Clinical trial NCT02039219
Conditions: Alcoholic Hepatitis
Sponsor: Naga P. Chalasani
Start date: 2014-11-03; Completion date: 2018-01-29
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to test the effectiveness of Obeticholic Acid when used in patients with moderately severe alcoholic hepatitis. The researchers suspect that individuals with alcoholic hepatitis have certain abnormalities in how their body handles bile acids (a product made by the liver on a daily basis) produced by the liver. Obeticholic acid has been shown to affect bile acid abnormalities and thus it is possible that obeticholic acid may improve liver condition in individuals with alcoholic hepatitis.

Detailed description:

Arms: arm 1: Placebo arm 2: 10 mg Obeticholic Acid (OCA) Study medication will be administered orally, once daily for 6 weeks.
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 6 weeks. intervention 2: 10 mg Obeticholic Acid (OCA) Study medication will be administered orally, once daily, approximately 30 minutes prior to breakfast for 6 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
TREAT – 002,   V.1.7 NOVEMBER 29, 2016                         (1) 
 
CONFIDENTIAL 
A Double-Blind, Placebo-Controlled Trial of Obeticholic Acid in 
Patients with moderately severe Alcoholic Hepatitis (AH)  
 
 
Clinical Trial Protocol TREAT - 002 
 
Version 1.7  
 
ClinicalTrials.Gov Identifier: NCT02039219 
IND Number: 120229 
Primary Investigator: Naga Chalasani, MD (Indiana University) 
 
Co-investigators:  Indiana University:  Drs. Suthat Liangpunsakul and, David 
Crabb; Mayo Clinic:  Drs. Vijay Shah, Greg Gores, Patrick Kamath;   Virginia 
Commonwealth University: Drs. Puneet Puri, Arun Sanyal 
 
Disclosure 
 
This study is conducted by the TREAT consortium which is funded by the National 
Institute of Alcohol Abuse and Alcoholism (NIAAA) to pursue translational 
investigations in alcoholic hepatitis.  The TREAT Consortium is made up of 
investigators from 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. 
 
 
 




 
TREAT – 002,   V.1.7 NOVEMBER 29, 2016                         (3) 
 
CONFIDENTIAL 
Table of Contents 
 
Page number 
Synopsis 
4 
Investigator’s affirmation 
7 
Abbreviations 
8 
Introduction & Rationale 
10 
Nonclinical experience with study medicine 
12 
Clinical experience with study medicine 
12 
Rationale for trial design and dose for study medicine 
15 
Summary of known risks of study medicine 
16 
Trial Objectives 
16 
Investigational plan 
17 
Patient selection (inclusion & exclusion criteria) 
19 
Patient withdrawal from the trial 
20 
Investigational product 
21 
Overdosage 
23 
Randomization 
24 
Unblinding procedures 
24 
Treatment Compliance 
25 
Trial procedures 
26 
Efficacy evaluations 
32 
Safety evaluations 
32 
Adverse events 
34 
Serious adverse event (SAE) 
36 
Reporting of AEs 
37 
Statistical methods 
39 
Data and safety monitoring committee 
41 
Administrative and regulatory considerations 
41 
Trial monitoring & auditing 
44 
List of planned laboratory values 
46 
Exploratory evaluations 
47 
References 
48 
Appendix 1 
51 
Appendix 2 
53 
Appendix 3 
55 
Appendix 4 
58 
Appendix 5 
59 
Tables 
Table 1: 
 
Schedule of trial procedures (Page 19) 
Table 2: 
 
Severity of AEs (Page 34) 
Table 3: 
 
Relationship of AEs to study medicine (Page 35) 
Table 4: 
 
Requirements for reporting AEs to various stakeholders (Page 36) 
Table 5: 
 
Exploratory evaluations (Page 47) 
Table 6: 
 
Total Blood Volumes (Page 47) 


 
TREAT – 002,   V.1.7 NOVEMBER 29, 2016                         (4) 
 
CONFIDENTIAL 
SYNOPSIS 
Title of Trial 
A Double-Blind, Placebo-Controlled Trial of Obeticholic Acid in Patients with 
moderately severe Alcoholic Hepatitis (AH)  
 
Name of Active Ingredient 
Obeticholic Acid (OCA; 6α-ethyl chenodeoxycholic acid; 6-ECDCA) also known as 
INT-747 
 
Indication 
Moderately severe Alcoholic Hepatitis 
 
Phase of Development 
Phase 2 
 
Planned Number of Investigational Sites 
Four investigational trial sites at Indiana University in Indianapolis, Mayo Clinic in 
Rochester, Virginia Commonwealth University in Richmond, and Einstein Medical 
Center in Philadelphia 
 
Planned Number of Patients 
Approximately 60 patients (30 patients per arm) will be randomized in a 1:1 ratio to 1 
of 2 treatment arms: (a) placebo, or (b) 10 mg OCA.   
 
Objectives 
To assess the effects of OCA in patients with moderately severe AH on: 
Primary 
• Change in MELD score at 6 weeks  
• Incidence of serious adverse events (SAEs) during the treatment phase 
 
Secondary 
• Any SAEs during the follow-up phase 
• SAEs attributable to the study medicine during the treatment and follow-up 
phases 
• AEs and discontinuation rates during the treatment and follow-up phases 
• Change in MELD score at 90 and 180 days 
• Change in Child-Pugh score at 6 weeks and at 90 and 180 days 
• Mortality rate at Week 6 and at 90 and 180 days 
• Rates of hospitalization and lengths of stay 


 
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CONFIDENTIAL 
• Changes in intestinal inflammation and bacterial translocation 
• Changes in serum oxidative stress, cytokines, and activation of innate 
immunity.   
 
Design 
This is a phase 2, double-blind, placebo-controlled trial of OCA in patients with 
moderately severe AH.  Approximately 60 patients (30 patients per arm) will be 
randomized in a 1:1 ratio to 1 of 2 treatment arms: (a) placebo, or (b) 10 mg OCA.  
Study medication will be administered orally, once daily for 6 weeks.   
Methodology 
Screening phase: This period will consist of an ≤ 8 week duration prior to 
randomization during which the eligibility criteria are determined and screening 
laboratories and an electrocardiogram are obtained.  Subjects must sign an informed 
consent prior to starting the screening phase.   
 
Randomization:  Subjects will be randomized to one of two treatment groups with 
stratification by site and block of size 4. Random assignment will be generated by 
the coordinating unit and provided to the site pharmacist for randomized packing for 
maintenance of blinding. 
 
Treatment phase: It will consist of randomization visit (day 0) where participants are 
assigned to one of the treatment groups (placebo or OCA 10 mg) and then 
continuing the study medication for 6 weeks.  Patients will have the on-treatment 
study visits at days 14, 28 and 42. At each visit, subjects will have brief medical 
history, physical examination, routine blood work, and safety evaluation. Compliance 
with study procedures including alcohol abstinence will be assessed. CBC, 
prothrombin time along with INR, and comprehensive metabolic profile (CMP, 
electrolytes, BUN, creatinine, and liver biochemistries) will be measured at each 
visit. Special investigations for this protocol consist of serum  FGF19, bile acid C4, 
OCA and conjugates, fasting free fatty acids, lipid profile, insulin, adiponectin, 
measures of bacterial translocation (plasma LPS and sCD14), cytokine 
measurements (serum TNF-α, IL-1, IL-6, and IL-8), markers of oxidative stress, 
apoptosis, and stool for calprotectin.  To promote compliance and to monitor safety, 
there will be telephone visits on days 7 and 21.  
 
Follow-up phase:  Subjects will return to the clinic on Days 90, 120 and 180. 
 
 
 


 
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CONFIDENTIAL 
Key Eligibility Criteria 
Inclusion Criteria:   
(a) Individuals ≥ 21 years with a diagnosis of acute AH. The diagnosis of 
acute alcoholic hepatitis will be based on clinical features and testing including 
hepatomegaly, jaundice, fever, leukocytosis, compatible liver biochemistries in the 
context of heavy alcohol consumption.  A liver biopsy is not mandatory, but will be 
required to confirm the diagnosis if a firm diagnosis of AH cannot be made on clinical 
and laboratory criteria 
(b) Moderate severity defined as MELD score > 11 and <  20 
(c) Heavy alcohol consumption (defined as > 40 grams per day on average in 
women and > 60 grams per day on average in men for a minimum of 6 months and 
within the 6 weeks prior to study enrollment) 
(d) Written informed consent  
(e) Negative urine pregnancy test where appropriate 
 
Exclusion Criteria: 
(a) Significant active infection (e.g., sepsis, or spontaneous bacterial 
peritonitis; SBP). Subjects can be reconsidered after the infection is under 
control.  
(b) Serum creatinine > 2.5 mg/dL 
(c) Must not have received systemic steroids for a duration of > 1 week during 
the Screening period or on the day of randomization and must not be receiving any 
experimental medicines for AH   
 
Treatment Regimen 
1 tablet of placebo or 10 mg OCA as directed, taken orally daily with water, 
approximately 30 minutes prior to breakfast.  The duration of treatment is 6 weeks.   
  
 
 
 


 
TREAT – 002,   V.1.7 NOVEMBER 29, 2016                         (7) 
 
CONFIDENTIAL 
Investigator’s Affirmation 
I have received and read the current version of the Investigator’s Brochure (IB) for 
OCA and this Protocol TREAT-002.  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 TREAT 
Consortium and from Intercept Pharmaceuticals and not previously published is 
confidential. This includes the IB, Clinical Trial Protocol, Case Report Forms (CRF) 
and any other preclinical and clinical data.  
I understand that no data are to be made public or published without prior 
knowledge and written approval by the TREAT Steering Committee. 
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 
– 002 and in accordance with Good Clinical Practice (CPMP/ICH/135/95), 21CFR 
Part 312 and all applicable regulatory requirements. 
I acknowledge that the Steering Committee of the TREAT Consortium has the right 
to discontinue this trial at any time. 
 
 
 
 
 
Investigator’s Name (Printed) 
 
 
 
 
 
 
Investigator’s Signature 
 
Date 
 


 
TREAT – 002,   V.1.7 NOVEMBER 29, 2016                         (8) 
 
CONFIDENTIAL 
ABBREVIATIONS 
Abbreviation 
Definition 
6-ECDCA  
6α-ethyl chenodeoxycholic acid 
AE(s) 
adverse event(s)  
ALT  
alanine aminotransferase 
ALP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
BL 
Baseline 
BP 
blood pressure 
BAS 
bile acid sequestrants 
BUN 
blood urea nitrogen 
CDCA 
chenodeoxycholic acid 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CRA 
Clinical Research Associate 
CRF 
case report form 
DCA 
deoxycholic acid 
DCU 
data coordinating unit 
dL 
deciliter(s) 
DSMC 
Data and Safety Monitoring Committee 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor-19 
FXR 
farnesoid X receptor 
GGT 
gamma-glutamyltransferase 
GMP 
Good Manufacturing Practice 
HDPE 
high-density polyethylene 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISF 
investigator site file 
IL-6 
Interleukin-6 
LTSE 
long term safety extension 
MELD 
Model for End Stage Liver Disease 
mg 
milligram(s) 
mL 
milliliter(s) 


 
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CONFIDENTIAL 
 
 
 
NAFLD 
nonalcoholic fatty liver disease 
NASH 
nonalcoholic steatohepatitis 
OCA 
obeticholic acid 
PBC 
primary biliary cirrhosis 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
SAE 
serious adverse event 
SUSAR 
suspected, unexpected serious adverse reaction 
TEAE(s) 
treatment-emergent adverse event(s) 
TIPS 
transjugular intrahepatic portosystemic shunt 
TNF-α 
tumor necrosis factor-alpha 
TNF-β 
tumor necrosis factor-beta 
UDCA 
ursodeoxycholic acid 
U/L 
units per liter 
ULN 
upper limit(s) of normal 
US 
United States (of America) 
vs 
Versus 
WBC 
white blood cell 


 
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CONFIDENTIAL 
1. INTRODUCTION AND RATIONALE 
RATIONALE, MEDICAL NEED &MECHANISM OF ACTION OF OCA IN AH   
 
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 currently not well understood 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. However, individuals 
with more severe AH have high mortality rates (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, hospitalizations for AH result in significant 
healthcare costs 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 liver 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) AMPK (11), 
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.   
 
