ Mannitol test)   
• 
Obtain Research Blood samples as outlined in Table 1: Schedule of Study Procedures 
• 
Obtain Stool Specimen (optional) 
• 
Perform an urine pregnancy test in females of childbearing potential 
 
Day 42 Follow-up Procedures (+/- 2 days) - Heavy Drinker Group Only 
• 
Record vital signs 
• 
Assess and record any Adverse Events  
• 
Assess concomitant medications 
• 
Obtain Safety Labs (CBC, CMP and PT/ INR) 
 
Unscheduled Safety Visits 
The investigator may schedule an at-clinic Unscheduled/Safety Visit at any time if clinically 
warranted.  Unscheduled and/or repeat assessments may be conducted.  As appropriate, the  
Safety Monitor should be contacted.  
 


 
Page 28 of 38 
 
7.3 
PHYSICAL EXAMINATION AND VITAL SIGNS 
Physical Examination 
To assess for clinical findings, the investigator or designee will perform a physical examination 
at the time points specified in the Schedule of Trial Procedures (Tables 1).  This includes 
height only at Screening.  
Vital Signs 
The following vital signs will be assessed at indicated visits: body temperature, sitting heart 
rate, and sitting blood pressure (BP).  When taking heart rate and BP readings, patients should 
be seated quietly for a minimum of 3 minutes before the reading is taken. The heart rate 
should be recorded over a 60 second period. 
7.4 
CLINICAL LABORATORY 
Blood samples for serum chemistry, hematology, and coagulopathy will be collected at every 
visit as detailed in the Schedule of Trial Procedures (Tables 1).  The number and volume of 
samples to be collected at each visit will be detailed in the Standard Operating Procedures. 
Full instructions concerning the number and type of samples to be collected at each visit, the 
required sample volumes, sample collection methods, sample processing, labeling, and 
shipping will be provided in a trial specific laboratory manual.  All patients with laboratory tests 
containing clinically significant abnormal values should be followed regularly until the values 
return to normal ranges, until a valid reason for the AE (other than study medication related 
AE) is identified, or until further follow up is deemed medically unnecessary. 
7.5 
ELECTROCARDIOGRAM 
Standard 12-lead ECGs will be collected. The investigator or designee will review the 12-lead 
ECG and findings will be recorded in the CRF as normal, abnormal but not clinically significant, 
or abnormal and clinically significant. Any clinically significant abnormalities on ECGs 
recorded after Day 0 will also be documented as AEs and entered on the AE page of the CRF.  
Investigative sites must retain a copy of all 12-lead ECGs evaluated by the investigator or 
designee.  These ECGs must be clearly labeled with the subject’s initials, Participant or Study 
ID Number, date and time.   
The ECG read will be completed by the investigator or designee.  At a minimum the following 
will be assessed: PR, QRS, QT and QTc intervals and a clinical evaluation for each ECG will 
be provided.   
8. ADVERSE EVENTS 
7.1  
DEFINITION AND REPORTING PERIOD FOR ADVERSE EVENTS   
Safety will be assessed in terms of AEs.  All AEs, whether observed by the investigator, 
reported by the subject, noted from laboratory findings, or identified by other means, will be 
recorded from the time the patient signs the ICF until the patient completes trial participation.  
AEs are defined as any untoward medical occurrence associated with the use of the study 
medication in humans, whether or not considered related to study medication.  An AE (also 
referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an 


