Conditions: Non-Alcoholic Steatohepatitis
Keywords: NAFLD activity score ASBTi MRI PDFF NAS NAFLD liver disease ASBT MRI proton density fat fraction nonalcoholic steatohepatitis apical sodium dependent bile acid transporter inhibitor fatty liver NASH
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 197
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if the investigational treatment volixibat (SHP626) is safe, tolerable and effective in adults with nonalcoholic steatohepatitis (NASH).

Detailed description:

Arms:
arm 1: Subject will be administered 5 mg SHP626 capsule by orally once daily in a double-blinded fashion arm 2: Subject will be administered 10 mg SHP626 capsule by orally once daily in a double-blinded fashion arm 3: Subject will be administered 20 mg SHP626 capsule by orally once daily in a double-blinded fashion arm 4: Subject will be administered SHP626 matching PBO capsule by orally once daily in a double-blinded fashion

Interventions: intervention 1: SHP626 intervention 2: Placebo
Intervention descriptions: intervention 1: 5 mg, 10 mg, and 20 mg of SHP626 capsule by orally once daily in a double-blinded fashion intervention 2: Matching placebo

Protocol document:
Prot_001.pdf: 
PROTOCOL: SHP626-201
TITLE:
A Phase 2 Double-blind, Randomized, Placebo-controlled, Dose-finding 
Study to Evaluate the Safety, Tolerability and Efficacy of Volixibat 
Potassium, an Apical Sodium-Dependent Bile Acid Transporter 
Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
DRUG:
Volixibat potassium  (SHP626)
IND:
123,847
EUDRACT NO.:
2016-000203-82
SPONSOR: 
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
Philip Newsome MD
Director of Centre for Liver Research 
University of Birmingham
Edgbaston, Birmingham B15 2TT UK
NATIONAL/
COORDINATING
INVESTIGATOR/UK
Guruprasad P Aithal MBBS, MD, FRCP, PhD
Head of the Division, Nottingham Digestive Diseases Centre
Director, NIHR Nottingham Digestive Diseases Biomedical Research 
Unit 
Nottingham University Hospitals and University of Nottingham
Queen's Medical Centre
Nottingham NG7 2UH
PROTOCOL 
HISTORY:
Amendment 4: 25 August 2017
Amendment 3: 22 March 2017
Amendment 2: 19 July 2016
Amendment 1: 8 April 2016
Original Protocol:  24 February 2016 
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations.  This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.


Shire 
CONFIDENTIAL 
Page 2 
SHP626-201 P•·otocol Amendment 4 
Volixibat potassium (SHP626) 
25 Aug 2017 
PROTOCOL SIGNATURE PAGE 
Date: 
\ 
;;_s /+JJ .2o 17 
,F 
pment Lead (GCDL)- Hepatology 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP626-201. 
Title: A Phase 2 Double-Blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate the 
Safety, Tolerability and Efficacy of Volix.ibat Potassium, an Apical Sodium-Dependent Bile Acid 
Transporter Inhibitor (ASBTi) in Adults with Nonalcohol ic Steatohepatitis (NASH) 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
T agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with ICH (The international Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use) guidelines on Good Clinical Practice and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my patticipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should J decide to withdraw from execution of the study 1 will communicate my intention 
immediately in writing to the sponsor. 
lnvestigator Name and Address: 
(please hand print or type) 
Signature: ------------------------ Date: _____ _ 


Shire
CONFIDENTIAL
Page 3
SHP626-201 Protocol Amendment 4
Volixibat potassium (SHP626)
25 Aug 2017
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
25 August 2017
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Emergency Contact Information
Updated information for the Shire 
study physician and ICON medical 
monitor.

To provide updated and 
correct information.
Synopsis
Reduced planned study period from 
July 2020 to January 2020.

Reduced planned study 
period due to elimination 
of the previously planned 
pause in enrollment.
Synopsis
Extended maximum duration of 
screening period from 56 days to 
70 days.

To accommodate 
additional tissue for liver 
biopsy central reads in 
addition to other 
procedures.
Synopsis, Section 9.6
The “Number of Subjects” was updated 
to reflect new numbers following 
elimination of the previously planned 
enrollment pause.

To provide updated and 
correct information.
Synopsis
The “Methodology” section was 
updated to reflect new numbers 
following elimination of the previously 
planned enrollment pause.

To provide updated and 
correct information.
Synopsis; Section 4.2
Updated exclusion criterion #15 to 
indicate that subjects with TB >2 ULN 
at screening would be excluded. 

To provide correct 
information consistent with 
the rest of the protocol.
Table 1, Section 3.1, Section 7.1, 
Section 7.1.1
Lengthened screening window from 8 
weeks (56 days) to 10 weeks (70 days).
Updated study design flow chart to 
reflect extended screening window.

To accommodate 
additional tissue for liver 
biopsy central reads in 
addition to other delays.
Section 3.1 , Section 9.6
Updated text to provide revised 
numbers of subjects expected to be 
enrolled, following elimination of the 
previously planned enrollment pause.

To provide updated and 
correct information.
Section 3.1
Revised the capping number for F0 
subjects; this will be capped at 88 if 1 
dose is dropped after the interim 
analysis and at 78 if 2 doses are 
dropped (% remains the same at 30%) 
following elimination of the previously 
planned enrollment pause.

To provide updated and 
correct information.


Shire
CONFIDENTIAL
Page 4
SHP626-201 Protocol Amendment 4
Volixibat potassium (SHP626)
25 Aug 2017
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
25 August 2017
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Section 3.1, Section 9.5.1
Removed sentence: “Study enrollment 
will be paused after 92 subjects have 
been randomized.”

This reflects elimination of 
the previously planned 
pause in enrollment.
Section 3.2
Revised subject’s maximum duration of 
participation as expected to be 
approximately 434 days.

This was revised as the 
screening period was 
lengthened to 10 weeks and 
this duration also did not 
previously include the 
screening period.
Section 5.2.1
Removed the phrase: “then the Shire 
GCDL”. 

To provide updated and 
correct information.
Section 6.2.2
Revised the capping number for F0 
subjects; this will be capped at 88 if 1 
dose is dropped after the interim 
analysis and at 78 if 2 doses are 
dropped (% remains the same at 30%) 
following elimination of the previously 
planned enrollment pause.

To provide updated and 
correct information.
Section 6.2.3 , Section 7.1.3
Removed sentence: “All assessments 
should be completed at least 30 minutes 
prior to administration of the IP.”

This stipulation is not 
necessary for this study as 
determined by Phase 1 
final results.
Section 6.2.4, Section 8.2.2, 
Section 8.2.3
Replaced “Shire GCDL” with “Shire 
study physician”

To provide correct 
information/ guidance.
Section 7.1, Section 7.1.1
Replaced “medical monitor” with 
“Shire study physician”

To provide correct 
information/ guidance.
Section 9.5.1
Removed the sentence: “Subjects will 
be randomized to 1 or 2 volixibat doses 
or to PBO.”

The sentence was 
redundant and this idea is 
presented elsewhere in the 
same paragraph.
Section 9.5.1
Added text indicating that the IA will 
also be performed by a 
gastroenterologist and hepatologist. 

To provide correct 
information/ guidance.
Section 10
Added text indicating that compliance
with current applicable regulations also 
constitutes compliance with the ethical 
principles in the Declaration of 
Helsinki.

To provide correct 
information/ guidance.


Shire
CONFIDENTIAL
Page 5
SHP626-201 Protocol Amendment 4
Volixibat potassium (SHP626)
25 Aug 2017
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
25 August 2017
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Section 10.1.1, Section 10.2.1
Added reference to ICH GCP E6 R2 
2017 guidelines.

To provide correct 
information/ guidance.
Appendix 5
Updated formatting to align with 
source document, and eliminated 
irrelevant footnote to this table. 
Added definition of baseline.

To improve clarity of the 
information in the table and 
adhere to the source table.
Throughout protocol
Minor changes to wording.

To improve clarity


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Page 6
SHP626-201 Protocol Amendment 4
Volixibat potassium (SHP626)
25 Aug 2017
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to:
Shire Global Drug Safety Department
Preferred method: scan and e-mail to globalpharmacovigilance@shire.com
OR fax to +44(0) 1256 89 4715 (Global); or +1 866 557 4473 (North America)
AND
Notification and/or a copy of this form must also be sent to the Shire study physician by e-mail 
using the details below:
Melissa Palmer, MD, FAASLD, GCDL-Hepatology
e-mail: mpalmer@shire.com  
For protocol- or safety-related issues during normal business hours 9:00 a.m. to 5:00 p.m. 
(Eastern Time), the investigator must contact the Contract Research Organization (CRO) 
Medical Monitor:
ICON Medical Monitor: Jack Martin, MD
Telephone number: +1 215 583 2257
Fax number: +1 215 616 3096
Mobile number: +1 215 593 9095
E-mail address: Jack.Martin@iconplc.com
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact ICON’s 24/7 Medical Emergency Coverage:
Chargeable global telephone number: +1 919 674 5468
NOTE: Investigative sites will be provided country-specific toll-free telephone numbers. Please
refer to this document, as applicable. Countries without a toll-free number will need to dial the 
chargeable number noted above.


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Page 7
SHP626-201 Protocol Amendment 4
Volixibat potassium (SHP626)
25 Aug 2017
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product (IP) quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products).  For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
PQC@shire.com
European Union and Rest of World
PQCROW@shire.com
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA) 
+1-888-300-6414 or +1-800-828-2088


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Volixibat potassium (SHP626)
25 Aug 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................6
PRODUCT QUALITY COMPLAINTS..........................................................................................7
TABLE OF CONTENTS.................................................................................................................8
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
ABBREVIATIONS .......................................................................................................................13
STUDY SYNOPSIS ......................................................................................................................16
1
BACKGROUND INFORMATION.......................................................................................26
1.1
Indication and Current Treatment Options ......................................................26
1.2
Product Background and Clinical Information................................................26
1.3
Benefits and Risks............................................................................................29
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................30
2.1
Rationale for the Study ....................................................................................30
2.2
Study Objectives ..............................................................................................31
2.2.1
Primary Objective..................................................................................................31
2.2.2
Secondary Objectives.............................................................................................31
2.2.3
Exploratory Objectives ..........................................................................................31
3
STUDY DESIGN ...................................................................................................................31
3.1
Study Design and Flow Chart..........................................................................31
3.2
Duration and Study Completion Definition.....................................................33
3.3
Sites and Regions.............................................................................................33
4
STUDY POPULATION.........................................................................................................33
4.1
Inclusion Criteria .............................................................................................33
4.2
Exclusion Criteria ............................................................................................34
4.3
Restrictions ......................................................................................................36
4.4
Reproductive Potential.....................................................................................37
4.4.1
Female Contraception............................................................................................37
4.4.2
Male Contraception................................................................................................37
4.5
Discontinuation of Subjects.............................................................................38
4.5.1
Subject Withdrawal Criteria ..................................................................................38
4.5.2
Reasons for Discontinuation..................................................................................38
4.5.3
Subjects Lost to Follow-up Prior to Last Scheduled Visit.....................................39
4.5.4
Safety-related Stopping Rules................................................................................39


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Volixibat potassium (SHP626)
25 Aug 2017
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................40
5.1
Prior Treatment ................................................................................................40
5.2
Concomitant Treatment ...................................................................................40
5.2.1
Permitted Treatment...............................................................................................40
5.2.2
Prohibited Treatment .............................................................................................41
6
INVESTIGATIONAL PRODUCT ........................................................................................41
6.1
Identity of Investigational Product...................................................................41
6.1.1
Blinding the Treatment Assignment......................................................................41
6.2
Administration of Investigational Product(s)...................................................42
6.2.1
Interactive Response Technology for Investigational Product Management ........42
6.2.2
Allocation of Subjects to Treatment ......................................................................42
6.2.3
Dosing....................................................................................................................43
6.2.4
Unblinding the Treatment Assignment..................................................................43
6.3
Labeling, Packaging, Storage, and Handling...................................................43
6.3.1
Labeling .................................................................................................................43
6.3.2
Packaging...............................................................................................................44
6.3.3
Storage ...................................................................................................................44
6.4
Drug Accountability.........................................................................................45
6.5
Subject Compliance .........................................................................................46
7
STUDY PROCEDURES........................................................................................................46
7.1
Study Schedule.................................................................................................46
7.1.1
Screening (Visit 1).................................................................................................46
7.1.2
Baseline (Visit 2) ...................................................................................................47
7.1.3
Treatment and Assessment Period (Visits 3 through 9/EOS)................................48
7.1.4
Follow-up (Visit 10) ..............................................................................................48
7.1.5
Additional Care of Subjects after the Study ..........................................................49
7.2
Study Evaluations and Procedures...................................................................49
7.2.1
Demographic and Other Baseline Characteristics .................................................49
7.2.2
Efficacy..................................................................................................................49
7.2.2.1
Liver Biopsy...........................................................................................49
7.2.2.2
MRI ........................................................................................................49
7.2.3
Safety .....................................................................................................................49
7.2.3.1
Medical History and Medications ..........................................................49
7.2.3.2
Physical Examination.............................................................................49
7.2.3.3
Adverse Event Collection.......................................................................50
7.2.3.4
Vital Signs..............................................................................................50
7.2.3.5
Clinical Laboratory Evaluations.............................................................50
7.2.3.6
Additional Laboratory Assessments.......................................................52


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25 Aug 2017
7.2.3.7
Pregnancy Test .......................................................................................52
7.2.3.8
Drug and Alcohol Testing......................................................................53
7.2.3.9
Electrocardiogram ..................................................................................53
7.2.3.10
Health-related Quality of Life Assessments...........................................53
7.2.3.11
Volume of Blood to be Drawn from Each Subject ................................53
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................54
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events ................................................................................................54
8.1.1
Severity Categorization..........................................................................................54
8.1.2
Relationship Categorization...................................................................................55
8.1.3
Outcome Categorization ........................................................................................55
8.1.4
Symptoms of the Disease Under Study .................................................................55
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................56
8.1.6
Criteria for Discontinuation of Treatment .............................................................56
8.1.7
Pregnancy...............................................................................................................56
8.1.8
Abuse, Misuse, Overdose, and Medication Error..................................................57
8.2
Serious Adverse Event Procedures..................................................................58
8.2.1
Reference Safety Information................................................................................58
8.2.2
Reporting Procedures.............................................................................................58
8.2.3
Serious Adverse Event Definition .........................................................................58
8.2.4
Serious Adverse Event Onset and Resolution Dates .............................................59
8.2.5
Fatal Outcome........................................................................................................59
8.2.6
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................59
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................60
9.1
Data Collection ................................................................................................60
9.2
Clinical Data Management ..............................................................................60
9.3
Data Handling Considerations.........................................................................60
9.4
Statistical Analysis Process..............................................................................60
9.5
Planned Interim Analysis and Data Monitoring Committee............................61
9.5.1
Planned Interim Analysis.......................................................................................61
9.5.2
Data Monitoring Committee..................................................................................61
9.6
Sample Size Calculation and Power Considerations .......................................62
9.7
Study Population..............................................................................................63
9.8
Efficacy Analyses ............................................................................................63
9.8.1
Primary Efficacy Endpoint ....................................................................................63
9.8.2
Secondary Efficacy Endpoints...............................................................................64
9.8.3
Exploratory Efficacy Endpoints.............................................................................65


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Volixibat potassium (SHP626)
25 Aug 2017
9.9
Safety Analyses................................................................................................65
9.10
Other Analyses.................................................................................................66
9.10.1 Health-related Quality of Life Analyses................................................................66
9.10.2 Stool Assessment ...................................................................................................66
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................66
10.1
Sponsor’s Responsibilities...............................................................................66
10.1.1 Good Clinical Practice Compliance.......................................................................66
10.1.2 Indemnity/Liability and Insurance.........................................................................67
10.1.3 Public Posting of Study Information......................................................................67
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................67
10.1.5 Study Suspension, Termination, and Completion..................................................67
10.2
Investigator’s Responsibilities.........................................................................68
10.2.1 Good Clinical Practice Compliance.......................................................................68
10.2.2 Protocol Adherence and Investigator Agreement..................................................68
10.2.3 Documentation and Retention of Records.............................................................69
10.2.3.1
Electronic Case Report Forms................................................................69
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................69
10.2.3.3
Audit/Inspection.....................................................................................70
10.2.3.4
Financial Disclosure...............................................................................70
10.3
Ethical Considerations .....................................................................................70
10.3.1 Informed Consent...................................................................................................70
10.3.2 Institutional Review Board or Ethics Committee..................................................71
10.4
Privacy and Confidentiality .............................................................................71
10.5
Study Results / Publication Policy...................................................................72
11 REFERENCES .......................................................................................................................74
12 APPENDICES ........................................................................................................................77
APPENDIX 1 Protocol History...............................................................................................78
APPENDIX 2 Fatty Liver Disease Histology Scoring............................................................79
APPENDIX 3 EQ-5D-5L Health Questionnaire UK Sample Only, Not for Official Use......81
APPENDIX 4 Criteria to Assess Severity of Liver-Related Adverse Events .........................84
APPENDIX 5 Stopping Rules for Liver-related Blood Tests .................................................85
APPENDIX 6 Bristol Stool Chart ...........................................................................................86


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Volixibat potassium (SHP626)
25 Aug 2017
LIST OF TABLES
Table 1
Schedule of Assessments..........................................................................22
LIST OF FIGURES
Figure 1
Study Design Flow Chart..........................................................................33


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Volixibat potassium (SHP626)
25 Aug 2017
ABBREVIATIONS
AE
adverse event
ALP 
alkaline phosphatase
ALT 
alanine aminotransferase
aPPT
activated partial thromboplastin time
ASBT
apical sodium-dependent bile acid transporter
ASBTi 
ASBT inhibitor
AST 
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BA 
bile acid
BMI
body mass index
C4
7-alpha-hydroxy-4-cholesten-3-one
CRA
clinical research associate
CRC 
clinical research center
CRO
contract research organization
DMC 
data monitoring committee
eCRF
electronic case report form
EQ-5D-5L 
EuroQol-5 Dimension-5 Level Questionnaire
ECG
electrocardiogram
EOS
end of study
EU
European Union
FAS
full analysis set
FBA 
fecal bile acid
FDA
Food and Drug Administration
FXR
farnesoid X receptor
GCDL 
Global Clinical Development Lead
GCP
Good Clinical Practice
GDS
Global Drug Safety
GGT 
gamma glutamyl transferase
GLP-1 RA
glucagon-like peptide-1 receptor agonists
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus


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Volixibat potassium (SHP626)
25 Aug 2017
HBVDNA
hepatitis B virus deoxyribonucleic acid
HCV
hepatitis C virus
HCVAb
hepatitis C virus antibody
HCVRNA
hepatitis C virus ribonucleic acid
HDL-C
high-density lipoprotein-cholesterol
HFD
high fat diet
HFF
hepatic fat fraction
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HOMA-%B 
homeostasis model assessment in β-cell function
HOMA-IR 
homeostasis model assessment insulin resistance
HRQoL 
health-related quality of life
IA 
interim analysis
IAS
interim analysis set
ICH
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IND 
investigational new drug
INR
international normalized ratio
IP
investigational product
IR
insulin resistance
IRB
Institutional Review Board
IRT
interactive response technology
LDL-C 
low-density lipoprotein-cholesterol
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MR
magnetic resonance
MRI 
magnetic resonance imaging
MRS
magnetic resonance spectroscopy
MOA
mechanism of action
NAFLD 
nonalcoholic fatty liver disease
NAS 
NAFLD Activity Score
NASH 
nonalcoholic steatohepatitis
NASH CRN
NASH Clinical Research Network
NOAEL 
no observed adverse effect level
PBC
primary biliary cirrhosis


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Volixibat potassium (SHP626)
25 Aug 2017
PBO
placebo
PDFF
proton density fat-fraction
PO
by mouth
POC
proof of concept
PRO 
patient-reported outcome
PSC
primary sclerosing cholangitis
PT
prothrombin time
QD 
once daily
RBC
red blood cell 
SAE 
serious adverse event
SAF
steatosis, activity, and fibrosis score
SAP 
statistical analysis plan
T2DM
type 2 diabetes mellitus
T3
triiodothyronine
TA
therapeutic area
TB
total bilirubin
TEAE
treatment-emergent adverse event
TGR5 
transmembrane G protein-coupled receptor
TPN
total parenteral nutrition
TSH
thyroid-stimulating hormone
TZD
thiazolidinediones
ULN
upper limit of normal
USA 
United States of America
VAS
visual analogue scale


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Volixibat potassium (SHP626)
25 Aug 2017
STUDY SYNOPSIS
Protocol number: SHP626-201
Drug: Volixibat potassium (SHP626)
Title of the study: A Phase 2 Double-Blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate 
the Safety, Tolerability and Efficacy of Volixibat Potassium, an Apical Sodium-Dependent Bile Acid 
Transporter Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
Number of subjects (total and for each treatment arm): The number of subjects screened and randomized 
will be dependent upon the number of dosing arms dropped following the interim analysis (IA). 

Approximately 899 subjects will be screened to randomize 292 subjects (81 per continued dosing arm, 
approximately 49 per dropped dosing arm) to achieve 201 completers if three arms (2 volixibat and 
1 placebo [PBO]) continue after the interim analysis (one dose is dropped after the IA). 

Approximately 807 subjects will be screened to randomize 260 subjects (81 per continued dosing arm, 
approximately 49 per dropped dosing arm) to achieve 134 completers if two arms (1 volixibat and 
1 PBO) continue after the IA (two doses are dropped after the IA).
Investigator(s):  Multicenter study
Site(s) and Region(s): 
Anticipated regions: US, Canada, and EU 
Estimated number of sites planned: 60 to 80
Study period (planned):
July 2016 to January 2020
Clinical phase:
2
Objectives:
Primary:  To evaluate the effect of volixibat compared to PBO on liver histology 
Secondary:  
•
To evaluate the safety and tolerability of volixibat compared to PBO
•
To evaluate the effect of volixibat compared to PBO on hepatic steatosis  (measured by MRI)
•
To evaluate the effect of volixibat compared to PBO on liver histology (measured by individual 
nonalcoholic fatty liver disease (NAFLD) activity score (NAS) components and fibrosis stage)
•
To evaluate the effect of volixibat compared to PBO on liver histology (measured by NASH resolution 
without worsening fibrosis)
•
To evaluate the effect of volixibat compared to PBO on serum liver-related biochemistry 
•
To evaluate the effect of volixibat compared to PBO on metabolic indicators (glucose, insulin,
hemoglobin A1c [HbA1c]) 
•
To evaluate the effect of volixibat compared to PBO on serum lipids (cholesterol, HDL-C, LDL-C, 
triglycerides) 
Rationale: Currently, there is no approved medication for the treatment of NASH. Volixibat is under 
development for the treatment of NASH based on its mechanism of action (MOA) and is supported by 
nonclinical and Phase 1 data.  This is a Phase 2, 48-week, dose-finding study to examine the efficacy, 
tolerability, and safety of volixibat in adults with NASH.
Investigational product, dose, and mode of administration:

Volixibat 5, 10, and 20 mg and matched PBO capsules by mouth (PO) once daily (QD). Investigational 
product (IP) should be given 30 minutes prior to the first meal of the day containing approximately 10-


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20 grams of fat. Also see Section 6.2.3 (Dosing).

Identical PBO will be used as comparator 

Subjects should take the IP at the same time each day and should not take more than one dose in a 
day if they miss a dose. If a dose is missed at the normally scheduled time, the subject can make 
up the dose that day as long as no more than 1 dose is taken in a 10-hour period.
Methodology:
This study will be a Phase 2, 48-week, multicenter, double-blind, randomized, PBO-controlled, parallel group, 
proof of concept, dose-finding study, with one IA after at least 80 subjects have received 24 weeks of treatment. 
There will be 3 active arms of volixibat (5, 10 and 20 mg) and a PBO arm. Subjects will be randomized to 
receive one of three doses of volixibat (5, 10, or 20 mg) once daily (QD) or PBO in a 1:1:1:1 ratio. Subjects 
with fibrosis stages F0 through F3 may be enrolled, but the number of F0 subjects will be capped at 88 if 1 dose 
is dropped after the IA and at 78 if 2 doses are dropped (approximately 30% of the total number of subjects). 
Depending on the outcome of the IA, one or more treatment arms will be discontinued or the study may be 
terminated. The follow-up period will be 4 weeks after last dose. Subjects will be expected to visit the study 
center at least 10 times. 
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions.
2.
Ability to voluntarily provide written, signed, and dated (personally or via a legally-authorized 
representative, as applicable) informed consent to participate in the study.
3.
Age 18-80 years inclusive.  This inclusion criterion will only be assessed at the first screening visit.
4.
Male, or non-pregnant, non-lactating female, who is sexually active and who agrees to comply with the 
contraceptive requirements of the protocol, or females of non-childbearing potential.  Males and 
females of child-bearing potential who are sexually active must agree to use acceptable contraception 
during the study and 30 days following the last dose of the IP.
5.
Presence of ≥5% steatosis on screening MRI from a centrally read radiologist performed either during 
the screening period or within 6 months prior to the first visit.
6.
Histologic confirmation of NASH without cirrhosis (F0-F3) from a centrally read liver biopsy 
performed either during the screening period or within 6 months prior to the first visit with a NAS of 
≥4 with a score of at least 1 in each component (steatosis, lobular inflammation, and hepatocyte 
ballooning).
Exclusion Criteria:
1.
Presence of or history of cirrhosis or evidence of decompensated liver disease (ie, ascites, variceal 
bleeding, etc.) or hepatocellular carcinoma.
2.
History or presence of other concomitant liver disease as assessed by the investigator or determined by 
laboratory findings including, but not limited to: active hepatitis B virus (HBV) infection (hepatitis B 
surface antigen (HBsAg) positive and/or HBVDNA positive; subjects who are hepatitis B core 
antibody (HBcAb) positive may be eligible as long as HBsAg is negative and HBVDNA is
nondetectable), active hepatitis C virus (HCV) infection (prior exposure to HCV [defined as HCVAb 
positive] without a current or prior history of a detectable HCVRNA) will be eligible, alcoholic liver 
disease, proven autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis 
(PSC), hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, bile duct obstruction, liver 
primary or metastatic cancer.
3.
Current or recurrent disease that could affect the action, absorption, disposition, or laboratory 
assessment of the IP (including bile salt metabolism in the intestine) eg, uncontrolled inflammatory 
bowel disease, uncontrolled celiac disease, gastric bypass procedures (gastric lap band or gastric sleeve 


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is acceptable), ileal or ileocecal resection, uncontrolled irritable bowel syndrome with predominant 
diarrhea, or history of chronic diarrhea or loose stools of any etiology.
4.
Weight change ≥5% after qualifying liver biopsy and/or MRI performed. If the subject had a liver 
biopsy and/or MRI within 6 months of screening, but experienced a weight change ≥5% since the date 
of liver biopsy and/or MRI, the liver biopsy and/or MRI must be repeated at screening.
5.
Contraindications to MRI (ie, claustrophobia, coronary stents, coronary implantable devices, girth, 
etc.). Stents or other devices may be allowed, at the investigator’s discretion, if they do not interfere 
with the functioning of the MRI machine.
6.
Current or relevant history of physical or psychiatric illness, any medical disorder that may require 
treatment or make the subject unlikely to complete the study.
7.
Treatment with Vitamin E, thiazolidinediones (TZD), or glucagon-like peptide-1 receptor agonists 
(GLP-1 RA) unless subject on a stable dose for 6 months prior to qualifying liver biopsy and not 
initiated after qualifying liver biopsy and will continue the same dosing regimen throughout study 
participation. 
8.
Uncontrolled diabetes defined as HbA1c of ≥9.5% within 60 days prior to enrollment. 
9.
Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) that 
could affect the action, absorption, or disposition of the IP, or clinical or laboratory assessment. 
(Current use is defined as use within 14 days of screening). Patients currently taking insulin will not be 
excluded; however, they must be on a stable dose for at least 30 days prior to screening, or a sliding 
scale of insulin is allowed as long as the subject’s HbA1c remains < 9.5%.
10. Use of drugs, herbs or supplements historically associated with causing or worsening NAFLD/NASH 
for less than 6 months prior to qualifying liver biopsy, or initiated any time after qualifying liver biopsy 
performed, including the use of total parenteral nutrition (TPN). 
11. Serum AST >7 times upper limit of normal (ULN) at screening.
12. Serum ALT >7 times ULN at screening.
13. Elevated serum creatinine ≥2.0 mg/dL.
14. International normalized ratio (INR) >1.3.
15. Total bilirubin (TB) >2 times ULN at screening (Except for documented Gilbert’s syndrome with 
bilirubin levels 20 µmol/L to 90 µmol/L (1.2 to 5.3 mg/dL) and with a ratio of 
unconjugated/conjugated bilirubin that is commensurately higher).
16. Platelet count <130 × 109L
17. Medical history of impaired hemostasis or current use of anticoagulant medication (use of antiplatelet 
medications, such as low-dose, ie, 81mg, aspirin (ASA) or clopidogrel (Plavix), will be allowed).
18. Uncontrolled thyroid disease.
19. Type 1 diabetes mellitus.
20. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or any of the 
stated ingredients.
21. Known history of alcohol or other substance abuse within the last year or at any time during the study 
based on investigator’s discretion.  Weekly alcohol intake greater than 21 grams/day for males and 14 
grams/day for females on average or inability to reliably quantify alcohol consumption based on 
investigator’s judgment.
22. Within 6 months of MRI and liver biopsy:

Have used any IP


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
Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study
23. Inability to safely obtain a liver biopsy.
24. Females who are pregnant, planning to become pregnant, or are breastfeeding, or males who are 
planning to father a child during study participation.
25. The anticipated need for a surgical procedure during the study that could interfere with the treatment. 
26. Known positivity for human immunodeficiency virus (HIV) infection.
27. Cancer within 5 years of screening, except for basal or squamous cell carcinoma of the skin or in situ 
cervical carcinoma that has been treated with no evidence of recurrence.
28. History of noncompliance with medical regimens, unreliability, mental instability or incompetence that
could compromise the validity of informed consent or lead to noncompliance with the study protocol.
29. Any other conditions or abnormalities which, in the opinion of the investigator, may compromise the 
safety of the subject, or interfere with the subject participating.
30. Subject is currently enrolled in this study at any study site (unless the subject is transferring to another 
qualified study site with prior sponsor approval).
31. Subjects who are employees at the unit of the investigational site that is conducting the study.
Maximum duration of subject involvement in the study:

Planned duration of screening period: 70 days 

Planned duration of treatment period: 336 days 

Planned duration of follow-up: 28 days 
Endpoints and statistical analysis:
Safety Analysis Set will consist of all subjects who take at least 1 dose of randomized IP, and have at least 1 
post-baseline safety assessment (eg, coming back for any visit, reporting of an adverse event (AE) or reporting 
the absence of AEs).
Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have at least 1 post-baseline 
efficacy assessment (eg, MRI, liver biopsy, serum liver-related biochemistry measurement).
Interim Analysis Set (IAS) will consist of all subjects in the Safety Analysis Set who have at least 1 post-
baseline efficacy assessment (eg, MRI, ALT biochemistry measurement) on or before the Week 24 visit at the 
time of the data cut for the IA.  
Screened Set will consist of all subjects who have signed an informed consent. 
Randomized Set will consist of all subjects in the Screened Set who have been randomized into the study. 
Efficacy Endpoints:

Primary: Binary response indicating (yes/no) whether a subject responded at Week 48 with a reduction 
of at least 2 points without worsening of fibrosis from baseline NAS.

Secondary: 

Change from baseline to Week 48 on liver histology as measured by the individual NAS 
components (ballooning, inflammation, steatosis).  

Change from baseline to Week 48 on hepatic steatosis as measured by MRI-PDFF.

Change from baseline to Week 48 on liver histology as measured by fibrosis stage. (NASH 
Clinical Research Network (CRN))

Resolution of NASH (defined as total absence of ballooning [score = 0] absent or mild 


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inflammation [score 0-1], steatosis can be present [score 0-3]), without worsening of fibrosis 
as assessed by liver histology at week 48.

Change from baseline to Week 48 on serum liver-related biochemistry as measured by:

alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

alkaline phosphatase (ALP)

gamma glutamyl transferase (GGT)

total bilirubin (TB)

Change from baseline to Week 48 on metabolic indicators as measured by:

fasting serum glucose levels

insulin levels

HbA1c 

Change from baseline to Week 48 on serum lipids measured by: 

fasting total cholesterol

HDL-C

LDL-C

triglycerides 
Primary hypotheses:

Null: The proportion of subjects at Week 48 with a reduction of at least 2 points without worsening of 
fibrosis from baseline NAS does not differ between any of the volixibat doses and PBO.