 
 
 
Farnesoid X receptor (FXR) was originally cloned as a bile salt receptor, and 
activation of FXR affects genes that control bile salt synthesis and transport.  


 
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CONFIDENTIAL 
Activation of FXR reduces the 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 (net result is decreased intracellular bile salt load).  
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 are being investigated in many 
liver conditions, including primary biliary cirrhosis (PBC) and NASH, and in an 
exploratory trial of portal hypertension in subjects with alcoholic cirrhosis. 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 AH (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. In an unpublished study, investigators from Indiana University 
have shown that alcohol feeding of mice for 4 weeks reduces the 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 


 
TREAT – 002,   V.1.7 NOVEMBER 29, 2016                         (12) 
 
CONFIDENTIAL 
pump, and reduction in the bile salt export pump, resulting in elevated plasma and 
hepatocyte bile salt levels.    
 
The ability of OCA to reverse the elevation of bile salts in patients with AH will be 
tested in this clinical trial (TREAT 002). Given the availability of this FXR agonist 
(OCA) already in phase 2 and 3 clinical trials (29, 30), this is an extremely promising 
therapeutic modality to explore.   
 
1.1 
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.  In addition, no adverse effects were 
noted in a pre and postnatal developmental toxicity study in rats (preliminary results).   
A summary of the toxicology studies is provided in the IB.   
1.2 
CLINICAL EXPERIENCE WITH OBETICHOLIC ACID (OCA) 
1.2.1 
Phase 1 
OCA was administered orally in a single ascending dose trial (Protocol 747-101) and 
a multiple ascending dose trial (Protocol 747-102) to evaluate the safety, tolerability 
and pharmacokinetics (PK) of OCA, administered orally, in healthy volunteers.  In 
Protocol 747-101, single doses of 50 to 500 mg of OCA were administered, while 
doses of 25 to 250 mg of OCA were administered once daily for 12 days in the 
multiple dose trial (747-102).  
No AEs of clinical concern were seen in the single dose trial.  In the multiple dose 
trial, clinically significant elevations in the aminotransferases were seen at the 
250 mg dose.  Minor aminotransferase increases of no clinical concern were seen at 
the 100 mg dose level.  However, in the 250 mg dose group, 6 of 8 subjects who 
received OCA had increases in aminotransferase(s); 4 subjects had elevations in 
both ALT and AST, while 2 subjects had increased ALT only.  These increased 
values were 3 to 5 times the ULN in some subjects and were considered to be dose 
limiting.  The increases in hepatocellular enzymes are thought to be attributable to 
detergent effects seen with other bile acids like CDCA.  It should be noted that this 
dose is more than 25 times higher than the doses that will be used in this trial.   
OCA is rapidly and extensively conjugated with glycine and taurine.  These 
conjugates are present in much greater concentrations than the parent drug, and are 


 
TREAT – 002,   V.1.7 NOVEMBER 29, 2016                         (13) 
 
CONFIDENTIAL 
equipotent FXR agonists to the parent drug.  OCA has demonstrated dose 
proportional increases in Cmax (50 - 500 mg range) and considerable enterohepatic 
circulation (lasting several days after the last dose was administered) was seen.  
Excretion is assumed to be primarily fecal, as is typical for a bile acid, and, at a low 
level, was recovered in the urine. 
1.2.2 
Phase 2 and Phase 3 
1.2.2.1 
OCA in Primary Biliary Cirrhosis (Protocols 747-202 and 747-201 and 
747-301) 
Two (2), very similar, blinded phase 2 trials in patients with PBC have been 
completed.  ALP (as assessed at central laboratories) was the primary endpoint in 
both trials.  The duration of treatment in each trial during the DB phase was  
3 months.   
Protocol 747-202 was a dose response trial evaluating 3 doses of OCA (10 mg, 
25 mg and 50 mg) versus placebo in patients with persistent elevations (> 1.5x ULN) 
in ALP levels on a stable dose of UDCA, followed by an open label LTSE phase 
(Protocol 747-202).  Thirty-three (33) trial sites in 8 countries participated.  The data 
for this trial demonstrated (31): 
Highly statistically and clinically significant relative and absolute reductions in ALP 
were seen with all 3 doses (10, 25 and 50 mg) of OCA versus placebo  
(p < 0.0001).  Mean ALP reductions were approximately 20 - 25% compared to 3% 
with 
placebo. 
 
Absolute 
ALP 
reductions 
ranged 
from 
approximately 
65 - 75 units per liter (U/L) versus 5 U/L for placebo.  Other evaluations of ALP 
response (e.g., response rates) showed similar statistically and clinically meaningful 
differences from placebo treatment.  
Statistically significant improvements were also seen in GGT and ALT levels with all 
3 doses, in AST at 10 mg and 25 mg, and in conjugated bilirubin (% change) at 
25 mg (mean pretreatment ALT, AST and bilirubin levels were all within the normal 
range). 
Safety:  Pruritus was the only clear clinically meaningful AE that differed between 
OCA treatment and placebo.  The incidence of pruritus was elevated at both the 
25 mg and 50 mg doses in these cholestatic patients (but not at 10 mg).  However, 
the severity of the pruritus and the incidence of discontinuations due to pruritus were 
dose related.  Overall, 10 mg appeared to be acceptably tolerated (and efficacious). 
The open label LTSE phase for protocol 747-202 is complete.  This LTSE trial gave 
subjects the opportunity to receive at least 1 year of open label OCA treatment 
following completion of the double-blind, placebo-controlled trial.   
 
Subjects continued to receive open label OCA in this phase, titrated from a starting 
dose of 10 mg to as high as 50 mg.  Over two thirds of the subjects were titrated to 
20 mg or more and one subject received a dose of 60 mg/daily.  Pruritus was the 


 
TREAT – 002,   V.1.7 NOVEMBER 29, 2016                         (14) 
 
CONFIDENTIAL 
most common AE, reported in 68 of the 78 subjects (87%) and was the cause of 10 
of 19 subject discontinuations in this phase. 
Highly statistically (p < 0.0001) and clinically significant reductions in ALP from DB 
baseline were seen with OCA from 3 months through 1 year. 
 
Protocol 747-201, a monotherapy trial comparing the effects of 10 mg and 50 mg 
OCA versus placebo, is ongoing in the LTSE phase (Protocol 747-201).  The 
following was observed in the DB phase of this trial (32): 
Highly statistically and clinically significant relative and absolute reductions in ALP 
were seen with both doses (10 and 50 mg) of OCA versus placebo  
(p < 0.0001) showing it has substantial efficacy in PBC when given as monotherapy. 
Statistically significant improvements were also seen in GGT and in conjugated 
bilirubin with both doses.  ALT and AST changes were not statistically significant 
though decreased by approximately 35% and 20%, respectively.    
Statistically significant changes were seen in several domains of the PBC-40 
questionnaire. 
Statistically significant reductions were seen in C-reactive protein and IgM. 
Safety:  As in the 747-202 PBC trial, pruritus was the most common AE.  The 
incidence of pruritus in the OCA groups, 50 mg (94%) and 10 mg (70%), was higher 
than in the placebo (30%) group.  Similarly, the severity of pruritus increased with 
the dose of OCA. This translated into a higher discontinuation rate for the treated 
patients, notably in the 50 mg group of which 38% discontinued due to pruritus. 
This trial is ongoing in the open label LTSE phase.  Additional details regarding the 
phase 2 PBC trials and current updates about the LTSE phases are provided in the 
current IB. 
Protocol 747-301, a phase 3, double-blind, placebo-controlled, parallel-group trial of 
OCA in patients with PBC is currently ongoing. This phase 3 trial has been designed 
to assess the efficacy, safety and tolerability of lower doses (5 mg and 10 mg) of 
OCA in patients with PBC.  The primary endpoints are ALP and total bilirubin, 
assessed together as a composite endpoint, and safety.   
Participating subjects are either continuing their pre-trial dose of UDCA or are not 
treated with UDCA, if they were unable to tolerate it previously. A five-year LTSE 
phase is planned to follow the initial 12 month DB phase of the trial. Enrollment has 
been completed and 217 patients have been randomized in a 1:1:1 ratio to 
(a) placebo, (b) 10 mg OCA, or (c) 5 mg titrating to 10 mg OCA.  During the open 
label LTSE phase, patients may receive up to 25 mg of OCA for up to 5 years and 
continue their pre-trial dose of UDCA.   
 


 
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CONFIDENTIAL 
1.2.2.2 
OCA in Diabetes & NAFLD 
An exploratory trial was conducted in 64 patients with Type 2 diabetes and non-
alcoholic fatty liver disease (NAFLD) to evaluate safety and any potential effect of 
OCA on insulin resistance and glucose homeostasis (33).  Patients received one of 
the following: placebo, 25 mg or 50 mg of OCA daily for 6 weeks.  A 2-step 
hyperinsulinemic, euglycemic clamp was conducted before and after treatment.  
Improvements in glucose infusion rates at both the low and high-dose insulin clamp 
steps were seen with the 25 mg dose and when both doses were evaluated 
together, versus placebo.  These effects are consistent with an improvement in 
metabolism and insulin sensitivity in both the liver and peripheral tissues.  Weight 
loss was seen in a dose related manner.  Improvements in GGT, ALT and AST were 
also seen in the patients who received OCA.  There were no clear, concerning 
safety signals. Significant increases in FGF19 were seen at day 42.  This protein is 
released in the small intestine under FXR control.  It is closely involved in the down 
regulation of bile acid production (there was a significant reduction in C4 at day 42) 
after a meal and has recently been shown to induce significant beneficial metabolic 
effects, independent of insulin, post-prandially. This trial demonstrated that small 
doses of an oral FXR agonist can induce meaningful improvements in glucose 
metabolism. 
 
1.3 
RATIONALE FOR TRIAL DESIGN AND DOSE FOR STUDY MEDICATION 
This proposed trial will evaluate OCA in approximately 60 moderately severe AH 
patients (30 patients per arm) who will be randomized to 1 of 2 treatment arms: (a) 
placebo, or (b) 10 mg OCA in a 1:1 ratio.   
1.3.1 
Rationale for Dose and Duration 
Our choice to administer OCA for 42 days is based on the study by Mudaliar et al 
(33) which showed significant reduction in C4 levels at day 42, indicating OCA’s 
efficacy in reducing bile salt synthesis by that time point.  
 
We chose 10 mg dose to investigate because (a) it is among the doses that is being 
used in ongoing PBC and non-alcoholic steatohepatitis (NASH) clinical trials, (b) it is 
among the doses 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).  
 