 
Page 29 of 38 
 
abnormal laboratory finding), symptom, or disease temporally associated with any use of the 
study medication, without any judgment about causality and irrespective of route of 
administration, formulation, or dose, including an overdose.  For this trial, study medication 
refers to OCA.   
AEs include, but are not limited to:  (1) a worsening or change in nature, severity, or frequency 
of condition(s) present at the start of the trial; (2) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction. 
Subjects should be questioned in a general way, without leading the patient or asking about 
the occurrence of any specific symptom.  The investigator should attempt to establish a 
diagnosis of the event based on signs, symptoms, and/or other clinical information.  The 
diagnosis and not the individual signs/symptoms should be documented as the AE.  For 
example, if the underlying disease process is a stroke, it would not be appropriate to record 
the AE by describing the symptoms “sudden numbness, dizziness, and difficulty 
speaking.”  The AE medical term of “stroke or cerebrovascular accident” should be recorded 
as it more accurately describes the AE.  
Following questioning and evaluation, all AEs, whether believed by the investigator to be 
related or unrelated to the study medication, must be documented in the subject’s medical 
records, in accordance with the investigator’s normal clinical practice and on the AE 
CRF.  Each AE is to be evaluated for duration, intensity, frequency, seriousness, outcome, 
other actions taken, and relationship to the study medication.  
Pretreatment Event(s) 
Untoward events that occur between the time the patient signs the ICF for the trial and the 
time when that patient is first administered the study medication are classified as "pre-
treatment" events.  Any pretreatment event should be recorded as medical history. 
7.2  
Severity of AEs 
AEs must be graded for severity (i.e., intensity).  A severity category of mild, moderate, or 
severe, as defined in Table 3, must be entered on the AE CRF.  It should be noted that the 
term “severe” used to grade intensity is not synonymous with the term “serious.”    The 
assessment of severity is made regardless of study medication relationship or of the 
seriousness of the AE. 
Table 2 
Severity of AEs 
Grade 
Clinical Description of Severity 
1 = Mild 
Causing no limitation of usual activities; the subject may experience 
slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the subject may experience 
annoying discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the subject may experience 
intolerable discomfort or pain. 
 
 


 
Page 30 of 38 
 
7.3  
Relationship of AEs to Study Medication 
The investigator will document her/his opinion of the relationship of the AE to treatment with 
study medication using the criteria outlined in Table 5.  An AE for which there is a ‘reasonable 
possibility’ that the study medication caused the AE is otherwise referred to as suspected 
adverse reaction (SAR).  ‘Reasonable possibility’ means there is evidence to suggest a causal 
relationship between the study medication and the AE.  
 
Table 3 
Relationship of AEs to Study Medication 
Relationship Description 
Definite 
A reaction that follows a reasonable temporal sequence from 
administration of the drug or in which the study medication level has 
been established in body fluids or tissue; that follows a known or 
expected response pattern to the suspected drug; and that is confirmed 
by improvement on stopping or reducing the dosage of the study 
medication, and reappearance of the reaction on repeated exposure. 
Probable  
A reaction that follows a reasonable temporal sequence from 
administration of the study medication; that follows a known or expected 
response pattern to the suspected study medication; that is confirmed 
by stopping or reducing the dosage of the study medication; and that 
could not be reasonably explained by the known characteristics of the 
subject’s clinical state. 
Possible 
A reaction that follows a reasonable temporal sequence from 
administration of the study medication; that follows a known or expected 
response pattern to the suspected study medication; but that could 
readily be produced by a number of other factors. 
Unlikely 
A reaction that does not follow a reasonable temporal sequence from 
administration of the study medication; that does not follow a known or 
suspected response pattern to the suspected study medication; and that 
could reasonably be explained by known characteristics of the subject’s 
clinical state. 
Not Related 
Any event that does not meet the above criteria. 
 
 
8.4 
SERIOUS ADVERSE EVENTS 
 
Definition of a Serious Adverse Event 
An adverse event or suspected adverse reaction is considered ‘serious’ if, in the view of the 
investigator, it results in any of the following outcomes: 
Death;  


 
Page 31 of 38 
 
Is life threatening;  
Results in hospitalization or prolongation of existing hospitalization; 
Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
A congenital anomaly/birth defect; 
An important medical event that may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
An AE is considered “life-threatening” if, in the view of the investigator, its occurrence places 
the patient or subject at immediate risk of death. It does not include an AE that, had it occurred 
in a more severe form, might have caused death. 
7.5  
Reporting SAEs 
In agreeing to the provisions of this protocol, the investigator accepts all legal responsibilities 
for immediate reporting of SAEs to the Safety Officer. 
The Safety Officer for this trial is: 
Samer Gawrieh, MD 
Telephone:  317-278-1216 
Email: sgawrieh@iu.edu 
SAE Email:  sgawrieh@iu.edu and sliangpu@iu.edu 
 