Alternative: The proportion of subjects at Week 48 with a reduction of at least 2 points without 
worsening of fibrosis from baseline NAS does differ between at least one volixibat dose and PBO.
The FAS will be used to assess the primary efficacy endpoint. The difference between a volixibat dose and PBO 
will be tested with a stratified Cochran-Mantel-Haenzel test. Subjects with missing data for the primary efficacy 
endpoint at the Week 48 visit will be considered as non-responders. The test will be stratified by presence or 
absence of Type 2 diabetes mellitus (T2DM) at baseline, and baseline NAS separated into two groups 
(NAS={4,5} or NAS={6,7,8}). Holm multiplicity adjustment will be applied prior to determining statistical 
significance at the 0.1 level. Histology will be read by one central hepatohistopathologist who will use the 
NASH CRN standard scoring system – NAS. The SAF Steatosis (S), Activity (A), and Fibrosis (F) scoring 
system will be determined for exploratory purposes.
The Safety Analysis Set will be used to assess the safety endpoints including AEs (including changes from 
baseline in physical examination findings), vital signs, ECGs, and clinical laboratory tests (chemistry, 
hematology, coagulation and urinalysis).
AEs will be coded using the agreed upon version of the Medical Dictionary for Regulatory Activities 
(MedDRA). TEAEs are defined as AEs that started or worsened on or after the date of the first dose of IP, and 
no later than the follow-up visit. The number of events, incidence, and percentage of TEAEs will be presented 
by system organ class, preferred term, and by treatment group. TEAEs will be further summarized by severity 
and the relationship to the IP. AEs related to the IP, AEs leading to withdrawal, SAEs, and death will be 
similarly summarized/listed.
Vital signs, ECG findings, and clinical laboratory tests will be summarized by treatment group and visit. 
Potentially clinically important findings will be summarized. Graphical presentation may be used when deemed 
necessary.
For safety parameters, baseline is defined as the last assessment prior to the first dose of the IP.
Planned Interim Analysis:
An IA will be conducted by an independent data monitoring committee (DMC) after at least 80 subjects have 
received 24 weeks of treatment. The IA will evaluate the safety, tolerability and efficacy of 3 doses of volixibat 


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each compared to PBO. 
Tolerability will be assessed by the number of discontinuations due to any one TEAE, presumably 
gastrointestinal events, most notably, diarrhea, loose stools, increased evacuations, and abdominal pain. Efficacy 
at the IA will be based on reduction of steatosis or ALT. Steatosis is assessed by MRI-PDFF. Depending on the 
results from the IA, one or more doses of volixibat may be discontinued or the study may be terminated.  If the 
study is not terminated, subjects will receive a total of 48 weeks of the IP.


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Table 1
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9c
EOS
10
In-Clinic
Week
-10 to 0
0
2
4
8
12
24
36
48
52
Study Day
-70 to -1
0
14
28
56
84
168
252
336
364
Informed consentd
X
Inclusion/exclusion criteria
X
X (review)
Demography, medical & medication 
history 
X
Physical examination
X
X
X
X
X
Heighte, weightf, waist circumference 
and waist:hip ratio
X
X
X
X
X
X
X
X
X
X
Vital signsg
X
X
X
X
X
X
X
X
X
X
PRO (EQ-5D-5L)
X
X
X
Liver biopsyh
X
X
MRIi
X
Xj
X
ECG (12-lead)
X
X
X
X
Biochemistry and Hematologyk
X
X
X
X
X
X
X
X
X
X
Serum Glucosel
X
X
X
X
X
X
X
X
X
X
Urinalysism
X
X
X
Urine Drug and Blood Alcohol Tests
X
X
Urine Pregnancy Testn
X
X
X
X
X
X
X
X
X
X
Lipid Panel0
X
X
X
X
X
X
X
X
X
X
Coagulation Panelp
X
X
X
X
X


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Table 1
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9c
EOS
10
In-Clinic
Week
-10 to 0
0
2
4
8
12
24
36
48
52
Study Day
-70 to -1
0
14
28
56
84
168
252
336
364
Vitamins A, D, and Et
X
X
X
X
HbA1ck
X
X
X
X
X
X
X
X
X
X
Serum Liver-Related Blood Testsk, q
X
X
X
X
X
X
X
X
X
X
Insulink
X
X
X
X
X
X
X
X
HIV, Hepatitis B/Ck, r
X
Thyroid testingk, s
X
X
X
X
X
X
X
C4 Sampling
X
X
X
X
X
IRT Accessed
X
X
X
X
X
X
X
X
X
X
Randomization
X
IP Dispensedt
X
X
X
X
X
X
X
IP Returned/Accountability & 
Compliance Assessed 
X
X
X
X
X
X
X
Stool Assessmentu
X
X
X
X
X
X
Adverse Eventsv
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
ECG=electrocardiogram; EOS=end of study; HOMA=Homeostasis Model Assessment; IA=interim analysis; IP=investigational product; IRT=Interactive Response Technology; 
MRI=magnetic resonance imaging; PRO=patient-reported outcome.
a Visit Windows (calculated from Visit 2): Bi-weekly (Visits 3-4): +/- 3 days; Monthly (Visits 5-6, Visit 10): +/-5 days; Tri-monthly (Visits 7-9/DC): +/- 7 days. 
b Subjects will be reminded not to eat prior to their scheduled visit.  Additionally, during the double-blind treatment period, they should not take their study drug prior to the visit. 
They should bring their study drug with them to the visit to take 30 minutes prior to their first meal of the day containing approximately 10-20 grams of fat. Also see Section 6.2.3


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Table 1
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9c
EOS
10
In-Clinic
Week
-10 to 0
0
2
4
8
12
24
36
48
52
Study Day
-70 to -1
0
14
28
56
84
168
252
336
364
c Subjects are to complete the Visit 9 liver biopsy and MRI procedures within +14 days of Visit 9. All other Visit 9 assessments are to be completed within a window of +/- 7 days.
d Subjects who completed screening and were designated as a screen failure may be rescreened. However, rescreened subjects must begin the screening procedure again, must be 
re-consented and will be assigned a new subject number.
e Height to be measured at screening only.
f BMI to be calculated programmatically by the sponsor or designee for the following visits: screening (Visit 1), baseline (Visit 2), Visits 7 and 9/DC.   
g Vital signs to include oral, temporal, or tympanic temperature, sitting blood pressure, pulse, and respiratory rate.
h Biopsy performed within 6 months of screening can be used. All biopsies will be centrally read by a hepatic histopathologist. See Sections 7.1.1 and 7.1.3 for additional details.   
i MRI from a centrally read radiologist performed either during the screening period or within 6 months prior to the first visit. 
j MRI at Visit 7 (Week 24) for the Interim Analysis Set only.
k All blood tests are fasting blood tests. Subjects are not required to have Vitamin A, D, and E testing at screening (Visit 1).
l HOMA-IR and HOMA-%B: will be calculated programmatically by the sponsor or designee for the following visits: screening (Visit 1), baseline (Visit 2), Visits 7, 9/DC, and 10.   
m Urinalysis to include oxalate testing.
n For all females of child-bearing potential (FOCP).  Positive on-site urine dipstick results must have serum -HCG testing performed by central lab.
Additional testing can be performed at the investigator’s discretion.
o Lipid Panel includes fasting total cholesterol, HDL-C, LDL-C, and triglycerides.
p Full coagulation panel will be done at screening and baseline, but only PT/INR is required at remaining time points to assess vitamin K level.
q Serum Liver-Related Blood Tests include ALT, AST, ALP, GGT, and total bilirubin.
r Hepatitis B/C testing includes HBcAb, HBsAg, HBVDNA and HCVAb (if HCVAb is positive an HCVRNA will be performed), respectively.
s Thyroid testing includes thyroid stimulating hormone (TSH) and triiodothyronine (T3).
t Investigational product may be dispensed at an unscheduled visit outside of this schedule as needed to replace lost or damaged product.
u Subjects will be queried about the number of stool evacuations during the 24- hour period before the clinical research center (CRC) visit and asked to describe the consistency of 
the softest stool during that 24- hour period using the Bristol Stool Chart.


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Table 1
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9c
EOS
10
In-Clinic
Week
-10 to 0
0
2
4
8
12
24
36
48
52
Study Day
-70 to -1
0
14
28
56
84
168
252
336
364
v Adverse events will be collected beginning from the signing of informed consent.  All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in the study. Closure indicates that an outcome is reached, stabilization achieved (the 
investigator does not expect any further improvement or worsening of the event), or the event is otherwise explained. When appropriate, medical tests and examinations are 
performed so that resolution of event(s) can be documented.


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1
BACKGROUND INFORMATION
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease 
worldwide (Vernon et al., 2011), and is estimated to occur in 30-40% of adults in the United 
States and up to 30% of European adults.  These numbers approach 95% in those with morbid 
obesity (Mathus-Vliegen et al., 2012).  NAFLD ranges from simple steatosis, which is typically 
nonprogressive, to nonalcoholic steatohepatitis (NASH), which has a 20% likelihood of 
progression to advanced disease including fibrosis, cirrhosis and its complications including liver 
failure and the need for a liver transplant (Angulo, 2002).  Hepatocellular carcinoma is also a 
complication of NASH that may occur with or without the presence of cirrhosis (Torres et al., 
2012).  NAFLD is typically associated  with type 2 diabetes mellitus (T2DM) (Adibi et al., 2007;
Loomba et al., 2012), central or visceral obesity (Souza et al., 2012), dyslipidemia (Assy et al., 
2000; National Cholesterol Education Program, 2002), and hypertension (Donati et al., 2004).  
Together these conditions comprise the metabolic syndrome, and NASH is considered to be the 
hepatic component of this syndrome (Hamaguchi et al., 2005; Neuschwander-Tetri, 2005;
Marchesini et al., 2005). Notably, NAFLD is a clinical condition occurring in individuals who do 
not drink excessive alcohol (>20 grams/day), yet have hepatic histology which is 
indistinguishable from that seen with alcoholic excess.  The pathophysiology of NASH is likely 
multifactorial and may include combinations of metabolic, genetic, environmental, and gut 
microbial factors.       
Most individuals with NASH are asymptomatic or have nonspecific symptoms such as fatigue. 
They typically first come to medical attention incidentally following routine blood testing or on 
imaging studies performed routinely or during the evaluation of an unrelated condition. While 
ultrasound and magnetic resonance imaging (MRI) can detect the presence of steatosis (Reeder 
et al., 2011), a liver biopsy is required to diagnose NASH and the extent of liver fibrosis. 
1.1
Indication and Current Treatment Options 
There are currently no drugs approved for the treatment of NASH and it is estimated that there 
are between 6-16 million people in the United States with NASH, of which 600,000 have severe 
disease (Williams et al., 2011 and Torres and Harrison, 2008), with similar percentages reported 
throughout most areas of the world (World Gastroenterology Organisation, 2012). Treatment of 
associated metabolic comorbidities, weight reduction, and incorporation of an exercise routine 
remain the cornerstone of management.  However, lifestyle changes are seldom successful. Thus, 
NASH represents a disease with an unmet medical need that is growing at an epidemic rate, and 
that if untreated, carries a risk of significant morbidity and mortality.
1.2
Product Background and Clinical Information
Volixibat potassium (SHP626; formerly LUM002), hereafter referred to as volixibat, is a highly 
selective inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that is being 
evaluated for the treatment of NASH.  


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Bile acids (BA) promote bile flow, activation of digestive enzymes, and micellization of fats and 
fat-soluble vitamins, thereby permitting their intestinal absorption.  BAs serve as signaling 
molecules acting via receptors, such as farnesoid X receptor (FXR) and transmembrane G 
protein-coupled receptor (TGR5), in the intestine, liver and other tissues which play an important 
role in regulating insulin homeostasis. (Halilbasic et al., 2013).  Lipid peroxidation and oxidant 
stress have been proposed as one link between the accumulation of fat and subsequent injury 
(Day and James, 1998).  All of these metabolic actions have important effects to prevent the 
ongoing liver damage in NASH. 
High fat diet (HFD) fed mice treated with an ASBT inhibitor (ASBTi) (SC-435 a surrogate 
SHP626) normalized hepatic triglycerides and serum cholesterol, significantly improved insulin 
resistance (IR), and decreased NAS, predominantly steatosis.  In addition the BA pool reflected 
increases in BA that were agonists to FXR and decreases in levels that were antagonist to the 
FXR (Rao et al., 2016). Miethke and colleagues found that pharmacological inhibition of the 
ileal, ASBT (SC-435 the surrogate molecule of volixibat), blocked progression of sclerosing 
cholangitis in mdr2–/– mice (Miethke et al., 2016). Beneficial effects in liver histology in these 
mice included a reduction in the severity of hepatic fibrosis, a decrease which correlated with a 
reduction of hepatic profibrogenic gene expression. While very encouraging, whether or not the 
findings in this mouse sclerosing cholangitis model can translate to histologic improvements in 
patients with NASH is unknown.
Volixibat, as a potent inhibitor of ASBT, increases BA excretion and facilitates signaling in the 
intestine that regulates serum and hepatic BA concentrations, glucose metabolism, serum 
cholesterol and fatty acid metabolism in the liver.  The combined events resulting from inhibiting 
BA reuptake are hypothesized to have a positive metabolic, anti-inflammatory, anti-steatotic, and 
potentially antifibrotic effect that will lead to a therapeutic benefit for patients with NASH. 
One of the factors contributing to the pathogenesis of NASH is abnormal cholesterol metabolism 
and the accumulation of free cholesterol in the liver. The free cholesterol is directly toxic to 
hepatocytes, which leads to inflammation and fibrosis (Musso et al., 2013). One treatment 
approach is to remove the cholesterol from the liver to decrease and possibly reverse the damage 
to the hepatocytes. This is one of the mechanisms by which SHP626 will treat NASH.
Due to the mechanism of action (MOA), volixibat is under development for the treatment of 
NASH and may also be able to improve the metabolic syndrome that is associated with NASH. 
Volixibat inhibits ASBT therefore BAs are excreted in the feces and this loss forces the liver to 
synthesize new BA which utilizes cholesterol in the liver and serum. Volixibat also has the 
potential to reduce IR, which is considered to be the most common underlying risk factor for the 
development of NASH (Pagano et al., 2002; Sanyal et al., 2001). 
Volixibat was initially being evaluated for its use as an intervention for dyslipidemia.  As a result 
of initial observations in animals that serum low-density lipoprotein cholesterol (LDL-C) and 
total liver cholesterol content could be decreased after administration of volixibat, additional 
work was undertaken to support the safety and tolerability of the drug in healthy volunteers. 
Clinical and non-clinical studies have demonstrated very low systemic exposure across species. 


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Oral administration of volixibat at doses up to 300 mg once daily and 50 mg administered daily 
for 14 days to healthy male subjects was generally safe.  A Phase 1 study revealed that volixibat 
is tolerated at the 10 mg dose for 28 days and that there were trends towards increasing high-
density lipoprotein cholesterol (HDL-C), decreasing LDL-C, and decreasing fasting glucose in 
patients with T2DM (LUM002-101 trial). 
A healthy volunteer study investigating 12 days of varying levels of repeat doses of volixibat has 
provided key pharmacodynamic information for dose selection as measured by the effect of 
volixibat on excreted fecal bile acid (FBA) levels (SHP626-101).  In addition, the study 
investigated safety and tolerability over the dose range that was considered for this Phase 2 
study.
Data from Phase 1 studies support the position that volixibat is basically a non-absorbed drug 
that works locally in the GI tract and results in virtually no systemic exposure. Thus 
pharmacokinetic sampling will not be done in this study.
The current proof of concept (POC) Phase 2 trial will evaluate the safety, tolerability, and 
efficacy of three doses of volixibat  (5, 10, and 20 mg) in adult subjects with NASH. Due to the 
MOA of volixibat, efficacy will be assessed at an interim analysis (IA) by a change of steatosis 
from baseline to Week 24 compared to placebo (PBO).  While the gold standard for 
quantification of steatosis has historically been an invasive liver biopsy, quantitative magnetic 
resonance (MR) imaging–based biomarkers for liver fat have evolved rapidly over the last 
decade, and are increasingly being incorporated into NASH clinical trials.  Both MR 
spectroscopy (S) and MR imaging (I) proton density fat-fraction (PDFF) provide non-invasive 
means of quantifying intrahepatic lipid content (Reeder et al., 2012).  Both techniques have been 
shown to be accurate, reproducible with a low degree of variability in interpretation, cost-
effective and reliable biomarkers of quantitative hepatic fat (Roldan-Valadez et al., 2010; Urdzik 
et al., 2012;  Raptis et al., 2012).  Importantly, studies demonstrate a close correlation with 
steatosis grade histologically (Qayyum et al., 2005; Schwenzer et al., 2009).  
In a study of 51 adult subjects with NAFLD, PDFF correlated well with the grade of histologic 
steatosis, as the mean fat-fraction values of 8.9%, 16.3%, and 25.0% corresponded to histologic 
steatosis grades 1, 2, and 3, respectively (P < .0001) (Permutt et al., 2012). Thus, MRI will be 
utilized to evaluate the degree of steatosis change from baseline in this study during the IA. The 
Mozart trial was a randomized, double-blind, PBO-controlled trial of 50 patients with NASH 
who were randomized to 24 weeks of either ezetimibe or PBO, evaluating the reduction of liver 
fat by MRI-PDFF as well as by histology. Results revealed that compared to histologic non-
responders, histologic responders, defined as a two-point reduction in NAFLD activity score 
(NAS) without worsening fibrosis, had a statistically significant reduction in net MRI-PDFF of 
-4.1% ± 4.9 vs. +0.6% ± 4.1 (P <0.036) with a mean percent change of -29.3% ± 33.0 vs. 
+2.0% ± 24.0 (P < 0.004), respectively (Loomba et al., 2015). Thus, in the current trial during 
the IA, a ≥5% steatosis reduction for an active dose compared to PBO will be a clinically 
meaningful change after 24 weeks of therapy.


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Intrahepatic lipid content of less than 1% is considered to be within the normal range (Springer et 
al., 2015), however, from a study of 2349 people in a general population undergoing MRS, it 
was concluded that a PDFF value of 5.56% represented the upper limit of the normal range, as 
determined from the 95th percentile of PDFF in 345 individuals who were not at increased risk 
for hepatic steatosis (Szczepaniak et al., 2005).  Thus, in the current trial, similar to other NASH 
trials utilizing MR for evaluation, an MRI ≥5% steatosis will be used as an inclusion criterion 
(Loomba et al., 2015).  
1.3
Benefits and Risks
By virtue of volixibat’s ability to inhibit ASBT bile acid reabsorption, there is an increase in BA 
excretion and signaling in the intestine that results in improvements in glucose metabolism and 
changes in cholesterol and fatty acid synthesis in the liver. Recently, HFD fed mice treated with 
an ASBTi (SC-435 a surrogate of SHP626) normalized hepatic triglycerides and serum 
cholesterol, significantly improved IR, and decreased NAS (predominantly steatosis). In 
addition, these HFD-fed mice did not gain weight when treated with SC-435, in spite of 
consuming increased calories. Finally, the BA pool in these mice changed to predominantly FXR 
agonist (Rao et al., 2016).
These metabolic actions and preclinical results may prove to be clinically relevant to subjects 
with NASH.
NASH has recently received considerable attention as awareness of the problem of liver damage 
and prevalence of the disorder has increased, paralleling the obesity epidemic.  Consequences of 
liver damage are detrimental and can lead to liver failure, hepatocellular carcinoma, and the need 
for liver transplantation. There is no currently approved medical therapy for NASH. The large 
unmet medical need and the increased medical resource burden have led to the search for 
potential therapies to treat NASH.
Nonclinical testing established that the no observed adverse effect level (NOAEL) for volixibat 
in rats and dogs following 13 weeks of once-daily administration were 1000 and 500 mg/kg/day, 
respectively. Similarly, testing confirmed that the NOAEL for volixibat in a 6-month study in 
rats and a 9-month study in dogs were 1000 and 500 mg/kg/day, respectively. In both cases, 
these were the highest doses tested. Genotoxicity testing has yielded negative findings. 
Volixibat is minimally absorbed (Siebers et al., 2017). The pharmacokinetic profiles performed 
in clinical studies completed to date repeatedly suggest negligible systemic exposure. 
Furthermore, there has been no observation of clinically relevant changes in fat absorption 
parameters such as those related to fat-soluble vitamins.
The most frequent TEAEs in the Phase 1 studies were GI and were considered mechanism-based 
due to elevated BA concentrations in the colon. The percentage of subjects reporting at least 1 
TEAE in the GI disorders SOC generally increased with an increasing volixibat dose level 
(Part 1 Study TDU10632 and Study LUM002-101). Most TEAEs were mild in intensity, and 
none were assessed as severe.


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In the multiple dose studies, the most commonly reported TEAEs in subjects (both healthy and 
with T2DM) who received volixibat for the longest duration of 28 days in Study LUM002-101 
included diarrhea and abdominal pain. The most commonly reported TEAEs in subjects 
receiving 50 mg volixibat for 14 days (part 3 Study TDR10633) were diarrhea and GI pain.
Overall, there were 2 SAEs (ALT increased and retinal detachment), both of which led to the 
discontinuation of volixibat. In part 3 of the initial Phase 1 study (TDU10633), 1 subject dosed 
with 50 mg volixibat  for 13 days was withdrawn from the study due to a mild TEAE (which 
became a SAE due to prolonged hospitalization) of ALT increased that was considered related to 
volixibat . The subject’s ALT level returned to normal after discontinuation of volixibat. A 
second subject dosed with 10 mg volixibat for 12 days in Study LUM002-101 reported a 
moderate SAE of ablation of the retina with a bleed in the vitreous body of the right eye that was 
considered not related to volixibat.
Overall, 3 subjects, all dosed with 5 mg volixibat in Study LUM002-101, discontinued volixibat 
due to non-serious TEAEs: 1 due to a related TEAE of mild hemorrhagic diarrhea, 1 due to an 
unrelated TEAE of moderate Epstein-Barr virus infection, and 1 due to mild related TEAEs of 
diarrhea and anal erosion.
Overall, the observed AEs attributable to volixibat have been self-limited as would be expected 
given the local MOA of ASBT inhibition in the terminal ileum. Generally, among subjects who 
experienced GI TEAEs, the events have been mild and diminished over the course of treatment. 
Please refer to the investigator’s brochure for additional information.
Volixibat is a novel drug candidate, demonstrating limited systemic exposure across species with 
the potential to affect important metabolic pathways associated with NASH. The overall safety, 
tolerability, and preliminary activity of volixibat in available clinical trials suggest that further 
investigation is warranted and that there is a positive benefit to risk profile.
Always refer to the latest version of the Volixibat Potassium (SHP626) Investigator’s Brochure 
for the overall risk/benefit assessment and the most accurate and current information regarding 
the drug metabolism, pharmacokinetics, efficacy, and safety of volixibat. 
See Appendix 1 for protocol history, including all amendments.
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Currently there is no approved medication for the treatment of NASH. Volixibat is under 
development for the treatment of NASH based on its MOA and is supported by nonclinical and 
Phase 1 data.  This is a Phase 2, 48-week, dose-finding study to examine the efficacy, 
tolerability, and safety of volixibat in adults with NASH.


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2.2
Study Objectives
2.2.1
Primary Objective
To evaluate the effect of volixibat compared to PBO on liver histology 
2.2.2
Secondary Objectives

To evaluate the safety and tolerability of volixibat  compared to PBO 

To evaluate the effect of volixibat compared to PBO on hepatic steatosis  (measured by 
MRI)

To evaluate the effect of volixibat  compared to PBO on liver histology (measured by 
individual NAS components and fibrosis stage)

To evaluate the effect of volixibat compared to PBO on liver histology (measured by 
NASH resolution without worsening fibrosis)

To evaluate the effect of volixibat compared to PBO on serum liver-related biochemistry 

To evaluate the effect of volixibat compared to PBO on metabolic indicators (glucose, 
insulin, hemoglobin A1c [HbA1c]) 

To evaluate the effect of volixibat compared to PBO on serum lipids (cholesterol, HDL-
C, LDL-C, triglycerides) 
2.2.3
Exploratory Objectives

To explore the effect of volixibat compared to PBO on liver histology (measured by 
individual SAF scoring components: Steatosis (S), Activity (A), and Fibrosis (F)) 

To explore the effect of volixibat compared to PBO on anthropometric measures (body 
weight, body mass index (BMI), waist circumference and waist-hip ratio) 

To explore the effect of volixibat compared to PBO on homeostasis model assessment-IR 
(HOMA-IR) and HOMA-beta cell function (HOMA-%B) in subjects with T2DM 

To explore the effect of volixibat compared to PBO on BA synthesis (7-alpha-hydroxy-4-
cholesten-3-one [C4])

To explore the effect of volixibat on patient-reported health-related quality of life 
(HRQoL) and overall health status.
3
STUDY DESIGN
3.1
Study Design and Flow Chart
This study will be a Phase 2, 48-week, multicenter, double-blind, randomized, PBO-controlled, 
parallel group, proof of concept, dose-finding study, with one IA after at least 80 subjects have 
24 weeks of treatment.  There will be 3 active arms of volixibat (5, 10 and 20 mg) and a PBO 
arm. Subjects will be randomized to receive one of three doses of volixibat (5, 10, or 20 mg once 
daily (QD) or PBO in a 1:1:1:1 ratio prior to the IA.  After randomization of at least 80 subjects 


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(20/treatment arm), a 24-week IA may eliminate at least one volixibat dose group based on the 
criteria provided to the Data Monitoring Committee (DMC). Following the IA, enrollment will 
continue in order to achieve the sample size target of 67 completers in each of the treatment 
groups that were not dropped at the IA (201 total if 3 arms continue, 134 if 2 arms continue).  
Accounting for a 20% dropout, 81 subjects will be randomized in each of the treatment groups 
that continue.  Including the projected approximately 49 additional subjects randomized to a dose 
that is dropped at the IA, 292 subjects (81 for each arm that continues + approximately 49 in the 
dropped arm) will be randomized if 3 arms (2 volixibat and 1 PBO) continue; 260 subject (81 for 
each arm that continues + approximately 49 for each of the dropped arms) will be randomized if 
2 arms (1 volixibat and 1 PBO) continue. Should the number of subjects randomized prior to the 
IA to a dose group that is dropped at the IA markedly deviate from the above projection, then the 
total number of subjects randomized will be adjusted accordingly, not to exceed approximately 
324 subjects. Subjects with fibrosis stages F0 through F3 may be enrolled, but the number of F0 
subjects will be capped at 88 if 1 dose is dropped after the IA and at 78 if 2 doses are dropped 
after the IA (approximately 30% of the total number of subjects randomized).
There will be up to 3 study periods (screening, treatment, and follow-up) and an IA. The duration 
of the Treatment period will be 48 weeks, with an IA at Week 24.  Depending on the results of 
the IA, the study may be terminated or the randomization to one or more doses may be stopped.  
The follow-up period will be 4 weeks after last dose.  Subjects will be expected to visit the study 
center at least 10 times.
The IA will be conducted by an independent DMC after at least 80 subjects have received 24 
weeks of treatment. The IA will evaluate the safety, tolerability and efficacy of 3 doses of 
volixibat each compared to PBO. 
Once decisions as to dose elimination are made, additional sites may be added. Subjects recruited 
into the study prior to the IA will continue with the same dosing regimen for the duration of the 
planned study participation. Subjects recruited into the study after completion of the IA will be
randomized evenly to the remaining dose groups (noted by “[1 or 2]… Dose TBD” in Figure 1) 
or PBO group by IRT. Thus, depending on the results from the IA, the study may be terminated, 
or one or more doses of volixibat may be discontinued. If the study is not terminated, subjects 
will receive a total of 48 weeks of investigational product (IP).
The study will be conducted over 3 periods: screening (10 weeks), treatment (48 weeks), and 
follow-up (4 weeks), with an IA at 24 weeks as outlined in Figure 1. 


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Figure 1
Study Design Flow Chart
Visit 1
V2
Baseline
Week -10 
Wk 
52
Screening
Wk
0
Double-blind Treatment
Safety 
Follow-
up
SHP626 20mg QD
SHP626 5mg QD
SHP626 10mg QD
Placebo QD
Wk
2
Wk
4
Wk
8
Wk
12
Wk
24
Wk
36
Wk
48
V10
V3
V4
V5
V6
V7
V8
V9
Clinic 
Visit
EOS
Interim 
Analysis
(1 or 2)
Dose
TBD
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 434 days. The 
last visit is an in-clinic safety follow-up visit. The study will be completed in approximately 
4 years.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment.  Please note that this includes the follow-up visit.  The 
Study Completion Date is used to ascertain timing for study results posting and reporting.
3.3
Sites and Regions
This study will be conducted at approximately 60 to 80 clinical sites in the USA, Canada, and 
EU.
4
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.


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1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.
2. Ability to voluntarily provide written, signed, and dated (personally or via a legally 
authorized representative, as applicable) informed consent to participate in the study.
3. Age 18-80 years inclusive. This inclusion criterion will only be assessed at the first screening 
visit.
4. Male, or non-pregnant, non-lactating female, who is sexually active and who agrees to 
comply with the contraceptive requirements of the protocol, or females of non-childbearing 
potential.  Males and females of child-bearing potential who are sexually active must agree to 
use acceptable contraception during the study and for 30 days following the last dose of the 
IP as described in Section 4.4.
5. Presence of ≥5% steatosis on screening MRI from a centrally read radiologist performed 
either during the screening period or within 6 months prior to the first visit.
6. Histologic confirmation of NASH without cirrhosis (F0-F3) from a centrally read liver 
biopsy performed either during the screening period or within 6 months prior to the first visit 
with a NAS of ≥4 with a score of at least 1 in each component (steatosis, lobular 
inflammation, and hepatocyte ballooning).
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Presence of or history of cirrhosis or evidence of decompensated liver disease (ie, ascites, 
variceal bleeding, etc.) or hepatocellular carcinoma.
2. History or presence of other concomitant liver disease as assessed by the investigator or 
determined by laboratory findings including, but not limited to: active hepatitis B virus 
(HBV) infection (hepatitis B surface antigen [HBsAg] positive and/or HBVDNA positive; 
subjects who are hepatitis B core antibody [HBcAb] positive may be eligible as long as 
HBsAg is negative and HBVDNA is nondetectable), active hepatitis C virus (HCV) infection 
(prior exposure to HCV [defined as HCVAb positive] without a current or prior history of a 
detectable HCVRNA) may be eligible, alcoholic liver disease, proven autoimmune hepatitis, 
primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, 
Wilson’s disease, alpha-1 antitrypsin deficiency, bile duct obstruction, liver primary or 
metastatic cancer.
3. Current or recurrent disease that could affect the action, absorption, disposition, or laboratory 
assessment of the investigational product (IP) (including bile salt metabolism in the intestine) 
eg, uncontrolled inflammatory bowel disease, uncontrolled celiac disease, gastric bypass 
procedures (gastric lap band or gastric sleeve is acceptable), ileal or ileocecal resection, 
uncontrolled irritable bowel syndrome with predominant diarrhea, or history of chronic 
diarrhea or loose stools of any etiology.
4. Weight change ≥5% after qualifying liver biopsy and/or MRI performed. If the subject had a 
liver biopsy and/or MRI within 6 months of screening, but experienced a weight change of 


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≥5% since the date of liver biopsy and/or MRI, the liver biopsy and/or MRI must be repeated 
at screening.
5. Contraindications to MRI (eg, claustrophobia, coronary stents, coronary implantable devices, 
girth, etc.). Stents or other devices may be allowed, at the investigator’s discretion, if they do 
not interfere with the functioning of the MRI machine. 
6. Current or relevant history of physical or psychiatric illness, any medical disorder that may 
require treatment or make the subject unlikely to complete the study.
7. Treatment with Vitamin E, thiazolidinediones (TZD), or glucagon-like peptide-1 receptor 
agonists (GLP-1 RA) unless subject on a stable dose for 6 months prior to qualifying liver 
biopsy and not initiated after qualifying liver biopsy and will continue the same dosing 
regimen throughout study participation (refer to Section 5.2.1, Permitted Treatment). 
8. Uncontrolled diabetes defined as HbA1c of ≥9.5% within 60 days prior to enrollment. 
9. Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations) that could affect the action, absorption, or disposition of the IP, or clinical or 
laboratory assessment.  (Current use is defined as use within 14 days of screening).  Patients 
currently taking insulin will not be excluded; however, they must be on a stable dose for at 
least 30 days prior to screening, or a sliding scale of insulin is allowed as long as the subject's 
HbA1c remains < 9.5%. Also refer to Section 5.2.2, Prohibited Treatment.
10. Use of drugs, herbs or supplements historically associated with causing or worsening 
NAFLD/NASH for less than 6 months prior to liver biopsy, or initiated any time after liver 
biopsy performed, including the use of total parenteral nutrition (TPN). Also refer to Section 
5.2.2, Prohibited Treatment.
11. Serum AST >7 times upper limit of normal (ULN) at screening.
12. Serum ALT >7 times ULN at screening.
13. Elevated serum creatinine ≥2.0 mg/dL.
14. International normalized ratio (INR) >1.3
15. TB >2 times ULN at screening (Except for documented Gilbert’s syndrome with bilirubin 
levels 20 µmol/L to 90 µmol/L (1.2 to 5.3 mg/dL) and with a ratio of 
unconjugated/conjugated bilirubin that is commensurately higher).
16. Platelet count <130 × 109/L
17. Medical history of impaired hemostasis or use of anticoagulant medication (use of 
antiplatelet medications, such as low-dose, ie 81 mg, aspirin (ASA) or clopidogrel (Plavix) 
will be allowed).
18. Uncontrolled thyroid disease.
19. Type 1 diabetes mellitus.
20. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or 
any of the stated ingredients.