 
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1.4 
SUMMARY OF KNOWN POTENTIAL RISKS WITH STUDY MEDICATION 
Pruritus has been observed in the multiple dose trials of OCA in primary biliary 
cirrhosis (PBC) and was the most common AE seen in the PBC 747-202 Trial, DB 
phase, with 67% of patients reporting a treatment emergent AE (TEAE) of pruritus.  
There was a relationship between the dose of OCA administered and the incidence 
(at 25 mg and 50 mg only), severity, and the timing of the onset of pruritus, which 
occurred almost invariably within the first 14 days of treatment at 50 mg.  Pruritus 
was least tolerated at 50 mg with 24% of patients discontinuing at this dose due to 
pruritus.   
In the 747-201 Trial, DB phase, pruritus was the most common AE that occurred in 
any treatment group, 50 mg (94%) and 10 mg (70%), and at a rate higher than in the 
placebo (30%) group.  Similarly, pruritus has been the most commonly reported AE 
in the 747-201 LTSE to date.  The severity of pruritus shows an apparent 
improvement with increasing dose of OCA in the LTSE.  This suggests that patients 
who do not develop severe pruritus at lower doses are likely to tolerate higher doses 
if titrated up.   
The mechanism of pruritus in cholestatic liver disease is unknown.  Recently, 
autotaxins and lysophosphatidic acid have been implicated in pruritus of cholestasis 
[Kremer 2009, 2010, 2011].  Recent data [Kremer 2011] suggest that autotaxins may 
be increased in patients with the worst pruritus taking 50 mg in the 747-202 trial and 
that patients with high autotaxin levels were more likely to develop severe pruritus.  
However, plasma autotaxin levels did not explain the pruritus in the majority of 
patients.  Assays of the plasma from the subjects receiving 250 mg dose in the 
multiple dose normal volunteers trial (747-102) did not show a difference in autotaxin 
levels between the pruritic and non-pruritic subjects.  Bile acid concentrations in the 
PBC trial 747-202 have not shown an association with pruritus.   
 
In the PBC 747-202 Trial, DB phase, besides pruritus, only nausea (mild or 
moderate) was seen more frequently in all 3 OCA groups than in the placebo group.  
In the 747-201 DB phase, only urinary tract infection was seen more frequently in 
both OCA groups than the placebo group.  The current IB outlines other AEs 
observed in association with the use of OCA. 
 
2. TRIAL OBJECTIVES 
Primary 
• Change in MELD score at 6 weeks  
• Incidence of serious adverse events (SAEs) during the treatment phase 
 
Secondary 
• Any SAEs during the follow-up phase 
• SAEs attributable to the study medicine during the treatment and follow-up 


 
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phases 
• AEs and discontinuation rates during the treatment and follow-up phases 
• Change in MELD score at 90 and 180 days 
• Change in Child-Pugh score at 6 weeks and at 90 and 180 days 
• Mortality rate at Week 6 and at 90 and 180 days 
• Rates of hospitalization and lengths of stay 
• Changes in intestinal inflammation and bacterial translocation 
• Changes in serum oxidative stress, cytokines, and activation of innate 
immunity.   
 
3. INVESTIGATIONAL PLAN 
3.1 
OVERALL TRIAL DESIGN AND PLAN 
Design 
This is a phase 2, double-blind, placebo-controlled trial of OCA in patients with 
moderately severe AH.  In the DB phase, approximately 60 patients (30 patients per 
arm) will be randomized in a 1:1 ratio to 1 of 2 treatment arms: (a) placebo, or (b) 10 
mg OCA.  Study medication will be administered orally, once daily for 6 weeks.   
3.2 
SCHEDULE OF TRIAL PROCEDURES 
The Schedule of Trial Procedures is provided in Table 1.


 
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Table 1:  Schedule of Trial Procedures 
 
 
Screening 
Treatment Phase1 
Follow-up phase 
D0 
D14 
D28 
D42 
D90 
D120 
D180 
Informed consent 
X 
 
 
 
 
 
 
 
Confirmation of eligibility criteria 
X 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
History and physical 
X 
X 
X 
X 
X 
X 
X 
X 
Assess Liver Scores: MELD, Child Pugh 
and/or Discriminant Function 
X 
X 
X 
X 
X 
X 
X 
X 
AUDIT and NIAAA Questionnaires 
X 
 
 
 
 
 
 
 
Timeline Followback Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicines 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
 
 
 
X 
 
 
 
Evaluation of compliance 
 
 
X 
X 
X 
 
 
 
Dispense study medication2 
 
X 
X 
X 
X 
 
 
 
CBC, CMP, INR 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test3 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Special investigations4 
 
X 
 
 
X 
 
 
 
Specimen Banking5 
 
X 
X 
X 
X 
X 
X 
X 
1 There is a telephone visit on D7 and D21.2 Bottle(s) will be dispensed to the subjects for at-home dosing at the D0 and D14 visits. Subjects will be instructed to 
dose at the clinic at the D14, D28 and D42 visits. 
3 A serum pregnancy test (in women of childbearing potential) will be done at Screening.  Urine pregnancy tests will otherwise be conducted. 
4 Special investigations for this protocol consist of serum FGF19, bile acid C4, OCA and conjugates, fasting free fatty acids, lipid profile, insulin, adiponectin, 
measures of bacterial translocation (plasma LPS and sCD14), cytokine measurements (serum TNF-α, IL-1, IL-6, and IL-8), markers of oxidative stress, apoptosis, 
and stool for calprotectin.  
5 Specimens to be banked include genomic DNA at D0, blood mononuclear cells at D0, D28 and D42 and blood ( serum and plasma) samples at D0, D14, D28, 
D42, D90, D120 and D180.  Stool samples collected at D0 and D42 will also be banked for future ancillary studies.  


 
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3.2.1. Duration of Trial by Phase 
 
Time expected for all patients to be enrolled: 
~ 15 months 
Duration of individual patient participation: 
42 days (6 weeks) during the 
treatment phase 
5 months during the follow up phase   
Total duration of trial (excluding data 
collection and analysis):    
21 months  
 
 
The end of this trial will occur when the last patient(s) completes the D180 visit.   
4. PATIENT SELECTION 
 
4.1 
PATIENT POPULATION 
This trial will be conducted at 3 sites with experience in treating patients with AH.  
Prospective patients will be identified primarily from the hospital and/or outpatient 
clinics, or may be referred by physicians from other hospitals.   
Throughout this protocol, the terms ‘Principal Investigator (PI)’, ‘investigator’ and 
‘investigator or designee’ is 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. 
Patients will be selected according to the following criteria. 
4.2 
INCLUSION CRITERIA 
If used, the term ‘baseline’ (BL) within this protocol, unless otherwise specified, is 
intended to mean, ‘prestudy’ or ‘pretreatment’ (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.  
Patients must meet all of the following criteria to enter the trial.   
(a) Individuals ≥ 21 years with a diagnosis of acute AH. The diagnosis of acute 
alcoholic hepatitis will be based on clinical features and testing including 
hepatomegaly, jaundice, fever, leukocytosis, compatible liver biochemistries in the 
context of heavy alcohol consumption.  A liver biopsy is not mandatory, but will be 
required to confirm the diagnosis if a firm diagnosis of AH cannot be made on clinical 
and laboratory criteria 


 
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(b) Moderate severity defined as MELD score > 11 and <  20  
 
(c) Heavy alcohol consumption (defined as > 40 grams per day on average in 
women and > 60 grams per day on average in men for a minimum of 6 months and 
within the 6 weeks prior to study enrollment) 
  
(d) Written informed consent  
 
(e) Negative urine pregnancy test where appropriate 
 
(f) Women of child bearing potential should be willing to practice contraception 
throughout the treatment period  
 
 
4.3  
EXCLUSION CRITERIA 
 
(a) Significant active infection (e.g. sepsis or SBP). Subjects can be reconsidered 
after the infection is under control.  
 
(b) Serum creatinine > 2.5 mg/dL 
 
(c) Must not have received systemic steroids for a duration of > 1 week during the 
screening period or on the day of randomization and must not be receiving any 
experimental medicines for AH 
 
(d) 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). 
(e) Participation in another investigational drug, biologic, or medical device trial 
within 30 days prior to screening 
 
4.3 
PATIENT WITHDRAWAL FROM THE TRIAL 
4.3.1 
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 the end of her pregnancy.  The mother (and infant) will be followed as 
considered appropriate by the investigator and the study designated physician (Dr. 
Chalasani or his designee).  For reporting purposes, pregnancy is not considered a 
serious adverse event (SAE). 
During the trial, if Maddrey’s Discriminant Factor (DF) increases by 5 points and also 
exceeds 32, or MELD scores increases by 5 points and also exceeds 20, the study 


 
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medication should be stopped, however the participant will remain in the trial, 
completing procedures as detailed in the Schedule of Procedures (Table 1).  
Treating physicians may offer any other treatment that is considered as medically 
indicated and appropriate.   
4.3.2 
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 at any time. 
• The patient experiences an adverse event that in the opinion of the site 
investigator or the primary investigator of the trial (i.e., study designated 
physician, Dr. Chalasani) 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. 
 
When possible, the investigator should discuss the potential discontinuation of a 
patient with the study designated physician (Dr. Chalasani or his designee) in 
advance.   
4.3.3 
Patient Discontinuation Notification 
The investigator must notify the study designated physician (Dr. Chalasani 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 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 determine the reason(s) that a patient 
fails to return for required trial visits or discontinues from the trial.   
If a subject stays in the study but discontinues study medication (either by 
participant’s choice, or by the investigator’s decision), then study measurements 
should be performed according to the Schedule of Trial Procedures, Table 1, (rather 
than expediting study visits, or measurements).  
5. 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’. 


 
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5.1.1 
Study Medication 
Intercept Pharmaceuticals will provide study medication (OCA and matching 
placebo) which are white or light blue-green round tablets engraved with ‘INT’ on 
one side and ‘3547’ on the other side.  All study medication will be provided as a 
tablet for oral administration.  The tablets are packaged in high density polyethylene 
(HDPE) bottles with 30 tablets per bottle and closed with an induction seal and child 
proof cap.  Bottles will also include two desiccant packets and cotton coil. 
All study medication (OCA and matching placebo) will be manufactured according to 
Good Manufacturing Practice (GMP). 
5.1.2 
Treatment Phase 
Study medication will be provided to each site (pharmacy) as open label product, 
overlabeled at each site and blinded based on the randomization scheduled, and 
then provided to subjects in a blinded manner (i.e., the investigator, site staff and 
patient will be unable to distinguish treatment assignment).  Study medication will 
consist of either 10 mg OCA or matching placebo tablets. 
5.2 
PACKAGING, LABELING, AND STORAGE 
The packaging and labeling of study medication for provision to the clinical trial sites 
will be performed according to GMP standards by designated qualified vendors. 
The designated IP distribution vendor will be responsible for the distribution of the 
study medication to the clinical trial sites.  Study medication should be stored at 
controlled room temperature (15°C to 30°C) and protected from excess humidity.  
Study medication will be packaged for the trial as described below. 
5.2.1 
Packaging and Labeling  
Study medication for the trial will be packaged and labeled as open label bottles 
containing 30 tablets and sent to each investigative site (pharmacy). Each site will 
be responsible for overlabeling (i.e., blinding) the bottles with a unique non 
sequential bottle number for the purpose of identifying and allocating the bottle. The 
bottle number will not reveal any information about the treatment dose contained in 
the bottle. The investigative pharmacist at each individual trial site will prepare the 
study medication for appropriate dispensing to the subjects according to standard 
operating procedures.    
5.3 
DOSE, ADMINISTRATION AND BLINDING 
Two 
(2) 
treatment 
groups 
will 
be 
evaluated 
in 
the 
trial:   
(a) placebo or (b) 10 mg OCA.  Study medication will be administered orally, once 
daily for 6 weeks (42 days) during the study.  Each daily dose will be made up of 1 
tablet.   


 
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Patients will be instructed to begin dosing on the day after the Day 0 visit (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. 
5.3.1 
Dispensing Procedures 
On Day 0, after confirmation of patient eligibility and randomization, the investigator 
or designee will dispense 1 bottle of study medication to the patient.  Before leaving 
the clinic/hospital, the study staff will ensure that the patient fully understands the 
dosing instructions.  Additional study medication (i.e., a second bottle) will be 
dispensed on Day 14.  The clinical trial site investigator may adjust the number of 
bottles (1 or 2) dispensed to the subject based on clinical judgment and visit 
scheduling to ensure an adequate supply of study medication is available for dosing 
between clinic visits.  
5.3.2 
Blinding 
All study medication will be visually identical for the OCA and placebo treatment 
arms, thus ensuring the double-blind nature of the trial.  Study medication bottles will 
not be labeled with either a patient randomization number or tablet strength, to 
ensure that neither patient nor investigator is unblinded.   
5.3.3 
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). 
5.3.4 
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 designated physician (Dr. Chalasani) should be notified 
immediately in the event of a significant overdose. 