All SAEs must be reported to the Safety Officer within 2 working days after the investigator 
identifies the SAE.  SAEs should be entered into the OnCore System within 2 working days 
of the investigator becoming aware of the event.    An initial report by telephone should be 
followed as soon as possible by completion of the SAE CRF.  Any supporting source 
documentation should be emailed to the assigned contact as soon as possible. At a minimum 
the following information should be provided at the time of the initial report:  patient number 
and initials, a description of the event, at least one criterion classifying the event as Serious, 
the name and title of the reporting individual, and information regarding study drug 
dosing.  Additionally, judgment of causality by the investigator must be provided as soon as 
possible to ensure timely reporting to regulatory authorities by the study Sponsor (e.g., CIOMS 
forms, FDA MedWatch Form 3500A or other equivalent form). Following the initial report, any 
additional information obtained by the investigator about the SAE must be reported promptly 
to the Safety Officer. 
The investigator will assess whether the event is causally related to the study medication.  The 
study designated physician (Dr. Liangpunsakul or designee) will consider the investigator’s 
assessment, however, since Dr. Liangpunsakul holds the IND and is primarily responsible for 
the overall safety of the participants, his causality assessment will take precedence over that 
of the site investigator.  The study designated physician will determine if a suspected, 
unexpected serious adverse reaction (SUSAR) in accordance with FDA regulations, 312.32 
(c)(1)(i) meets the criteria as being reportable as a 7-day or a 15-day safety report and will 
submit reports as required to FDA.  
Upon becoming aware of an SAE during the conduct of the study, the study designated 
physician shall inform Intercept of the SAE within the time frames and using the format defined 
in the table below. Follow-up information shall be shared using the same time frames and 


 
Page 32 of 38 
 
formats. Additionally, approximately every six months, the study designated physician shall 
provide Intercept with a list of all SAEs that were received during the previous six months. 
Type of SAE: 
Format 
Time Frame 
All SUSARs  
MedWatch 
or 
CIOMS, 
with 
narrative 
≤ 5 Calendar Days 
SAEs 
(not 
meeting 
criteria 
for 
SUSAR) 
Aggregate SAE 
listing with case 
narratives or 
MedWatch/CIOMS 
for each SAE,  
Every 6 months 
 
SUSAR and SAE reports are to be sent to Intercept at clinsafety@interceptpharma.com. 
Intercept may request, in writing, additional information about an SAE at any time, and the 
study designated physician (or designee) shall respond to the request as efficiently and 
completely as possible. 
The investigator is responsible for submitting information on SUSARs/SAEs received from the 
Sponsor to her/his local IRB/IEC.  The Sponsor will also notify the appropriate regulatory 
agencies as well as all participating investigators of all SUSARs/SAEs that occur during the 
trial within the time frames required by each regulatory agency.  Documentation of the 
submissions to IEC/IRBs and health authorities must be retained in the appropriate trial 
file(s).  7-day or 15-day safety reports should be retained in the appropriate trial files, or with 
the IB. The Sponsor will follow country specific and local reporting requirements for all 
SAEs/SUSARs. 
 
Additional Principal Investigator Responsibilities for SAEs 
The safety data recorded in the CRF represent the official record of all AEs and SAEs reported 
in the trial.  The investigator should comply with requests by the Safety Officer to record the 
SAE on the patient’s AE CRF and, if necessary, provide a copy of this CRF to the 
sponsor.  Other supporting documents such as radiology reports, hospital discharge 
summaries and autopsy reports should also be provided, when appropriate.  Additionally, 
upon request by the Safety Officer, the investigator should provide input into the SAE narrative 
and provide timely information to ensure prompt follow up and closure of the SAE report. 
The investigator and supporting personnel responsible for patient care should discuss with 
the Safety Officer any need for supplemental investigations of SAE(s).  
8.6 
 NOTIFICATION OF POST-TRIAL SAES 
If the investigator becomes aware of an SAE that may be attributable to the study 
medication at any time after the end of the trial, the study designated physician should 
be notified within 2 working days.  
All SAEs that occur within 30 days following the cessation of study medication, 
whether or not they are related to the study medication, must be reported to the 