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21. Known history of alcohol or other substance abuse within the last year or at any time during 
the study based on investigator’s discretion.  Refer to Section 7.2.3.8, Drug and Alcohol 
screening. Weekly alcohol intake greater than 21 grams/day for males and 14 grams/day for 
females on average or inability to reliably quantify alcohol consumption based on 
investigator’s judgment.
22. Within 6 months of MRI and liver biopsy:

Have used any IP

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study
23. Inability to safely obtain a liver biopsy.
24. Females who are pregnant, planning to become pregnant, or are breastfeeding, or males who 
are planning to father a child during study participation.
25. The anticipated need for a surgical procedure during the study that could interfere with the 
treatment. 
26. Known positivity for human immunodeficiency virus (HIV) infection.
27. Cancer within 5 years of screening, except for basal or squamous cell carcinoma of the skin 
or in situ cervical carcinoma that has been treated with no evidence of recurrence.
28. History of noncompliance with medical regimens, unreliability, mental instability or 
incompetence that could compromise the validity of informed consent or lead to 
noncompliance with the study protocol.
29. Any other conditions or abnormalities which, in the opinion of the investigator, may 
compromise the safety of the subject, or interfere with the subject participating.
30. Subject is currently enrolled in this study at any study site (unless the subject is transferring 
to another qualified study site with prior sponsor approval).
31. Subjects who are employees at the unit of the investigational site that is conducting the study.
4.3
Restrictions 
Subjects must adhere to the following restrictions for the duration of the study:

Subjects must remain compliant with inclusion/exclusion criteria.

Subjects should not become pregnant, father a child, or nurse/breastfeed a baby. 

Subjects should be encouraged to adhere to the same exercise routine and a healthy diet 
throughout the study.


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4.4
Reproductive Potential
4.4.1
Female Contraception
Sexually active females of child-bearing potential should use an acceptable form of 
contraception. Females of child-bearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 30 days following the last dose of the IP. If 
hormonal contraceptives are used they should be administered according to the package insert. 
Female subjects should be either:

Post-menopausal (12 consecutive months of spontaneous amenorrhea and age 51 years)

Surgically sterile (having undergone one of the following surgical acts:  hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of child-bearing potential with a negative urine and/or serum -human chorionic 
gonadotropin (-HCG) pregnancy test each study visit. Females of child-bearing 
potential must agree to abstain from sexual activity that could result in pregnancy or 
agree to use acceptable methods of highly-effective contraception.
Acceptable methods of highly-effective contraception (ie, methods that result in a failure rate of 
<1% per year) are:

Combined (estrogen and progestogen containing) hormonal contraceptives associated 
with inhibition of ovulation (oral, intravaginal, transdermal) stabilized for at least 30 days 
prior to the screening visit (Visit 1) plus a barrier method (eg, condoms or diaphragms 
with spermicidal gel or foam)

Progestogen-only hormonal contraception associated with inhibition of ovulation plus a 
barrier method 

Intrauterine device (IUD) 

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Male sterilization/vasectomized partner

True abstinence: When this is in line with the preferred and usual lifestyle of the subject 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], 
declaration of abstinence for the duration of exposure to IMP, and withdrawal are not 
acceptable methods of contraception.)
4.4.2
Male Contraception
Contraception is required for all sexually-active male subjects and their partners. All male 
subjects (including those who are sterile) agree not to donate sperm, and to use 1 of the following 


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approved methods of contraception from the baseline visit on Day 0 until 30 days following 
study discharge:

Male condom with spermicide

Sterile sexual partner

Intrauterine device with spermicide (use by female sexual partner)

Female condom with spermicide (use by female sexual partner)

Contraceptive sponge with spermicide (use by female sexual partner)

Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with spermicide, or a 
cervical cap with spermicide) (use by female sexual partner)

Oral, implantable, transdermal, or injectable hormonal contraceptive (use by female 
sexual partner) plus a barrier method
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety).  The investigator is 
encouraged to discuss withdrawal of a subject from the IP with the CRO Medical Monitor when 
possible.
If the IP is discontinued, regardless of the reason, the evaluations listed for both Visit 9/end of 
study (EOS) and Visit 10/Follow-up, are to be performed as completely as possible; however, the 
EOS liver biopsy will not be required for patients discontinuing prior to Week 44. 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
source documents.  The reason for termination, date of stopping the IP, and the total amount of 
the IP taken must be recorded in the electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Medically important events that in the opinion of the investigator, medical monitor or sponsor 
would compromise the subject’s ability to safely continue in the study may result in withdrawal 
of the subject from the study.  Subjects who become pregnant or demonstrate disease 
progression, defined as the development of signs or symptoms of hepatic decompensation (ie, 
esophageal variceal hemorrhage, hepatic encephalopathy, ascites, or hepatocellular carcinoma), 
will be withdrawn from the study and followed as set forth in the protocol.
4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the eCRF.  If a subject is withdrawn for more than 1 reason, each reason 


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should be documented in the source document and the most clinically relevant reason should be 
entered on the eCRF.  
Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol violation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Death

Screen failure 

Noncompliance with study drug

Physician decision

Pregnancy

Progressive disease (refer to Section 4.5.1)

Study terminated by sponsor

Other - If “Other” is selected, the investigator must specify the reason on the eCRF 
4.5.3
Subjects Lost to Follow-up Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact clinic visit.  At least 1 of these documented
attempts must include a written communication sent to the subject’s last known address via 
courier or mail (with an acknowledgement of receipt request) asking that they return to the site 
for final safety evaluations and return any unused IP.
4.5.4
Safety-related Stopping Rules
Refer to Appendix 4 and Appendix 5 for criteria to assess severity of liver-related AEs and 
stopping rules for liver-related blood tests, respectively.
An urgent safety review will be conducted within 7 days by the sponsor and in consultation with 
the DMC if 1 or more of the following criteria are met:

Death that is considered related to the study drug

Two SAEs of similar type (defined as same or similar Medical Dictionary for Regulatory 
Activities (MedDRA) higher level group code), and considered related to the study drug.
The urgent review will be performed by a sponsor safety review group, which will include the 
study Global Safety Lead (GSL) and the Global Drug Safety (GDS) therapeutic area (TA) Head, 


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and in consultation with the DMC. The GDS TA Head, not the GSL involved in the study, may 
be unblinded as part of this urgent safety review, if required. Following the sponsor’s review of 
safety data and consultation with the DMC, one of the following actions will be taken with 
respect to study status:

Continue study with protocol unchanged

Continue study with modifications to the protocol

Terminate study
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment.
5
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to signing informed consent at the screening visit (Visit 1) and through the 
final study contact (including protocol-defined follow-up period) must be recorded on the 
appropriate eCRF page.
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
and behavioral treatment, non-pharmacological treatment, such as psychotherapy, as 
appropriate), received within 30 days of the date of first dose of the IP. Prior treatment 
information must be recorded on the appropriate eCRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of the IP 
and the end of the follow-up period, inclusive.  Concomitant treatment information must be 
recorded on the appropriate eCRF page.
5.2.1
Permitted Treatment
Medications and supplements including but not limited to vitamin E, betaine, s-adenosyl-l-
methionine, ursodeoxycholic acid, milk thistle, gemfibrozil, anti-TNF therapies, probiotics 
biguanides (metformin), thiazolidinediones (TZDs) and GLP-1 RAs that have been used to treat 
NAFLD/NASH are allowed during the course of the study if the subject has been on a stable 
dosing regimen (ie, same dose and frequency in the previous 6 months prior to the qualifying 
liver biopsy and not initiated after qualifying liver biopsy) and will continue this dosing regimen 
throughout study participation. Use of antiplatelet medications is also allowed.  The investigator 
must contact the CRO medical monitor to discuss any changes to concomitant medications that 
may impact the study.


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5.2.2
Prohibited Treatment
The following list of prohibited drugs cannot have been taken for more than 2 weeks within the 6 
months prior to randomization and are excluded while on study.

Systemic Glucocorticoids

Tamoxifen

Amiodarone

Methotrexate

Alcohol (see Section 4.2)

Griseofulvin

Total parenteral nutrition

Obeticholic acid

Valproate

Nucleoside Analogues (except 
acyclovir)

Tetracycline (high dose; >1g)

Estrogens at doses greater than 2 
mg QD used for hormone 
replacement

Anabolic steroids

Bile acid sequestrants such as 
cholestyramine or colestipol

Any other known hepatotoxins 
including over-the counter 
therapies and herbal therapies 
such as germander, chaparral and 
ma-huang.
This is not a comprehensive list.  Treatments not listed above are generally considered allowable, 
unless considered a potential hepatotoxin.  Antidiarrheals will be allowed at the discretion of the 
investigator, with the exception of BA sequestrants.
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is volixibat potassium (volixibat), which will be provided in 5, 10 and 20 mg 
capsule form.  Additional information is provided in the current Volixibat Potassium (SHP626) 
Investigator’s Brochure.
The reference/comparator product is an identical PBO which will be provided in capsule form.  
6.1.1
Blinding the Treatment Assignment
The IP will be supplied as double-blind blister packs. The actual double-blind treatment given to 
individual subjects is determined by a randomization schedule which will be automatically 
assigned by the interactive response technology (IRT). Placebo capsules, which exactly match 
the IP, will be used in the blister packs to provide the same number and size capsules for each of 
the doses within the treatment groups.


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6.2
Administration of Investigational Product(s)
All IP and supplies will be provided by Shire or its designee. At each visit, subjects will be 
supplied with enough IP to last until the subsequent visit. Lost or damaged IP will be replaced as 
needed. Volixibat will be supplied to the clinical research center (CRC) as powder in capsule. 
Volixibat will be supplied in identical capsules in strengths of 5, 10, and 20 mg (with matched 
PBO). 
6.2.1
Interactive Response Technology for Investigational Product Management
IRT will be used for the following investigational tasks:

Randomization

Supply management

Inventory management and supply ordering

Expiration tracking

Returns

Emergency unblinding
6.2.2
Allocation of Subjects to Treatment 
This is a double-blind, PBO-controlled study. The actual treatment given to individual subjects is 
determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to the IP allocated to the 
subject, once eligibility has been determined.  
Individual subject treatment is automatically assigned by the IRT.
Once a randomization number/unique identifier has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study.  If a randomization number/unique 
identifier is allocated incorrectly, the clinical research associate (CRA)/study monitor must be 
notified as soon as the error is discovered. 
IP packaging identification numbers, separate from randomization numbers/unique identifiers, 
may also be assigned to subjects for specific treatment assignment as dictated by the study.  In 
these cases, the same IP packing identification number may not be assigned to more than 1 
subject.


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Subjects will be equally allocated to all volixibat doses and PBO if their randomization precedes 
the 24 week IA. If a subject’s randomization occurs after the 24 week IA, subjects will be 
equally allocated to all remaining volixibat doses (determined based on the results of the IA) and 
PBO. The randomization will be stratified by baseline T2DM and NAS ≥6 or NAS = {4,5}. 
Subjects with fibrosis stages F0 through F3 may be enrolled, but the number of F0 subjects will 
be capped at 88 if 1 dose is dropped after the IA and at 78 if 2 doses are dropped (approximately 
30% of the total number of subjects randomized).
6.2.3
Dosing
All doses of volixibat or matching PBO will be administered orally as a capsule in a double-
blinded fashion.  The first dose of IP for each subject will be administered in the clinic. The dose 
will be administered with 240 mL of water and should be given 30 minutes prior to the first meal 
of the day containing approximately 10-20 grams of fat. The subject should make all attempts to 
consistently take the IP around the same time each day.  If a dose is missed at the normally 
scheduled time, the subject can make up the dose that day as long as no more than 1 dose is 
taken in a 10-hour period. 
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the IP is required for further treatment of the subject. The investigator 
should contact the CRO medical monitor and the Shire study physician at the same time and as 
soon as possible after the investigator has been unblinded.  
In the event that the treatment assignment is broken, the date and the signature of the person who 
broke the code are to be recorded in the source documents and the IRT, and the reason for 
breaking the code will be recorded in the source documents and the clinical database.  Upon 
breaking the blind, the subject is withdrawn from the study, but should be followed up for safety 
purposes. Any code-breaks that occur must be reported to the CRO medical monitor.  Code-
break information is held by the pharmacist/designated person at the site and by the CRO 
medical monitor for the study or designee.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the IP container. 
All IP is labeled with a minimum of the protocol number, medication identification number, 
dosage form (including product name and quantity in pack), directions for use, storage 
conditions, expiry date (if applicable), batch number and/or packaging reference, the statements 
‘For clinical trial use only’, and/or ‘CAUTION: New Drug - Limited by Federal (or USA) Law 
to Investigational Use’, ‘Keep out of reach of children’, and the sponsor's name and address. Any 
additional labeling requirements for participating countries will also be included on the label.


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Additional labels may, on a case-by-case basis, be applied to the IP in order to satisfy local or 
institutional requirements, but must not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
The sponsor or designee will provide the IP for this study. The IP is packaged in the following 
labeled containers:

Volixibat 5 mg capsules

Volixibat 10 mg capsules

Volixibat 20 mg capsules

Volixibat PBO capsules
6.3.3
Storage
The investigator has overall responsibility for ensuring that the IP is stored in a secure, limited-
access location.  Limited responsibility may be delegated to the pharmacy or member of the 
study team, but this delegation must be documented.  
IPs are distributed by the pharmacy or designated member of the study team. The 
pharmacist/nominated team member will enter the unique subject identifier on the IP labels as 
they are distributed. 
All IP must be stored at the clinic at 20 - 25oC (68 - 77oF); excursions are allowed between 15 -
30oC (59 - 86oF).
IPs must be stored in accordance with labeled storage conditions.  Temperature monitoring is 
required at the storage location to ensure that the IP is maintained within an established 
temperature range. The investigator is responsible for ensuring that the temperature is monitored 
throughout the duration of the study and that records are maintained; the temperature should be 
monitored continuously by using either an in-house system, a mechanical recording device such 
as a calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.  Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording.  The sponsor must be notified immediately upon discovery of any excursion below 
15oC (59oF) or above 30oC (86oF); these excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the IP and will 
provide supportive documentation as necessary.  Under no circumstances should the product be 


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dispensed to subjects until the impact has been determined and the product is deemed appropriate 
for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the IP 
that could affect the integrity of the product(s), eg, fumigation of a storage room or a change in 
storage location.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the IP to carry out this protocol for the 
agreed number of subjects.  The investigator or designee will acknowledge receipt of the IP, 
documenting shipment content and condition.  Accurate records of all IP dispensed, used, 
returned, and/or destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing the IP.  Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator.  This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the IP only to subjects included in this study 
following the procedures set out in the study protocol.  Each subject will be given only the IP 
carrying his/her treatment assignment. All dispensed IP will be documented on the eCRFs and/or 
other IP record. The investigator is responsible to ensure the retrieval of all study supplies from 
subjects.
No IP stock or returned inventory from a Shire-sponsored study may be removed from the site 
where originally shipped without prior knowledge and consent by the sponsor.  If such transfer is 
authorized by the sponsor, all applicable local, state, and national laws must be adhered to for the 
transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.  The site must ensure that the accountability and destruction 
records are complete, accurate, and ready for verification at each monitoring visit.
The process for return and destruction of IP must be determined and documented during the 
study start-up phase.
With the written agreement by the sponsor of the site’s IP destruction procedures, all unused 
stock, subject returned IP, and empty/used IP packaging may be destroyed at the site or a local 
facility on an ongoing basis throughout the study and at the end of the study following 
verification of accountability by the CRA/study monitor. In this case, destruction records 
identifying what was destroyed, when, how, and by whom, must be obtained with copies 
provided to the sponsor. Destruction of IP must be in accordance with local, state, and national 
laws.


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Alternatively, in the absence of written agreement by the sponsor of the site’s IP destruction 
procedures, all unused stock, subject-returned IP, and empty/used IP packaging may be required 
to be sent to a nominated contractor on behalf of the sponsor for IP destruction on an ongoing 
basis throughout the study and at the end of the study. IP being returned to the sponsor’s 
designated contractors also must be counted and verified by clinical site personnel and the 
CRA/study monitor. For unused supplies where the original supplied tamper-evident feature is 
verified as intact, the tamper-evident feature must not be broken and the labeled amount is to be 
documented in lieu of counting. Shipment return forms, when used, must be signed prior to 
shipment from the site. Validated electronic return systems (ie, IRT) do not require a shipment 
form. Returned IP must be packed in a tamper-evident manner to ensure product integrity. 
Contact the sponsor for authorization to return any IP prior to shipment. Shipment of all returned 
IP must comply with local, state, and national laws.
6.5
Subject Compliance
Subjects must be instructed to bring their unused IP and empty/used IP packaging to every visit. 
Drug accountability must be assessed at the container/packaging level for unused IP that is 
contained within the original tamper-evident sealed container (eg, blister pack) or at the 
individual count level for opened containers/packaging. The pharmacist/nominated person will 
record details on the drug accountability form.
7
STUDY PROCEDURES
7.1
Study Schedule
This study will consist of a screening period of up to 70 days (the screening period may be 
minimally extended under special circumstances only with the explicit approval of the Shire 
study physician, a 48-week Treatment period, and a Follow-up visit 4 weeks after treatment 
ends. A detailed display of all study procedures is provided in Table 1. 
Patients will be assessed according to the following schedule:

Screening – Visit 1  (Weeks -10 to 0 [Day -70 to Day -1])

Baseline – Visit 2  (Week 0 [Day 0])

Treatment and Assessments – Visits 3 through 9 (Week 2 through Week 48)

Follow-up – Visit 10 (Week 52, 4 weeks after completion of dosing) 
7.1.1
Screening (Visit 1) 
Screening procedures must be completed within 70 days prior to randomization for the first dose 
of the IP. The screening period may be minimally extended under special circumstances only 
with the explicit approval of the Shire study physician. At the screening visit, considered Visit 1 
(Week -10 to 0, Day -70 to -1), all screening assessments and procedures are to be performed by 
the principal investigator or a qualified designee. See Table 1 for a complete list of screening 
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Written, signed, and dated informed consent from the subject prior to the performance of any 
study-related procedures must be obtained by the principal investigator or a designee. A copy of 
the signed informed consent form must be given to the subject for their records.
The following screening procedures should be assessed at the beginning of the visit window, 
preferably between Day -70 and Day -49: inclusion/exclusion criteria, collection of subject 
information (demographics, medical and medication history AEs, and concomitant medications), 
a physical examination including vital signs, height, weight, and waist/hip measurements; 
collection of blood and urine samples for screening and safety assessments, performance of an 
electrocardiogram (ECG), and scheduling of MRI and liver biopsy. MRI and liver biopsy (if one 
has not been completed in the previous 6 months) should be performed with sufficient time to 
ensure results are received prior to the baseline visit. 
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered the 
IP. A subject who had been designated a screen failure may be re-screened up to one time. 
However, re-screened subjects must begin the screening procedure again, must be re-consented, 
and will be assigned a new subject number. Additionally, a subject’s abnormal screening lab 
results may be repeated once for confirmation before designating a subject as a screen failure.
An investigative site may provide additional liver biopsy tissue to the central reader to be 
evaluated when the following criteria are met: 1.) the subject qualifies for the study on all 
inclusion/exclusion parameters except for liver histology, and 2.) the investigator's clinical 
assessment of the subject's local liver histology differs from that of the centrally read results, and 
3.) the request to provide more tissue to the central reader for a second read must be requested 
before the patient is declared a screen failure. Any additional tissue samples provided must be 
read by the central reader and the central reader determines the final histological assessment.
7.1.2
Baseline (Visit 2)
Following the screening visit, subjects will return to the clinic within 70 days for Visit 2, 
(considered Week 0, Day 0), for baseline assessments including review of the 
inclusion/exclusion criteria, adverse events, and concomitant medications; physical examination 
with vital signs, weight, and waist/hip measurements; ECG; collection of blood and urine 
samples; stool assessment; and completion of the patient-reported outcome (PRO) EuroQol-5 
Dimension-5 Level Questionnaire (EQ-5D-5L) survey. After completion of these assessments, 
subjects are randomized using Interactive Response Technology (IRT) to 1 of 4 treatment arms 
receiving volixibat 5 mg, 10 mg, or 20 mg, or PBO before the IA and then to 1 of the remaining
arms after the IA. The initial supply of study drug is dispensed to ensure adequate daily dosing 
until the next scheduled study visit.


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7.1.3
Treatment and Assessment Period (Visits 3 through 9/EOS) 
During the 48 weeks of double-blind treatment, 7 clinic visits are scheduled to occur as follows:

Visit 3 - Week 2, Day 14 (+/- 3 days)

Visit 4 - Week 4, Day 28 (+/- 3 days)

Visit 5 - Week 8, Day 56 (+/- 5 days)

Visit 6 - Week 12, Day 84 (+/- 5 days)

Visit 7 - Week 24, Day 168 (+/- 7 days) – Interim Analysis

Visit 8 - Week 36, Day 252 (+/- 7 days)

Visit 9 - Week 48, Day 336 (+/- 7 days) – End of Study
Subjects are reminded not to eat and not to take their study drug on the day of scheduled study 
visits prior to completion of assessments. They should bring their study drug with them to the 
visit. IP should be taken 30 minutes prior to the first meal of the day containing approximately 
10-20 grams of fat. 
The Schedule of Assessments provided in Table 1 details the procedures to be completed at each 
visit. All Treatment visits (3 through 9) will include weight and waist/hip measurements, 
assessment of vital signs, and blood sampling for completion of biochemistry, hematology, 
serum glucose, lipid panel, HbA1c, and serum liver-related blood tests. At all visits, adverse 
events, and concomitant medications will be collected for all subjects, and female subjects of 
childbearing potential will have a urine pregnancy test. Subjects will return containers of unused 
study drug for assessment of accountability and compliance which will be documented in the 
IRT. New supplies of study drug will be dispensed at Visits 3 through 8. 
Additional assessments will also occur less frequently during the Treatment Period for vitamin 
A, vitamin D, vitamin E, vitamin K via PT/INR, insulin, thyroid testing, urinalysis, ECG, 
physical examinations, stool assessment, and completion of the EQ-5D-5L. 
An MRI will be repeated at Visit 7 for the 24-week IA and at Visit 9 (Week 48) for all subjects. 
A final liver biopsy will be performed at Visit 9 (Week 48) for all subjects unless a subject 
discontinues prior to Week 44, in which case the EOS liver biopsy is not required.
Sites that have supplied local slides for central reading for subject eligibility at Screening must 
also provide local liver histology slides for the subject to be centrally read for the Week 48 EOS 
liver biopsy. The central reader will provide the final liver histology assessment for Week 48.
7.1.4
Follow-up (Visit 10)
The follow-up period for this protocol is 4 weeks after the last dose of study drug with a final 
Follow-up visit scheduled for Week 52. Procedures to be completed at this final visit include 
physical examination, weight, waist/hip measurements, vital signs, samples for biochemistry and 
hematology, serum glucose, lipid panel, HbA1c, serum liver-related blood tests, insulin, thyroid 


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testing, stool assessment, and urine pregnancy test (for women of childbearing potential). 
Adverse events and concomitant medications will be recorded. All AEs and SAEs that are not 
resolved at the time of this contact will be followed to closure (see Section 8.1).
7.1.5
Additional Care of Subjects after the Study
No after care is planned for this study.
7.2
Study Evaluations and Procedures
All assessments and procedures are to be performed by the Investigator or a qualified designee 
who has been trained in the protocol. Assessments are to be performed according to the 
schedules shown in Table 1. If a subject terminates the study early, the CRC will make 
reasonable effort to perform the EOS and safety follow-up assessments and procedures for the 
subject’s safety and well-being.
7.2.1
Demographic and Other Baseline Characteristics
Demographic details will be obtained at screening and recorded on the eCRF. Data collected will 
include age, gender, ethnicity, height, and weight.
7.2.2
Efficacy
7.2.2.1
Liver Biopsy
Liver biopsies will provide histologic data for confirmation of the diagnosis of NASH, 
assessment and grading of NASH activity, and scoring of steatosis, lobular inflammation, 
ballooning, as well as fibrosis and additional features (see Appendix 2 and Laboratory Manual 
for additional information). 
7.2.2.2
MRI
The presence of ≥5% steatosis on screening MRI from a centrally read radiologist will be 
performed either during the screening period or within 6 months prior to the first visit. Steatosis 
is assessed by MRI hepatic fat fraction.  The Week 24 MRI will be conducted for subjects in the 
IA set only.
7.2.3
Safety
7.2.3.1
Medical History and Medications 
Medical history including important medical events and concomitant medication and illnesses 
will be obtained at screening and will be recorded on the eCRF. Any existing medical condition 
present prior to the time of randomization should be reported as medical history
7.2.3.2
Physical Examination 
A complete physical examination will be performed with a thorough review of body systems at 
screening, baseline prior to randomization, and at study visits specified in Table 1.  Physical 


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examinations will include a review of the subject’s general appearance, as well as evaluation of 
the body systems including:

Eyes, ears, nose, throat

Lymph nodes

Cardiovascular

Skin

Abdomen

Neurological

Spine and extremities
Abnormalities identified at the screening visit (Visit 1) will be documented in the subject’s 
source documents and on the medical history eCRF. Changes after the screening visit (Visit 1) 
will be captured as AEs on the AE eCRF page, if deemed clinically significant by the 
investigator.
Height will be measured at the screening visit only while weight and waist and hip 
circumference will be recorded at all study visits. BMI will be calculated programmatically.   
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”).  
Adverse events are collected from the time informed consent is signed.  (Please refer to Section 
8, Adverse and Serious Adverse Events Assessment.)
7.2.3.4
Vital Signs
Vital signs include oral, temporal, or tympanic temperature, sitting blood pressure, pulse, and 
respiratory rate. Blood pressure should be determined by cuff (using the same method, the same 
arm, and in the same position throughout the study). Any deviations from baseline (Visit 2) vital 
signs which are deemed clinically significant in the opinion of the investigator are to be recorded 
as an AE.
7.2.3.5
Clinical Laboratory Evaluations 
All clinical laboratory assays will be performed according to the central laboratory’s normal 
procedures.  Reference ranges supplied by the central laboratory will be used to assess the 
clinical laboratory data for clinical significance and out-of-range pathological changes.  The 
investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Clinically 
significant findings should be evaluated for recording as adverse events on the eCRF. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 


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condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry
Albumin (ALB)
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT; SGPT)
Aspartate aminotransferase (AST; SGOT)
Blood urea nitrogen (BUN)
C4
Calcium (Ca)
Bicarbonate (CO2)
Chloride (Cl)
Creatinine
Creatine kinase
Gamma glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
Magnesium (Mg)
Phosphate (P)
Potassium (K)
Sodium (Na)
Total and direct bilirubin
Total cholesterol
Protein
Triiodothyronine (T3)
Thyroid-stimulating hormone 
(TSH)
Triglycerides
Uric acid
Hematology
Hemoglobin 
Hematocrit
Mean corpuscular hemoglobin (MCH)
Mean corpuscular volume (MCV)
Platelets
Red blood cell (RBC) 
White blood cell (WBC) count with 
differential
Prothrombin time (PT)
Activated partial thromboplastin time 
(aPTT)
International normalized ratio (INR)


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Urinalysis
Appearance (clarity and color)
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Microscopic examination of sediment
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Oxalate
7.2.3.6
Additional Laboratory Assessments
Laboratory samples will be collected and assessed for:

HIV testing and assessment of Hepatitis B/C including HBcAb, HBsAg, HBVDNA, and 
HCVAb (if HCVAb is positive an HCVRNA will be performed) will occur at the 
screening visit only

Lipid panel including fasting total cholesterol, HDL-C, LDL-C, and triglycerides at each 
scheduled study visit (Visits 1 through 10)

HbA1c will be tested at every scheduled visit (Visits 1 through 10)

Full coagulation panel will be done at screening and baseline, but only PT/INR is 
required at remaining time points at Visits 4, 7, and 9

Insulin will be tested at screening, baseline, at Visit 4 and Visits 6 through 10

HOMA-IR and HOMA-%B: will be calculated programmatically from serum glucose 
tested at screening, baseline, Visits 7, 9, and 10

Vitamin A, Vitamin D, Vitamin E, and Vitamin K (via PT/INR) will be tested at baseline, 
and Visits 4, 7, and 9.

Thyroid testing including TSH and T3 will be tested at screening, baseline, and Visits 4, 
6, 7, 9, and 10

C4 samples will be collected at baseline and Visits 6, 7, 9, and 10
7.2.3.7
Pregnancy Test 
A urine pregnancy test is performed on all females of child-bearing potential at the screening 
visit (Visit 1), baseline visit (Visit 2), at each Treatment visit (Visits 3 through 9) and at the Final 
visit (Visit 10), or if pregnancy is suspected, or on withdrawal of the subject from the study. A 
positive urine pregnancy test must be followed with a serum pregnancy test performed by the 
central laboratory. Additional testing can be performed at the investigator’s discretion. Also, 
refer to Section 8.1.7.


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7.2.3.8
Drug and Alcohol Testing 
A urine screen for drugs of abuse and blood test for alcohol will be performed at screening and 
baseline as described in Table 1. Additional drug and alcohol screens may be performed at the 
investigator’s discretion.
Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiate metabolite, and phencyclidine. 
Results of drug and alcohol screens will be reviewed and verified by the study monitor, but will 
not be collected in the eCRF database.
Any positive result for drugs of abuse at the screening or baseline visits may exclude the subject 
from further participation in the study. A positive test for drugs of abuse or alcohol done at the 
investigator’s discretion discovered at any time during the study will be grounds for study 
discontinuation.
7.2.3.9
Electrocardiogram 
An ECG (12-lead) will be performed at the times specified in Table 1 in accordance with the 
clinical site’s standard practice(s) and equipment supplied by the CRC.  Recordings of ECGs 
will be read locally at the clinical site by the investigator or designee. The ECG will include 
assessments of heart rate and PR, RR, QRS, and QT intervals. Identification of any clinically 
significant findings and/or abnormalities will be recorded on the eCRF. 
7.2.3.10
Health-related Quality of Life Assessments
The EuroQol (EuroQol. 2016. Available at: http://www.euroqol.org. [Accessed 17 February 
2016]) EQ-5D-5L (“EQ-5D”) is a widely used standardized questionnaire that assesses generic 
HRQoL and is also recommended for health-economic evaluations.  The EQ-5D includes two 
components: a descriptive profile and a visual analogue scale (VAS).  The descriptive profile 
includes five dimensions (ie, pain/discomfort, mobility, usual activities, self-care and 
anxiety/depression), each with five levels (ie, no problems, slight problems, moderate problems, 
severe problems, extreme problems). An EQ-5D index can also be derived from the data which 
summarizes health status using a single value (ie, health-state utility).  The psychometric 
properties of the EQ-5D-5L have been established and well documented (see Appendix 3).
7.2.3.11
Volume of Blood to be Drawn from Each Subject
During this study, it is expected that approximately 146 mL of blood will be drawn from all 
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 146 mL. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments may be combined. 