 
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5.4 
RANDOMIZATION 
5.4.1 
Method of Assigning Patients to Treatment Groups 
The trial will be conducted in a double-blind, placebo-controlled manner.  Allocation 
to 1 of 2 treatment arms will occur on a 1:1 ratio within each sites with a block of size 
4 based on a predefined randomization code generated by the TREAT data 
coordinating unit (DCU).   
The investigator or designee will be required to register the patient on the OnCore 
system (TREAT’s data management system) and will provide patient data to 
properly randomize and allocate the patient to treatment.  A randomization number 
will be assigned and study medication dispensing information (e.g.., bottle 
number(s)) will be provided. 
5.4.2 
Site Numbers 
Each trial site selected to participate in this trial will be assigned a Site Number by 
the TREAT consortium. The Site Number will be used to categorize patient data and 
to identify the site and or investigator within trial documents. 
5.4.3 
Screening Numbers 
At the Screening Visit, after the patient has provided written informed consent, the 
patient will be assigned a unique 5 digit subject ID number.  
5.4.4 
Randomization Numbers and Schedule 
Subjects will be randomized to one of two treatment groups with stratification by site 
and block of size 4. Random assignment will be generated by the coordinating unit 
and provided to the site pharmacist for randomized packing for maintenance of 
blinding. 
5.5 
UNBLINDING PROCEDURES 
5.5.1 
Unscheduled, Emergency Unblinding 
The site pharmacist will be unblinded to randomization codes and corresponding 
treatment assignment as s/he will overlabel each bottle to apply the blind, prior to 
dispensing to any subjects at the site.  Additionally, the randomization codes and 
corresponding treatment assignment will be maintained by the TREAT DCU.  The 
study designated physician (Dr. Chalasani or his designee), or the individual 
investigators will not have access to this information. In the event that a medical 
emergency necessitates unblinding (i.e., in situations where knowledge of the 
blinded treatment is necessary for further medical management of the patient), the 
site investigator (or his/her designee) will contact the designated study physician to 
discuss the rationale for unblinding. If there is a difference of opinion between the 
designated study physician and the site investigator, then the site investigator 
retains the final right to seek unblinding.  The designated study physician will 


 
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communicate with the DCU about the decision to unblind the subject and then the 
DCU will unblind the subject by interacting directly with the site investigator.  
The Data and Safety Monitoring Committee (DSMC) will be able to unblind patients. 
Cases of premature unblinding (as noted above) will be reviewed by the DSMC.  
Access to randomization codes and corresponding treatment assignment will also be 
made available to the designated study physician who is responsible for reporting 
SAEs and suspected unexpected serious adverse reactions (SUSARs) to the 
Regulatory Authorities and should be accessed only in the event that reporting 
necessitates unblinding. Aside from the site pharmacist who conducts the drug 
overlabeling, no other site personnel will have direct access to blinded patient 
treatment codes until all trial data have been entered onto the trial database and 
validated, and the database locked. 
5.6 
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. 
5.7 
TREATMENT COMPLIANCE 
The investigator should assess the patient’s compliance with dosing of study 
medication on an ongoing basis, at least at each visit, and confirm by conducting 
drug accountability (i.e., count of returned tablets). 
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 that has 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 designated study 
physician accordingly.  Continued trial eligibility should be assessed based on the 
patient’s compliance with study medication dosing and clinic visits. 
5.8 
STUDY MEDICATION ACCOUNTABILITY AND RETENTION 
Intercept Pharmaceuticals, Inc.’s representative will send study medication to the 
trial sites 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 at controlled room 
temperature until verification of the contents is possible (ideally, within 1 business 
day from receipt).  The pharmacist or designee should verify the study medication 


 
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against the shipment documentation. The pharmacist or designee should contact the 
designee of 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.  
The ‘Clinical Research Associate’ (CRA), will review accountability records against 
study medication dispensed and that remaining in stock, during on-site monitoring 
visits and when the trial is completed, or if it is prematurely terminated.  The CRA will 
retrieve documentation detailing and confirming the return or destruction of the study 
medication.   
5.9 
TRIAL OR SITE TERMINATION 
The TREAT consortium 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 DSMC, it may be necessary to stop the 
trial before all patients have completed the trial.   
It is the responsibility of the individual site’s PI to report to their Institutional Review 
Board (IRB) of discontinuation of the trial and the reason for doing so in a timely 
fashion according to institutional policies. 
6. TRIAL PROCEDURES 
6.1 
SCREENING 
6.1.1 
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.  
6.1.2 
Patient Identification Assignment 
After the patient has met eligibility criteria and enrolls into the study, the patient will 
be assigned a unique 5 digit ID number. This 5 digit number will be used to identify 
the participant throughout the trial and during the data analysis.  


 
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6.2 
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.   
6.2.1 
Screening Period 
The screening period will consist of ≤ 8 weeks prior to the randomization visit (Day 0. 
During the screening period, participants’ eligibility criteria must be confirmed.  
Participants must sign an informed consent prior to initiating any of the screening 
procedures.  Patients who do not fulfill all eligibility criteria cannot continue in the 
protocol (screening failures).    
Screening period procedures are as follows: 
• The participant 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 
• Verify inclusion and exclusion criteria for eligibility 
• Assess Liver Score: MELD 
• Collect medical history including the alcohol consumption specifics 
• The participant is to complete the AUDIT, NIAAA and Timeline Followback 
Questionnaires 
• Perform a physical examination, including height and weight 
• Record vital signs 
• Record prior (within 30 days of Day 0) and current concomitant medications 
• Perform a standard 12-lead electrocardiogram (ECG) 
• Assess availability of liver biopsy samples (if applicable) which may have been 
obtained as part of standard of care  
• Obtain blood samples for serum chemistry, hematology and coagulation tests 
• Perform a serum pregnancy test in females of childbearing potential 
• The subject should be reminded that fasting (8 hours) is required prior to his/her 
next visit.  
 
6.2.2 
Day 0 Procedures (Randomization) – Must present after at least 8 
hours of fasting 
• Collect medical history including the alcohol consumption specifics 
• Perform a physical examination 


 
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• Record vital signs 
• Alcohol consumption history – Timeline Followback Questionnaire 
• Assess and record any pretreatment emergent AEs 
• Record prior (within 30 days of Day 0) and current concomitant medications.   
Ascertain that participant is not receiving concomitant systemic corticosteroids on 
the day of randomization 
• Perform a urine pregnancy test in females of childbearing potential 
• Confirm inclusion and exclusion criteria for eligibility 
• Assess Liver Scores: MELD, Child Pugh and Discriminant Function 
• Randomize the patient only if s/he meets all inclusion criteria and no exclusion 
criteria 
• Obtain blood samples for serum chemistry, hematology and coagulation tests 
• Obtain blood samples for special investigations as outlined in section 3.2 
• Obtain blood and stool samples for specimen banking as outlined in section 3.2.  
• Dispense study medication and instruct the patient to begin dosing on the day 
after the Day 0 visit (i.e., on Day 1) and to take study medication with water, 
approximately 30 minutes prior to breakfast.  Instruct the patient to swallow the 
tablet whole; s/he must not chew, divide, or crush the tablet. 
• The subject should be reminded that fasting (8 hours) is required prior to his/her 
next visit. The subject should not take study medication on the morning of the 
next clinic (D14) visit as s/he will dose at the clinic.   
 
6.2.3 
D7 Procedures (± 1 days) 
• This consists of a telephone visit where the participant will be inquired about 
his/her well-being, compliance with IP, concomitant medications and alcohol use. 
• The subject should be reminded that fasting (8 hours) is required prior to his/her 
next visit. The subject should not take study medication on the morning of the 
next clinic visit (D14) as s/he will dose at the clinic.   
Ascertain that participant is not receiving concomitant systemic corticosteroids 
 
6.2.4 
D14 Procedures (± 2 days) - Must present after at least 8 hours of 
fasting 
• Perform a physical examination 
• Record vital signs 


 
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• History and physical examination  
• Assess Liver Scores: MELD, Child Pugh and Discriminant Function 
• Alcohol consumption history  – Timeline Followback Questionnaire 
• Assess and record AEs 
• Review and record concomitant medications. Confirm that participant is not 
receiving concomitant systemic corticosteroids.  
• Evaluation of compliance  
• Obtain blood samples for serum chemistry, hematology and coagulation tests 
• Urine pregnancy test in females of childbearing potential  
• Assess study medication compliance and perform accountability 
• Instruct the patient to take the daily dose of study medication, at the clinic, with 
water and approximately 30 minutes prior to eating. 
• Dispense study medication for at-home dosing and remind the patient to take 
study medication with water, approximately 30 minutes prior to breakfast.  
Instruct the patient to swallow the tablet whole; s/he must not chew, divide, or 
crush the tablet. 
• The subject should be reminded that fasting (8 hours) is required prior to his/her 
next visit. The subject should not take study medication on the morning of the 
next clinic visit (D28) as s/he will dose at the clinic.   
• Perform biosample banking for future use 
 
6.2.5.       Day 21 procedures (± 2 days) 
• This consists of a telephone visit where the participant will be inquired about 
his/her well-being, compliance with IP, concomitant medications and alcohol use.  
• The subject should be reminded that fasting (8 hours) is required prior to his/her 
next visit. The subject should not take study medication on the morning of the 
next clinic visit (D28) as s/he will dose at the clinic.  Confirm that participant is not 
receiving concomitant systemic corticosteroids. 
6.2.6.    D28 Procedures (± 2 days) - Must present after at least 8 hours of 
fasting 
• Perform a physical examination 
• Record vital signs 
• Alcohol consumption history – Timeline Followback Questionnaire 
• Assess and record AEs 


 
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• Assess Liver Scores: MELD, Child Pugh and Discriminant Function 
• Review and record concomitant medications. Confirm that participant is not 
receiving concomitant systemic corticosteroids. 
• Assess study medication compliance and perform accountability 
• Obtain blood samples for serum chemistry, hematology and coagulation tests 
• Urine pregnancy test in females of childbearing potential  
• Instruct the patient to take the daily dose of study medication, at the clinic, with 
water and approximately 30 minutes prior to eating  
• The subject should be reminded that fasting (8 hours) is required prior to his/her 
next visit. The subject should not take study medication on the morning of the 
next clinic visit (D42) as s/he will dose at the clinic.   
• Perform biosample banking for future use 
 
6.2.7.      Day 42 Procedures (+ 2 days) - Must present after at least 8 hours of 
fasting 
 
• Perform a physical examination 
• Record vital signs 
• Assess Liver Scores: MELD, Child Pugh and Discriminant Function 
• Alcohol consumption history -– Timeline Followback Questionnaire  
• Assess and record AEs 
• Review and record concomitant medications. Confirm that participant is not 
receiving concomitant systemic corticosteroids.   
• Assess study medication compliance and perform accountability and obtain any 
remaining study medication from patient 
• Obtain blood samples for serum chemistry, hematology and coagulation tests 
• Perform a urine pregnancy test in females of childbearing potential 
• Perform a standard 12-lead electrocardiogram (ECG) 
• Obtain blood samples for special investigations as outlined in section 3.2 
• Instruct the patient to take the final dose of study medication, at the clinic, with 
water and approximately 30 minutes prior to eating  
• Perform biosample (blood and stool) banking for future use 
 


 
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6.2.8. Follow up phase D90, D120 and D180 (± 2 weeks) – Must present after at 
least 8 hours of fasting 
• Perform a physical examination 
• Record vital signs 
• Alcohol consumption history- – Timeline Followback Questionnaire 
• Assess and record AEs 
• Assess Liver Scores: MELD, Child Pugh and Discriminant Function 
• Review and record concomitant medications 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests 
• Perform biosample banking for future use 
 
6.2.9. Early Termination Procedures 
Subjects who withdraw consent or discontinue treatment prematurely during the 
Treatment Phase should complete the assessments required on Day 42.  Subjects 
who discontinue prematurely during the Follow-up Phase should complete the 
assessments required on Day 180. 
6.2.10. 
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 designated study physician should be contacted. 
 