 
Page 33 of 38 
 
study designated physician within 2 working days by following the instructions provided 
in Section 7.5. 
8.7 
FOLLOW UP OF AES 
All AEs, including clinically significant laboratory values or physical examination findings 
relative to pretreatment assessments, must be followed until the AE resolves, is no longer of 
clinical concern, has stabilized or is otherwise explained, or the patient is lost to follow up. 
AEs ongoing at the final visit that are deemed to be ‘possibly, probably, or definitely” related 
or of other clinical significance must be followed for as long as necessary to adequately 
evaluate the safety of the patient or until the event stabilizes, resolves, or is no longer of 
clinical concern.  If resolved, a resolution date for the AE should be documented on the 
CRF.  The investigator must ensure that follow up includes any supplemental investigations 
indicated to elucidate the nature and/or causality of the AE.  This may include additional 
laboratory tests or investigations, or consultation with other healthcare professionals, as 
considered clinically appropriate by the investigator. 
8. DRUG INTERACTION 
OCA 10 mg has shown potential weak inhibition on CYP1A2, BCRP, OATP1B1, and 
OATP1B3 (Rosuvastatin), and CYP2C19 (Omeprazole).  The list of the medications (if any) 
of subjects will be reviewed by the PI before the study.  Additionally, considering warfarin, 
metabolized by CYP2C9, is a narrow therapeutic drug, we will exclude subjects who are on 
warfarin from the study.   
9. STATISTICAL METHODS 
9.1      Cross-sectional Component: 
Primary end point: The mean(SD) will be used to summarize the baseline  the C4 and 
FGF19 level at baseline. The primary analysis is to compare the C4 and FGF19 level at 
baseline between the 15 health control and 30 heavy drinker using independent two-sample 
t-tests. The distribution assumption of C4 and FGF19 will be examined for the distribution 
assumption. If there is an assumption violation, appropriate transformation will be used to 
correct the assumption violation. We will also perform analysis of covariance (ANCOVA) 
analysis with C4(FGF19) at baseline as the outcome variable, group(health control vs. 
heavy drinker) as the main predictor adjusting for patients’ characteristics.  
The secondary endpoints (a) fasting serum bile salt levels, oxidative stress and CYP2E1 
activity; (c) gut permeability, bacterial translocation, and intestinal inflammation; and (d) 
activation of innate immunity at baseline will also be compared using two-sample t-test and 
the ANCOVA models in a similar way to C4 and FGF19. 
Power analysis:  For the cross-sectional study, there are 15 health and 30 heavy drinker. 
We use two-sample t-test for comparison of the primary endpoint C4 and FGF19. With these 
sample size, we will have 83% power to detect any difference in C4(or FGF19) of effect size 
equal to or greater than 0.95(mean/SD) with a 5% Type I error rate. 
9.2      Longitudinal component: 


 
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Primary endpoint: In the intervention phase, the main goal is to see whether OCA will 
alternate or reverse the C4(FGF19).  So the main analysis to use two-sample t-test to 
compare the change of C4(FGF19) from baseline to 4 weeks between the randomized 
treated and placebo arm. The secondary analysis for the primary end points is to compare 
the C4 (FEF19) level at 4 week using two-sample t-tests to see whether the C4 level of the 
treated group has recover to the normal control level after 4 weeks treatment.  
The secondary endpoint will be compared using two-sample t-tests in a similar way to the 
primary endpoints.  
Power analysis:  For the intervention study, there are 15 subjects in each group. We use 
two-sample t-test for comparison of the change of C4 and FGF19. With these sample size, 
we will have 82% power to detect any difference in change of C4(or FGF19) of effect size 
equal to or greater than 1.11(mean/SD) with a 5% Type I error rate. 
 