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8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4.  This includes events occurring during the screening phase of the 
study, regardless of whether or not the IP is administered.  Where possible, a diagnosis rather 
than a list of symptoms should be recorded.  If a diagnosis has not been made, then each 
symptom should be listed individually.  All AEs should be captured on the appropriate AE pages 
in the eCRF and in source documents.  In addition to untoward AEs, unexpected benefits outside 
the IP indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study.  Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained.  When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity.  An event that changes in severity should be captured as a new 
event.  Worsening of pre-treatment events, after initiation of the IP, must be recorded as new 
AEs (for example, if a subject experiences mild intermittent dyspepsia prior to dosing of the IP, 
but the dyspepsia becomes severe and more frequent after first dose of the IP has been 
administered, a new AE of severe dyspepsia (with the appropriate date of onset) is recorded on 
the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of daily 
living.
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.


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Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Appendix 4 provides criteria to assess the severity of liver-related adverse events.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to the IP for each AE.  The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the IP.  If there is no valid reason for 
suggesting a relationship, then the AE should be classified as “not related”.  Otherwise, if there is 
any valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect 
relationship between the IP and the occurrence of the AE, then the AE should be considered 
“related”.  The causality assessment must be documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the IP is 
compelling and/or follows a known or suspected response pattern to that product, and 
the event cannot be explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the IP and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF.  Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown.
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation of the disease and are part of the efficacy data to be collected in 
the study; however, significant worsening of the symptoms should be recorded as an AE.


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8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the IP, a shift of a parameter is 
observed from a normal value to an abnormal value, or a further worsening of an already 
abnormal value.  When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range, either while continuing treatment or after 
the end of treatment with the IP, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Criteria for Discontinuation of Treatment
Appendix 5 provides guidelines for discontinuation of treatment based on elevated ALT, AST, 
TB, and associated signs and symptoms.  
8.1.7
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.
Any report of pregnancy for any female study participant (or the female partner of a male 
participant) must be reported within 24 hours to the Shire Global Drug Safety (formerly 
Pharmacovigilance and Risk Management) Department using the Shire Investigational and 
Marketed Products Pregnancy Report Form.  A copy of the Shire Investigational and Marketed 
Products Pregnancy Report Form (and any applicable follow-up reports) must also be sent to the 
CRO medical monitor and the Shire study physician using the details specified in the Emergency 
Contact Information section of the protocol. The pregnant female study participant must be 
withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 


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and Non-serious AEs Required by the Protocol Form.  Note:  An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and Non-
serious AEs Required by the Protocol Form as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form.  The test date of the first positive serum/urine -HCG test or 
ultrasound result will determine the pregnancy onset date.
8.1.8
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2.  Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of the IP when used for a non-medical 
purpose (eg, to alter one’s state of consciousness or get high) in a manner that may be 
detrimental to the individual and/or society

Misuse – Intentional use of the IP other than as directed or indicated at any dose (Note: 
this includes a situation where the IP is not used as directed at the dose prescribed by the 
protocol)

Overdose – Intentional or unintentional intake of a dose of an IP exceeding a pre-
specified total daily dose of the product.  

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an IP.  For studies, medication errors are reportable to the sponsor only as defined 
below.
Cases of subjects missing doses of the IP are not considered reportable as medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired IP should be considered as a reportable medication 
error.


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8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the Volixibat Potassium (SHP626) 
Investigator’s Brochure which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety (formerly Pharmacovigilance and Risk Management) Department and the Shire 
study physician within 24 hours of the first awareness of the event.  Note: The 24-hour reporting 
requirement for SAEs does not apply to reports of abuse, misuse, overdose, or medication errors 
(see Section 8.1.8) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note:  Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Drug Safety 
Department. A copy of the Shire Clinical Study Serious Adverse Event and Non-serious AEs 
Required by the Protocol Form (and any applicable follow-up reports) must also be sent to the 
Shire study physician using the details specified in the Emergency Contact Information section 
of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to the IP or not) that at any dose:

Results in death

Is life-threatening.  Note: The term ‘life-threatening’ in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization.  Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs.  For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event.  Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 


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require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions 
that do not result in inpatient hospitalization; or the development of drug dependency or 
drug abuse.  
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4, and must be reported 
to the Shire Global Drug Safety Department and the Shire study physician within 24 hours of the 
first awareness of the event. 
In addition, any SAE(s) considered “related” to the IP and discovered by the investigator at any 
interval after the study has completed must be reported to the Shire Global Drug Safety 
Department within 24 hours of the first awareness of the event.
8.2.4
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic.  In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.5
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date.  
For all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another IP action was previously taken (eg, drug interrupted, reduced, withdrawn), the action 
taken with the IP should be recorded as “dose not changed” or “not applicable” (if the subject 
never received the IP). The IP action of “withdrawn” should not be selected solely as a result of 
the subject’s death. 
8.2.6
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The CRO is responsible for notifying the relevant regulatory authorities as appropriate: USA 
central IRBs/EU central ECs of related, unexpected SAEs.
In addition the CRO is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the SHP626-201 program.  


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The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan.  
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification are 
to be communicated to the site for resolution.  Only authorized personnel will make corrections 
to the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (eg, treatment allocation, and IP 
preparation/accountability data) will be handled with special care during the data cleaning and 
review process. These data will be handled in such a way that, prior to unblinding, any data that 
may unblind study team personnel will be presented as blinded information or otherwise will not 
be made available. If applicable, unblinded data may be made available to quality assurance 
representatives for the purposes of conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.  
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, IP exposure, and prior and concomitant medications.  The SAP will also include 
a description of how missing, unused and spurious data will be addressed.


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The SAP will be finalized prior to unblinding to preserve the integrity of the statistical analysis 
and study conclusions.  
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513). 
9.5
Planned Interim Analysis and Data Monitoring Committee 
9.5.1
Planned Interim Analysis
The IA will be conducted after at least 80 subjects have received 24 weeks of treatment. To 
protect study integrity, the IA will be performed by an independent statistician and statistical 
reporting group as well as a gastroenterologist and hepatologist who are not involved in the 
clinical trial conduct and are not responsible for the final analysis of clinical trial data. The IA 
will be performed to evaluate the safety, tolerability, and efficacy of 3 doses of volixibat each 
compared to PBO and may be used to drop 1 or 2 doses of volixibat, or to terminate the trial. 
The criteria for deciding whether or not to continue randomizing to a particular volixibat dose 
following the Week 24 IA will be specified in the DMC charter.  In general, randomization to 
any volixibat dose determined to be unsafe, intolerable or ineffective/futile at the IA will be 
discontinued.   If all of the volixibat doses are determined to be intolerable or ineffective/futile 
the clinical trial will be terminated. If none of the volixibat doses are determined to be unsafe, 
intolerable or ineffective/futile then randomization to the volixibat dose that is the least 
promising or least helpful in characterizing the dose-response relationship (as specified in the 
DMC charter) may be discontinued. Tolerability will be assessed by comparing the number of 
discontinuations due to any one TEAE (presumably gastrointestinal events, most notably, 
diarrhea, loose stools, increased evacuations, and abdominal pain) between each volixibat dose 
group and PBO group.  Efficacy will be assessed based on a reduction of steatosis (assessed by 
MRI-PDFF) and ALT by comparing the change from baseline in MRI-PDFF and percent change 
from baseline in ALT at Week 24 between each volixibat dose group and PBO group.
Subjects recruited into the study prior to the IA will continue with the same dosing regimen for 
the duration of the planned study participation. That is, a subject receiving a dose to which 
randomization is stopped after the IA will continue to receive that same dose throughout the 
course of the study, and complete all required assessments, unless a dose is determined to be 
unsafe, in which case the affected subjects would be discontinued from the study and followed as 
per Section 4.5. Subjects recruited into the study after completion of the IA will be randomized 
evenly to the remaining volixibat dose groups or PBO group by IRT.  Thus, depending on the 
results from the IA, the study may be terminated, or one or two doses of volixibat may be 
discontinued.  If the study is not terminated, subjects will receive a total of 48 weeks of IP.
9.5.2
Data Monitoring Committee
An independent DMC will be established to assess safety, tolerability, and efficacy during the 
study, as well as to ensure the validity and scientific merit of the trial.  The DMC will monitor 
ongoing data generated by the study at regular intervals for the duration of the study. Their role 
is to protect the interests of the subjects in the study and of those still to be entered, by review of 


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accumulating data generated in the study. If a safety concern is identified (eg, if either of the 
criteria are met in Section 4.5.4, Safety-related Stopping Rules), the DMC may recommend an 
action to the sponsor on further study conduct, including stopping the study at any time.
In addition, the DMC will review the results of the Week 24 IA and make recommendations 
concerning study discontinuation due to intolerability or futility, or the continued randomization 
of 1 or more volixibat dose groups and PBO.  
The roles, responsibilities, and rules governing operation of the DMC will be discussed in full in 
a DMC charter. The DMC charter will define the primary responsibilities of the DMC; guide its 
activities, its relationship with other study components, its membership, and the purpose and 
timings of its meetings. It will provide the procedures for ensuring confidentiality, formal 
communication, and outline of the content of reports that will be provided by the DMC. 
Appropriate summary statistics and data listings will be provided to the DMC by an independent 
statistician supported by an independent statistical reporting group not otherwise assigned to the 
study.  
The recommendations made by the DMC to alter the conduct of the study or to stop the study 
will be forwarded to Shire for final decision.  The implementation of any DMC recommendation 
is solely the responsibility of the sponsor.  Shire will forward such decisions to regulatory 
authorities, as appropriate.
9.6
Sample Size Calculation and Power Considerations 
These are the primary hypotheses that are being tested in this study:

Null: The proportion of subjects at Week 48 with a reduction of at least 2 points without 
worsening of fibrosis from baseline NAS does not differ between any of the volixibat 
doses and PBO.

Alternative: The proportion of subjects at Week 48 with a reduction of at least 2 points 
without worsening of fibrosis from baseline NAS does differ between at least one 
volixibat dose and PBO.
Response rates of 21% (PBO) and 45% (active) were reported in the FLINT trial 
(Neuschwander-Tetri et al., 2015) using the same primary end-point of reduction of NAS by at 
least two points (without worsening of fibrosis).   Based on those response rates, 67 subjects per 
group completing the trial are needed for 80% power with a 10% type I error.  Holm multiplicity 
adjustment was included in the sample size estimate.
Approximately 899 subjects will be screened to randomize 292 subjects to achieve 201 
completers in the three arms (2 volixibat and 1 PBO) that continue after the IA (one dose is 
dropped at the IA); approximately 807 subjects will be screened to randomize 260 subjects to 
achieve 134 completers in the two arms (1 volixibat and 1 PBO) that continue after the IA (two 


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doses are dropped at the IA). After randomization of at least 80 subjects (20/treatment arm), a 
24-week IA may eliminate at least one active dose group based on the criteria provided to the 
DMC. The sample size target for this study is 67 completers in each of the treatment groups that 
were not dropped at the IA (201 total if 3 arms continue, 134 if 2 arms continue).  Accounting 
for a 20% dropout, 81 subjects will be randomized in each of the treatment groups that continue.  
Including the projected approximately 49 additional subjects randomized to a dose that is 
dropped at the IA, 292 subjects (81 for each arm that continues + 49 in the dropped arm) will be 
randomized if 3 arms (2 volixibat and 1 PBO) continue; 260 subject (81 for each arm that 
continues + 49 for each of the dropped arms) will be randomized if 2 arms (1 volixibat and 1 
PBO) continue. Should the number of subjects randomized prior to the IA to a dose group that is 
dropped at the IA markedly deviate from the above projection, then the total number of subjects 
randomized will be adjusted accordingly, not to exceed approximately 324 subjects.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Randomized Set will consist of all subjects in the Screened Set who have been randomized 
into the study.
The Safety Analysis Set will consist of all subjects who take at least 1 dose of randomized IP, 
and have at least 1 post-baseline safety assessment (eg, coming back for any visit, reporting of an 
AE or reporting the absence of AEs).
The Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have at 
least 1 post-baseline efficacy assessment (eg, MRI, liver biopsy, serum liver-related biochemistry 
measurement).
The Interim Analysis Set (IAS) will consist of all subjects in the Safety Analysis Set who have at 
least 1 post-baseline efficacy assessment (eg, MRI, ALT biochemistry measurement) on or 
before the Week 24 visit at the data cut time of the IA. 
9.8
Efficacy Analyses
All efficacy analyses will be based on the FAS and all statistical tests will be 2-sided hypothesis 
tests performed at the 10% level of significance on those doses continued after the IA, 
accounting for the number of doses dropped at the IA. Also, all confidence intervals will be 
2-sided confidence intervals, unless otherwise stated.
9.8.1
Primary Efficacy Endpoint
The primary endpoint is the binary response indicating (yes/no) whether a subject responded at 
Week 48 with a reduction of at least 2 points, without worsening of fibrosis, from baseline NAS. 
The FAS will be used to assess the primary efficacy endpoint. The proportion of subjects at 
Week 48 with a reduction of at least 2 points without worsening of fibrosis from baseline NAS 


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will be analyzed. The difference between a volixibat dose and PBO will be tested with a 
stratified Cochran-Mantel-Haenzel test. The test will be stratified by presence or absence of 
T2DM at baseline and baseline NAS separated into two groups (NAS={4,5} or NAS={6,7,8}). 
Subjects with missing data for the primary efficacy endpoint at the Week 48 visit will be 
considered as non-responders. Holm multiplicity adjustment will be applied prior to determining 
statistical significance at the 0.1 level.
Analyses which explore the impact of the missing data on the primary efficacy endpoint will be 
conducted. These analyses may compare imputations of the missing values which favor the PBO 
and/or imputations which favor the active.  In addition, analyses utilizing existing HFF and/or 
ALT data may be performed.  Further, if the pattern of missing values does not appear uniformly 
distributed among the treatment arms, imputation method(s) based on informative missingness 
may also be performed.  Analyses investigating the impact of missing data will be detailed in the 
Statistical Analysis Plan.
9.8.2
Secondary Efficacy Endpoints
Descriptive statistics will be presented for each time point at which the variable is measured (see 
Table 1) for the secondary efficacy endpoints.  Binary secondary efficacy endpoints will be 
analyzed with the same method (stratified Cochran-Mantel-Haenzel test) as the primary efficacy 
endpoint.  Continuous secondary efficacy endpoints will be analyzed with an ANCOVA model 
with change from baseline as the outcome variable; treatment group, presence or absence of 
T2DM at baseline, and baseline NAS separated into 2 groups (NAS={4,5} or NAS={6,7,8}) as 
factors and baseline values as a covariate.  Endpoints include:

Change from baseline to Week 48 on liver histology as measured by the individual NAS 
components (ballooning, inflammation, steatosis).

Change from baseline to Week 48 on hepatic steatosis as measured by MRI-PDFF.

Change from baseline to Week 48 on liver histology as measured by fibrosis stage.
(NASH CRN) 

Resolution of NASH (defined as total absence of ballooning [score = 0], absent or mild 
inflammation [score 0-1], steatosis can be present [score 0-3]) without worsening of 
fibrosis as assessed by liver histology at Week 48.

Change from baseline to Week 48 on serum liver-related biochemistry as measured by:

alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

alkaline phosphatase (ALP)

gamma glutamyl transferase (GGT)

total bilirubin (TB)

Change from baseline to Week 48 on metabolic indicators as measured by:

fasting serum glucose levels


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
insulin levels

HbA1c

Change from baseline to Week 48 on serum lipids measured by:

fasting total cholesterol

HDL-C

LDL-C

triglycerides
9.8.3
Exploratory Efficacy Endpoints
Descriptive statistics will be presented for each time point at which the variable is measured (see 
Table 1) for the exploratory efficacy endpoints.  Binary exploratory efficacy endpoints will be 
analyzed with the same method (stratified Cochran-Mantel-Haenzel test) as the primary efficacy 
endpoint.  Continuous exploratory efficacy endpoints will be analyzed with an ANCOVA model 
with change from baseline as the outcome variable; treatment group, presence or absence of 
T2DM at baseline, and baseline NAS separated into 2 groups (NAS={4,5} or NAS={6,7,8}) as 
factors and baseline values as a covariate.  Endpoints include:

Change from baseline to Week 48 on liver histology as measured by the SAF scoring 
components: Steatosis (S), Activity (A), and Fibrosis (F)

Change from baseline to Week 48 on anthropomorphic measures: 

body weight

BMI 

waist circumference 

waist-hip ratio 

Change from baseline to Week 48 in subjects with T2DM on homeostasis measured by: 

Homeostasis model assessment -IR (HOMA-IR) 

HOMA-beta cell function (HOMA-%B) 
9.9
Safety Analyses
The Safety Analysis Set will be used to assess the safety endpoints. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  
Treatment-emergent AEs are defined as AEs that start or worsen on or after the date of the first 
dose of IP, and no later than the follow-up visit. The number of events, incidence, and percentage 
of TEAEs will be calculated by SOC, by preferred term, and by treatment group. 
Treatment-emergent AEs will be further summarized by severity and relationship to the IP. 
Adverse events related to the IP, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized/listed.


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Vital signs, ECG findings, and clinical laboratory tests will be summarized by treatment group 
and visit. Potentially clinically important findings will be summarized. Graphical presentation 
may be used when deemed necessary.
9.10 Other Analyses
9.10.1
Health-related Quality of Life Analyses

Change from baseline to Week 48 on the EQ-5D index (Appendix 3). The EQ-5D index 
will be derived using published UK-based preference weights. Univariate descriptive 
statistics and multivariate regression analyses adjusting for selected baseline covariates 
will be undertaken.

Change from baseline to Week 48 on the EQ-5D VAS score. Univariate descriptive 
statistics and multivariate regression analyses adjusting for selected baseline covariates 
will be undertaken.

Change from baseline to Week 48 in the proportion of subjects reporting having 
problems (none, slight, moderate, severe, extreme) with pain/discomfort, mobility, usual-
activities, self-care, anxiety/depression in the EQ-5D questionnaire.  Proportions and 
95% confidence intervals will also be generated for the baseline and Week 48 values as 
well as for change from baseline.
9.10.2
Stool Assessment
Stool hardness and number of evacuations will be assessed throughout the study. Stool hardness 
will be assessed for the softest evacuation within 24 hours of each clinic visit using the Bristol 
Stool Chart, a medical aid designed to classify the form of human feces into 7 categories where 
Type 1 is the hardest and Type 7 is the softest. Appendix 6 provides a sample of the Bristol Stool 
Chart.  Number of evacuations within the past 24 hours prior to the clinic visit will be recorded 
at specified times as per Table 1. Descriptive statistics by treatment group will be presented for 
each time point at which the variable is measured.
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 


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applicable industry regulations, ICH GCP Guideline E6 (1996) and E6 R2 (2017), EU Directive 
2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study.  The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of the IP 
for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites.  
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP.  This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason.  
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.


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The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.do
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory requirements and 
guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification.  Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies.  Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation.  The 
investigator will also return all the IP, containers, and other study materials to the sponsor.  Upon 
study completion, the investigator will provide the sponsor, IRB/EC, and regulatory agency with 
final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 


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multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Study eCRFs are supplied by the sponsor and should be handled in accordance with instructions 
from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation.  Study eCRFs must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
All eCRF data must be endorsed by the investigator.
The CRA/study monitor will verify the contents of the eCRF against the source data per the 
monitoring plan. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents.  The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, images, etc.).  Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.


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Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other 
USA national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor.  The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in the IP; any significant equity 
interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments.  All consent 
documentation must be in accordance with applicable regulations and GCP.  Each subject or the 
subject’s legally-authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally-authorized representative, as applicable. This document may 
require translation into the local language.  Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form which was 
reviewed by the IRB/EC and which received their favorable opinion/approval.  A copy of the 
IRB/EC’s written favorable opinion/approval of these documents must be provided to the 
sponsor, prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to study start that another party (ie, sponsor 
or coordinating principal investigator) is responsible for this action.  Additionally, if the IRB/EC 
requires modification of the sample subject information and consent document provided by the 
sponsor, the documentation supporting this requirement must be provided to the sponsor.


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10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
IP supplies will not be released until the sponsor or its designee has received written IRB/EC 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions.  The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All USA-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996.  A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the sponsor or its designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study.  These records and data may, 
in addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market volixibat; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed.  The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.


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Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded.  They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted.  The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative.  Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire.  The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.  The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study.  To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications.  To the extent that the principal investigator has such sole, 
joint or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.


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If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results.  If such a multicenter publication is not submitted to 
a journal for publication by the sponsor within an 18-month period after conclusion, 
abandonment, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section.  The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards.  Participation as an investigator does not confer any rights to 
authorship of publications.


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11
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Neuschwander-Tetri, B. A., Loomba, R., Sanyal, A. J., Lavine, J. E., Van Natta, M. L., 
Abdelmalek, M. F., Chalasani, N., Dasarathy, S., Diehl, A. M., Hameed, B., Kowdley, K. 
V., McCullough, A., Terrault, N., Clark, J. M., Tonascia, J., Brunt, E. M., Kleiner, D. E. 
& Doo, E. 2015. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, 
non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled 
trial. Lancet, 385, 956-65.
Pagano, G., Pacini, G., Musso, G., Gambino, R., Mecca, F., Depetris, N., Cassader, M., David, 
E., Cavallo-Perin, P. & Rizzetto, M. 2002. Nonalcoholic steatohepatitis, insulin 
resistance, and metabolic syndrome: further evidence for an etiologic association. 
Hepatology, 35, 367-72.
Permutt, Z., Le, T. A., Peterson, M. R., Seki, E., Brenner, D. A., Sirlin, C. & Loomba, R. 2012. 
Correlation between liver histology and novel magnetic resonance imaging in adult 
patients with non-alcoholic fatty liver disease - MRI accurately quantifies hepatic 
steatosis in NAFLD. Aliment Pharmacol Ther, 36, 22-9.
Qayyum, A., Goh, J. S., Kakar, S., Yeh, B. M., Merriman, R. B. & Coakley, F. V. 2005. 
Accuracy of liver fat quantification at MR imaging: comparison of out-of-phase gradient-
echo and fat-saturated fast spin-echo techniques--initial experience. Radiology, 237, 507-
11.
Rao, A., Kosters, A., Mells, J. E., Zhang, W., Setchell, K. D., Amanso, A. M., Wynn, G. M., Xu, 
T., Keller, B. T., Yin, H., Banton, S., Jones, D. P., Wu, H., Dawson, P. A. & Karpen, S. J. 
2016. Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease 
in high-fat diet-fed mice. Sci Transl Med, 8, 357ra122.
Raptis, D. A., Fischer, M. A., Graf, R., Nanz, D., Weber, A., Moritz, W., Tian, Y., Oberkofler, 
C. E. & Clavien, P. A. 2012. MRI: the new reference standard in quantifying hepatic 
steatosis? Gut, 61, 117-27.
Reeder, S. B., Cruite, I., Hamilton, G. & Sirlin, C. B. 2011. Quantitative Assessment of Liver Fat 
with Magnetic Resonance Imaging and Spectroscopy. J Magn Reson Imaging, 34, 1011-
1014.
Reeder, S. B., Hu, H. H. & Sirlin, C. B. 2012. Proton density fat-fraction: a standardized MR-
based biomarker of tissue fat concentration. J Magn Reson Imaging, 36, 1011-4.
Roldan-Valadez, E., Favila, R., Martinez-Lopez, M., Uribe, M., Rios, C. & Mendez-Sanchez, N. 
2010. In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty 
liver disease: Correlation with biochemical method and morphometry. J Hepatol, 53,
732-7.
Sanyal, A. J., Campbell-Sargent, C., Mirshahi, F., Rizzo, W. B., Contos, M. J., Sterling, R. K., 
Luketic, V. A., Shiffman, M. L. & Clore, J. N. 2001. Nonalcoholic steatohepatitis: 


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association of insulin resistance and mitochondrial abnormalities. Gastroenterology, 120,
1183-92.
Schwenzer, N. F., Springer, F., Schraml, C., Stefan, N., Machann, J. & Schick, F. 2009. Non-
invasive assessment and quantification of liver steatosis by ultrasound, computed 
tomography and magnetic resonance. J Hepatol, 51, 433-45.
Siebers, N., Palmer, M., Silberg, D. G., Jennings, L., Bliss, C. & Martin, P. T. 2017. Absorption, 
Distribution, Metabolism, and Excretion of [14C]-Volixibat in Healthy Men: Phase 1 
Open-Label Study. European Journal of Drug Metabolism and Pharmacokinetics.
Souza, M. R., Diniz Mde, F., Medeiros-Filho, J. E. & Araujo, M. S. 2012. Metabolic syndrome 
and risk factors for non-alcoholic fatty liver disease. Arq Gastroenterol, 49, 89-96.
Springer, F., Ballweg, V., Schweizer, R., Schick, F., Ranke, M. B., Binder, G. & Ehehalt, S. 
2015. Changes in whole-body fat distribution, intrahepatic lipids, and insulin resistance 
of obese adolescents during a low-level lifestyle intervention. Eur J Pediatr, 174, 1603-
12.
Szczepaniak, L. S., Nurenberg, P., Leonard, D., Browning, J. D., Reingold, J. S., Grundy, S., 
Hobbs, H. H. & Dobbins, R. L. 2005. Magnetic resonance spectroscopy to measure 
hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am 
J Physiol Endocrinol Metab, 288, E462-8.
Torres, D. M. & Harrison, S. A. 2008. Diagnosis and therapy of nonalcoholic steatohepatitis. 
Gastroenterology, 134, 1682-98.
Torres, D. M., Williams, C. D. & Harrison, S. A. 2012. Features, diagnosis, and treatment of 
nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol, 10, 837-58.
Urdzik, J., Bjerner, T., Wanders, A., Weis, J., Duraj, F., Haglund, U. & Noren, A. 2012. The 
value of pre-operative magnetic resonance spectroscopy in the assessment of 
steatohepatitis in patients with colorectal liver metastasis. J Hepatol, 56, 640-6.
Vernon, G., Baranova, A. & Younossi, Z. M. 2011. Systematic review: the epidemiology and 
natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in 
adults. Aliment Pharmacol Ther, 34, 274-85.
Williams, C. D., Stengel, J., Asike, M. I., Torres, D. M., Shaw, J., Contreras, M., Landt, C. L. & 
Harrison, S. A. 2011. Prevalence of nonalcoholic fatty liver disease and nonalcoholic 
steatohepatitis among a largely middle-aged population utilizing ultrasound and liver 
biopsy: a prospective study. Gastroenterology, 140, 124-31.
World Gastroenterology Organisation 2012. World Gastroenterology Organisation Global 
Guidelines: Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis.


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12
APPENDICES


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APPENDIX 1
PROTOCOL HISTORY 
Document
Date
Global/Country/Site Specific
Original Protocol
24 February 2016
Global
Amendment 1
8 April 2016
Global
Amendment 2
19 July 2016
Global
Amendment 3
22 March 2017
Global
Amendment 4
25 August 2017
Global


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APPENDIX 2
FATTY LIVER DISEASE HISTOLOGY SCORING
Diagnosis: NASH, Suspicious/Borderline NASH (type a or b), NAFLD, Not NAFLD
NAS SCORING
Steatosis
0       <5%
1        5-33%
2        34-66%
3        67-100%
Lobular Inflammation
0        no foci
1        < 2 foci per 200x field
2        2-4 foci per 200x field
3        > 4 foci per 200 x field
Ballooning
0       None
1       Rare or diagnostically borderline
2       Many or Prominent ballooned hepatocytes
            SAF SCORING
Steatosis
0         <5%
1        5-33%
2        34-66%
3        67-100%
Ballooning
0        normal hepatocytes with  cuboidal shape and pink cytoplasm
1       clusters of hepatocytes with rounded shape and pale cytoplasm usually  reticulated      
2       grade 1 plus enlarged hepatocytes, 2 x bigger than normal cells. 
Lobular Inflammation
0       none
1       < 2 foci per 200x field
2       >2 foci per 200x field
Steatosis 1,2,3 + Ballooning 1,2 + Lobular Inflammation  1,2 = NASH
Steatosis 1,2,3 +Ballooning 0 + Lobular Inflammation 0,1,2 = NAFLD
Steatosis 1,2,3 + Ballooning 1,2 + Lobular 0 = NAFLD
Steatosis 0 = no NAFLD
FIBROSIS SCORE
None
0
Mild zone 3 perisinusoidal (requires trichrome)
1a
Moderate Zone 3 perisinusoidal (visible on H&E)
1b
Portal/periportal only
1c
Portal, periportal and perisinusoidal
2
Bridging
3
Cirrhosis
4
References: Kleiner et al., 2005; Bedossa, 2012


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ADDITIONAL SCORING FEATURES
Expanded Balloon Score
0: None
1: Few Non classic
2: Few Classic
3. Many Classic
4: Severe Classic
Portal Inflammation
0: None
1: Minimal
2: Mild
3: More than Mild
Megamitochondria
0: None
1: Present
Acidophil Bodies
0: None or rare
1: Present
Fibrosis location if ≥ stage 2
Portal Predominant
Central Predominant
No predominance
Steatosis Zone
Zone 1 predominant
Zone 3 predominant
Azonal
Panacinar
Glycogenosis
None
Focal
Diffuse


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APPENDIX 3
EQ-5D-5L HEALTH QUESTIONNAIRE
UK SAMPLE ONLY, NOT FOR OFFICIAL USE


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Under each heading, piease tick the ONE box that best describes your health TODAY. 
MOB ILITY 
I have no problems in walking about 
I have sJight problems in walking about 
I have moderate probJems in walking about 
I have severe prob~ms in walking about 
I am unable 10 walk about 
SELF-CARE 
I have no problems washing or dressing mys.elf 
I have slight problems washing or dressing myself 
I have moderate probtems washing or dressing mysetf 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, housework, famHy or 
leisure activities) 
I have no problems doing my usual activities 
I have sJtght problems doing my usual activities 
I have moderate problems doing my usual activities 
I have severe probtems doing my usuaJ activities 
I am unable to do my usual activities 
PAIN I DISCOMFORT 
I have no pain or discomfort 
I have sHght pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
ANXIETY I DEPRESSION 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderatety anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
2 
to< (Engish) (> 2C09 Eun>Qol Grocf> E~N Gallade"""* dille Eun>Qol Grocf> 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 


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• 
We would like to know how good or bad your health is TODAY. 
• 
This scale is numbered from 0 to 100. 
• 
100 means the best health you can imagine. 
0 means the worst heafth you can imagine. 
• 
Mar1t an X on the scale to indicate how your heafth is TODAY. 
• 
Now, please write the number you marked on the scate in the box 
below. 
YOUR HEALTH TODAY = D 
3 
t.M (Entjish)C~ 2.()()fl EIIOQol <iroq:) EQ.SDno i:sa trademark clfhe EJXOQol Gn:ql 
1he best ~alth 
you can imagine 
100 
95 
go 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
The worst health 
you c..m imagine 
15 
10 
5 
0 


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APPENDIX 4
CRITERIA TO ASSESS SEVERITY OF LIVER-RELATED 
ADVERSE EVENTS
Parameter
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
ALT
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
AST
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
Alkaline 
Phosphatase
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
GGT
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
Bilirubin
Normal
>1.0-1.5
>1.5-2.5
>2.5-5
>5
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = 
gamma glutamyl transferase. 
Note: Values expressed as multiples of the upper limit of the normal range (ULN).


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APPENDIX 5
STOPPING RULES FOR LIVER-RELATED BLOOD TESTS
Treatment-Emergent ALT
Treatment-Emergent TBL
Symptoms
Action
Normal baselinea: ALT >5 × ULN
Elevated baseline: ALT >3 × 
baseline or >300 U/L (whichever 
occurs first)
Normal
For patients with Gilbert’s 
syndrome: No change in 
baseline TBL
None
Repeat ALT, AST, 
ALP, TBL,  in 2–5 days
Follow-up for 
symptoms.
Normal baseline: ALT >8 × ULN
Elevated baseline: ALT >8 × 
baseline or >500 U/L (whichever 
occurs first)
Normal
Patients with Gilbert’s 
syndrome: No change in 
baseline TBL
None
Interrupt study drug.
Initiate close 
monitoring and workup 
for competing 
etiologies.
Study drug can be 
restarted only if another 
etiology is identified 
and liver enzymes 
return to baseline.
Normal baseline: ALT >5 × ULN
Elevated baseline: ALT >3 × 
baseline or >300 U/L (whichever 
occurs first)
TBL >2 × ULN
For patients with Gilbert’s 
syndrome: Doubling of direct 
bilirubin
None
Interrupt study drug.
Initiate close 
monitoring and workup 
for competing 
etiologies.
Study drug can be 
restarted only if another 
etiology is identified 
and liver enzymes 
return to baseline.
Normal baseline: ALT >5 x ULN
Elevated baseline: ALT >3 x 
baseline or >300 U/L (whichever 
occurs first)
Normal or elevated
i.e. Severe 
fatigue, nausea, 
vomiting, right 
upper quadrant 
pain
Interrupt study drug.
Initiate close 
monitoring and workup 
for completing 
etiologies.
Study drug can be 
restarted only if another 
etiology is identified 
and liver enzymes 
return to baseline.
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; TBL=total bilirubin; ULN=upper 
limit of normal.
aBaseline is Visit 2
Source: Chalasani and Regev, 2016.