6.2.11. Specimen Banking 
Specimens to be banked include genomic DNA at D0, blood mononuclear cells at 
D0, D28 and D42, and blood (serum and plasma) samples at D0, D14, D28, D42, 
D90, D120 and D180. Stool samples collected at D0 and D42 will also be banked for 
future ancillary studies.   
 
7. 
EFFICACY EVALUATIONS 
TO ASSESS THE EFFECTS OF OCA IN PATIENTS WITH MODERATELY SEVERE AH ON: 
PRIMARY OBJECTIVE 
• Changes in MELD score at 6 weeks of treatment  
• Incidence of SAEs during the treatment phase 
 


 
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Secondary Objectives 
• Any SAEs during the follow-up phase 
• SAEs attributable to the study medicine during the treatment and follow-up 
phases 
• AEs and discontinuation rates during the treatment and follow-up phases 
• Change in MELD score at 90 and 180 days 
• Change in Child-Pugh score at 6 weeks and 90 and 180 days 
• Mortality rate at 6 weeks, 90 days and 180 days 
• Rates of hospitalization and lengths of stay 
• Changes in intestinal inflammation and bacterial translocation 
• Changes in serum oxidative stress, cytokines, and activation of innate 
immunity.   
8. 
SAFETY EVALUATIONS 
8.1. 
ADVERSE EVENTS 
Adverse event (AE) data will be collected from Day 0 through the DB phase, until the 
patient fully completes her/his trial participation at the Follow Up visit. 
8.2. 
PHYSICAL EXAMINATION AND VITAL SIGNS 
8.2.1. 
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 
(Table 1).  This includes height only at Screening. The physical examination must 
include the following: 
-General appearance 
-Weight 
-Eyes 
-Ears, nose, and throat 
-Neck 
-Respiratory system 
-Cardiovascular system 
-Abdominal region 
-Mental status 
-Neurological system  


 
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8.2.2. 
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. 
8.3. 
CLINICAL LABORATORY 
Blood samples for serum chemistry, hematology, and coagulation will be collected at 
every visit as detailed in the Schedule of Trial Procedures (section 3.2.).  The 
number and volume of samples to be collected at each visit will be detailed in a 
separate document. These tests will be conducted at local laboratories at 3 
participating sites.  
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. 
8.4. 
ELECTROCARDIOGRAM 
Standard 12-lead ECGs will be collected at screening and Day 42 visits. 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 5 
digit study number, Screening or Randomization Number, date and time.  There is 
no central review of the ECGs.  The following variables will be assessed: PR, QRS, 
QT and QTc intervals and a clinical evaluation for each ECG will be provided.   
8.5. 
OTHER SAFETY RELATED CLINICAL OUTCOMES 
The following clinical outcomes will be assessed: 
• Death (from hepatic and non-hepatic related causes) 
• Complications of portal hypertension including gastroesophageal bleeding, 
interventions 
to 
manage 
variceal 
bleeding 
(e.g., 
variceal 
banding/sclerotherapy or TIPS placement) and diuretic resistant ascites 
• Complications of Cirrhosis: new-onset ascites, hepatic encephalopathy, 
hepatorenal syndrome (type I or II), and spontaneous bacterial peritonitis). 
• Hospitalization 
Each of these events including hospitalizations will be adjudicated by the site 


 
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investigator as expected as part of the natural history of moderately severe AH, or 
unexpected (e.g., suicide, motor vehicle accident, or myocardial infarction).  
9. ADVERSE EVENTS 
9.1. 
DEFINITION OF ADVERSE EVENTS 
9.1.1. 
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 Day 0 until the patient completes trial 
participation (D-180).   
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 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 double blind OCA or 
placebo in the DB phase. 
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.  
9.1.1.1. 
Pretreatment Event(s) 
Untoward events that occur during screening phase (prior to randomization) should 
be recorded as medical history. 


 
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9.1.2. Severity of AEs 
AEs must be graded for severity (i.e., intensity).  A severity category of mild, 
moderate, or severe, as defined in Table 2, 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.”   For example, severe headache is a severe AE, but may not 
be a serious AE.  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. 
9.1.3. 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 3.  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.  


 
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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 other 
factors. 
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. 
 
9.2. 
SERIOUS ADVERSE EVENTS 
9.2.1. 
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: 
(a) Death;  
(b) Is life threatening; 
(c) Results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions; 
(d) A congenital anomaly/birth defect; 
(e) Requires in-patient hospitalization or prolongs an existing hospitalization;  
(f) 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. 


 
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9.2.2. 
Reporting SAEs 
In agreeing to the provisions of this protocol, the investigator accepts all legal 
responsibilities for immediate reporting of SAEs to the study designated physician 
(Dr. Chalasani or his designee) as described below. 
Table 4:  Requirements for Reporting AEs to various stakeholders 
  
 
Local IRB 
 
NIAAA 
 
DSMB 
 
Other 
centers 
 
Intercept 
 
FDA 
AEs 
Continuing 
Review 
Annual 
Report 
Every 6 
months 
DSMB 
reports (every 
6 months) 
DSMB reports 
(every 6 
months) 
Annual 
Report 
TEAEs 
Continuing 
Review 
Annual 
Report 
Every 6 
months 
DSMB 
reports (every 
6 months) 
DSMB reports 
(every 6 
months) 
Annual 
Report 
SAEs 
Continuing 
Review 
2 
working 
days 
Every 6 
months 
DSMB 
reports (every 
6 months) 
DSMB reports 
(every 6 
months) 
Annual 
Report 
SUSAR 
5 days 
 
2 
working 
days 
 
2 working 
days 
 
2 working 
days 
 
2 working 
days 
7 days if 
death 
15 days if 
other 
Fatality  
If unrelated Follow SAE timeline 
If related follow SUSAR timeline 
AE: Adverse Event; TEACs:  Treatment Emergent Adverse Event; SAE: Serious Adverse Event; 
SUSAR: Serious Unsuspected Adverse Reaction; DSMB: Data and Safety Monitoring Board 
 
The study designated physician for TREAT 002 is Naga Chalasani, MD. 
Safety Officer for the DCU of the TREAT Consortium is Samer Gawrieh, MD.  
All SAEs must be reported to the DCU (i.e., 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 information as soon as possible. At a minimum the following information 
should be provided at the time of the initial report:   5-digit Study ID, a description of 
the event, at least one criterion classifying the event as Serious and the name and 
title of the reporting individual.  Additionally, judgment of causality by the investigator 
must be provided as soon as possible to ensure timely reporting to regulatory 
authorities. 


 
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Following the initial report, any additional information obtained by the investigator 
about the SAE must be reported promptly to the DCU.  
The site investigator will assess whether the event is causally related to the study 
medication.  The study designated physician (Dr. Chalasani) will consider the 
investigator’s assessment, however, since he 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 an SAE meets the criteria for an IND safety report (suspected, 
unexpected serious adverse reaction (SUSAR) in accordance with the FDA 
regulations, 312.32(c)(1)(i).  
9.2.2.1. 
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 
designated study physician to record the SAE on the patient’s AE CRF and, if 
necessary, provide a copy of this CRF to the DCU.  Other supporting documents 
such as radiology reports, hospital discharge summaries and autopsy reports should 
also be provided, when appropriate, in anonymized fashion.  Additionally, upon 
request by the designated study physician, 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 designated study physician any need for supplemental 
investigations of SAE(s).  The results of these additional assessments must be 
reported to the designated study physician.    
9.3. 
SAES THAT ARE ANTICIPATED TO OCCUR IN THE STUDY POPULATION (EXPECTED 
SAES)  
Certain SAEs are anticipated to occur in this study population at some frequency 
independent of drug exposure. These expected SAEs have been identified as: 
variceal bleeding, ascites, spontaneous bacterial peritonitis, jaundice, hepatorenal 
syndrome, or hepatic encephalopathy. These expected SAEs as well as any related 
hospitalization will not be expeditiously reported as IND safety reports, but will be 
reported in the manner described above (9.2.2). However, if an aggregate analysis 
indicates that these events are occurring more frequently in the drug treatment 
group than in a concurrent or historical control group, the SAEs will be reported as 
an IND safety report (21 CRF 312.32(c)(1)(c)). 
 
9.4. 
FOLLOW UP OF AES 
All AEs, including clinically significant laboratory values or physical examination 
findings relative to pretreatment assessments, must be followed during the trial until 


 
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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. 
10. STATISTICAL METHODS 
10.1. ANALYSIS SETS 
Primary end point:  Analysis will be based on intention-to-treat principle. We will 
evaluate the main outcome, change in MELD score at day 42, in the framework of 
the repeated measurements analysis of covariance (ANCOVA) model.  Specifically, 
MELD score at each follow-up visit will be used as the outcome variable. The main 
predictor is treatment group (GROUP). We will adjust for time (visit) and baseline 
MELD score and include the interaction between GROUP and visit. The interaction 
term allows evaluation of GROUP difference at each visit. The main comparison is 
the differences of MELD score change at day # 28 between two groups. A random 
intercept will be used to adjust for the correlation among the observations from the 
same subject. We will also evaluate the GROUP difference at 90 and 180 days in 
the framework of above repeated ANCOVA model.    
 
SAEs during treatment: The primary analysis is to compare the proportion of patients 
having at least one SAE during the treatment period between the two groups using 
Chi-square tests. SAE during follow-up will be analyzed similarly.  Other safety 
outcomes include AEs, discontinuations, pre-defined laboratory abnormalities, and 
predefined EKG abnormalities.  Other continuous outcomes will be analyzed in a 
similar way to MELD score, binary outcomes will be analyzed in a similar way to 
SAE, and censored time-to-event outcomes will be analyzed using appropriate 
survival analysis tools (e.g., Kaplan-Meier plots, Cox models).   
 
10.2. DETERMINATION OF SAMPLE SIZE 
We examined the power of testing the difference in change of MELD score from 
baseline to day 28 with sample size of 30 in each group. Assuming a 10% drop out 
rate at day 28, we will have 27 subjects in each group. Using a two-sample t-test, we 
will have 80% power to detect any difference in effect size ≥ 78% of one standard 
deviation (smallest detectable effect size=0.78). The analysis using repeated-
measurement ANCOVA will be more powerful than a two-sample t-test.  