9.3     Safety Analysis: Descriptive statistics will be used to summarize the AEs if occur.   
Adverse Events 
AEs will be coded using the Medical Dictionary of Regulatory Activities (MedDRA).  Summary 
tables of treatment-emergent AEs will be provided.  A TEAE is any AE that newly appeared, 
increased in frequency, or worsened in severity following initiation of study medication.  The 
incidence of TEAEs will be tabulated by system organ class and preferred term for each 
treatment group, and by severity and relationship to treatment.  Tables of TEAEs leading to 
study medication discontinuation and SAEs will be provided. 
HANDLING OF MISSING DATA  
Missing values will not be imputed and only observed values will be used in data analyses 
and presentations.   
DATA AND SAFETY MONITORING BOARD (DSMB) 
A local DSMB (to be announced) will be formed to review safety data at periodic intervals from 
this trial.  Members of the DSMB will not be allowed to participate as investigators in this trial 
and will not otherwise consult for the Sponsor.   
The DSMB will review safety data to ensure the safe and proper treatment of patients.  Based 
on review of these data, the DSMB will advise the Sponsor on the validity and scientific merit 
of continuing the trial.   
The DSMB will operate under an appropriate charter (in compliance with relevant regulatory 
guidances) that will define its organization and operation.  The DSMB will prepare written 
minutes of both its open and closed sessions.   
All investigators and responsible IRB will be informed of any decisions made by the Sponsor 
based on recommendations from the DSMB relating to patient safety, which alter the conduct 
of this trial.  The investigators will inform the patients of such actions and the protocol and ICF 
will be revised, as appropriate. 


 
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10. ADMINISTRATIVE AND REGULATORY CONSIDERATIONS 
10.1 ETHICAL CONDUCT OF THE TRIAL 
This trial will be conducted in accordance with 21CFR Part 312, Good Clinical Practice 
(CPMP/ICH/135/95), and with the ethical principles laid down in the Declaration of Helsinki 
and applicable regulatory requirements. 
10.2 INSTITUTIONAL REVIEW BOARD (IRB)  
A properly convened IRB at each participating site will review and approve this study prior to 
its initiation. All protocol amendments will be reviewed and approved by the IRBs. 
Amendments can be implemented only following the IRB approval unless the amendment is 
necessary to reduce immediate risk to trial participants. 
The IRB will be informed of any new safety information that negatively affects the risk 
assessment of the trial as soon as it becomes available. 
Investigators or the Sponsor or its designee will provide reports to the IRB/IEC as requested, 
as a minimum annually, and after the trial is complete. 
10.3 PATIENT CONFIDENTIALITY AND DATA PROTECTION 
All information obtained during the conduct of the trial with respect to the patient will be 
regarded as confidential and confidentiality of all patients will be maintained.  Monitors, 
auditors and inspectors will require access to a patient’s medical notes for the purpose of 
source document verification but the patient’s confidentiality will be maintained at all times.  
An agreement for disclosure of any such information will be obtained in writing and is included 
in the statement of informed consent.  The trial data shall not be disclosed to a third party 
(with the exception of auditors, Intercept as the supporter and/or regulatory authorities) 
without the written consent of the Sponsor.  All data shall be secured against unauthorized 
access. 
Apart from the site investigators, no one will have access to participant’s identify. Each site 
will securely maintain the code that links participants’ identity to their study numbers to prevent 
access to unauthorized third parties. Participants will be identified according their study 
numbers in the data management system (OnCore) and by the investigators during any 
communications. 
The written ICF will explain that, for data verification purposes, authorized representatives of 
Intercept (the supporter), a regulatory authority, or an IEC / IRB may require direct access to 
parts of the hospital or practice records relevant to the trial, including patient’s medical history. 
10.4 ACCESS TO SOURCE DOCUMENTS AND DATA 
 
Source documents 
Source documents may include, but are not limited to, medical records, charts, appointment 
books, patient questionnaires, original laboratory records, equipment print-outs.  All source 
documents must be made available to the CRA. The following data must be included in the 
source data: 


 
Page 36 of 38 
 
(a) consent to participate in Trial  
(b) patient visit dates 
(c) Screening and Randomization Numbers 
(d) demographic information 
(e) medical history 
(f) disease history 
(g) physical examination  
(h) vital signs 
(i) laboratory assessments (copy of laboratory reports) 
(j) AEs and concomitant medications 
(k) dates of dispensing study medication 
(l) ECGs 
(m) patient questionnaires 
(n) drug accountability 
(o) issues with protocol compliance 
(p) completion of, or withdrawal from, trial 
 
Case Report Forms  
A  CRF to capture trial data will be completed by trial site staff for each patient who has signed 
the ICF and is assigned a patient number. The CRF may be developed in paper format or 
within an electronic data capture (EDC) system.  Data management vendors will be detailed 
within a separate trial document.   
The CRF must be completed promptly after each patient visit.  


 
 
 
 
 
 
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