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APPENDIX 6
BRISTOL STOOL CHART


PROTOCOL: SHP626-201
TITLE:
A Phase 2 Double-blind, Randomized, Placebo-controlled, Dose-finding 
Study to Evaluate the Safety, Tolerability and Efficacy of Volixibat 
Potassium, an Apical Sodium-Dependent Bile Acid Transporter 
Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
DRUG:
Volixibat potassium  (SHP626)
IND:
123,847
EUDRACT NO.:
2016-000203-82
SPONSOR: 
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
Philip Newsome MD
Director of Centre for Liver Research 
University of Birmingham
Edgbaston, Birmingham B15 2TT UK
NATIONAL/
COORDINATING
INVESTIGATOR/UK
Guruprasad P Aithal MBBS, MD, FRCP, PhD
Head of the Division, Nottingham Digestive Diseases Centre
Director, NIHR Nottingham Digestive Diseases Biomedical Research 
Unit 
Nottingham University Hospitals and University of Nottingham
Queen's Medical Centre
Nottingham NG7 2UH
PROTOCOL 
HISTORY:
Amendment 3: 22 March 2017
Amendment 2: 19 July 2016
Amendment 1: 8 April 2016
Original Protocol:  24 February 2016 
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations.  This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.


PROTOCOL SIGNATURE PAGE 
Sponsor’s (Shire) Approval 
Signature: 
Date: 
Melissa Palmer, MD, FAASLD 
Global Clinical Development Lead (GCDL) - Hepatology 
 
Investigator’s Acknowledgement 
I have read this protocol for Shire Study SHP626-201. 
Title: A Phase 2 Double-Blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate the 
Safety, Tolerability and Efficacy of Volixibat Potassium, an Apical Sodium-Dependent Bile Acid 
Transporter Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH)  
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor.  It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with ICH (The International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use) guidelines on Good Clinical Practice and with the 
applicable regulatory requirements.  
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing.  Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
 
 
 
 
Signature: 
 
Date: 
 
24 Mar 2017
Shire 
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Volixibat potassium (SHP626) 
 
22 Mar 2017 
 


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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
22 March 2017
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Study Synopsis
Extended planned study period 
from July 2019 to July 2020.

To accommodate a longer
enrollment period.
Study Synopsis
Revised 1) Eligibility criteria; 2) 
sample size description; and 3) 
definition of secondary endpoint 
“Resolution of NASH”

To improve clarity

To align with changes in 
the study protocol body.
Table 1 Schedule of Assessments, 
Section 7.2.3.4 Vital Signs
Revised footnote “g” and text to 
include temporal temperature 
measurement.

To allow for collection of 
temperature temporally.
Table 1 Schedule of Assessments
Revised footnote “h” to describe 
the process for providing additional 
liver biopsy tissue to the central 
reader.

To allow additional liver 
tissue to be sent to the 
central reader.
Table 1 Schedule of Assessments
Revised footnote “k” to clarify that 
subjects are not required to have 
Vitamin A, D, and E testing at the 
screening visit.

To eliminate additional 
blood tests.
Table 1 Schedule of Assessments
Revised footnote “r” to clarify that 
HCVRNA would be performed 
only if HCVAb is positive.

To improve clarity.
Table 1 Schedule of Assessments
Added footnote “c” to indicate that 
Visit 9 MRI and liver biopsy 
procedures are required to be 
completed within +14 days of Visit 
9.

Ensures that Visit 9 liver 
biopsy and MRI are done 
after the last dose of study 
drug.
Table 1 Schedule of Assessments
Added footnote “d” to clarify that 
subjects who have failed screening 
may be re-screened.

To allow the rescreening of 
subjects who previously 
screen failed, once their 
eligibility status has 
changed from the initial 
screening visit.
Section 3.1 Study Design and 
Flow Chart, Synopsis
Added mention that the number of 
F0 subjects will be capped at 81 if 1 
dose is dropped after the interim 
analysis and at 62 if 2 doses are 
dropped.

To allow for a limited 
number of subjects without 
fibrosis to be enrolled.
Section 3.1 Study Design and 
Flow Chart, Synopsis
Added mention that 208 subjects 
are needed for analysis if 1 or 2 
doses of SHP626 are dropped after 
the interim analysis.

To improve clarity.


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
22 March 2017
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Section 4.1 Inclusion Criteria, 
Synopsis
Criterion #6 was revised to allow 
for F0 (fibrosis score), in addition 
to F1-F3.

To allow for subjects 
without fibrosis to be 
eligible for enrollment.
Section 4.2 Exclusion Criteria, 
Synopsis
Revised criterion #5 to include: 
“Stents or other devices may be 
allowed, at the investigator’s 
discretion, if they do not interfere 
with the functioning of the MRI 
machine.”

To allow for inclusion of 
subjects having these 
devices, at the discretion of 
the investigator.
Section 4.2 Exclusion Criteria, 
Synopsis
Criterion #8 was revised to update 
the definition of uncontrolled 
diabetes (HbA1c ≥9.5% within 60 
days prior to enrollment).

To allow for patients with 
up to 9.5% HbA1c to be 
eligible for participation.
Section 4.2 Exclusion Criteria, 
Synopsis
Revised criterion #9 to clarify that 
insulin dose may be adjusted after 
screening/enrollment as long as the 
subject’s HbA1c remains <9.5%.

To allow for inclusion of 
subjects who may need to 
adjust insulin dose during 
the study.
Section 4.2 Exclusion Criteria, 
Synopsis
Revised criteria #11 and #12 to 
allow for enrollment of subjects 
with elevation in AST (#11) and 
ALT (#12) up to 7 times the ULN 
(instead of 5 times the ULN).

It was determined that 
elevations up to this point 
(≤7 times ULN) in AST 
and ALT should not 
preclude subject 
participation and does not 
expose such subjects to any 
additional safety risks.
Section 4.2 Exclusion Criteria, 
Synopsis
Revised criterion #30 to remove 
exclusion of subjects who 
previously failed screening.

To allow the rescreening of 
subjects who previously 
screen failed, once their 
eligibility status has 
changed from the initial 
screening visit.
Section 4.2 Exclusion Criteria, 
Synopsis
Revised criterion #31 regarding 
exclusion of investigational study 
site employees.

To improve clarity.
Section 5.2.2 Prohibited 
Treatment
Added obeticholic acid to the list of 
prohibited treatments.

Prohibited this medication 
as there is potential for a 
drug to affect NASH.
Section 5.2.2 Prohibited 
Treatment
Clarified that tetracycline dose limit 
is ≤1 g per day.

To improve clarity.
Section 5.2.2 Prohibited 
Treatment
Clarified that estrogen dose >2 mg 
QD is prohibited.

To improve clarity.


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
22 March 2017
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Section 5.2.2 Prohibited 
Treatment
Changed text from “drugs cannot 
have been taken for more than 2 
weeks within the year prior to 
randomization” to:
“drugs cannot have been taken for 
more than 2 weeks within the 6 
months prior to randomization”

To enable a less strict 
requirement without 
affecting safety.
Section 6.2.2 Allocation of 
Subjects to Treatment
Added mention that the number of 
F0 subjects will be capped at 81 if 1 
dose is dropped after the interim 
analysis and at 62 if 2 doses are 
dropped.

To allow for a limited 
number of subjects without 
fibrosis to be enrolled.
Section 6.2.3 Dosing
Added mention that if a dose is 
missed at the normally scheduled 
time, the subject can make up the 
dose that day as long as no more 
than 1 dose is taken in a 10-hour 
period.

To specify parameters 
regarding dosing time  if a 
dose is missed
Section 7.1.1 Screening (Visit 1)
Revised passage to indicate subjects 
designated as screen failures could 
be re-screened once.

To allow the rescreening of 
subjects who previously 
screen failed when their 
eligibility status has 
changed from the initial 
screening visit.
Section 7.1.1 Screening (Visit 1)
Added description of process for
providing additional liver tissue to 
the central reader.

To allow additional liver
tissue to be sent to the 
central reader.
Section 7.1.2 Baseline (Visit 2)
Added mention that subjects are 
randomized using IRT before the 
IA and then to 1 of the remaining 
arms after the IA.

To improve clarity.
Section 7.1.3 Treatment and 
Assessment Period (Visits 3 
through 9/EOS)
Added details of the liver histology 
assessment at Week 48.

To improve clarity.
Section 7.2.3.6 Additional 
Laboratory Assessments
Clarified that HCVRNA would be 
performed only if HCVAb is 
positive.

To improve clarity.
Section 7.2.3.6 Additional 
Laboratory Assessments
Revised to clarify that Vitamin A, 
D, and E testing are not required at 
screening.

To improve clarity.

Alignment with Table 1.


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
22 March 2017
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Section 9.3 Data Handling and
Considerations
Removed “IP serum concentrations, 
antibiotics to investigation product”
from the parenthetical list of data 
items that could potentially unblind 
treatment assignement.

To correct an error.
Section 9.6 Sample Size 
Calculation and Power 
Considerations, Synopsis
Increased approximate number of 
subjects screened from 334 to 677 
subjects.

To accommodate a higher 
screen failure rate.
Section 9.6 Sample Size 
Calculation and Power 
Considerations, Synopsis
Added specificity with regard to 
number of subjects needed for 
analysis if more than 1 dose/dosing 
arm is dropped following the 
interim analysis.

To improve clarity.
Section 9.7 Study Population
Added definition of “The 
Randomized Set.”

To improve clarity.
Section 9.8 Efficacy Analyses
Clarified that the efficacy analyses 
involving statistical testing will 
only be done for the doses that are 
not dropped at the interim analysis.

To improve clarity.
Section 9.8.1 Primary Efficacy 
Endpoint
Clarified that the method for 
handling missing data in the 
primary analysis is non-responder 
imputation.

To improve clarity.
Section 9.8.2 Secondary Efficacy 
Endpoints
The definition of “Resolution of 
NASH” was revised.

To allow consistency with 
newly revised and 
recommended definition.
Throughout protocol.
Minor changes to format and 
correct typos.

To improve clarity.


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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to:
Shire Global Drug Safety Department
Preferred method: scan and e-mail to globalpharmacovigilance@shire.com
OR fax to +44(0) 1256 89 4715 (Global); or +1 866 557 4473 (North America)
AND
A copy of this form must also be sent to the Shire GCDL by fax or e-mail using the details 
below:
Melissa Palmer, MD, FAASLD, GCDL-Hepatology
fax number: +1 781 482 1822
e-mail: mpalmer@shire.com 
For protocol- or safety-related issues during normal business hours 9:00 a.m. to 5:00 p.m. 
(Eastern Time), the investigator must contact the Contract Research Organization (CRO) 
Medical Monitor:
ICON Medical Monitor: Anthony Japour, MD
Telephone number: +1 215 616 6439
Fax number: +1 215 616 3096
Mobile number: +1 267 429 6601
E-mail address: Anthony.Japour@iconplc.com
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact ICON’s 24/7 Medical Emergency Coverage:
Chargeable global telephone number: +1 919 674 5468
NOTE: Investigative sites will be provided country-specific toll-free telephone numbers. Please 
refer to this document, as applicable. Countries without a toll-free number will need to dial the 
chargeable number noted above.


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product (IP) quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products).  For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
PQC@shire.com
European Union and Rest of World
PQCROW@shire.com
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA) 
1-888-300-6414 or 1-800-828-2088


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................7
PRODUCT QUALITY COMPLAINTS..........................................................................................8
TABLE OF CONTENTS.................................................................................................................9
LIST OF TABLES.........................................................................................................................13
LIST OF FIGURES .......................................................................................................................13
LIST OF APPENDICES................................................................................................................13
ABBREVIATIONS .......................................................................................................................14
STUDY SYNOPSIS ......................................................................................................................17
1.
BACKGROUND INFORMATION.......................................................................................27
1.1
Indication and Current Treatment Options...............................................................27
1.2
Product Background and Clinical Information ........................................................27
1.3
Benefits and Risks....................................................................................................30
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................31
2.1
Rationale for the Study.............................................................................................31
2.2
Study Objectives ......................................................................................................32
2.2.1
Primary Objective..................................................................................................32
2.2.2
Secondary Objectives.............................................................................................32
2.2.3
Exploratory Objectives ..........................................................................................32
3.
STUDY DESIGN ...................................................................................................................32
3.1
Study Design and Flow Chart ..................................................................................32
3.2
Duration and Study Completion Definition .............................................................34
3.3
Sites and Regions .....................................................................................................34
4.
STUDY POPULATION.........................................................................................................34
4.1
Inclusion Criteria......................................................................................................34
4.2
Exclusion Criteria.....................................................................................................35
4.3
Restrictions...............................................................................................................37
4.4
Reproductive Potential .............................................................................................38
4.4.1
Female Contraception............................................................................................38
4.4.2
Male Contraception................................................................................................39
4.5
Discontinuation of Subjects .....................................................................................39
4.5.1
Subject Withdrawal Criteria ..................................................................................39
4.5.2
Reasons for Discontinuation..................................................................................40
4.5.3
Subjects Lost to Follow-up Prior to Last Scheduled Visit.....................................40


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4.5.4
Safety-related Stopping Rules................................................................................41
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................41
5.1
Prior Treatment ........................................................................................................41
5.2
Concomitant Treatment............................................................................................42
5.2.1
Permitted Treatment...............................................................................................42
5.2.2
Prohibited Treatment .............................................................................................42
6.
INVESTIGATIONAL PRODUCT ........................................................................................43
6.1
Identity of Investigational Product...........................................................................43
6.1.1
Blinding the Treatment Assignment ......................................................................43
6.2
Administration of Investigational Product(s)...........................................................43
6.2.1
Interactive Response Technology for Investigational Product Management ........43
6.2.2
Allocation of Subjects to Treatment ......................................................................43
6.2.3
Dosing....................................................................................................................44
6.2.4
Unblinding the Treatment Assignment..................................................................44
6.3
Labeling, Packaging, Storage, and Handling ...........................................................45
6.3.1
Labeling .................................................................................................................45
6.3.2
Packaging...............................................................................................................45
6.3.3
Storage ...................................................................................................................46
6.4
Drug Accountability.................................................................................................46
6.5
Subject Compliance..................................................................................................47
7.
STUDY PROCEDURES........................................................................................................48
7.1
Study Schedule.........................................................................................................48
7.1.1
Screening (Visit 1).................................................................................................48
7.1.2
Baseline (Visit 2) ...................................................................................................49
7.1.3
Treatment and Assessment Period (Visits 3 through 9/EOS)................................49
7.1.4
Follow-up (Visit 10) ..............................................................................................50
7.1.5
Additional Care of Subjects after the Study ..........................................................50
7.2
Study Evaluations and Procedures ...........................................................................50
7.2.1
Demographic and Other Baseline Characteristics .................................................51
7.2.2
Efficacy..................................................................................................................51
7.2.2.1
Liver Biopsy...........................................................................................51
7.2.2.2
MRI ........................................................................................................51
7.2.3
Safety .....................................................................................................................51
7.2.3.1
Medical History and Medications ..........................................................51
7.2.3.2
Physical Examination.............................................................................51
7.2.3.3
Adverse Event Collection.......................................................................52
7.2.3.4
Vital Signs..............................................................................................52
7.2.3.5
Clinical Laboratory Evaluations.............................................................52


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7.2.3.6
Additional Laboratory Assessments.......................................................53
7.2.3.7
Pregnancy Test .......................................................................................54
7.2.3.8
Drug and Alcohol Testing......................................................................54
7.2.3.9
Electrocardiogram ..................................................................................55
7.2.3.10
Health-related Quality of Life Assessments...........................................55
7.2.3.11
Volume of Blood to be Drawn from Each Subject ................................55
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................55
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................55
8.1.1
Severity Categorization..........................................................................................56
8.1.2
Relationship Categorization...................................................................................56
8.1.3
Outcome Categorization ........................................................................................57
8.1.4
Symptoms of the Disease Under Study .................................................................57
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................57
8.1.6
Criteria for Discontinuation of Treatment .............................................................58
8.1.7
Pregnancy...............................................................................................................58
8.1.8
Abuse, Misuse, Overdose, and Medication Error..................................................58
8.2
Serious Adverse Event Procedures ..........................................................................59
8.2.1
Reference Safety Information................................................................................59
8.2.2
Reporting Procedures.............................................................................................59
8.2.3
Serious Adverse Event Definition .........................................................................60
8.2.4
Serious Adverse Event Onset and Resolution Dates .............................................61
8.2.5
Fatal Outcome........................................................................................................61
8.2.6
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................61
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................61
9.1
Data Collection.........................................................................................................61
9.2
Clinical Data Management.......................................................................................62
9.3
Data Handling Considerations..................................................................................62
9.4
Statistical Analysis Process......................................................................................62
9.5
Planned Interim Analysis and Data Monitoring Committee....................................63
9.5.1
Planned Interim Analysis.......................................................................................63
9.5.2
Data Monitoring Committee..................................................................................63
9.6
Sample Size Calculation and Power Considerations................................................64
9.7
Study Population ......................................................................................................65
9.8
Efficacy Analyses.....................................................................................................65
9.8.1
Primary Efficacy Endpoint ....................................................................................65
9.8.2
Secondary Efficacy Endpoints...............................................................................66


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9.8.3
Exploratory Efficacy Endpoints.............................................................................67
9.9
Safety Analyses........................................................................................................67
9.10
Other Analyses .........................................................................................................68
9.10.1 Health-related Quality of Life Analyses................................................................68
9.10.2 Stool Assessment ...................................................................................................68
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................68
10.1
Sponsor’s Responsibilities .......................................................................................69
10.1.1 Good Clinical Practice Compliance.......................................................................69
10.1.2 Indemnity/Liability and Insurance.........................................................................69
10.1.3 Public Posting of Study Information......................................................................69
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................69
10.1.5 Study Suspension, Termination, and Completion..................................................69
10.2
Investigator’s Responsibilities .................................................................................70
10.2.1 Good Clinical Practice Compliance.......................................................................70
10.2.2 Protocol Adherence and Investigator Agreement..................................................70
10.2.3 Documentation and Retention of Records.............................................................71
10.2.3.1
Electronic Case Report Forms................................................................71
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................71
10.2.3.3
Audit/Inspection.....................................................................................72
10.2.3.4
Financial Disclosure...............................................................................72
10.3
Ethical Considerations..............................................................................................72
10.3.1 Informed Consent...................................................................................................72
10.3.2 Institutional Review Board or Ethics Committee..................................................73
10.4
Privacy and Confidentiality......................................................................................73
10.5
Study Results / Publication Policy ...........................................................................74
11. REFERENCES .......................................................................................................................76
12. APPENDICES ........................................................................................................................79


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LIST OF TABLES
Table 1
Schedule of Assessments..........................................................................23
LIST OF FIGURES
Figure 1
Study Design Flow Chart..........................................................................34
LIST OF APPENDICES
APPENDIX 1
Protocol History........................................................................................80
APPENDIX 2
Fatty Liver Disease Histology Scoring.....................................................81
APPENDIX 3
EQ-5D-5L Health Questionnaire UK Sample Only, Not for Official 
Use............................................................................................................83
APPENDIX 4
Criteria to Assess Severity of Liver-Related Adverse Events..................86
APPENDIX 5
Stopping Rules for Liver-related Blood Tests..........................................87
APPENDIX 6
Bristol Stool Chart....................................................................................88


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ABBREVIATIONS
AE
adverse event
ALP 
alkaline phosphatase
ALT 
alanine aminotransferase
aPPT
activated partial thromboplastin time
ASBT
apical sodium-dependent bile acid transporter
ASBTi 
ASBT inhibitor
AST 
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BA 
bile acid
BMI
body mass index
C4
7-alpha-hydroxy-4-cholesten-3-one
CRA
clinical research associate
CRC 
clinical research center
CRO
contract research organization
DMC 
data monitoring committee
eCRF
electronic case report form
EQ-5D-5L 
EuroQol-5 Dimension-5 Level Questionnaire
ECG
electrocardiogram
EOS
end of study
EU
European Union
FAS
full analysis set
FBA 
fecal bile acid
FDA
Food and Drug Administration
FXR
farnesoid X receptor
GCDL 
Global Clinical Development Lead
GCP
Good Clinical Practice
GDS
Global Drug Safety
GGT 
gamma glutamyl transferase
GLP-1 RA
glucagon-like peptide-1 receptor agonists
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus


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HBVDNA
hepatitis B virus deoxyribonucleic acid
HCV
hepatitis C virus
HCVAb
hepatitis C virus antibody
HCVRNA
hepatitis C virus ribonucleic acid
HDL-C
high-density lipoprotein-cholesterol
HFD
high fat diet
HFF
hepatic fat fraction
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HOMA-%B 
homeostasis model assessment in β-cell function
HOMA-IR 
homeostasis model assessment insulin resistance
HRQoL 
health-related quality of life
IA 
interim analysis
IAS
interim analysis set
ICH
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IND 
investigational new drug
INR
international normalized ratio
IP
investigational product
IR
insulin resistance
IRB
Institutional Review Board
IRT
interactive response technology
LDL-C 
low-density lipoprotein-cholesterol
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MR
magnetic resonance
MRI 
magnetic resonance imaging
MRS
magnetic resonance spectroscopy
MOA
mechanism of action
NAFLD 
nonalcoholic fatty liver disease
NAS 
NAFLD Activity Score
NASH 
nonalcoholic steatohepatitis
NASH CRN
NASH Clinical Research Network
NOAEL 
no observed adverse effect level
PBC
primary biliary cirrhosis


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PBO
placebo
PDFF
proton density fat-fraction
PO
by mouth
POC
proof of concept
PRO 
patient-reported outcome
PSC
primary sclerosing cholangitis
PT
prothrombin time
QD 
once daily
RBC
red blood cell 
SAE 
serious adverse event
SAF
steatosis, activity, and fibrosis score
SAP 
statistical analysis plan
T2DM
type 2 diabetes mellitus
T3
triiodothyronine
TA
therapeutic area
TB
total bilirubin
TEAE
treatment-emergent adverse event
TGR5 
transmembrane G protein-coupled receptor
TPN
total parenteral nutrition
TSH
thyroid-stimulating hormone
TZD
thiazolidinediones
ULN
upper limit of normal
USA 
United States of America
VAS
visual analogue scale


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STUDY SYNOPSIS
Protocol number: SHP626-201
Drug: Volixibat potassium (SHP626)
Title of the study: A Phase 2 Double-Blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate 
the Safety, Tolerability and Efficacy of Volixibat Potassium, an Apical Sodium-Dependent Bile Acid 
Transporter Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
Number of subjects (total and for each treatment arm): Approximately 677 subjects will be screened to 
enroll 266 subjects to achieve 201 completers. After enrollment of at least 80 subjects (20/treatment arm – 3 
active and 1 placebo [PBO]) a 24-week interim analysis (IA) will eliminate at least one dose group based on the 
criteria provided to the Data Monitoring Committee; enrollment will continue to include approximately 67 
subjects in each of the remaining arms. The sample size target for this study is 67 completers in each of the 
treatment groups (201 total if 3 arms continue). Including an additional 20 subjects to account for one dose 
dropped at the IA, 221 subjects are needed. Therefore, approximately 266 (accounts for 20% of 221 dropping 
out) subjects will be randomized if three arms (2 SHP626 and 1 PBO) continue; 208 (accounts for 20% of 
dropouts) subjects are needed if two SHP626 doses are dropped at the IA.
Investigator(s):  Multicenter study
Site(s) and Region(s): 
Anticipated regions -US, Canada, and EU 
Estimated number of sites planned – 60 to 80
Study period (planned):
July 2016 to July 2020
Clinical phase:
2
Objectives:
Primary:  To evaluate the effect of volixibat compared to PBO on liver histology 
Secondary:  
•
To evaluate the safety and tolerability of volixibat compared to PBO
•
To evaluate the effect of volixibat compared to PBO on hepatic steatosis  (measured by MRI)
•
To evaluate the effect of volixibat compared to PBO on liver histology (measured by individual 
nonalcoholic fatty liver disease (NAFLD) activity score (NAS) components and fibrosis stage)
•
To evaluate the effect of volixibat compared to PBO on liver histology (measured by NASH resolution 
without worsening fibrosis)
•
To evaluate the effect of volixibat compared to PBO on serum liver-related biochemistry 
•
To evaluate the effect of volixibat compared to PBO on metabolic indicators (glucose, insulin, 
hemoglobin A1c [HbA1c]) 
•
To evaluate the effect of volixibat compared to PBO on serum lipids (cholesterol, HDL-C, LDL-C, 
triglycerides) 
Rationale: Currently, there is no approved medication for the treatment of NASH. Volixibat is under 
development for the treatment of NASH based on its mechanism of action (MOA) and is supported by 
nonclinical and Phase 1 data.  This is a Phase 2, 48-week, dose-finding study to examine the efficacy, 
tolerability, and safety of volixibat in adults with NASH.
Investigational product, dose, and mode of administration:

Volixibat 5, 10, and 20 mg and matched PBO capsules by mouth (PO) once daily (QD). Investigational 
product (IP) should be given 30 minutes prior to the first meal of the day containing approximately 10-20 


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grams of fat. Also see Section 6.2.3 (Dosing).

Identical PBO will be used as comparator 

Subjects should take the IP at the same time each day and should not take more than one dose in a 
day if they miss a dose. If a dose is missed at the normally scheduled time, the subject can make 
up the dose that day as long as no more than 1 dose is taken in a 10-hour period.
Methodology:
This study will be a Phase 2, 48-week, multicenter, double-blind, randomized, PBO-controlled, parallel group, 
proof of concept, dose-finding study, with one IA after at least 80 subjects have received 24 weeks of treatment. 
There will be 3 active arms of volixibat (5, 10 and 20 mg) and a PBO arm. Subjects will be randomized to 
receive one of three doses of volixibat (5, 10, or 20 mg once daily (QD) or PBO in a 1:1:1:1 ratio. Subjects with
fibrosis stages F0 through F3 may be enrolled, but the number of F0 subjects will be capped at 81 if 1 dose is 
dropped after the interim analysis and at 62 if 2 doses are dropped. Depending on the results of the IA, the study 
may be terminated or the randomization to one or two doses will be stopped. The follow-up period will be 4 
weeks after last dose. Subjects will be expected to visit the study center at least 10 times. 
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions.
2.
Ability to voluntarily provide written, signed, and dated (personally or via a legally-authorized 
representative, as applicable) informed consent to participate in the study.
3.
Age 18-80 years inclusive.  This inclusion criterion will only be assessed at the first screening visit.
4.
Male, or non-pregnant, non-lactating female, who is sexually active and who agrees to comply with the 
contraceptive requirements of the protocol, or females of non-childbearing potential.  Males and 
females of child-bearing potential who are sexually active must agree to use acceptable contraception 
during the study and 30 days following the last dose of the IP.
5.
Presence of ≥5% steatosis on screening MRI from a centrally read radiologist performed either during 
the screening period or within 6 months prior to the first visit.
6.
Histologic confirmation of NASH without cirrhosis (F0-F3) from a centrally read liver biopsy 
performed either during the screening period or within 6 months prior to the first visit with a NAS of 
≥4 with a score of at least 1 in each component (steatosis, lobular inflammation, and hepatocyte 
ballooning).
Exclusion Criteria:
1.
Presence of or history of cirrhosis or evidence of decompensated liver disease (ie, ascites, variceal 
bleeding, etc.) or hepatocellular carcinoma.
2.
History or presence of other concomitant liver disease as assessed by the investigator or determined by 
laboratory findings including, but not limited to: active hepatitis B virus (HBV) infection (hepatitis B 
surface antigen (HBsAg) positive and/or HBVDNA positive; subjects who are hepatitis B core 
antibody (HBcAb) positive may be eligible as long as HBsAg is negative and HBVDNA is
nondetectable), active hepatitis C virus (HCV) infection (prior exposure to HCV [defined as HCVAb 
positive] without a current or prior history of a detectable HCVRNA) will be eligible, alcoholic liver 
disease, proven autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis 
(PSC), hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, bile duct obstruction, liver 
primary or metastatic cancer.
3.
Current or recurrent disease that could affect the action, absorption, disposition, or laboratory 
assessment of the IP (including bile salt metabolism in the intestine) eg, uncontrolled inflammatory 
bowel disease, uncontrolled celiac disease, gastric bypass procedures (gastric lap band or gastric sleeve 
is acceptable), ileal or ileocecal resection, uncontrolled irritable bowel syndrome with predominant 


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diarrhea, or history of chronic diarrhea or loose stools of any etiology.
4.
Weight change ≥5% after qualifying liver biopsy and/or MRI performed. If the subject had a liver 
biopsy and/or MRI within 6 months of screening, but experienced a weight change ≥5% since the date 
of liver biopsy and/or MRI, the liver biopsy and/or MRI must be repeated at screening.
5.
Contraindications to MRI (ie, claustrophobia, coronary stents, coronary implantable devices, girth, 
etc.). Stents or other devices may be allowed, at the investigator’s discretion, if they do not interfere 
with the functioning of the MRI machine.
6.
Current or relevant history of physical or psychiatric illness, any medical disorder that may require 
treatment or make the subject unlikely to complete the study.
7.
Treatment with Vitamin E, thiazolidinediones (TZD), or glucagon-like peptide-1 receptor agonists 
(GLP-1 RA) unless subject on a stable dose for 6 months prior to qualifying liver biopsy and not 
initiated after qualifying liver biopsy and will continue the same dosing regimen throughout study 
participation. 
8.
Uncontrolled diabetes defined as HbA1c of ≥9.5% within 60 days prior to enrollment. 
9.
Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) that 
could affect the action, absorption, or disposition of the IP, or clinical or laboratory assessment. 
(Current use is defined as use within 14 days of screening). Patients currently taking insulin will not be 
excluded; however, they must be on a stable dose for at least 30 days prior to screening, or a sliding 
scale of insulin is allowed as long as the subject’s HbA1c remains < 9.5%.
10. Use of drugs, herbs or supplements historically associated with causing or worsening NAFLD/NASH 
for less than 6 months prior to qualifying liver biopsy, or initiated any time after qualifying liver biopsy 
performed, including the use of total parenteral nutrition (TPN). 
11. Serum AST >7 times upper limit of normal (ULN) at screening.
12. Serum ALT >7 times ULN at screening.
13. Elevated serum creatinine ≥2.0 mg/dL.
14. International normalized ratio (INR) >1.3.
15. Total bilirubin (TB) ≥2.0 x ULN at screening (Except for documented Gilbert’s syndrome with 
bilirubin levels 20 µmol/L to 90 µmol/L (1.2 to 5.3 mg/dL) and with a ratio of 
unconjugated/conjugated bilirubin that is commensurately higher).
16. Platelet count <130 × 109L
17. Medical history of impaired hemostasis or current use of anticoagulant medication (use of antiplatelet 
medications, such as low-dose, ie, 81mg, aspirin (ASA) or clopidogrel (Plavix), will be allowed).
18. Uncontrolled thyroid disease.
19. Type 1 diabetes mellitus.
20. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or any of the 
stated ingredients.
21. Known history of alcohol or other substance abuse within the last year or at any time during the study 
based on investigator’s discretion.  Weekly alcohol intake greater than 21 grams/day for males and 14 
grams/day for females on average or inability to reliably quantify alcohol consumption based on 
investigator’s judgment.
22. Within 6 months of MRI and liver biopsy:

Have used any IP

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 


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opinion, may impact this Shire-sponsored study
23. Inability to safely obtain a liver biopsy.
24. Females who are pregnant, planning to become pregnant, or are breastfeeding, or males who are 
planning to father a child during study participation.
25. The anticipated need for a surgical procedure during the study that could interfere with the treatment. 
26. Known positivity for human immunodeficiency virus (HIV) infection.
27. Cancer within 5 years of screening, except for basal or squamous cell carcinoma of the skin or in situ 
cervical carcinoma that has been treated with no evidence of recurrence.
28. History of noncompliance with medical regimens, unreliability, mental instability or incompetence that 
could compromise the validity of informed consent or lead to noncompliance with the study protocol.
29. Any other conditions or abnormalities which, in the opinion of the investigator, may compromise the 
safety of the subject, or interfere with the subject participating.
30. Subject is currently enrolled in this study at any study site (unless the subject is transferring to another 
qualified study site with prior sponsor approval).
31. Subjects who are employees at the unit of the investigational site that is conducting the study.
Maximum duration of subject involvement in the study:

Planned duration of screening period:  56 days 

Planned duration of enrollment period: 364 days

Planned duration of treatment period: 336 days 

Planned duration of follow-up: 28 days 
Endpoints and statistical analysis:
Safety Analysis Set will consist of all subjects who take at least 1 dose of randomized IP, and have at least 1 
post-baseline safety assessment (eg, coming back for any visit, reporting of an adverse event (AE) or reporting 
the absence of AEs).
Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have at least 1 post-baseline 
efficacy assessment (eg, MRI, liver biopsy, serum liver-related biochemistry measurement).
Interim Analysis Set (IAS) will consist of all subjects in the Safety Analysis Set who have at least 1 post-
baseline efficacy assessment (eg, MRI, ALT biochemistry measurement) on or before the Week 24 visit at the 
time of the data cut for the IA.  
Screened Set will consist of all subjects who have signed an informed consent. 
Randomized Set will consist of all subjects in the Screened Set who have been randomized into the study. 
Efficacy Endpoints:

Primary: Binary response indicating (yes/no) whether a subject responded at Week 48 with a reduction 
of at least 2 points without worsening of fibrosis from baseline NAS.