 
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10.3. SAFETY ANALYSIS 
Descriptive statistics will be used to summarize safety data to allow a comparison 
between groups. 
Safety data, including AEs, clinical and laboratory observations and physical 
examination findings, and other safety related outcomes will be summarized by 
treatment group.  
10.3.1. 
AEs 
AEs will be labeled according to standard medical terminology using the case report 
forms provided.  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. 
10.3.2. 
Clinical Laboratory Evaluations 
Descriptive statistics summarizing central laboratory data (hematology, chemistry, 
and coagulogram) will be presented for all trial visits.  Changes from pretreatment to 
each trial visit will also be summarized by treatment group/arm. 
10.3.3. 
Additional Safety and Clinical Findings 
Additional safety assessments include vital signs, physical examinations, and ECGs.  
Descriptive statistics of the vital sign and ECG parameters will be presented by 
treatment group and trial visit, as well as the change from BL at each visit.  The 
percentage of patients in each treatment group with clinically significant abnormal 
ECG findings will be summarized. 
10.3.4. 
Other Safety Related Clinical Outcomes 
The following clinical outcomes will be assessed: 
• Death (from hepatic and non-hepatic related causes) 
• Complications of portal hypertension including gastroesophageal bleeding, 
interventions 
to 
manage 
variceal 
bleeding 
(e.g., 
variceal 
banding/sclerotherapy or TIPS placement) and diuretic resistant ascites 
• Complications of Cirrhosis: new-onset ascites, hepatic encephalopathy, 
hepatorenal syndrome (type I or II), and spontaneous bacterial peritonitis). 
• Hospitalization 
 


 
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10.4. INTERIM ANALYSES 
An interim efficacy analysis during the DB phase is not planned.     
10.5. HANDLING OF MISSING DATA 
Missing values will not be imputed and only observed values will be used in data 
analyses and presentations.   
10.6. DATA AND SAFETY MONITORING COMMITTEE (DSMC) 
An independent DSMC will be formed to review safety data at periodic intervals from 
this and all other TREAT studies.  Members of the DSMC will not be allowed to 
participate as investigators in this trial.   
The DSMC will review blinded safety data and unblinded safety data (as necessary 
in their opinion) to ensure the safe and proper treatment of patients.  The frequency 
of their standard meetings will be according to the agreed upon DSMC charter. In 
addition, Chair of the DSMC or the designated study physician may call for an ad-
hoc DSMC if deemed necessary by either party. Based on review of these data, the 
DSMC will send a written report to the designated study physician and to the DCU. It 
is the responsibility of the designated study physician and the DCU to distribute 
these reports to all other stakeholders (NIAAA, FDA, Intercept, and individual sites)  
The DSMC will operate under an appropriate charter (in compliance with relevant 
regulatory guidance) that will define its organization and operation.  The DSMC will 
prepare written minutes of both its open and closed sessions.  The closed minutes 
will be made available to the investigators only after the database is locked and the 
blind for the trial has been broken. 
All investigators and responsible IRBs will be informed of any decisions made which 
alter the conduct of this trial based on recommendations from the DSMC relating to 
patient safety.  The investigators will inform the participants of such actions and the 
protocol and ICF will be revised, as appropriate. 
Changes to the protocol or to the ICS may be initiated by any investigator, but it is 
the final responsibility of the designated study physician as the IND holder to 
approve/finalize any such changes and to communicate to other stakeholder.  
11. ADMINISTRATIVE AND REGULATORY CONSIDERATIONS 
11.1. 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. 


 
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11.2. INSTITUTIONAL REVIEW BOARD (IRB)  
A properly convened IRB at each participating site will review and approve this study 
prior to its initiation. Currently, the IRBs of the Mayo Clinic and the Indiana University 
School of Medicine have reciprocal agreements in place for selected protocols and it 
is probable that this protocol will be eligible for reciprocity between these two IRBs. 
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 will report various categories of the AEs to the IRB according the 
schedule described in Table 4.  
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.  
Clinical monitors (e.g., CRAs), 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 and/or regulatory authorities) without the written consent of the 
TREAT consortium.  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 the funding agency, IRB or Intercept which is supplying the study 
medicine 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 
10.4.1. 
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: 


 
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(a) Consent to participate in Trial  
(b) Letter to Primary Care Physician, if applicable 
(c) Patient visit dates 
(d) Screening and Randomization Numbers 
(e) Demographic information 
(f) Medical history 
(g) Disease history 
(h) Physical examination  
(i) Vital signs 
(j) Laboratory assessments (copy of laboratory reports) 
(k) AEs and concomitant medications 
(l) Dates of dispensing study medication 
(m)ECGs 
(n) Liver biopsy reports (if applicable) 
(o) Patient questionnaires 
(p) Drug accountability 
(q) Issues with protocol compliance 
(r) Completion of, or withdrawal from, trial 
10.4.2. 
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 5-digit participant ID. The CRF must be 
completed promptly after each patient visit.   
10.5. INVESTIGATOR OBLIGATIONS 
The investigator or a medically trained designee will be responsible for obtaining 
written informed consent and for the care of the patients for the duration of the trial.  
If the investigator is not present in the clinical research facility during the 
assessment, he or she will leave instructions for the trial site staff and a telephone 
number where he or she can be reached. 
10.5.1. 
AE Reporting 
The investigator is responsible for recording AEs reported by the patient or 
discovered by any other means during the trial.  In agreeing to the provisions of this 
protocol, the investigator accepts all legal responsibilities for immediate reporting of 
SAEs to the designated study physician. 


 
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10.5.2. 
 Protocol Deviations 
The investigator is not permitted to deviate from the protocol in any significant way 
without proper notification to the DCU and the study designated physician (Dr. Naga 
Chalasani). Changes to the protocol or to the ICS may be initiated by any 
investigator, but it is the final responsibility of the designated study physician as the 
IND holder to approve/finalize any such changes and to communicate to other 
stakeholder Although protocol amendments can be initiated by any study personnel, 
it is the final responsibility of the designated study physician as the IND holder to 
approve/finalize any protocol amendments. Any protocol amendments can be 
implemented at each site only after their local IRB approval. The only exception is 
when the investigator considers a participant’s safety to be compromised if 
immediate action is not taken. 
10.5.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and 
maintained: 
(a) Approved ICF 
(b) IRB approvals (of protocol/amendments, patient questionnaires, etc.) 
(c) Form FDA 1572 equivalent 
(d) Current medical license of the primary site investigator 
(e) Financial disclosure forms 
10.6. DATA QUALITY ASSURANCE AND QUALITY CONTROL 
Logic and consistency checks will be performed on all data entered into the CRF to 
ensure accuracy and completeness.   
Training sessions, regular monitoring of the trial at the trial sites, instruction 
manuals, data verification, cross-checking and data audits will be performed to 
ensure quality of all trial data.  Investigators’ meetings and/or on-site trial initiations 
will be performed to prepare investigators and other trial site personnel for 
appropriate collection of trial data. 
10.7. SITE MONITORING & AUDITING 
10.7.1. 
Trial Monitoring 
Trial records at each site will be monitored at regular intervals by a clinical research 
associate (CRA).  The role of the CRA is to aid the investigator in the maintenance 
and documentation of complete, accurate, legible, well organized and easily 
retrievable data.  In addition, the CRA will ensure the investigator's understanding of 
all applicable regulations concerning the clinical evaluation of the study medication 
and will ensure an understanding of the protocol, reporting responsibilities and the 
validity of the data. This will include ensuring that full and appropriate essential 


 
TREAT – 002,   V.1.7 NOVEMBER 29, 2016                         (45) 
 
CONFIDENTIAL 
documentation is available.  Responsibility for properly implementing the protocol 
and maintaining complete trial records remain with each investigator. 
In order to perform this role, the CRA must perform source data verification (SDV) 
and as such must be given access to the patient’s primary source documentation 
(e.g., paper or electronic medical records) that support data entries in the CRF.  The 
investigator may exercise judgment in allowing the CRA access to particular 
sections of the patient's medical records if these are deemed irrelevant to the 
performance, observations or conduct of this trial. 
10.7.2. 
Trial Auditing 
The investigator should understand that it may be necessary for the IRB and / or a 
regulatory agency to conduct one or more site audits during or after the trial and 
agrees to allow access to all trial related documentation and information and be 
available for discussion about the trial.   
10.8. ARCHIVING AND RECORD RETENTION 
The investigator should retain all correspondence relating to this trial in the 
Investigator Site File (ISF).  Any trial documents stored elsewhere should have their 
location referenced in the ISF. 
All documents relating to the trial including the ISF itself, source documents and 
patient medical files (retained per country specific regulations), completed trial 
patient log and confidential patient identification list will be retained by the 
investigator for a minimum period of 15 years, in accordance with regulations.  In the 
event that storage of records becomes a problem at any time during this period, the 
Sponsor should be consulted for assistance.  At the end of the minimum period, the 
investigator should obtain written authorization from the Sponsor prior to the 
destruction of any records.  The investigator will notify the Sponsor if ownership of 
documents or responsibility for the trial site is transferred.  The Sponsor will inform 
investigators should it become aware of any changes in storage requirements. 
10.9. PUBLICATION POLICY 
No data are to be made public or published without prior knowledge and written 
approval by the TREAT Consortium Steering Committee.   
The TREAT consortium publication policies will be applied. Intercept will have the 
opportunity to review each paper prior to its submission for publication. 


TREAT – 002,   v.1.7 November 29, 2016                      (46) 
CONFIDENTIAL 
11. LIST OF PLANNED LABORATORY ANALYTES  
 
Serum Chemistry  
 sodium 
 potassium 
 calcium 
 chloride 
 bicarbonate 
albumin  
BUN  
creatinine  
total bilirubin  
unconjugated (indirect) bilirubin  
conjugated (direct) bilirubin  
aspartate aminotransferase (AST; SGOT)  
alanine transaminase (ALT; SGPT)  
alkaline phosphatase (ALP)  
glucose  
total protein  
 
MELD Score Calculation  
http://www.mayoclinic.org/meld/mayomodel6.html 
 Hematology  
 hemoglobin  
 hematocrit  
 WBC with differential  
 platelets  
 RBC count (incl. MCV, HBE [MCH],  MCHC)  
 prothrombin time (PT and INR)  
  
Urine and Serum pregnancy test 
 
Special investigations 
serum  FGF19 
bile acid C4 
fasting free fatty acids 
lipid profile 
insulin 
adiponectin, 
bacterial translocation (plasma LPS and sCD14) 
cytokine measurements (serum TNF-α, IL-1, IL-6, and IL-8) 
markers of oxidative stress 
apoptosis 
stool for calprotectin 


TREAT – 002,   v.1.7 November 29, 2016                      (47) 
CONFIDENTIAL 
EXPLORATORY EVALUATIONS 
The following are the analyses that might be analyzed in the serum/plasma and 
peripheral blood mononuclear cells (PBMC).   
   
Table 5: Exploratory evaluations 
 
Cytokines/chemokines Serum TNF-α, IL-1, IL-6, IL-8, and others as described in section 
D.  
NK cells 
Flow cytometry of PBMC for CD3–CD56+ cells.  Cytotoxic activity 
will be measured by assessing intracellular perforin and granzyme 
expression.  
Cytotoxic T cells  
Flow cytometry of PBMC for CD3+CD56+ cells.  Cytotoxic activity 
will be measured by assessing intracellular perforin and granzyme 
expression. 
Dendritic Cells (DC) 
Flow cytometry for the number and phenotype (HLA-DR level).  
DCs in PBMCs lack CD3, CD14hi, CD19, and CD56, but strongly 
express HLA-DR.  Spontaneous ex-vivo cytokine production will 
be analyzed.   
Complement 
activation 
Plasma C3a levels and plasma circulating immune complexes  
 
 
Table 6: Total Blood Volumes¶ 
 
Sample Blood Volume (ml) 
 
Sample Type 
Screen 
Day 
0 
Day 
14 
Day 
28 
Day 
42 
Day 
90 
Day 
120 
Day 
180 
Total 
Volume 
(ml) 
Chemistry 
5 
5 
5 
5 
5 
5 
5 
5 
40 
Hematology 
 
 3 
3 
3 
3 
3 
3 
3 
3 
24 
Coagulation 
3 
3 
3 
3 
3 
3 
3 
3 
24 
Serum 
Pregnancy 
3 
 
 
 
 
 
 
 
3 
Biospecimen 
Banking1 
 
38 
12 
32 
32 
12 
12 
12 
150 
Special 
Investigations 
 
20 
 
 
20 
 
 
 
40 
Total 
14 
69 
23 
43 
63 
23 
23 
23 
 281 
 
¶These are estimated volume and may vary from center to center, depending on local laboratory 
requirements. 
1 This volume may be lower if a particular center does not collect PBMCs as part of biospecimen 
banking.  
 


TREAT – 002,   v.1.7 November 29, 2016                      (48) 
CONFIDENTIAL 
12. REFERENCES 
 
 
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Metab 2008 Jul;295(1):E10-E16. 
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pathogenesis of alcoholic and nonalcoholic hepatic steatosis. Semin Liver Dis 
2010 Nov;30(4):378-390. 
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25;360(26):2758-2769. 
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Gastroenterol Clin North Am 2011 Sep;40(3):611-639. 
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al. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J 
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2005 Feb;41(2):353-358. 
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hepatitis patients in the United States. J Clin Gastroenterol 2011 
Sep;45(8):714-719. 
 9.  O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Am J 
Gastroenterol 2010 Jan;105(1):14-32. 
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binding activity of peroxisome proliferator-activated receptor alpha is inhibited 
by ethanol metabolism. A novel mechanism for the development of ethanol-
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 11.  You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW. The role of AMP-
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 12.  You M, Fischer M, Deeg MA, Crabb DW. Ethanol induces fatty acid synthesis 
pathways by activation of sterol regulatory element-binding protein (SREBP). J 
Biol Chem 2002 Aug 9;277(32):29342-29347. 
 13.  Liangpunsakul S, Sozio MS, Shin E, Zhao Z, Xu Y, Ross RA, et al. Inhibitory 
effect of ethanol on AMPK phosphorylation is mediated in part through elevated 
ceramide levels. Am J Physiol Gastrointest Liver Physiol 2010 
Jun;298(6):G1004-G1012. 
 14.  Fischer M, You M, Matsumoto M, Crabb DW. Peroxisome proliferator-activated 
receptor alpha (PPARalpha) agonist treatment reverses PPARalpha 
dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice. J 
Biol Chem 2003 Jul 25;278(30):27997-28004. 
 15.  Liangpunsakul S, Rahmini Y, Ross RA, Zhao Z, Xu Y, Crabb DW. Imipramine 
blocks ethanol-induced ASMase activation, ceramide generation, and PP2A 
activation, and ameliorates hepatic steatosis in ethanol-fed mice. Am J Physiol 
Gastrointest Liver Physiol 2011 Dec 22. 
 16.  Ajmo JM, Liang X, Rogers CQ, Pennock B, You M. Resveratrol alleviates 
alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 2008 
Oct;295(4):G833-G842. 
 17.  Balesaria S, Pell RJ, Abbott LJ, Tasleem A, Chavele KM, Barley NF, et al. 
Exploring possible mechanisms for primary bile acid malabsorption: evidence 
for different regulation of ileal bile acid transporter transcripts in chronic 
diarrhoea. Eur J Gastroenterol Hepatol 2008 May;20(5):413-422. 
 18.  Gutierrez A, Ratliff EP, Andres AM, Huang X, McKeehan WL, Davis RA. Bile 
acids decrease hepatic paraoxonase 1 expression and plasma high-density 
lipoprotein levels via FXR-mediated signaling of FGFR4. Arterioscler Thromb 
Vasc Biol 2006 Feb;26(2):301-306. 
 19.  Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, Bifulco G, et al. The 
bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and 
immune response to experimental colitis. PLoS One 2011;6(10):e25637. 
 20.  Pols TW, Nomura M, Harach T, Lo SG, Oosterveer MH, Thomas C, et al. TGR5 
activation inhibits atherosclerosis by reducing macrophage inflammation and 
lipid loading. Cell Metab 2011 Dec 7;14(6):747-757. 
 21.  Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid 
membrane receptor TGR5: a valuable metabolic target. Dig Dis 2011;29(1):37-
44. 
 22.  Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid 
membrane receptor TGR5 as an emerging target in metabolism and 
inflammation. J Hepatol 2011 Jun;54(6):1263-1272. 


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 23.  Fiorucci S, Rizzo G, Donini A, Distrutti E, Santucci L. Targeting farnesoid X 
receptor for liver and metabolic disorders. Trends Mol Med 2007 Jul;13(7):298-
309. 
 24.  Nissenbaum M, Chedid A, Mendenhall C, Gartside P. Prognostic significance of 
cholestatic alcoholic hepatitis. VA Cooperative Study Group #119. Dig Dis Sci 
1990 Jul;35(7):891-896. 
 25.  Trinchet JC, Gerhardt MF, Balkau B, Munz C, Poupon RE. Serum bile acids 
and cholestasis in alcoholic hepatitis. Relationship with usual liver tests and 
histological features. J Hepatol 1994 Aug;21(2):235-240. 
 26.  Vendemiale G, Altomare E, Lieber CS. Altered biliary excretion of 
acetaminophen in rats fed ethanol chronically. Drug Metab Dispos 1984 
Jan;12(1):20-24. 
 27.  Ackehed G, Hedenborg G, Wisen O, Norman A. Faecal bile acid excretion 
during detoxification in patients with alcohol abuse. Scand J Gastroenterol 1996 
Dec;31(12):1205-1210. 
 28.  Cai SY, He H, Nguyen T, Mennone A, Boyer JL. Retinoic acid represses 
CYP7A1 expression in human hepatocytes and HepG2 cells by FXR/RXR-
dependent and independent mechanisms. J Lipid Res 2010 Aug;51(8):2265-
2274. 
 29.  Lindor KD. Farnesoid X receptor agonists for primary biliary cirrhosis. Curr Opin 
Gastroenterol 2011 May;27(3):285-288. 
 30.  Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin 
Pharmacol 2010 May;32(4):247-288. 
 
31. Mason A, Luketic V, Lindor K, et al. Farnesoid-X receptor agonists: A new class 
of drugs for the treatment of PBC? An international study evaluating the 
addition of INT-747 to ursodeoxycholic acid. J Hepatol. 2010;52(Suppl 1):S1 
32.  Kowdley V.K., D. Jones, V. Luketic, et al. An international study evaluating the 
farnesoid X receptor agonist obeticholic acid as monotherapy in PBC. Journal 
of Hepatology. 2011. Volume 54, Supplement 1 , Page S13. 
33. Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the Farnesoid X 
Receptor agonist obeticholic acid in patients with type 2 diabetes and 
nonalcoholic fatty liver disease. Gastroenterology 2013;145:574-582 
 
 


TREAT – 002,   v.1.7 November 29, 2016                      (51) 
CONFIDENTIAL 
APPENDIX 1 – PROTOCOL AMENDMENT 1 (PROTOCOL VERSION 
1.1):  SUMMARY OF CHANGES 
1.  Background 
Protocol TREAT-002 has been prepared as a phase 2 trial to evaluate the 
efficacy of OCA in Patients with moderately severe AH.   
Protocol Version 1.0 was submitted to the US FDA.  Based on comments 
raised by the FDA, Amendment 1 (Protocol Version 1.1) was prepared with 
minor clarifications.   
2. Summary of Changes 
The following revisions were made to the protocol under Amendment 1.  
(Note:  Differences have been indicated in bold font.) 
 
Section 
Original Text 
Revised Text 
All pages 
Header:  TREAT-002, v.1, October 10, 
2013 
TREAT-002, v.1.1, November 20, 
2013 
Page 1 
Version 1 
Version 1.1 
Page 5 and 
19; Inclusion 
Criteria 
(b) Moderate severity defined as MELD 
score > 11 and < 20 
(b) Moderate severity defined as 
MELD score > 11 and < 19 
Page 5 and 
19; Inclusion 
Criteria 
(c) Must not be receiving  systemic 
steroids > 1 week at the time of  
Screening or any experimental 
medicines for AH   
 
(c) Must not have received  
systemic steroids for a duration of > 
1 week during the  Screening period 
or on the day of randomization 
and must not be receiving any 
experimental medicines for AH   
6.2.2, p. 27; 
6th bullet 
• 
Record prior (within 30 days of Day 
0) and current concomitant 
medications.    
• 
Record prior (within 30 days of 
Day 0) and current concomitant 
medications.   Ascertain that 
participant is not receiving 
concomitant systemic 
corticosteroids on the day of 
randomization. 
6.2.3, p. 28 
3rd bullet added. 
• 
Ascertain that participant is not 
receiving concomitant systemic 
corticosteroids 
6.2.4, p. 28 
• 
Review and record concomitant 
medications.  
 
• 
Review and record concomitant 
medications. Confirm that 
participant is not receiving 
concomitant systemic 
corticosteroids.  
 


TREAT – 002,   v.1.7 November 29, 2016                      (52) 
CONFIDENTIAL 
Section 
Original Text 
Revised Text 
6.2.5, p. 29 
2nd bullet edited. 
• 
The subject should be reminded 
that fasting (8 hours) is required 
prior to his/her next visit. The 
subject should not take study 
medication on the morning of the 
next clinic visit (D28) as s/he will 
dose at the clinic.  Confirm that 
participant is not receiving 
concomitant systemic 
corticosteroids. 
6.2.6, 6.2.7, 
p. 29/30 
5th bullet edited. 
• 
Review and record concomitant 
medications. Confirm that 
participant is not receiving 
concomitant systemic 
corticosteroids.  
 
 
 
 
 


TREAT – 002,   v.1.7 November 29, 2016                      (53) 
CONFIDENTIAL 
APPENDIX 2 – PROTOCOL AMENDMENT 2 (PROTOCOL VERSION 
1.2):  SUMMARY OF CHANGES 
1.  Background 
Protocol Version 1.1 was reviewed by the TREAT Consortium Investigators. 
Based on comments by the investigators, Amendment 2 (Protocol Version 
1.2) was prepared with minor changes.   
2. Summary of Changes 
The following revisions were made to the protocol under Amendment 2.  
(Note:  Differences have been indicated in bold font.) 
Section 
Original Text 
Revised Text 
All pages 
Header:  TREAT-002, v.1.1, 
November 20, 2013 
Header: TREAT-002, v.1.2, January 
17, 2014 
Page 1 
Version 1.1 
Version 1.2 
Page 1 
ClinicalTrials.Gov Identifier: Pending 
ClinicalTrials.Gov Identifier: 
NCT02039219 
Page 1 
None 
IND Number: 120229 
 
Page 3 
Table of 
Contents 
None 
Table 6: Total Blood Volumes (Page 
48) 
Page 18 
Table 1 
5 Specimens to be banked include 
genomic DNA at D0, and blood 
(mononuclear cells, serum and 
plasma) samples at D0, D14, D28, 
D42, D90, D120 and D180.  Stool 
samples collected at D0 and D42 will 
also be banked for future ancillary 
studies 
5 Specimens to be banked include 
genomic DNA at D0, blood 
mononuclear cells at D0, D28 and 
D42 and blood (serum and plasma) 
samples at D0, D14, D28, D42, D90, 
D120 and D180.  Stool samples 
collected at D0 and D42 will also be 
banked for future ancillary studies 
Page 31 
Section 
6.2.10 
Specimen 
Banking 
Specimens to be banked include 
genomic DNA at D0, and blood 
(mononuclearcells, 
serum 
and 
plasma) samples at D0, D14, D28, 
D42, D90, D120 and D180. Stool 
samples collected at D0 and D42 will 
also be banked for future ancillary 
studies.   
 
Specimens to be banked include 
genomic 
DNA 
at 
D0, 
blood 
mononuclear cells at D0, D28 and 
D42, and blood (serum and plasma) 
samples at D0, D14, D28, D42, D90, 
D120 
and 
D180. 
Stool 
samples 
collected at D0 and D42 will also be 
banked for future ancillary studies.   
 
Page 37 
Section 
9.2.2  
Safety officer for the TREAT 
Consortium is Suthat 
Liangpunsakul, MD 
Safety officer for the TREAT 
Consortium is Samer Gawrieh, MD  


TREAT – 002,   v.1.7 November 29, 2016                      (54) 
CONFIDENTIAL 
Section 
Original Text 
Revised Text 
Page 47 
Table 6  
None 
Table 6 added to show total blood 
volumes. 
 