Secondary: 

Change from baseline to Week 48 on liver histology as measured by the individual NAS 
components (ballooning, inflammation, steatosis).  

Change from baseline to Week 48 on hepatic steatosis as measured by MRI-PDFF.

Change from baseline to Week 48 on liver histology as measured by fibrosis stage. (NASH 
Clinical Research Network (CRN))


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
Resolution of NASH (defined as total absence of ballooning [score = 0] absent or mild 
inflammation [score 0-1], steatosis can be present [score 0-3]), without worsening of fibrosis 
as assessed by liver histology at week 48.

Change from baseline to Week 48 on serum liver-related biochemistry as measured by:

alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

alkaline phosphatase (ALP)

gamma glutamyl transferase (GGT)

total bilirubin (TB)

Change from baseline to Week 48 on metabolic indicators as measured by:

fasting serum glucose levels

insulin levels

HbA1c 

Change from baseline to Week 48 on serum lipids measured by: 

fasting total cholesterol

HDL-C

LDL-C

triglycerides 
Primary hypotheses:

Null: The proportion of subjects at Week 48 with a reduction of at least 2 points without worsening of 
fibrosis from baseline NAS does not differ between any of the volixibat doses and PBO.

Alternative: The proportion of subjects at Week 48 with a reduction of at least 2 points without 
worsening of fibrosis from baseline NAS does differ between at least one volixibat dose and PBO.
The FAS will be used to assess the primary efficacy endpoint. The difference between a volixibat dose and PBO 
will be tested with a stratified Cochran-Mantel-Haenzel test. Subjects with missing data for the primary efficacy 
endpoint at the Week 48 visit will be considered as non-responders. The test will be stratified by presence or 
absence of Type 2 diabetes mellitus (T2DM) at baseline, and baseline NAS separated into two groups 
(NAS={4,5} or NAS={6,7,8}). Holm multiplicity adjustment will be applied prior to determining statistical
significance at the 0.1 level. Histology will be read by one central hepatohistopathologist who will use the 
NASH CRN standard scoring system – NAS. The SAF Steatosis (S), Activity (A), and Fibrosis (F) scoring 
system will be determined for exploratory purposes.
The Safety Analysis Set will be used to assess the safety endpoints including AEs (including changes from 
baseline in physical examination findings), vital signs, ECGs, and clinical laboratory tests (chemistry, 
hematology, coagulation and urinalysis).
AEs will be coded using the agreed upon version of the Medical Dictionary for Regulatory Activities 
(MedDRA). TEAEs are defined as AEs that started or worsened on or after the date of the first dose of IP, and 
no later than the follow-up visit. The number of events, incidence, and percentage of TEAEs will be presented 
by system organ class, preferred term, and by treatment group. TEAEs will be further summarized by severity 
and the relationship to the IP. AEs related to the IP, AEs leading to withdrawal, SAEs, and death will be 
similarly summarized/listed.
Vital signs, ECG findings, and clinical laboratory tests will be summarized by treatment group and visit. 
Potentially clinically important findings will be summarized. Graphical presentation may be used when deemed 
necessary.
For safety parameters, baseline is defined as the last assessment prior to the first dose of the IP.
Planned Interim Analysis:
An IA will be conducted by an independent data monitoring committee (DMC) after at least 80 subjects have 


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received 24 weeks of treatment. The IA will evaluate the safety, tolerability and efficacy of 3 doses of volixibat 
each compared to PBO. 
Tolerability will be assessed by the number of discontinuations due to any one TEAE, presumably 
gastrointestinal events, most notably, diarrhea, loose stools, increased evacuations, and abdominal pain. Efficacy 
at the IA will be based on reduction of steatosis or ALT. Steatosis is assessed by MRI-PDFF. Depending on the 
results from the IA, one or more doses of volixibat may be discontinued or the study may be terminated.  If the 
study is not terminated, subjects will receive a total of 48 weeks of the IP.


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Table 1
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9c
EOS
10
In-Clinic
Week
-8 to 0
0
2
4
8
12
24
36
48
52
Study Day
-56 to -1
0
14
28
56
84
168
252
336
364
Informed consentd
X
Inclusion/exclusion criteria
X
X (review)
Demography, medical & medication 
history 
X
Physical examination
X
X
X
X
X
Heighte, weightf, waist circumference 
and waist:hip ratio
X
X
X
X
X
X
X
X
X
X
Vital signsg
X
X
X
X
X
X
X
X
X
X
PRO (EQ-5D-5L)
X
X
X
Liver biopsyh
X
X
MRIi
X
Xj
X
ECG (12-lead)
X
X
X
X
Biochemistry and Hematologyk
X
X
X
X
X
X
X
X
X
X
Serum Glucosel
X
X
X
X
X
X
X
X
X
X
Urinalysism
X
X
X
Urine Drug and Blood Alcohol Tests
X
X
Urine Pregnancy Testn
X
X
X
X
X
X
X
X
X
X
Lipid Panel0
X
X
X
X
X
X
X
X
X
X
Coagulation Panelp
X
X
X
X
X


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Table 1
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9c
EOS
10
In-Clinic
Week
-8 to 0
0
2
4
8
12
24
36
48
52
Study Day
-56 to -1
0
14
28
56
84
168
252
336
364
Vitamins A, D, and Et
X
X
X
X
HbA1ck
X
X
X
X
X
X
X
X
X
X
Serum Liver-Related Blood Testsk, q
X
X
X
X
X
X
X
X
X
X
Insulink
X
X
X
X
X
X
X
X
HIV, Hepatitis B/Ck, r
X
Thyroid testingk, s
X
X
X
X
X
X
X
C4 Sampling
X
X
X
X
X
IRT Accessed
X
X
X
X
X
X
X
X
X
X
Randomization
X
IP Dispensedt
X
X
X
X
X
X
X
IP Returned/Accountability & 
Compliance Assessed 
X
X
X
X
X
X
X
Stool Assessmentu
X
X
X
X
X
X
Adverse Eventsv
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
ECG=electrocardiogram; EOS=end of study; HOMA=Homeostasis Model Assessment; IA=interim analysis; IP=investigational product; IRT=Interactive Response Technology; 
MRI=magnetic resonance imaging; PRO=patient-reported outcome.
a Visit Windows (calculated from Visit 2): Bi-weekly (Visits 3-4): +/- 3 days; Monthly (Visits 5-6, Visit 10): +/-5 days; Tri-monthly (Visits 7-9/DC): +/- 7 days. 
b Subjects will be reminded not to eat prior to their scheduled visit.  Additionally, during the double-blind treatment period, they should not take their study drug prior to the visit. 
They should bring their study drug with them to the visit to take 30 minutes prior to their first meal of the day containing approximately 10-20 grams of fat. Also see Section 6.2.3


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Table 1
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9c
EOS
10
In-Clinic
Week
-8 to 0
0
2
4
8
12
24
36
48
52
Study Day
-56 to -1
0
14
28
56
84
168
252
336
364
c Subjects are to complete the Visit 9 liver biopsy and MRI procedures within +14 days of Visit 9. All other Visit 9 assessments are to be completed within a window of +/- 7 days.
d Subjects who completed screening and were designated as a screen failure may be rescreened. However, rescreened subjects must begin the screening procedure again, must be 
re-consented and will be assigned a new subject number.
e Height to be measured at screening only.
f BMI to be calculated programmatically by the sponsor or designee for the following visits: screening (Visit 1), baseline (Visit 2), Visits 7 and 9/DC.   
g Vital signs to include oral, temporal, or tympanic temperature, sitting blood pressure, pulse, and respiratory rate.
h Biopsy performed within 6 months of screening can be used. All biopsies will be centrally read by a hepatic histopathologist. See Sections 7.1.1 and 7.1.3 for additional details.  
iMRI from a centrally read radiologist performed either during the screening period or within 6 months prior to the first visit. 
j MRI at Visit 7 (Week 24) for the Interim Analysis Set only.
k All blood tests are fasting blood tests. Subjects are not required to have Vitamin A, D, and E testing at screening (Visit 1).
l HOMA-IR and HOMA-%B: will be calculated programmatically by the sponsor or designee for the following visits: screening (Visit 1), baseline (Visit 2), Visits 7, 9/DC, and 10.   
m Urinalysis to include oxalate testing.
n For all females of child-bearing potential (FOCP).  Positive on-site urine dipstick results must have serum -HCG testing performed by central lab.
Additional testing can be performed at the investigator’s discretion.
o Lipid Panel includes fasting total cholesterol, HDL-C, LDL-C, and triglycerides.
p Full coagulation panel will be done at screening and baseline, but only PT/INR is required at remaining time points to assess vitamin K level. 
q Serum Liver-Related Blood Tests include ALT, AST, ALP, GGT, and total bilirubin.
r Hepatitis B/C testing includes HBcAb, HBsAg, HBVDNA and HCVAb (if HCVAb is positive an HCVRNA will be performed), respectively.
s Thyroid testing includes thyroid stimulating hormone (TSH) and triiodothyronine (T3).
t Investigational product may be dispensed at an unscheduled visit outside of this schedule as needed to replace lost or damaged product.
u Subjects will be queried about the number of stool evacuations during the 24- hour period before the clinical research center (CRC) visit and asked to describe the consistency of 
the softest stool during that 24- hour period using the Bristol Stool Chart.


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Table 1
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9c
EOS
10
In-Clinic
Week
-8 to 0
0
2
4
8
12
24
36
48
52
Study Day
-56 to -1
0
14
28
56
84
168
252
336
364
v Adverse events will be collected beginning from the signing of informed consent.  All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in the study. Closure indicates that an outcome is reached, stabilization achieved (the 
investigator does not expect any further improvement or worsening of the event), or the event is otherwise explained. When appropriate, medical tests and examinations are 
performed so that resolution of event(s) can be documented.


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1.
BACKGROUND INFORMATION
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease 
worldwide (Vernon et al. 2011), and is estimated to occur in 30-40% of adults in the United 
States and up to 30% of European adults.  These numbers approach 95% in those with morbid 
obesity (Mathus-Vliegen et al. 2012).  NAFLD ranges from simple steatosis, which is typically 
nonprogressive, to nonalcoholic steatohepatitis (NASH), which has a 20% likelihood of 
progression to advanced disease including fibrosis, cirrhosis and its complications including liver 
failure and the need for a liver transplant (Angulo 2002).  Hepatocellular carcinoma is also a 
complication of NASH that may occur with or without the presence of cirrhosis (Torres et al. 
2012).  NAFLD is typically associated  with type 2 diabetes mellitus (T2DM) (Adibi et al. 2007;
Loomba et al. 2012), central or visceral obesity (Souza et al. 2012), dyslipidemia (Assy et al.
2000; National Cholesterol Education Program 2002), and hypertension (Donati et al. 2004).  
Together these conditions comprise the metabolic syndrome, and NASH is considered to be the 
hepatic component of this syndrome (Hamaguchi et al. 2005; Neuschwander-Tetri 2005;
Marchesini et al. 2005). Notably, NAFLD is a clinical condition occurring in individuals who do 
not drink excessive alcohol (>20 grams/day), yet have hepatic histology which is 
indistinguishable from that seen with alcoholic excess.  The pathophysiology of NASH is likely 
multifactorial and may include combinations of metabolic, genetic, environmental, and gut 
microbial factors.       
Most individuals with NASH are asymptomatic or have nonspecific symptoms such as fatigue. 
They typically first come to medical attention incidentally following routine blood testing or on 
imaging studies performed routinely or during the evaluation of an unrelated condition. While 
ultrasound and magnetic resonance imaging (MRI) can detect the presence of steatosis (Reeder 
et al. 2011), a liver biopsy is required to diagnose NASH and the extent of liver fibrosis. 
1.1
Indication and Current Treatment Options 
There are currently no drugs approved for the treatment of NASH and it is estimated that there 
are between 6-16 million people in the United States with NASH, of which 600,000 have severe 
disease (Williams et al. 2011 and Torres and Harrison 2008), with similar percentages reported 
throughout most areas of the world (World Gastroenterology Organisation 2012). Treatment of 
associated metabolic comorbidities, weight reduction, and incorporation of an exercise routine 
remain the cornerstone of management.  However, lifestyle changes are seldom successful. Thus, 
NASH represents a disease with an unmet medical need that is growing at an epidemic rate, and 
that if untreated, carries a risk of significant morbidity and mortality.
1.2
Product Background and Clinical Information
Volixibat potassium (SHP626; formerly LUM002), hereafter referred to as volixibat, is a highly 
selective inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that is being 
evaluated for the treatment of NASH.  


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Bile acids (BA) promote bile flow, activation of digestive enzymes, and micellization of fats and 
fat-soluble vitamins, thereby permitting their intestinal absorption.  BAs serve as signaling 
molecules acting via receptors, such as farnesoid X receptor (FXR) and transmembrane G 
protein-coupled receptor (TGR5), in the intestine, liver and other tissues which play an important 
role in regulating insulin homeostasis. (Halilbasic et al. 2013).  Lipid peroxidation and oxidant 
stress have been proposed as one link between the accumulation of fat and subsequent injury 
(Day and James 1998).  All of these metabolic actions have important effects to prevent the 
ongoing liver damage in NASH. 
High fat diet (HFD) fed mice treated with an ASBT inhibitor (ASBTi) (SC-435 a surrogate 
SHP626) normalized hepatic triglycerides and serum cholesterol, significantly improved insulin 
resistance (IR), and decreased NAS, predominantly steatosis.  In addition the BA pool reflected 
increases in BA that were agonists to FXR and decreases in levels that were antagonist to the 
FXR (Karpen et al. oral presentation AASLD 2015; Rao et al. 2015). Miethke and colleagues
(2016) found that pharmacological inhibition of the ileal, ASBT (SC-435 the surrogate molecule 
of volixibat), blocked progression of sclerosing cholangitis in mdr2–/– mice. Beneficial effects in 
liver histology in these mice included a reduction in the severity of hepatic fibrosis, a decrease 
which correlated with a reduction of hepatic profibrogenic gene expression. While very 
encouraging, whether or not the findings in this mouse sclerosing cholangitis model can translate 
to histologic improvements in patients with NASH is unknown.
Volixibat, as a potent inhibitor of ASBT, increases BA excretion and facilitates signaling in the 
intestine that regulates serum and hepatic BA concentrations, glucose metabolism, serum 
cholesterol and fatty acid metabolism in the liver.  The combined events resulting from inhibiting 
BA reuptake are hypothesized to have a positive metabolic, anti-inflammatory, anti-steatotic, and 
potentially antifibrotic effect that will lead to a therapeutic benefit for patients with NASH. 
One of the factors contributing to the pathogenesis of NASH is abnormal cholesterol metabolism 
and the accumulation of free cholesterol in the liver. The free cholesterol is directly toxic to 
hepatocytes, which leads to inflammation and fibrosis (Musso et al. 2013). One treatment 
approach is to remove the cholesterol from the liver to decrease and possibly reverse the damage 
to the hepatocytes. This is one of the mechanisms by which SHP626 will treat NASH.
Due to the mechanism of action (MOA), volixibat is under development for the treatment of 
NASH and may also be able to improve the metabolic syndrome that is associated with NASH. 
Volixibat inhibits ASBT therefore BAs are excreted in the feces and this loss forces the liver to 
synthesize new BA which utilizes cholesterol in the liver and serum. Volixibat also has the 
potential to reduce IR, which is considered to be the most common underlying risk factor for the 
development of NASH (Pagano et al. 2002; Sanyal et al. 2001). 
Volixibat was initially being evaluated for its use as an intervention for dyslipidemia.  As a result 
of initial observations in animals that serum low-density lipoprotein cholesterol (LDL-C) and 
total liver cholesterol content could be decreased after administration of volixibat, additional 
work was undertaken to support the safety and tolerability of the drug in healthy volunteers. 
Clinical and non-clinical studies have demonstrated very low systemic exposure across species. 


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Oral administration of volixibat at doses up to 300 mg once daily and 50 mg administered daily 
for 14 days to healthy male subjects was generally safe.  A Phase 1 study revealed that volixibat 
is tolerated at the 10 mg dose for 28 days and that there were trends towards increasing high-
density lipoprotein cholesterol (HDL-C), decreasing LDL-C, and decreasing fasting glucose in 
patients with T2DM (LUM002-101 trial). 
A healthy volunteer study investigating 12 days of varying levels of repeat doses of volixibat has 
provided key pharmacodynamic information for dose selection as measured by the effect of 
volixibat on excreted fecal bile acid (FBA) levels (SHP626-101).  In addition, the study 
investigated safety and tolerability over the dose range that was considered for this Phase 2 
study.
Data from Phase 1 studies support the position that volixibat is basically a non-absorbed drug 
that works locally in the GI tract and results in virtually no systemic exposure. Thus 
pharmacokinetic sampling will not be done in this study.
The current proof of concept (POC) Phase 2 trial will evaluate the safety, tolerability, and 
efficacy of three doses of volixibat  (5, 10, and 20 mg) in adult subjects with NASH. Due to the 
MOA of volixibat, efficacy will be assessed at an interim analysis (IA) by a change of steatosis 
from baseline to Week 24 compared to placebo (PBO).  While the gold standard for 
quantification of steatosis has historically been an invasive liver biopsy, quantitative magnetic 
resonance (MR) imaging–based biomarkers for liver fat have evolved rapidly over the last 
decade, and are increasingly being incorporated into NASH clinical trials.  Both MR 
spectroscopy (S) and MR imaging (I) proton density fat-fraction (PDFF) provide non-invasive 
means of quantifying intrahepatic lipid content (Reeder et al. 2012).  Both techniques have been 
shown to be accurate, reproducible with a low degree of variability in interpretation, cost-
effective and reliable biomarkers of quantitative hepatic fat (Roldan-Valadez et al. 2010; Urdzik 
et al. 2012;  Raptis et al. 2012).  Importantly, studies demonstrate a close correlation with 
steatosis grade histologically (Qayyum et al. 2005; Schwenzer et al. 2009).  
In a study of 51 adult subjects with NAFLD, PDFF correlated well with the grade of histologic 
steatosis, as the mean fat-fraction values of 8.9%, 16.3%, and 25.0% corresponded to histologic 
steatosis grades 1, 2, and 3, respectively (P < .0001) (Permutt et al. 2012). Thus, MRI will be 
utilized to evaluate the degree of steatosis change from baseline in this study during the IA. The 
Mozart trial was a randomized, double-blind, PBO-controlled trial of 50 patients with NASH 
who were randomized to 24 weeks of either ezetimibe or PBO, evaluating the reduction of liver 
fat by MRI-PDFF as well as by histology. Results revealed that compared to histologic non-
responders, histologic responders, defined as a two-point reduction in NAFLD activity score 
(NAS) without worsening fibrosis, had a statistically significant reduction in net MRI-PDFF of 
-4.1% ± 4.9 vs. +0.6% ± 4.1 (P <0.036) with a mean percent change of -29.3% ± 33.0 vs. 
+2.0% ± 24.0 (P < 0.004), respectively (Loomba et al. 2015). Thus, in the current trial during the 
IA, a ≥5% steatosis reduction for an active dose compared to PBO will be a clinically 
meaningful change after 24 weeks of therapy.


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Intrahepatic lipid content of less than 1% is considered to be within the normal range (Springer et 
al. 2015), however, from a study of 2349 people in a general population undergoing MRS, it was 
concluded that a PDFF value of 5.56% represented the upper limit of the normal range, as 
determined from the 95th percentile of PDFF in 345 individuals who were not at increased risk 
for hepatic steatosis (Szczepaniak et al. 2005).  Thus, in the current trial, similar to other NASH 
trials utilizing MR for evaluation, an MRI ≥5% steatosis will be used as an inclusion criterion 
(Loomba et al. 2015).  
1.3
Benefits and Risks
By virtue of volixibat’s ability to inhibit ASBT bile acid reabsorption, there is an increase in BA 
excretion and signaling in the intestine that results in improvements in glucose metabolism and 
changes in cholesterol and fatty acid synthesis in the liver. Recently, HFD fed mice treated with 
an ASBTi (SC-435 a surrogate of SHP626) normalized hepatic triglycerides and serum 
cholesterol, significantly improved IR, and decreased NAS (predominantly steatosis). In 
addition, these HFD-fed mice did not gain weight when treated with SC-435, in spite of 
consuming increased calories. Finally, the BA pool in these mice changed to predominantly FXR 
agonist (Karpen et al. oral presentation AASLD 2015; Rao et al. 2015).
These metabolic actions and preclinical results may prove to be clinically relevant to subjects 
with NASH.
NASH has recently received considerable attention as awareness of the problem of liver damage 
and prevalence of the disorder has increased, paralleling the obesity epidemic.  Consequences of 
liver damage are detrimental and can lead to liver failure, hepatocellular carcinoma, and the need 
for liver transplantation. There is no currently approved medical therapy for NASH. The large 
unmet medical need and the increased medical resource burden have led to the search for 
potential therapies to treat NASH.
Nonclinical testing established that the no observed adverse effect level (NOAEL) for volixibat 
in rats and dogs following 13 weeks of once-daily administration were 1000 and 500 mg/kg/day, 
respectively. Similarly, testing confirmed that the NOAEL for volixibat in a 6-month study in 
rats and a 9-month study in dogs were 1000 and 500 mg/kg/day, respectively. In both cases, 
these were the highest doses tested. Genotoxicity testing has yielded negative findings. 
Volixibat is minimally absorbed. The pharmacokinetic profiles performed in clinical studies 
completed to date repeatedly suggest negligible systemic exposure. Furthermore, there has been 
no observation of clinically relevant changes in fat absorption parameters such as those related to 
fat-soluble vitamins.
The most frequent TEAEs in the Phase 1 studies were GI and were considered mechanism-based 
due to elevated BA concentrations in the colon. The percentage of subjects reporting at least 1 
TEAE in the GI disorders SOC generally increased with an increasing volixibat dose level (Part 
1 Study TDU10632 and Study LUM002-101). Most TEAEs were mild in intensity, and none 
were assessed as severe.


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In the multiple dose studies, the most commonly reported TEAEs in subjects (both healthy and 
with T2DM) who received volixibat for the longest duration of 28 days in Study LUM002-101 
included diarrhea and abdominal pain. The most commonly reported TEAEs in subjects 
receiving 50 mg volixibat for 14 days (part 3 Study TDR10633) were diarrhea and GI pain.
Overall, there were 2 SAEs (ALT increased and retinal detachment), both of which led to the 
discontinuation of volixibat. In part 3 of the initial Phase 1 study (TDU10633), 1 subject dosed 
with 50 mg volixibat  for 13 days was withdrawn from the study due to a mild TEAE (which 
became a SAE due to prolonged hospitalization) of ALT increased that was considered related to 
volixibat . The subject’s ALT level returned to normal after discontinuation of volixibat. A 
second subject dosed with 10 mg volixibat for 12 days in Study LUM002-101 reported a 
moderate SAE of ablation of the retina with a bleed in the vitreous body of the right eye that was 
considered not related to volixibat.
Overall, 3 subjects, all dosed with 5 mg volixibat in Study LUM002-101, discontinued volixibat 
due to non-serious TEAEs: 1 due to a related TEAE of mild hemorrhagic diarrhea, 1 due to an 
unrelated TEAE of moderate Epstein-Barr virus infection, and 1 due to mild related TEAEs of 
diarrhea and anal erosion.
Overall, the observed AEs attributable to volixibat have been self-limited as would be expected 
given the local MOA of ASBT inhibition in the terminal ileum. Generally, among subjects who 
experienced GI TEAEs, the events have been mild and diminished over the course of treatment. 
Please refer to the investigator’s brochure for additional information.
Volixibat is a novel drug candidate, demonstrating limited systemic exposure across species with 
the potential to affect important metabolic pathways associated with NASH. The overall safety, 
tolerability, and preliminary activity of volixibat in available clinical trials suggest that further 
investigation is warranted and that there is a positive benefit to risk profile.
Always refer to the latest version of the Volixibat Potassium (SHP626) Investigator’s Brochure 
for the overall risk/benefit assessment and the most accurate and current information regarding 
the drug metabolism, pharmacokinetics, efficacy, and safety of volixibat. 
See Appendix 1 for protocol history, including all amendments.
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Currently there is no approved medication for the treatment of NASH. Volixibat is under 
development for the treatment of NASH based on its MOA and is supported by nonclinical and 
Phase 1 data.  This is a Phase 2, 48-week, dose-finding study to examine the efficacy, 
tolerability, and safety of volixibat in adults with NASH.


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2.2
Study Objectives
2.2.1
Primary Objective
To evaluate the effect of volixibat compared to PBO on liver histology 
2.2.2
Secondary Objectives

To evaluate the safety and tolerability of volixibat  compared to PBO 

To evaluate the effect of volixibat compared to PBO on hepatic steatosis  (measured by 
MRI)

To evaluate the effect of volixibat  compared to PBO on liver histology (measured by 
individual NAS components and fibrosis stage)

To evaluate the effect of volixibat compared to PBO on liver histology (measured by 
NASH resolution without worsening fibrosis)

To evaluate the effect of volixibat compared to PBO on serum liver-related biochemistry 

To evaluate the effect of volixibat compared to PBO on metabolic indicators (glucose, 
insulin, hemoglobin A1c [HbA1c]) 

To evaluate the effect of volixibat compared to PBO on serum lipids (cholesterol, HDL-
C, LDL-C, triglycerides) 
2.2.3
Exploratory Objectives

To explore the effect of volixibat compared to PBO on liver histology (measured by 
individual SAF scoring components: Steatosis (S), Activity (A), and Fibrosis (F)) 

To explore the effect of volixibat compared to PBO on anthropometric measures (body 
weight, body mass index (BMI), waist circumference and waist-hip ratio) 

To explore the effect of volixibat compared to PBO on homeostasis model assessment-IR 
(HOMA-IR) and HOMA-beta cell function (HOMA-%B) in subjects with T2DM 

To explore the effect of volixibat compared to PBO on BA synthesis (7-alpha-hydroxy-4-
cholesten-3-one [C4])

To explore the effect of volixibat on patient-reported health-related quality of life 
(HRQoL) and overall health status.
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This study will be a Phase 2, 48-week, multicenter, double-blind, randomized, PBO-controlled, 
parallel group, proof of concept, dose-finding study, with one IA after at least 80 subjects have 
24 weeks of treatment.  There will be 3 active arms of volixibat (5, 10 and 20 mg) and a PBO 
arm. Subjects will be randomized to receive one of three doses of volixibat (5, 10, or 20 mg once 
daily (QD) or PBO in a 1:1:1:1 ratio such that a target of 266 subjects is achieved (221x1.2 is


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approximately 266).  The 221 subjects include 201 subjects for the three arms analyzed at 48 
weeks plus an additional 20 subjects to account for one dose dropped at the IA. Therefore, 
approximately 266 (accounts for 20% of 221 dropping out) subjects will be randomized if three 
arms (2 SHP626 and 1 PBO) continue; 208 (accounts for 20% of dropouts) subjects are needed if 
2 SHP626 doses are dropped at the IA. Subjects with fibrosis stages F0 through F3 may be 
enrolled, but the number of F0 subjects will be capped at 81 if 1 dose is dropped after the IA and 
at 62 if 2 doses are dropped after the IA. Attempt will be made to perform the IA before any 
subject has had their 48-week post-treatment liver biopsy, although this will be dependent upon 
the rate of enrollment and dropout.
There will be up to 3 periods (screening, treatment, and follow-up) and an IA. The duration of 
the Treatment period will be 48 weeks, with an IA at Week 24.  Depending on the results of the 
IA, the study may be terminated or the randomization to one or more doses will be stopped.  The 
follow-up period will be 4 weeks after last dose.  Subjects will be expected to visit the study 
center at least 10 times.
The IA will be conducted by an independent data monitoring committee (DMC) after at least 
80 subjects have received 24 weeks of treatment. Study enrollment will be paused after 
92 subjects have been randomized. The IA will evaluate the safety, tolerability and efficacy of 3 
doses of volixibat each compared to PBO. 
Once decisions as to dose elimination are made, study enrollment will be reopened and 
additional sites may be added. Subjects recruited into the study prior to the IA will continue with 
the same dosing regimen for the duration of the planned study participation. Subjects recruited
into the study after completion of the IA will be randomized evenly to the remaining dose groups 
(noted by “[1 or 2]… Dose TBD” in Figure 1) or PBO group by IRT. Thus, depending on the 
results from the IA, the study may be terminated, or one or more doses of volixibat will be 
discontinued. If the study is not terminated, subjects will receive a total of 48 weeks of 
investigational product (IP).
The study will be conducted over 3 periods: screening (8 weeks), treatment (48 weeks), and 
follow-up (4 weeks), with an IA at 24 weeks as outlined in Figure 1.  


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Figure 1
Study Design Flow Chart
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 364 days. The 
last visit is an in-clinic safety follow-up visit. The study will be completed in approximately 4 
years.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment.  Please note that this includes the follow-up visit.  The 
Study Completion Date is used to ascertain timing for study results posting and reporting.
3.3
Sites and Regions
This study will be conducted at approximately 60 to 80 clinical sites in the USA, Canada, and 
EU.
4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.