 


TREAT – 002,   v.1.7 November 29, 2016                      (55) 
CONFIDENTIAL 
APPENDIX 3 – PROTOCOL AMENDMENT  3 (PROTOCOL VERSION 
1.3):  SUMMARY OF CHANGES 
1.  Background 
Protocol Version 1.2 was reviewed by the TREAT Consortium Investigators at 
the annual consortium meeting. Based on the discussion by the investigators, 
Amendment 3 (Protocol Version 1.3) was prepared with minor changes.   
2. Summary of Changes 
The following revisions were made to the protocol under Amendment 3.  
(Note:  Differences have been indicated in bold font.) 
Section 
Original Text 
Revised Text 
All pages 
Header:  TREAT-002, v.1.2, 
January 17, 2014 
Header: TREAT-002, v.1.3, April 15, 
2014 
Page 1 
Version 1.2 
Version 1.3 
Page 3 
Table of Contents 
None 
Appendix 3 – page 57 
Page 18 
Table 1: 
Schedule of 
Procedures 
Row 14: Gut permeability & 
Hepatic CYP2E1 
Row 5: Alcohol Consumption 
History 
Row 6: None 
Row 14: Gut permeability & Hepatic 
CYP2E1(optional) 
Row 5: AUDIT and NIAAA 
Questionnaires 
Row 6: Timeline Followback 
Questionnaire 
Page 28  
Section 6.2.1 
Screening Period 
None 
The participant is to complete the 
AUDIT, NIAAA and Timeline 
Followback Questionnaires 
 
Page 29 
Section 6.2.2 
Day 0 Procedure 
None 
Perform a standard 12-lead 
electrocardiogram (ECG) 
 
Page 29 
Section 6.2.2 
Day 0 
Procedures 
Perform gut permeability study 
 
Perform CYP2E1 Hepatic 
measurement study 
 
Alcohol Consumption History 
Perform 
gut 
permeability 
study 
(Subjects may opt out) 
Perform CYP2E1 Hepatic measurement 
study (Subjects may opt out) 
Alcohol consumption history – Timeline 
Followback Questionnaire 
Page 30 
Section 6.2.4  
Day 14 
Procedures 
Alcohol Consumption History 
Alcohol consumption history – Timeline 
Followback Questionnaire 


TREAT – 002,   v.1.7 November 29, 2016                      (56) 
CONFIDENTIAL 
Section 
Original Text 
Revised Text 
Page 31 
Section 6.2.6  
Day 28 
Procedures 
Alcohol Consumption History 
Alcohol consumption history – Timeline 
Followback Questionnaire 
Page 31 
Section 6.2.7 
Day 42 
Procedures 
Perform gut permeability study 
 
Perform CYP2E1 Hepatic 
measurement study 
 
Alcohol Consumption History 
Perform 
gut 
permeability 
study 
(Subjects may opt out) 
Perform CYP2E1 Hepatic measurement 
study (Subjects may opt out) 
Alcohol consumption history – Timeline 
Followback Questionnaire 
Page 32 
Section 6.2.8  
Follow up Phase 
Alcohol Consumption History 
Alcohol consumption history – Timeline 
Followback Questionnaire 
Page 37 
Section 9.2.2 
Table 4:  
Requirements for 
Reporting AEs to 
various 
stakeholders 
Table Column: 
NIAAA 
 
None 
 
NIAAA 
AEs – Annual Report 
TEAEs – Annual Report 
SAEs – 2 working days 
SUSAR- 2 working days 
Page 37 
Section 9.2.2 
Table 4:  
Requirements for 
Reporting AEs to 
various 
stakeholders 
Table Row: 
SUSAR 
 
Local IRB – 5 days. Report to 
NIAAA in 48 hours 
DSMB – 7 days if death. 15 days if 
other 
Other Centers: 5 days 
Intercept: 5 days 
FDA: – 7 days if death. 15 days if 
other 
 
Local IRB – 5 days 
NIAAA- 2 working days 
DSMB – 2 working days 
Other Centers: 2 working days 
Intercept:  2 working days 
FDA: – 7 days if death. 15 days if other 
Page 37 
Section 9.2.2 
Reporting SAE 
All SAEs must be reported to the 
DCU (i.e., within 24 hours or the 
next working day after the 
investigator identifies the 
SAE.  SAEs should be entered into 
the OnCore system within 24 
hours (or the next working day) of 
the investigator becoming aware of 
the event.   
All SAEs must be reported to the DCU 
(i.e., 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.   
 
 


TREAT – 002,   v.1.7 November 29, 2016                      (57) 
CONFIDENTIAL 
Section 
Original Text 
Revised Text 
Page 37 
Section 9.2.2 
Reporting SAE 
Any supporting source 
documentation should be faxed or 
emailed to the assigned contact 
information as soon as possible. At 
a minimum the following 
information should be provided at 
the time of the initial report:   5-digit 
participant ID, a description of the 
event, at least one criterion 
classifying the event as Serious 
and the name and title of the 
reporting individual. 
Any supporting source documentation 
should be emailed to the assigned 
contact information as soon as possible. 
At a minimum the following information 
should be provided at the time of the 
initial report:   5-digit Study ID, a 
description of the event, at least one 
criterion classifying the event as 
Serious and the name and title of the 
reporting individual. 
 
 
  
 
 
 


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CONFIDENTIAL 
APPENDIX 4 – PROTOCOL AMENDMENT  4 (PROTOCOL VERSION 
1.4):  SUMMARY OF CHANGES 
1.  Background 
Protocol Version 1.3 was reviewed and was noted that further clarification 
was needed in the study procedure section of the protocol 
2. Summary of Changes 
The following revisions were made to the protocol under Amendment 4.  
(Note:  Differences have been indicated in bold font.) 
Section 
Original Text 
Revised Text 
All pages 
Header:  TREAT-002, v.1.3, 
April 15, 2014 
Header: TREAT-002, v.1.4, May 15, 2014 
Page 1 
Version 1.3 
Version 1.4 
Page 18 
Table 1 
None 
Assess Liver Scores: MELD, Child 
Pugh and/ or Discriminant Function 
Page 27 
6.2.1 
Screening 
Period 
None 
Assess Liver Scores: MELD 
Page 28 
6.2.2 Day 0 
Procedures 
None 
Assess Liver Scores: MELD, Child 
Pugh and Discriminant Function 
Page 28 
6.2.2 Day 0 
Procedures 
Perform a Standard 12- lead 
electrocardiogram (ECG) 
None 
Page 29 
6.2.4 Day 14 
Procedures 
None 
Assess Liver Scores: MELD, Child 
Pugh and Discriminant Function 
Page 30 
6.2.6 Day 28 
Procedures 
None 
Assess Liver Scores: MELD, Child 
Pugh and Discriminant Function 
Page 30 
6.2.7 Day 42 
Procedures 
None 
Assess Liver Scores: MELD, Child 
Pugh and Discriminant Function 
Page 30 
6.2.7 Day 42 
Procedures 
None 
Perform a Standard 12- lead 
electrocardiogram (ECG) 
Page 31 
6.2.8 Follow up 
None 
Assess Liver Scores: MELD, Child 
Pugh and Discriminant Function 
 


TREAT – 002,   v.1.7 November 29, 2016                      (59) 
CONFIDENTIAL 
APPENDIX 5 – PROTOCOL AMENDMENT  5 (PROTOCOL VERSION 
1.5):  SUMMARY OF CHANGES 
1.  Background 
Progress of recruitment and obstacles was discussed at the annual TREAT 
Face to Face meeting in March 2015. A decision was made to remove the 
sub studies (Gut Permeability test and Hepatic CYP2E1 Measurement study).  
2. Summary of Changes 
The following revisions were made to the protocol under Amendment 4.  
(Note:  Differences have been indicated in bold font.) 
Section 
Original Text 
Revised Text 
All pages 
Header: TREAT-002, v.1.4, May 15, 2014 
Header: TREAT-002, v.1.5, 
April 15, 2015 
Page 1 
Version 1.4 
Version 1.5 
Page 4-5 
Objectives 
Secondary 
• 
Changes in hepatic CYP2E1 activity 
• 
Changes in intestinal permeability 
 
 
Page 16-17 
Trial 
Objectives 
Secondary 
• 
Changes in hepatic CYP2E1 activity 
• 
Changes in intestinal permeability 
 
 
Page 18 
Table 1 
Schedule of 
Procedures 
Gut Permeability and Hepatic CYP2E1 
(optional) 
 
Page 28 
Section 6.2.2 
Day 0 
Procedures 
• 
Perform 
gut 
permeability 
study 
(Subjects may opt out) 
• 
Perform CYP2E1 activity measurement 
(Subjects may opt out) 
 
 
Page 30 
Section 6.2.7 
Day 42 
Procedures 
• 
Perform 
gut 
permeability 
study 
(Subjects may opt out) 
• 
Perform CYP2E1 activity measurement 
(Subjects may opt out) 
 
 
Page 32 
Section 7 
Efficacy 
Evaluations 
Secondary 
Objectives 
 Changes in hepatic CYP2E1 activity 
Changes in intestinal permeability 
 
 


TREAT – 002,   v.1.7 November 29, 2016                      (60) 
CONFIDENTIAL 
Section 
Original Text 
Revised Text 
Page 47 
Table 6: 
Total Blood 
Volumes 
Hepatic CYP2E1  
Row Deleted and total Blood 
volumes adjusted 
 
 
 


TREAT – 002,   v.1.7 November 29, 2016                      (61) 
CONFIDENTIAL 
APPENDIX 6 – PROTOCOL AMENDMENT  6 (PROTOCOL VERSION 
1.6):  SUMMARY OF CHANGES 
1. Background 
TREAT Consortium made decision to increase inclusion MELD score to <20. 
Language regarding the gut permeability test and hepatic CYP2E1 
measurements was removed from the synopsis to correctly reflect the 
changes made in protocol version 1.5. 
2. Summary of Changes 
The following revisions were made to the protocol under Amendment 6.  
(Note:  Differences have been indicated in bold font.) 
Section 
Original Text 
Revised Text 
All pages 
Header: TREAT-002, v.1.5, April 15, 2015 
Header: TREAT-002, v.1.6, 
December 10, 201 
Page 1 
Version 1.5 
Version 1.6 
Page 5 
Treatment 
Phase 
Gut permeability and hepatic CYP2E1 
activity will be measured at days 0 and 42, 
with additional special investigations at days 
0 and 42. 
None 
Page 6 
Key Eligibility 
Criteria: 
Inclusion 
Criteria 
 
(b) Moderate severity defined as MELD 
score > 11 and <  19 
 
 
(b) Moderate severity defined as 
MELD score > 11 and <  20 
 
Page 20 
Section 4: 
Patient 
Selection  
4.2 Inclusion 
Criteria 
(b) Moderate severity defined as MELD 
score > 11 and <  19  
 
(b) Moderate severity defined 
as MELD score > 11 and <  20  
 
 
 
 


TREAT – 002,   v.1.7 November 29, 2016                      (62) 
CONFIDENTIAL 
APPENDIX 6 – PROTOCOL AMENDMENT  7 (PROTOCOL VERSION 
1.7):  SUMMARY OF CHANGES 
1. Background 
TREAT Consortium added Einstein Medical Center as a study site. The 
protocol has been updated to reflect the addition of the new study site. 
2. Summary of Changes 
The following revisions were made to the protocol under Amendment 7.  
(Note:  Differences have been indicated in bold font.) 
Section 
Original Text 
Revised Text 
All pages 
Header: TREAT-002, v.1.6, 
December 10, 201 
Header: TREAT-002, v.1.7, 
November 29, 2016 
Page 1 
Version 1.6 
Version 1.7 
Page 5 
Planned 
Number of 
Investigational 
Sites 
 
Three investigational trial sites at 
Indiana University in Indianapolis, 
Mayo Clinic in Rochester, and Virginia 
Commonwealth University in 
Richmond 
 
Four investigational trial sites at 
Indiana University in Indianapolis, 
Mayo Clinic in Rochester, Virginia 
Commonwealth University in 
Richmond, and Einstein Medical 
Center in Philadelphia