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1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.
2. Ability to voluntarily provide written, signed, and dated (personally or via a legally 
authorized representative, as applicable) informed consent to participate in the study.
3. Age 18-80 years inclusive. This inclusion criterion will only be assessed at the first screening 
visit.
4. Male, or non-pregnant, non-lactating female, who is sexually active and who agrees to 
comply with the contraceptive requirements of the protocol, or females of non-childbearing 
potential.  Males and females of child-bearing potential who are sexually active must agree to 
use acceptable contraception during the study and for 30 days following the last dose of the 
IP as described in Section 4.4.
5. Presence of ≥5% steatosis on screening MRI from a centrally read radiologist performed 
either during the screening period or within 6 months prior to the first visit.
6. Histologic confirmation of NASH without cirrhosis (F0-F3) from a centrally read liver 
biopsy performed either during the screening period or within 6 months prior to the first visit 
with a NAS of ≥4 with a score of at least 1 in each component (steatosis, lobular 
inflammation, and hepatocyte ballooning).
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Presence of or history of cirrhosis or evidence of decompensated liver disease (ie, ascites, 
variceal bleeding, etc.) or hepatocellular carcinoma.
2. History or presence of other concomitant liver disease as assessed by the investigator or 
determined by laboratory findings including, but not limited to: active hepatitis B virus 
(HBV) infection (hepatitis B surface antigen [HBsAg] positive and/or HBVDNA positive; 
subjects who are hepatitis B core antibody [HBcAb] positive may be eligible as long as 
HBsAg is negative and HBVDNA is nondetectable), active hepatitis C virus (HCV) infection 
(prior exposure to HCV [defined as HCVAb positive] without a current or prior history of a 
detectable HCVRNA) may be eligible, alcoholic liver disease, proven autoimmune hepatitis, 
primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, 
Wilson’s disease, alpha-1 antitrypsin deficiency, bile duct obstruction, liver primary or 
metastatic cancer.
3. Current or recurrent disease that could affect the action, absorption, disposition, or laboratory 
assessment of the investigational product (IP) (including bile salt metabolism in the intestine) 
eg, uncontrolled inflammatory bowel disease, uncontrolled celiac disease, gastric bypass 
procedures (gastric lap band or gastric sleeve is acceptable), ileal or ileocecal resection, 
uncontrolled irritable bowel syndrome with predominant diarrhea, or history of chronic 
diarrhea or loose stools of any etiology.
4. Weight change ≥5% after qualifying liver biopsy and/or MRI performed. If the subject had a 
liver biopsy and/or MRI within 6 months of screening, but experienced a weight change of 


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≥5% since the date of liver biopsy and/or MRI, the liver biopsy and/or MRI must be repeated 
at screening.
5. Contraindications to MRI (eg, claustrophobia, coronary stents, coronary implantable devices, 
girth, etc.). Stents or other devices may be allowed, at the investigator’s discretion, if they do 
not interfere with the functioning of the MRI machine. 
6. Current or relevant history of physical or psychiatric illness, any medical disorder that may 
require treatment or make the subject unlikely to complete the study.
7. Treatment with Vitamin E, thiazolidinediones (TZD), or glucagon-like peptide-1 receptor 
agonists (GLP-1 RA) unless subject on a stable dose for 6 months prior to qualifying liver 
biopsy and not initiated after qualifying liver biopsy and will continue the same dosing 
regimen throughout study participation (refer to Section 5.2.1, Permitted Treatment). 
8. Uncontrolled diabetes defined as HbA1c of ≥9.5% within 60 days prior to enrollment. 
9. Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations) that could affect the action, absorption, or disposition of the IP, or clinical or 
laboratory assessment.  (Current use is defined as use within 14 days of screening).  Patients 
currently taking insulin will not be excluded; however, they must be on a stable dose for at 
least 30 days prior to screening, or a sliding scale of insulin is allowed as long as the subject's 
HbA1c remains < 9.5%. Also refer to Section 5.2.2, Prohibited Treatment.
10. Use of drugs, herbs or supplements historically associated with causing or worsening 
NAFLD/NASH for less than 6 months prior to liver biopsy, or initiated any time after liver 
biopsy performed, including the use of total parenteral nutrition (TPN). Also refer to Section 
5.2.2, Prohibited Treatment.
11. Serum AST >7 times upper limit of normal (ULN) at screening.
12. Serum ALT >7 times ULN at screening.
13. Elevated serum creatinine ≥2.0 mg/dL.
14. International normalized ratio (INR) >1.3
15. TB ≥2.0 x ULN at screening (Except for documented Gilbert’s syndrome with bilirubin 
levels 20 µmol/L to 90 µmol/L (1.2 to 5.3 mg/dL) and with a ratio of 
unconjugated/conjugated bilirubin that is commensurately higher).
16. Platelet count <130 × 109/L
17. Medical history of impaired hemostasis or use of anticoagulant medication (use of 
antiplatelet medications, such as low-dose, ie 81 mg, aspirin (ASA) or clopidogrel (Plavix) 
will be allowed).
18. Uncontrolled thyroid disease.
19. Type 1 diabetes mellitus.
20. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or 
any of the stated ingredients.


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21. Known history of alcohol or other substance abuse within the last year or at any time during 
the study based on investigator’s discretion.  Refer to Section 7.2.3.8, Drug and Alcohol 
screening. Weekly alcohol intake greater than 21 grams/day for males and 14 grams/day for 
females on average or inability to reliably quantify alcohol consumption based on 
investigator’s judgment.
22. Within 6 months of MRI and liver biopsy:

Have used any IP

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study
23. Inability to safely obtain a liver biopsy.
24. Females who are pregnant, planning to become pregnant, or are breastfeeding, or males who 
are planning to father a child during study participation.
25. The anticipated need for a surgical procedure during the study that could interfere with the 
treatment. 
26. Known positivity for human immunodeficiency virus (HIV) infection.
27. Cancer within 5 years of screening, except for basal or squamous cell carcinoma of the skin 
or in situ cervical carcinoma that has been treated with no evidence of recurrence.
28. History of noncompliance with medical regimens, unreliability, mental instability or 
incompetence that could compromise the validity of informed consent or lead to 
noncompliance with the study protocol.
29. Any other conditions or abnormalities which, in the opinion of the investigator, may 
compromise the safety of the subject, or interfere with the subject participating.
30. Subject is currently enrolled in this study at any study site (unless the subject is transferring 
to another qualified study site with prior sponsor approval).
31. Subjects who are employees at the unit of the investigational site that is conducting the study.
4.3
Restrictions 
Subjects must adhere to the following restrictions for the duration of the study:

Subjects must remain compliant with inclusion/exclusion criteria.

Subjects should not become pregnant, father a child, or nurse/breastfeed a baby. 

Subjects should be encouraged to adhere to the same exercise routine and a healthy diet 
throughout the study.


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4.4
Reproductive Potential
4.4.1
Female Contraception
Sexually active females of child-bearing potential should use an acceptable form of 
contraception. Females of child-bearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 30 days following the last dose of the IP. If 
hormonal contraceptives are used they should be administered according to the package insert. 
Female subjects should be either:

Post-menopausal (12 consecutive months of spontaneous amenorrhea and age 51 years)

Surgically sterile (having undergone one of the following surgical acts:  hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of child-bearing potential with a negative urine and/or serum -human chorionic 
gonadotropin (-HCG) pregnancy test each study visit. Females of child-bearing 
potential must agree to abstain from sexual activity that could result in pregnancy or 
agree to use acceptable methods of highly-effective contraception.
Acceptable methods of highly-effective contraception (ie, methods that result in a failure rate of 
<1% per year) are:

Combined (estrogen and progestogen containing) hormonal contraceptives associated 
with inhibition of ovulation (oral, intravaginal, transdermal) stabilized for at least 30 days 
prior to the screening visit (Visit 1) plus a barrier method (eg, condoms or diaphragms 
with spermicidal gel or foam)

Progestogen-only hormonal contraception associated with inhibition of ovulation plus a 
barrier method 

Intrauterine device (IUD) 

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Male sterilization/vasectomized partner

True abstinence: When this is in line with the preferred and usual lifestyle of the subject 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], 
declaration of abstinence for the duration of exposure to IMP, and withdrawal are not 
acceptable methods of contraception.)


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4.4.2
Male Contraception
Contraception is required for all sexually-active male subjects and their partners. All male 
subjects (including those who are sterile) agree not to donate sperm, and to use 1 of the following 
approved methods of contraception from the baseline visit on Day 0 until 30 days following 
study discharge:

Male condom with spermicide

Sterile sexual partner

Intrauterine device with spermicide (use by female sexual partner)

Female condom with spermicide (use by female sexual partner)

Contraceptive sponge with spermicide (use by female sexual partner)

Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with spermicide, or a 
cervical cap with spermicide) (use by female sexual partner)

Oral, implantable, transdermal, or injectable hormonal contraceptive (use by female 
sexual partner) plus a barrier method
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety).  The investigator is 
encouraged to discuss withdrawal of a subject from the IP with the CRO Medical Monitor when 
possible.
If the IP is discontinued, regardless of the reason, the evaluations listed for both Visit 9/end of 
study (EOS) and Visit 10/Follow-up, are to be performed as completely as possible; however, the 
EOS liver biopsy will not be required for patients discontinuing prior to Week 44. 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
source documents.  The reason for termination, date of stopping the IP, and the total amount of 
the IP taken must be recorded in the electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Medically important events that in the opinion of the investigator, medical monitor or sponsor 
would compromise the subject’s ability to safely continue in the study may result in withdrawal 
of the subject from the study.  Subjects who become pregnant or demonstrate disease 
progression, defined as the development of signs or symptoms of hepatic decompensation (ie, 


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esophageal variceal hemorrhage, hepatic encephalopathy, ascites, or hepatocellular carcinoma), 
will be withdrawn from the study and followed as set forth in the protocol.
4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the eCRF.  If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the eCRF.  
Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol violation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Death

Screen failure 

Noncompliance with study drug

Physician decision

Pregnancy

Progressive disease (refer to Section 4.5.1)

Study terminated by sponsor

Other - If “Other” is selected, the investigator must specify on the eCRF 
4.5.3
Subjects Lost to Follow-up Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact clinic visit.  At least 1 of these documented 
attempts must include a written communication sent to the subject’s last known address via 
courier or mail (with an acknowledgement of receipt request) asking that they return to the site 
for final safety evaluations and return any unused IP.


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4.5.4
Safety-related Stopping Rules
Refer to Appendix 4 and Appendix 5 for criteria to assess severity of liver-related AEs and 
stopping rules for liver-related blood tests, respectively.
An urgent safety review will be conducted within 7 days by the sponsor and in consultation with 
the DMC if 1 or more of the following criteria are met:

Death that is considered related to the study drug

Two SAEs of similar type (defined as same or similar Medical Dictionary for Regulatory 
Activities (MedDRA) higher level group code), and considered related to the study drug.
The urgent review will be performed by a sponsor safety review group, which will include the 
study Global Safety Lead (GSL) and the Global Drug Safety (GDS) therapeutic area (TA) Head, 
and in consultation with the DMC. The GDS TA Head, not the GSL involved in the study, may 
be unblinded as part of this urgent safety review, if required. Following the sponsor’s review of 
safety data and consultation with the DMC, one of the following actions will be taken with 
respect to study status:

Continue study with protocol unchanged

Continue study with modifications to the protocol

Terminate study
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment.
5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to signing informed consent at the screening visit (Visit 1) and through the 
final study contact (including protocol-defined follow-up period) must be recorded on the 
appropriate eCRF page.
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
and behavioral treatment, non-pharmacological treatment, such as psychotherapy, as 
appropriate), received within 30 days of the date of first dose of the IP. Prior treatment 
information must be recorded on the appropriate eCRF page.


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5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of the IP 
and the end of the follow-up period, inclusive.  Concomitant treatment information must be 
recorded on the appropriate eCRF page.
5.2.1
Permitted Treatment
Medications and supplements including but not limited to vitamin E, betaine, s-adenosyl-l-
methionine, ursodeoxycholic acid, milk thistle, gemfibrozil, anti-TNF therapies, probiotics 
biguanides (metformin), thiazolidinediones (TZDs) and GLP-1 RAs that have been used to treat 
NAFLD/NASH are allowed during the course of the study if the subject has been on a stable 
dosing regimen (ie, same dose and frequency in the previous 6 months prior to the qualifying 
liver biopsy and not initiated after qualifying liver biopsy) and will continue this dosing regimen 
throughout study participation. Use of antiplatelet medications is also allowed.  The investigator 
must contact the CRO medical monitor then the Shire GCDL to discuss any changes to 
concomitant medications that may impact the study.
5.2.2
Prohibited Treatment
The following list of prohibited drugs cannot have been taken for more than 2 weeks within the 6 
months prior to randomization and are excluded while on study.

Systemic Glucocorticoids

Tamoxifen

Amiodarone

Methotrexate

Alcohol (see Section 4.2)

Griseofulvin

Total parenteral nutrition

Obeticholic acid

Valproate

Nucleoside Analogues (except 
acyclovir)

Tetracycline (high dose; >1g)

Estrogens at doses greater than 2 
mg QD used for hormone 
replacement

Anabolic steroids

Bile acid sequestrants such as 
cholestyramine or colestipol

Any other known hepatotoxins 
including over-the counter 
therapies and herbal therapies 
such as germander, chaparral and 
ma-huang.
This is not a comprehensive list. Treatments not listed above are generally considered allowable, 
unless considered a potential hepatotoxin.  Antidiarrheals will be allowed at the discretion of the 
investigator, with the exception of BA sequestrants.


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is volixibat potassium (volixibat), which will be provided in 5, 10 and 20 mg 
capsule form.  Additional information is provided in the current Volixibat Potassium (SHP626) 
Investigator’s Brochure.
The reference/comparator product is an identical PBO which will be provided in capsule form.  
6.1.1
Blinding the Treatment Assignment
The IP will be supplied as double-blind blister packs. The actual double-blind treatment given to 
individual subjects is determined by a randomization schedule which will be automatically 
assigned by the interactive response technology (IRT). Placebo capsules, which exactly match 
the IP, will be used in the blister packs to provide the same number and size capsules for each of 
the doses within the treatment groups.
6.2
Administration of Investigational Product(s)
All IP and supplies will be provided by Shire or its designee. At each visit, subjects will be 
supplied with enough IP to last until the subsequent visit. Lost or damaged IP will be replaced as 
needed. Volixibat will be supplied to the clinical research center (CRC) as powder in capsule. 
Volixibat will be supplied in identical capsules in strengths of 5, 10, and 20 mg (with matched 
PBO). 
6.2.1
Interactive Response Technology for Investigational Product Management
IRT will be used for the following investigational tasks:

Randomization

Supply management

Inventory management and supply ordering

Expiration tracking

Returns

Emergency unblinding
6.2.2
Allocation of Subjects to Treatment 
This is a double-blind, PBO-controlled study. The actual treatment given to individual subjects is 
determined by a randomization schedule.


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Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to the IP allocated to the 
subject, once eligibility has been determined.  
Individual subject treatment is automatically assigned by the IRT.
Once a randomization number/unique identifier has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study.  If a randomization number/unique
identifier is allocated incorrectly, the clinical research associate (CRA)/study monitor must be 
notified as soon as the error is discovered. 
IP packaging identification numbers, separate from randomization numbers/unique identifiers, 
may also be assigned to subjects for specific treatment assignment as dictated by the study.  In 
these cases, the same IP packing identification number may not be assigned to more than 1 
subject.
Subjects will be equally allocated to all volixibat doses and PBO if their randomization precedes 
the 24 week IA. If a subject’s randomization occurs after the 24 week IA, subjects will be 
equally allocated to all remaining volixibat doses (determined based on the results of the IA) and 
PBO. The randomization will be stratified by baseline T2DM and NAS ≥6 or NAS = {4,5}. 
Subjects with fibrosis stages F0 through F3 may be enrolled, but the number of F0 subjects will 
be capped at 81 if 1 dose is dropped after the interim analysis and at 62 if 2 doses are dropped.
6.2.3
Dosing
All doses of volixibat or matching PBO will be administered orally as a capsule in a double-
blinded fashion.  The first dose of IP for each subject will be administered in the clinic. The dose 
will be administered with 240 mL of water and should be given 30 minutes prior to the first meal 
of the day containing approximately 10-20 grams of fat. All assessments should be completed at 
least 30 minutes prior to administration of the IP. The subject should make all attempts to 
consistently take the IP around the same time each day.  If a dose is missed at the normally 
scheduled time, the subject can make up the dose that day as long as no more than 1 dose is 
taken in a 10-hour period.
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the IP is required for further treatment of the subject. The investigator 
should contact the CRO medical monitor and the Shire GCDL at the same time and as soon as 
possible after the investigator has been unblinded.  
In the event that the treatment assignment is broken, the date and the signature of the person who 
broke the code are to be recorded in the source documents and the IRT, and the reason for 


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breaking the code will be recorded in the source documents and the clinical database.  Upon 
breaking the blind, the subject is withdrawn from the study, but should be followed up for safety 
purposes. Any code-breaks that occur must be reported to the CRO medical monitor.  Code-
break information is held by the pharmacist/designated person at the site and by the CRO 
medical monitor for the study or designee.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the IP container.
All IP is labeled with a minimum of the protocol number, medication identification number, 
dosage form (including product name and quantity in pack), directions for use, storage 
conditions, expiry date (if applicable), batch number and/or packaging reference, the statements 
‘For clinical trial use only’, and/or ‘CAUTION: New Drug - Limited by Federal (or USA) Law 
to Investigational Use’, ‘Keep out of reach of children’, and the sponsor's name and address. Any 
additional labeling requirements for participating countries will also be included on the label.
Additional labels may, on a case-by-case basis, be applied to the IP in order to satisfy local or 
institutional requirements, but must not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
The sponsor or designee will provide the IP for this study. The IP is packaged in the following 
labeled containers:

Volixibat 5 mg capsules

Volixibat 10 mg capsules

Volixibat 20 mg capsules

Volixibat PBO capsules


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6.3.3
Storage
The investigator has overall responsibility for ensuring that the IP is stored in a secure, limited-
access location.  Limited responsibility may be delegated to the pharmacy or member of the 
study team, but this delegation must be documented.  
IPs are distributed by the pharmacy or nominated member of the study team. The 
pharmacist/nominated team member will enter the unique subject identifier on the IP labels as 
they are distributed. 
All IP must be stored at the clinic at 20 - 25oC (68 - 77oF); excursions are allowed between 15 -
30oC (59 - 86oF).
IPs must be stored in accordance with labeled storage conditions.  Temperature monitoring is 
required at the storage location to ensure that the IP is maintained within an established 
temperature range. The investigator is responsible for ensuring that the temperature is monitored 
throughout the duration of the study and that records are maintained; the temperature should be 
monitored continuously by using either an in-house system, a mechanical recording device such 
as a calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.  Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording.  The sponsor must be notified immediately upon discovery of any excursion below 
15oC (59oF) or above 30oC (86oF); these excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the IP and will 
provide supportive documentation as necessary.  Under no circumstances should the product be 
dispensed to subjects until the impact has been determined and the product is deemed appropriate 
for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the IP 
that could affect the integrity of the product(s), eg, fumigation of a storage room or a change in 
storage location.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the IP to carry out this protocol for the 
agreed number of subjects.  The investigator or designee will acknowledge receipt of the IP, 
documenting shipment content and condition.  Accurate records of all IP dispensed, used, 
returned, and/or destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing the IP.  Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator.  This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the IP only to subjects included in this study 


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following the procedures set out in the study protocol.  Each subject will be given only the IP 
carrying his/her treatment assignment. All dispensed IP will be documented on the eCRFs and/or 
other IP record. The investigator is responsible to ensure the retrieval of all study supplies from 
subjects.
No IP stock or returned inventory from a Shire-sponsored study may be removed from the site 
where originally shipped without prior knowledge and consent by the sponsor.  If such transfer is 
authorized by the sponsor, all applicable local, state, and national laws must be adhered to for the 
transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.  The site must ensure that the accountability and destruction 
records are complete, accurate, and ready for verification at each monitoring visit.
The process for return and destruction of IP must be determined and documented during the 
study start-up phase.
With the written agreement by the sponsor of the site’s IP destruction procedures, all unused 
stock, subject returned IP, and empty/used IP packaging may be destroyed at the site or a local 
facility on an ongoing basis throughout the study and at the end of the study following 
verification of accountability by the CRA/study monitor. In this case, destruction records 
identifying what was destroyed, when, how, and by whom, must be obtained with copies 
provided to the sponsor. Destruction of IP must be in accordance with local, state, and national 
laws.
Alternatively, in the absence of written agreement by the sponsor of the site’s IP destruction 
procedures, all unused stock, subject-returned IP, and empty/used IP packaging may be required 
to be sent to a nominated contractor on behalf of the sponsor for IP destruction on an ongoing 
basis throughout the study and at the end of the study. IP being returned to the sponsor’s 
designated contractors also must be counted and verified by clinical site personnel and the 
CRA/study monitor. For unused supplies where the original supplied tamper-evident feature is 
verified as intact, the tamper-evident feature must not be broken and the labeled amount is to be 
documented in lieu of counting. Shipment return forms, when used, must be signed prior to 
shipment from the site. Validated electronic return systems (ie, IRT) do not require a shipment 
form. Returned IP must be packed in a tamper-evident manner to ensure product integrity. 
Contact the sponsor for authorization to return any IP prior to shipment. Shipment of all returned 
IP must comply with local, state, and national laws.
6.5
Subject Compliance
Subjects must be instructed to bring their unused IP and empty/used IP packaging to every visit. 
Drug accountability must be assessed at the container/packaging level for unused IP that is 
contained within the original tamper-evident sealed container (eg, blister pack) or at the 
individual count level for opened containers/packaging. The pharmacist/nominated person will 
record details on the drug accountability form.


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7.
STUDY PROCEDURES
7.1
Study Schedule
This study will consist of a screening period of up to 56 days (the screening period may be 
minimally extended under special circumstances only with the explicit approval of the medical 
monitor), a 48-week Treatment period, and a Follow-up visit 4 weeks after treatment ends. A 
detailed display of all study procedures is provided in Table 1. 
Patients will be assessed according to the following schedule:

Screening – Visit 1  (Weeks -8 to 0 [Day -56 to Day -1])

Baseline – Visit 2  (Week 0 [Day 0])

Treatment and Assessments – Visits 3 through 9 (Week 2 through Week 48)

Follow-up – Visit 10 (Week 52, 4 weeks after completion of dosing) 
7.1.1
Screening (Visit 1) 
Screening procedures must be completed within 56 days prior to randomization for the first dose 
of the IP. The screening period may be minimally extended under special circumstances only 
with the explicit approval of the medical monitor. At the screening visit, considered Visit 1 
(Week -8 to 0, Day -56 to -1), all screening assessments and procedures are to be performed by 
the principal investigator or a qualified designee. See Table 1 for a complete list of screening 
procedures to be performed.
Written, signed, and dated informed consent from the subject prior to the performance of any 
study-related procedures must be obtained by the principal investigator or a designee. A copy of 
the signed informed consent form must be given to the subject for their records.
The following screening procedures should be assessed at the beginning of the visit window, 
preferably between Day -56 and Day -49: inclusion/exclusion criteria, collection of subject 
information (demographics, medical and medication history AEs, and concomitant medications), 
a physical examination including vital signs, height, weight, and waist/hip measurements; 
collection of blood and urine samples for screening and safety assessments, performance of an 
electrocardiogram (ECG), and scheduling of MRI and liver biopsy. MRI and liver biopsy (if one 
has not been completed in the previous 6 months) should be performed with sufficient time to 
ensure results are received prior to the baseline visit. 
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered the 
IP. A subject who had been designated a screen failure may be re-screened up to one time. 
However, re-screened subjects must begin the screening procedure again, must be re-consented,


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and will be assigned a new subject number. Additionally, a subject’s abnormal screening lab 
results may be repeated once for confirmation before designating a subject as a screen failure.
An investigative site may provide additional liver biopsy tissue to the central reader to be 
evaluated when the following criteria are met: 1.) the subject qualifies for the study on all 
inclusion/exclusion parameters except for liver histology, and 2.) the investigator's clinical 
assessment of the subject's local liver histology differs from that of the centrally read results, and 
3.) the request to provide more tissue to the central reader for a second read must be requested 
before the patient is declared a screen failure. Any additional tissue samples provided must be 
read by the central reader and the central reader determines the final histological assessment.
7.1.2
Baseline (Visit 2)
Following the screening visit, subjects will return to the clinic within 56 days for Visit 2, 
(considered Week 0, Day 0), for baseline assessments including review of the 
inclusion/exclusion criteria, adverse events, and concomitant medications; physical examination 
with vital signs, weight, and waist/hip measurements; ECG; collection of blood and urine 
samples; stool assessment; and completion of the patient-reported outcome (PRO) EuroQol-5 
Dimension-5 Level Questionnaire (EQ-5D-5L) survey. After completion of these assessments, 
subjects are randomized using Interactive Response Technology (IRT) to 1 of 4 treatment arms 
receiving volixibat 5 mg, 10 mg, or 20 mg, or PBO before the IA and then to 1 of the remaining 
arms after the IA. The initial supply of study drug is dispensed to ensure adequate daily dosing 
until the next scheduled study visit.
7.1.3
Treatment and Assessment Period (Visits 3 through 9/EOS) 
During the 48 weeks of double-blind treatment, 7 clinic visits are scheduled to occur as follows:

Visit 3 - Week 2, Day 14 (+/- 3 days)

Visit 4 - Week 4, Day 28 (+/- 3 days)

Visit 5 - Week 8, Day 56 (+/- 5 days)

Visit 6 - Week 12, Day 84 (+/- 5 days)

Visit 7 - Week 24, Day 168 (+/- 7 days) – Interim Analysis

Visit 8 - Week 36, Day 252 (+/- 7 days)

Visit 9 - Week 48, Day 336 (+/- 7 days) – End of Study
Subjects are reminded not to eat and not to take their study drug on the day of scheduled study 
visits prior to completion of assessments. They should bring their study drug with them to the 
visit. All assessments should be completed at least 30 minutes prior to administration of the IP.
IP should be taken 30 minutes prior to the first meal of the day containing approximately 10-20 
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The Schedule of Assessments provided in Table 1 details the procedures to be completed at each 
visit. All Treatment visits (3 through 9) will include weight and waist/hip measurements, 
assessment of vital signs, and blood sampling for completion of biochemistry, hematology, 
serum glucose, lipid panel, HbA1c, and serum liver-related blood tests. At all visits, adverse 
events, and concomitant medications will be collected for all subjects, and female subjects of 
childbearing potential will have a urine pregnancy test. Subjects will return containers of unused 
study drug for assessment of accountability and compliance which will be documented in the 
IRT. New supplies of study drug will be dispensed at Visits 3 through 8. 
Additional assessments will also occur less frequently during the Treatment Period for vitamin 
A, vitamin D, vitamin E, vitamin K via PT/INR, insulin, thyroid testing, urinalysis, ECG, 
physical examinations, stool assessment, and completion of the EQ-5D-5L. 
An MRI will be repeated at Visit 7 for the 24-week IA and at Visit 9 (Week 48) for all subjects. 
A final liver biopsy will be performed at Visit 9 (Week 48) for all subjects unless a subject 
discontinues prior to Week 44, in which case the EOS liver biopsy is not required.
Sites that have supplied local slides for central reading for subject eligibility at Screening must 
also provide local liver histology slides for the subject to be centrally read at for the Week 48
EOS liver biopsy.  The central reader will provide the final liver histology assessment for Week 
48.
7.1.4
Follow-up (Visit 10)
The follow-up period for this protocol is 4 weeks after the last dose of study drug with a final 
Follow-up visit scheduled for Week 52. Procedures to be completed at this final visit include 
physical examination, weight, waist/hip measurements, vital signs, samples for biochemistry and 
hematology, serum glucose, lipid panel, HbA1c, serum liver-related blood tests, insulin, thyroid 
testing, stool assessment, and urine pregnancy test (for women of childbearing potential). 
Adverse events and concomitant medications will be recorded. All AEs and SAEs that are not 
resolved at the time of this contact will be followed to closure (see Section 8.1).
7.1.5
Additional Care of Subjects after the Study
No after care is planned for this study.
7.2
Study Evaluations and Procedures
All assessments and procedures are to be performed by the Investigator or a qualified designee 
who has been trained in the protocol. Assessments are to be performed according to the 
schedules shown in Table 1. If a subject terminates the study early, the CRC will make 
reasonable effort to perform the EOS and safety follow-up assessments and procedures for the 
subject’s safety and well-being.


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7.2.1
Demographic and Other Baseline Characteristics
Demographic details will be obtained at screening and recorded on the eCRF. Data collected will 
include age, gender, ethnicity, height, and weight.
7.2.2
Efficacy
7.2.2.1
Liver Biopsy
Liver biopsies will provide histologic data for confirmation of the diagnosis of NASH, 
assessment and grading of NASH activity, and scoring of steatosis, lobular inflammation, 
ballooning, as well as fibrosis and additional features (see Appendix 2 and Laboratory Manual 
for additional information). 
7.2.2.2
MRI
The presence of ≥5% steatosis on screening MRI from a centrally read radiologist will be 
performed either during the screening period or within 6 months prior to the first visit. Steatosis 
is assessed by MRI hepatic fat fraction.  The Week 24 MRI will be conducted for subjects in the 
IA set only.
7.2.3
Safety
7.2.3.1
Medical History and Medications 
Medical history including important medical events and concomitant medication and illnesses 
will be obtained at screening and will be recorded on the eCRF. Any existing medical condition 
present prior to the time of randomization should be reported as medical history
7.2.3.2
Physical Examination 
A complete physical examination will be performed with a thorough review of body systems at 
screening, baseline prior to randomization, and at study visits specified in Table 1.  Physical 
examinations will include a review of the subject’s general appearance, as well as evaluation of 
the body systems including:

Eyes, ears, nose, throat

Lymph nodes

Cardiovascular

Skin

Abdomen

Neurological

Spine and extremities


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Abnormalities identified at the screening visit (Visit 1) will be documented in the subject’s 
source documents and on the medical history eCRF. Changes after the screening visit (Visit 1) 
will be captured as AEs on the AE eCRF page, if deemed clinically significant by the 
investigator.
Height will be measured at the screening visit only while weight and waist and hip 
circumference will be recorded at all study visits. BMI will be calculated programmatically.   
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”).  
Adverse events are collected from the time informed consent is signed.  (Please refer to Section 
8, Adverse and Serious Adverse Events Assessment.)
7.2.3.4
Vital Signs
Vital signs include oral, temporal, or tympanic temperature, sitting blood pressure, pulse, and 
respiratory rate. Blood pressure should be determined by cuff (using the same method, the same 
arm, and in the same position throughout the study). Any deviations from baseline (Visit 2) vital 
signs which are deemed clinically significant in the opinion of the investigator are to be recorded 
as an AE.
7.2.3.5
Clinical Laboratory Evaluations 
All clinical laboratory assays will be performed according to the central laboratory’s normal 
procedures.  Reference ranges supplied by the central laboratory will be used to assess the 
clinical laboratory data for clinical significance and out-of-range pathological changes.  The 
investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Clinically 
significant findings should be evaluated for recording as adverse events on the eCRF. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry
Albumin (ALB)
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT; SGPT)
Aspartate aminotransferase (AST; SGOT)
Blood urea nitrogen (BUN)
C4
Lactate dehydrogenase (LDH)
Magnesium (Mg)
Phosphate (P)
Potassium (K)
Sodium (Na)
Total and direct bilirubin


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Calcium (Ca)
Bicarbonate (CO2)
Chloride (Cl)
Creatinine
Creatine kinase
Gamma glutamyl transferase (GGT)
Glucose
Total cholesterol
Protein
Triiodothyronine (T3)
Thyroid-stimulating hormone 
(TSH)
Triglycerides
Uric acid
Hematology
Hemoglobin 
Hematocrit
Mean corpuscular hemoglobin (MCH)
Mean corpuscular volume (MCV)
Platelets
Red blood cell (RBC) 
White blood cell (WBC) count with 
differential
Prothrombin time (PT)
Activated partial thromboplastin time 
(aPTT)
International normalized ratio (INR)
Urinalysis
Appearance (clarity and color)
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Microscopic examination of sediment
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Oxalate
7.2.3.6
Additional Laboratory Assessments
Laboratory samples will be collected and assessed for:

HIV testing and assessment of Hepatitis B/C including HBcAb, HBsAg, HBVDNA, and 
HCVAb (if HCVAb is positive an HCVRNA will be performed) will occur at the 
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
Lipid panel including fasting total cholesterol, HDL-C, LDL-C, and triglycerides at each 
scheduled study visit (Visits 1 through 10)

HbA1c will be tested at every scheduled visit (Visits 1 through 10)

Full coagulation panel will be done at screening and baseline, but only PT/INR is 
required at remaining time points at Visits 4, 7, and 9

Insulin will be tested at screening, baseline, at Visit 4 and Visits 6 through 10

HOMA-IR and HOMA-%B: will be calculated programmatically from serum glucose 
tested at screening, baseline, Visits 7, 9, and 10

Vitamin A, Vitamin D, Vitamin E, and Vitamin K (via PT/INR) will be tested at baseline, 
and Visits 4, 7, and 9.

Thyroid testing including TSH and T3 will be tested at screening, baseline, and Visits 4, 
6, 7, 9, and 10

C4 samples will be collected at baseline and Visits 6, 7, 9, and 10
7.2.3.7
Pregnancy Test 
A urine pregnancy test is performed on all females of child-bearing potential at the screening 
visit (Visit 1), baseline visit (Visit 2), at each Treatment visit (Visits 3 through 9) and at the Final 
visit (Visit 10), or if pregnancy is suspected, or on withdrawal of the subject from the study. A 
positive urine pregnancy test must be followed with a serum pregnancy test performed by the 
central laboratory. Additional testing can be performed at the investigator’s discretion. Also, 
refer to Section 8.1.7.
7.2.3.8
Drug and Alcohol Testing 
A urine screen for drugs of abuse and blood test for alcohol will be performed at screening and 
baseline as described in Table 1. Additional drug and alcohol screens may be performed at the 
investigator’s discretion.
Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiate metabolite, and phencyclidine. 
Results of drug and alcohol screens will be reviewed and verified by the study monitor, but will 
not be collected in the eCRF database.
Any positive result for drugs of abuse at the screening or baseline visits may exclude the subject 
from further participation in the study. A positive test for drugs of abuse or alcohol done at the 
investigator’s discretion discovered at any time during the study will be grounds for study 
discontinuation.


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7.2.3.9
Electrocardiogram 
An ECG (12-lead) will be performed at the times specified in Table 1 in accordance with the 
clinical site’s standard practice(s) and equipment supplied by the CRC.  Recordings of ECGs 
will be read locally at the clinical site by the investigator or designee. The ECG will include 
assessments of heart rate and PR, RR, QRS, and QT intervals. Identification of any clinically 
significant findings and/or abnormalities will be recorded on the eCRF. 
7.2.3.10
Health-related Quality of Life Assessments
The EuroQol (EuroQol. 2016. Available at: http://www.euroqol.org. [Accessed 17 February 
2016]) EQ-5D-5L (“EQ-5D”) is a widely used standardized questionnaire that assesses generic 
HRQoL and is also recommended for health-economic evaluations.  The EQ-5D includes two 
components: a descriptive profile and a visual analogue scale (VAS).  The descriptive profile 
includes five dimensions (ie, pain/discomfort, mobility, usual activities, self-care and 
anxiety/depression), each with five levels (ie, no problems, slight problems, moderate problems, 
severe problems, extreme problems). An EQ-5D index can also be derived from the data which 
summarizes health status using a single value (ie, health-state utility).  The psychometric 
properties of the EQ-5D-5L have been established and well documented (see Appendix 3).
7.2.3.11
Volume of Blood to be Drawn from Each Subject
During this study, it is expected that approximately 146 mL of blood will be drawn from all 
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 146 mL. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments may be combined. 
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4.  This includes events occurring during the screening phase of the 
study, regardless of whether or not the IP is administered.  Where possible, a diagnosis rather 
than a list of symptoms should be recorded.  If a diagnosis has not been made, then each 
symptom should be listed individually.  All AEs should be captured on the appropriate AE pages 


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in the eCRF and in source documents.  In addition to untoward AEs, unexpected benefits outside
the IP indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study.  Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained.  When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity.  An event that changes in severity should be captured as a new 
event.  Worsening of pre-treatment events, after initiation of the IP, must be recorded as new 
AEs (for example, if a subject experiences mild intermittent dyspepsia prior to dosing of the IP, 
but the dyspepsia becomes severe and more frequent after first dose of the IP has been 
administered, a new AE of severe dyspepsia (with the appropriate date of onset) is recorded on 
the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of daily 
living.
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Appendix 4 provides criteria to assess the severity of liver-related adverse events.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to the IP for each AE.  The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the IP.  If there is no valid reason for 
suggesting a relationship, then the AE should be classified as “not related”.  Otherwise, if there is 
any valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect 
relationship between the IP and the occurrence of the AE, then the AE should be considered 
“related”.  The causality assessment must be documented in the source document.


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The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the IP is 
compelling and/or follows a known or suspected response pattern to that product, and 
the event cannot be explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the IP and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF.  Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown.
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation of the disease and are part of the efficacy data to be collected in 
the study; however, significant worsening of the symptoms should be recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the IP, a shift of a parameter is 
observed from a normal value to an abnormal value, or a further worsening of an already 
abnormal value.  When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range, either while continuing treatment or after 
the end of treatment with the IP, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment value observed closest to the start of study 


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treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Criteria for Discontinuation of Treatment
Appendix 5 provides guidelines for discontinuation of treatment based on elevated ALT, AST, 
TB, and associated signs and symptoms.  
8.1.7
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.
Any report of pregnancy for any female study participant (or the female partner of a male 
participant) must be reported within 24 hours to the Shire Global Drug Safety (formerly 
Pharmacovigilance and Risk Management) Department using the Shire Investigational and 
Marketed Products Pregnancy Report Form.  A copy of the Shire Investigational and Marketed 
Products Pregnancy Report Form (and any applicable follow-up reports) must also be sent to the 
CRO medical monitor and the Shire clinical physician using the details specified in the 
Emergency Contact Information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days post 
partum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form.  Note:  An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and Non-
serious AEs Required by the Protocol Form as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form.  The test date of the first positive serum/urine -HCG test or 
ultrasound result will determine the pregnancy onset date.
8.1.8
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 


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in Section 8.2.  Note: The 24-hour reporting requirement for SAEs does not apply to reports of
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of the IP when used for a non-medical
purpose (eg, to alter one’s state of consciousness or get high) in a manner that may be 
detrimental to the individual and/or society

Misuse – Intentional use of the IP other than as directed or indicated at any dose (Note: 
this includes a situation where the IP is not used as directed at the dose prescribed by the 
protocol)

Overdose – Intentional or unintentional intake of a dose of an IP exceeding a pre-
specified total daily dose of the product.  

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an IP.  For studies, medication errors are reportable to the sponsor only as defined 
below.
Cases of subjects missing doses of the IP are not considered reportable as medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired IP should be considered as a reportable medication 
error.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the Volixibat Potassium (SHP626) 
Investigator’s Brochure which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety (formerly Pharmacovigilance and Risk Management) Department and the Shire 
GCDL within 24 hours of the first awareness of the event.  Note: The 24-hour reporting 
requirement for SAEs does not apply to reports of abuse, misuse, overdose, or medication errors 
(see Section 8.1.8) unless they result in an SAE. 


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The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note:  Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Drug Safety
Department. A copy of the Shire Clinical Study Serious Adverse Event and Non-serious AEs 
Required by the Protocol Form (and any applicable follow-up reports) must also be sent to the 
Shire GCDL using the details specified in the Emergency Contact Information section of the 
protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to the IP or not) that at any dose:

Results in death

Is life-threatening.  Note: The term ‘life-threatening’ in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization.  Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs.  For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event.  Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions 
that do not result in inpatient hospitalization; or the development of drug dependency or 
drug abuse.  
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4, and must be reported 
to the Shire Global Drug Safety Department and the Shire GCDL within 24 hours of the first 
awareness of the event. 


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In addition, any SAE(s) considered “related” to the IP and discovered by the investigator at any 
interval after the study has completed must be reported to the Shire Global Drug Safety
Department within 24 hours of the first awareness of the event.
8.2.4
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic.  In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.5
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date.  
For all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another IP action was previously taken (eg, drug interrupted, reduced, withdrawn), the action 
taken with the IP should be recorded as “dose not changed” or “not applicable” (if the subject 
never received the IP). The IP action of “withdrawn” should not be selected solely as a result of 
the subject’s death. 
8.2.6
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The CRO is responsible for notifying the relevant regulatory authorities as appropriate: USA 
central IRBs/EU central ECs of related, unexpected SAEs.
In addition the CRO is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the SHP626-201 program.  
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 


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between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan.  
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification are 
to be communicated to the site for resolution.  Only authorized personnel will make corrections 
to the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (eg, treatment allocation, and IP 
preparation/accountability data) will be handled with special care during the data cleaning and 
review process. These data will be handled in such a way that, prior to unblinding, any data that 
may unblind study team personnel will be presented as blinded information or otherwise will not 
be made available. If applicable, unblinded data may be made available to quality assurance 
representatives for the purposes of conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.  
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, IP exposure, and prior and concomitant medications.  The SAP will also include 
a description of how missing, unused and spurious data will be addressed.
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical analysis 
and study conclusions.  
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513). 


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9.5
Planned Interim Analysis and Data Monitoring Committee 
9.5.1
Planned Interim Analysis
Study enrollment will be paused after 92 subjects have been randomized in order for an IA to be 
conducted after at least 80 subjects have received 24 weeks of treatment. To protect study 
integrity, the IA will be performed by an independent statistician and statistical reporting group 
who are not involved in the clinical trial conduct and are not responsible for the final analysis of 
clinical trial data. The IA will be performed to evaluate the safety, tolerability, and efficacy of 3 
doses of volixibat each compared to PBO and be used to drop 1 or 2 doses of volixibat, or to 
terminate the trial. 
The criteria for deciding whether or not to continue randomizing to a particular volixibat dose 
following the Week 24 IA will be specified in the DMC charter.  In general, randomization to 
any volixibat dose determined to be unsafe, intolerable or ineffective/futile at the IA will be 
discontinued.   If all of the volixibat doses are determined to be intolerable or ineffective/futile 
the clinical trial will be terminated. If none of the volixibat doses are determined to be unsafe, 
intolerable or ineffective/futile then randomization to the volixibat dose that is the least 
promising or least helpful in characterizing the dose-response relationship (as specified in the 
DMC charter) will be discontinued. Tolerability will be assessed by comparing the number of 
discontinuations due to any one TEAE (presumably gastrointestinal events, most notably, 
diarrhea, loose stools, increased evacuations, and abdominal pain) between each volixibat dose 
group and PBO group.  Efficacy will be assessed based on a reduction of steatosis (assessed by 
MRI-PDFF) and ALT by comparing the change from baseline in MRI-PDFF and percent change 
from baseline in ALT at Week 24 between each volixibat dose group and PBO group.
Subjects recruited into the study prior to the IA will continue with the same dosing regimen for 
the duration of the planned study participation. That is, a subject receiving a dose to which 
randomization is stopped after the IA will continue to receive that same dose throughout the 
course of the study, and complete all required assessments, unless a dose is determined to be 
unsafe, in which case the affected subjects would be discontinued from the study and followed as 
per Section 4.5. Subjects recruited into the study after completion of the IA will be randomized 
evenly to the remaining volixibat dose groups or PBO group by IRT.  Subjects will be 
randomized to 1 or 2 volixibat doses or to PBO.  Thus, depending on the results from the IA, the 
study may be terminated, or one or two doses of volixibat will be discontinued.  If the study is 
not terminated, subjects will receive a total of 48 weeks of IP.
9.5.2
Data Monitoring Committee
An independent DMC will be established to assess safety, tolerability, and efficacy during the 
study, as well as to ensure the validity and scientific merit of the trial.  The DMC will monitor 
ongoing data generated by the study at regular intervals for the duration of the study. Their role 
is to protect the interests of the subjects in the study and of those still to be entered, by review of 
accumulating data generated in the study. If a safety concern is identified (eg, if either of the 
criteria are met in Section 4.5.4, Safety-related Stopping Rules), the DMC may recommend an 
action to the sponsor on further study conduct, including stopping the study at any time.


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In addition, the DMC will review the results of the Week 24 IA and make recommendations 
concerning study discontinuation due to intolerability or futility, or the continued randomization 
of 1 or more volixibat dose groups and PBO.  
The roles, responsibilities, and rules governing operation of the DMC will be discussed in full in 
a DMC charter. The DMC charter will define the primary responsibilities of the DMC; guide its 
activities, its relationship with other study components, its membership, and the purpose and 
timings of its meetings. It will provide the procedures for ensuring confidentiality, formal 
communication, and outline of the content of reports that will be provided by the DMC. 
Appropriate summary statistics and data listings will be provided to the DMC by an independent 
statistician supported by an independent statistical reporting group not otherwise assigned to the 
study.  
The recommendations made by the DMC to alter the conduct of the study or to stop the study 
will be forwarded to Shire for final decision.  The implementation of any DMC recommendation 
is solely the responsibility of the sponsor.  Shire will forward such decisions to regulatory 
authorities, as appropriate.
9.6
Sample Size Calculation and Power Considerations 
These are the primary hypotheses that are being tested in this study:

Null: The proportion of subjects at Week 48 with a reduction of at least 2 points without 
worsening of fibrosis from baseline NAS does not differ between any of the volixibat 
doses and PBO.

Alternative: The proportion of subjects at Week 48 with a reduction of at least 2 points 
without worsening of fibrosis from baseline NAS does differ between at least one 
volixibat dose and PBO.
Response rates of 21% (PBO) and 45% (active) were reported in the FLINT trial 
(Neuschwander-Tetri et al. 2015) using the same primary end-point of reduction of NAS by at 
least two points (without worsening of fibrosis).   Based on those response rates, 67 subjects per 
group completing the trial are needed for 80% power with a 10% type I error for a study 
comparing two volixibat doses to PBO.  Holm multiplicity adjustment was included in the 
sample size estimate.
Approximately 677 subjects will be screened to enroll 266 subjects to achieve 201 completers. 
After at least 80 subjects (20/treatment arm – 3 active and 1 PBO) have received 24 weeks of 
treatment, an IA will eliminate at least one dose group based on the criteria provided to the 
DMC; enrollment will continue to include approximately 67 subjects in each of the remaining 
arms. The sample size target for this study is 67 completers in each of the treatment groups (201 
total if 3 arms continue). Including an additional 20 subjects to account for one dose dropped at 
the IA, 221 subjects are needed. Therefore, approximately 266 (accounts for 20% of 221 


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dropping out) subjects will be randomized if three arms (2 active and 1 PBO) continue; 208 
(accounts for 20% dropping out) subjects are needed if 2 active doses are dropped at the IA.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Randomized Set will consist of all subjects in the Screened Set who have been randomized 
into the study.
The Safety Analysis Set will consist of all subjects who take at least 1 dose of randomized IP, 
and have at least 1 post-baseline safety assessment (eg, coming back for any visit, reporting of an 
AE or reporting the absence of AEs).
The Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have at 
least 1 post-baseline efficacy assessment (eg, MRI, liver biopsy, serum liver-related biochemistry 
measurement).
The Interim Analysis Set (IAS) will consist of all subjects in the Safety Analysis Set who have at 
least 1 post-baseline efficacy assessment (eg, MRI, ALT biochemistry measurement) on or 
before the Week 24 visit at the data cut time of the IA. 
9.8
Efficacy Analyses
All efficacy analyses will be based on the FAS and all statistical tests will be 2-sided hypothesis 
tests performed at the 10% level of significance on those doses continued after the IA, 
accounting for the number of doses dropped at the IA.. Also, all confidence intervals will be 2-
sided confidence intervals, unless otherwise stated.
9.8.1
Primary Efficacy Endpoint
The primary endpoint is the binary response indicating (yes/no) whether a subject responded at 
Week 48 with a reduction of at least 2 points, without worsening of fibrosis, from baseline NAS. 
The FAS will be used to assess the primary efficacy endpoint. The proportion of subjects at 
Week 48 with a reduction of at least 2 points without worsening of fibrosis from baseline NAS 
will be analyzed. The difference between a volixibat dose and PBO will be tested with a 
stratified Cochran-Mantel-Haenzel test. The test will be stratified by presence or absence of 
T2DM at baseline and baseline NAS separated into two groups (NAS={4,5} or NAS={6,7,8}). 
Subjects with missing data for the primary efficacy endpoint at the Week 48 visit will be 
considered as non-responders. Holm multiplicity adjustment will be applied prior to determining 
statistical significance at the 0.1 level.
Analyses which explore the impact of the missing data on the primary efficacy endpoint will be 
conducted. These analyses may compare imputations of the missing values which favor the PBO 
and/or imputations which favor the active.  In addition, analyses utilizing existing HFF and/or 


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ALT data may be performed.  Further, if the pattern of missing values does not appear uniformly 
distributed among the treatment arms, imputation method(s) based on informative missingness 
may also be performed.  Analyses investigating the impact of missing data will be detailed in the 
Statistical Analysis Plan.
9.8.2
Secondary Efficacy Endpoints
Descriptive statistics will be presented for each time point at which the variable is measured (see 
Table 1) for the secondary efficacy endpoints.  Binary secondary efficacy endpoints will be 
analyzed with the same method (stratified Cochran-Mantel-Haenzel test) as the primary efficacy 
endpoint.  Continuous secondary efficacy endpoints will be analyzed with an ANCOVA model 
with change from baseline as the outcome variable; treatment group, presence or absence of 
T2DM at baseline, and baseline NAS separated into 2 groups (NAS={4,5} or NAS={6,7,8}) as 
factors and baseline values as a covariate.  Endpoints include:

Change from baseline to Week 48 on liver histology as measured by the individual NAS 
components (ballooning, inflammation, steatosis).

Change from baseline to Week 48 on hepatic steatosis as measured by MRI-PDFF.

Change from baseline to Week 48 on liver histology as measured by fibrosis stage.
(NASH CRN) 

Resolution of NASH (defined as total absence of ballooning [score = 0], absent or mild 
inflammation [score 0-1], steatosis can be present [score 0-3]) without worsening of 
fibrosis as assessed by liver histology at Week 48.

Change from baseline to Week 48 on serum liver-related biochemistry as measured by:

alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

alkaline phosphatase (ALP)

gamma glutamyl transferase (GGT)

total bilirubin (TB)

Change from baseline to Week 48 on metabolic indicators as measured by:

fasting serum glucose levels

insulin levels

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
Change from baseline to Week 48 on serum lipids measured by:

fasting total cholesterol

HDL-C

LDL-C

triglycerides
9.8.3
Exploratory Efficacy Endpoints
Descriptive statistics will be presented for each time point at which the variable is measured (see 
Table 1) for the exploratory efficacy endpoints.  Binary exploratory efficacy endpoints will be 
analyzed with the same method (stratified Cochran-Mantel-Haenzel test) as the primary efficacy 
endpoint.  Continuous exploratory efficacy endpoints will be analyzed with an ANCOVA model 
with change from baseline as the outcome variable; treatment group, presence or absence of 
T2DM at baseline, and baseline NAS separated into 2 groups (NAS={4,5} or NAS={6,7,8}) as 
factors and baseline values as a covariate.  Endpoints include:

Change from baseline to Week 48 on liver histology as measured by the SAF scoring 
components: Steatosis (S), Activity (A), and Fibrosis (F)

Change from baseline to Week 48 on anthropomorphic measures: 

body weight

BMI 

waist circumference 

waist-hip ratio 

Change from baseline to Week 48 in subjects with T2DM on homeostasis measured by: 

Homeostasis model assessment -IR (HOMA-IR) 

HOMA-beta cell function (HOMA-%B) 
9.9
Safety Analyses
The Safety Analysis Set will be used to assess the safety endpoints. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  
Treatment-emergent AEs are defined as AEs that start or worsen on or after the date of the first 
dose of IP, and no later than the follow-up visit. The number of events, incidence, and percentage 
of TEAEs will be calculated by SOC, by preferred term, and by treatment group. 


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Treatment-emergent AEs will be further summarized by severity and relationship to the IP. 
Adverse events related to the IP, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized/listed.
Vital signs, ECG findings, and clinical laboratory tests will be summarized by treatment group 
and visit. Potentially clinically important findings will be summarized. Graphical presentation 
may be used when deemed necessary.
9.10 Other Analyses
9.10.1
Health-related Quality of Life Analyses

Change from baseline to Week 48 on the EQ-5D index (Appendix 3). The EQ-5D index 
will be derived using published UK-based preference weights. Univariate descriptive 
statistics and multivariate regression analyses adjusting for selected baseline covariates 
will be undertaken.

Change from baseline to Week 48 on the EQ-5D VAS score. Univariate descriptive 
statistics and multivariate regression analyses adjusting for selected baseline covariates 
will be undertaken.

Change from baseline to Week 48 in the proportion of subjects reporting having 
problems (none, slight, moderate, severe, extreme) with pain/discomfort, mobility, usual-
activities, self-care, anxiety/depression in the EQ-5D questionnaire.  Proportions and 
95% confidence intervals will also be generated for the baseline and Week 48 values as 
well as for change from baseline.
9.10.2
Stool Assessment
Stool hardness and number of evacuations will be assessed throughout the study. Stool hardness 
will be assessed for the softest evacuation within 24 hours of each clinic visit using the Bristol 
Stool Chart, a medical aid designed to classify the form of human feces into 7 categories where 
Type 1 is the hardest and Type 7 is the softest. Appendix 6 provides a sample of the Bristol Stool 
Chart.  Number of evacuations within the past 24 hours prior to the clinic visit will be recorded 
at specified times as per Table 1. Descriptive statistics by treatment group will be presented for 
each time point at which the variable is measured.
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.


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10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study.  The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of the IP 
for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites.  
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP.  This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason.  
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 


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agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.do
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification.  Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies.  Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation.  The 
investigator will also return all the IP, containers, and other study materials to the sponsor.  Upon 
study completion, the investigator will provide the sponsor, IRB/EC, and regulatory agency with 
final reports and summaries as required by (inter)national regulations.


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Communication with local IRBs/ECs, to ensure accurate and timely information is provided at
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
eCRFs are supplied by the sponsor and should be handled in accordance with instructions from 
the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. eCRFs must be completed by 
the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
All eCRF data must be endorsed by the investigator.
The CRA/study monitor will verify the contents of the eCRF against the source data per the 
monitoring plan. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents.  The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, images, etc.).  Non-study site personnel will not 
disclose any personal information or personal medical information.


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These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other 
USA national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor.  The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in the IP; any significant equity 
interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments.  All consent 
documentation must be in accordance with applicable regulations and GCP.  Each subject or the 
subject’s legally-authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally-authorized representative, as applicable. This document may 
require translation into the local language.  Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form which was 
reviewed by the IRB/EC and which received their favorable opinion/approval.  A copy of the 
IRB/EC’s written favorable opinion/approval of these documents must be provided to the 
sponsor, prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to study start that another party (ie, sponsor 


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or coordinating principal investigator) is responsible for this action.  Additionally, if the IRB/EC 
requires modification of the sample subject information and consent document provided by the 
sponsor, the documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
IP supplies will not be released until the sponsor or its designee has received written IRB/EC 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions.  The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All USA-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996.  A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the sponsor or its designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study.  These records and data may, 
in addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market volixibat; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed.  The sponsor and/or its representatives accessing the records 


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and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded.  They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted.  The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative.  Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire.  The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.  The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study.  To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications.  To the extent that the principal investigator has such sole, 
joint or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 


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submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication
of the compiled and analyzed study results.  If such a multicenter publication is not submitted to 
a journal for publication by the sponsor within an 18-month period after conclusion, 
abandonment, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section.  The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards.  Participation as an investigator does not confer any rights to 
authorship of publications.


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11.
REFERENCES 
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Angulo, P. 2002. Nonalcoholic fatty liver disease. N Engl J Med, 346, 1221-31.
Assy, N., Kaita, K., Mymin, D., Levy, C., Rosser, B. & Minuk, G. 2000. Fatty infiltration of 
liver in hyperlipidemic patients. Dig Dis Sci, 45, 1929-34.
Bedossa, P. 2012. Lesions in nanolcoholic fatty liver disease. Rev Prat, 62, 1419.
Chalasani, N. & Regev, A. 2016. Drug-Induced Liver Injury in Patients With Preexisting 
Chronic Liver Disease in Drug Development: How to Identify and Manage? 
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Day, C. P. & James, O. F. 1998. Steatohepatitis: a tale of two "hits"? Gastroenterology, 114, 
842-5.
Donati, G., Stagni, B., Piscaglia, F., Venturoli, N., Morselli-Labate, A. M., Rasciti, L. & 
Bolondi, L. 2004. Increased prevalence of fatty liver in arterial hypertensive patients with 
normal liver enzymes: role of insulin resistance. Gut, 53, 1020-3.
Halilbasic, E., Claudel, T. & Trauner, M. 2013. Bile acid transporters and regulatory nuclear 
receptors in the liver and beyond. J Hepatol, 58, 155-68.
Hamaguchi, M., Kojima, T., Takeda, N., Nakagawa, T., Taniguchi, H., Fujii, K., Omatsu, T., 
Nakajima, T., Sarui, H., Shimazaki, M., Kato, T., Okuda, J. & Ida, K. 2005. The 
metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med,
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Ferrell, L. D., Liu, Y. C., Torbenson, M. S., Unalp-Arida, A., Yeh, M., McCullough, A. J. 
& Sanyal, A. J. 2005. Design and validation of a histological scoring system for 
nonalcoholic fatty liver disease. Hepatology, 41, 1313-21.
Loomba, R., Abraham, M., Unalp, A., Wilson, L., Lavine, J., Doo, E., Bass, N. M. & 
Nonalcoholic Steatohepatitis Clinical Research, N. 2012. Association between diabetes, 
family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. 
Hepatology, 56, 943-51.
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Kono, Y., Bhatt, A., Hernandez, L., Nguyen, P., Noureddin, M., Haufe, W., Hooker, C., 
Yin, M., Ehman, R., Lin, G. Y., Valasek, M. A., Brenner, D. A. & Richards, L. 2015. 
Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel 
magnetic resonance imaging and magnetic resonance elastography in a randomized trial 
(MOZART trial). Hepatology, 61, 1239-50.
Marchesini, G., Marzocchi, R., Agostini, F. & Bugianesi, E. 2005. Nonalcoholic fatty liver 
disease and the metabolic syndrome. Curr Opin Lipidol, 16, 421-7.
Mathus-Vliegen, L., Toouli, J., Fried, M., Khan, A. G., Garisch, J., Hunt, R., Fedail, S., Stimac, 
D., Lemair, T., Krabshuis, J., Kaufmann, P., Roberts, E. & Riccardi, G. 2012. World 
Gastroenterology Organisation global guidelines on obesity. J Clin Gastroenterol, 46, 
555-61.
Miethke, A. G., Zhang, W., Simmons, J., Taylor, A. E., Shi, T., Shanmukhappa, S. K., Karns, R., 
White, S., Jegga, A. G., Lages, C. S., Nkinin, S., Keller, B. T. & Setchell, K. D. 2016. 
Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile 


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composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 
knockout mice. Hepatology, 63, 512-23.
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non-alcoholic steatohepatitis. Prog Lipid Res, 52, 175-91.
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Neuschwander-Tetri, B. A. 2005. Nonalcoholic steatohepatitis and the metabolic syndrome. Am 
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Abdelmalek, M. F., Chalasani, N., Dasarathy, S., Diehl, A. M., Hameed, B., Kowdley, K. 
V., McCullough, A., Terrault, N., Clark, J. M., Tonascia, J., Brunt, E. M., Kleiner, D. E. 
& Doo, E. 2015. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, 
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Pagano, G., Pacini, G., Musso, G., Gambino, R., Mecca, F., Depetris, N., Cassader, M., David, 
E., Cavallo-Perin, P. & Rizzetto, M. 2002. Nonalcoholic steatohepatitis, insulin 
resistance, and metabolic syndrome: further evidence for an etiologic association. 
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Permutt, Z., Le, T. A., Peterson, M. R., Seki, E., Brenner, D. A., Sirlin, C. & Loomba, R. 2012. 
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Qayyum, A., Goh, J. S., Kakar, S., Yeh, B. M., Merriman, R. B. & Coakley, F. V. 2005. 
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Rao, A., Kosters, A., Mells, J., Keller, B., Yin, H., Banton, S., Li, S., Jones, D. P., Wu, H., 
Dawson, P. & Karpen, S. 2015. Administration of an ileal apical sodium-dependent bile 
acid transporter inhibitor protects against non-alcoholic fatty liver disease in high fat diet-
fed mice. Hepatology, 62, 217A.
Raptis, D. A., Fischer, M. A., Graf, R., Nanz, D., Weber, A., Moritz, W., Tian, Y., Oberkofler, 
C. E. & Clavien, P. A. 2012. MRI: the new reference standard in quantifying hepatic 
steatosis? Gut, 61, 117-27.
Reeder, S. B., Cruite, I., Hamilton, G. & Sirlin, C. B. 2011. Quantitative Assessment of Liver Fat 
with Magnetic Resonance Imaging and Spectroscopy. J Magn Reson Imaging, 34, 1011-
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Reeder, S. B., Hu, H. H. & Sirlin, C. B. 2012. Proton density fat-fraction: a standardized MR-
based biomarker of tissue fat concentration. J Magn Reson Imaging, 36, 1011-4.
Roldan-Valadez, E., Favila, R., Martinez-Lopez, M., Uribe, M., Rios, C. & Mendez-Sanchez, N. 
2010. In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty 
liver disease: Correlation with biochemical method and morphometry. J Hepatol, 53, 
732-7.
Sanyal, A. J., Campbell-Sargent, C., Mirshahi, F., Rizzo, W. B., Contos, M. J., Sterling, R. K., 
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association of insulin resistance and mitochondrial abnormalities. Gastroenterology, 120, 
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Schwenzer, N. F., Springer, F., Schraml, C., Stefan, N., Machann, J. & Schick, F. 2009. Non-
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Souza, M. R., Diniz Mde, F., Medeiros-Filho, J. E. & Araujo, M. S. 2012. Metabolic syndrome 
and risk factors for non-alcoholic fatty liver disease. Arq Gastroenterol, 49, 89-96.
Springer, F., Ballweg, V., Schweizer, R., Schick, F., Ranke, M. B., Binder, G. & Ehehalt, S. 
2015. Changes in whole-body fat distribution, intrahepatic lipids, and insulin resistance 
of obese adolescents during a low-level lifestyle intervention. Eur J Pediatr, 174, 1603-
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Szczepaniak, L. S., Nurenberg, P., Leonard, D., Browning, J. D., Reingold, J. S., Grundy, S., 
Hobbs, H. H. & Dobbins, R. L. 2005. Magnetic resonance spectroscopy to measure 
hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am 
J Physiol Endocrinol Metab, 288, E462-8.
Torres, D. M. & Harrison, S. A. 2008. Diagnosis and therapy of nonalcoholic steatohepatitis. 
Gastroenterology, 134, 1682-98.
Torres, D. M., Williams, C. D. & Harrison, S. A. 2012. Features, diagnosis, and treatment of 
nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol, 10, 837-58.
Urdzik, J., Bjerner, T., Wanders, A., Weis, J., Duraj, F., Haglund, U. & Noren, A. 2012. The 
value of pre-operative magnetic resonance spectroscopy in the assessment of 
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Vernon, G., Baranova, A. & Younossi, Z. M. 2011. Systematic review: the epidemiology and 
natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in 
adults. Aliment Pharmacol Ther, 34, 274-85.
Williams, C. D., Stengel, J., Asike, M. I., Torres, D. M., Shaw, J., Contreras, M., Landt, C. L. & 
Harrison, S. A. 2011. Prevalence of nonalcoholic fatty liver disease and nonalcoholic 
steatohepatitis among a largely middle-aged population utilizing ultrasound and liver 
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12.
APPENDICES


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APPENDIX 1
PROTOCOL HISTORY 
Document
Date
Global/Country/Site Specific
Original Protocol
24 February 2016
Global
Amendment 1
8 April 2016
Global
Amendment 2
19 July 2016
Global
Amendment 3
22 March 2017
Global


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APPENDIX 2
FATTY LIVER DISEASE HISTOLOGY SCORING
Diagnosis: NASH, Suspicious/Borderline NASH (type a or b), NAFLD, Not NAFLD
NAS SCORING
Steatosis
0       <5%
1        5-33%
2        34-66%
3        67-100%
Lobular Inflammation
0        no foci
1        < 2 foci per 200x field
2        2-4 foci per 200x field
3        > 4 foci per 200 x field
Ballooning
0       None
1       Rare or diagnostically borderline
2       Many or Prominent ballooned hepatocytes
            SAF SCORING
Steatosis
0         <5%
1        5-33%
2        34-66%
3        67-100%
Ballooning
0        normal hepatocytes with  cuboidal shape and pink cytoplasm
1       clusters of hepatocytes with rounded shape and pale cytoplasm usually  reticulated      
2       grade 1 plus enlarged hepatocytes, 2 x bigger than normal cells. 
Lobular Inflammation
0       none
1       < 2 foci per 200x field
2       >2 foci per 200x field
Steatosis 1,2,3 + Ballooning 1,2 + Lobular Inflammation  1,2 = NASH
Steatosis 1,2,3 +Ballooning 0 + Lobular Inflammation 0,1,2 = NAFLD
Steatosis 1,2,3 + Ballooning 1,2 + Lobular 0 = NAFLD
Steatosis 0 = no NAFLD
FIBROSIS SCORE
None
0
Mild zone 3 perisinusoidal (requires trichrome)
1a
Moderate Zone 3 perisinusoidal (visible on H&E)
1b
Portal/periportal only
1c
Portal, periportal and perisinusoidal
2
Bridging
3
Cirrhosis
4
References: Kleiner et al. 2005; Bedossa 2012


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ADDITIONAL SCORING FEATURES
Expanded Balloon Score
0: None
1: Few Non classic
2: Few Classic
3. Many Classic
4: Severe Classic
Portal Inflammation
0: None
1: Minimal
2: Mild
3: More than Mild
Megamitochondria
0: None
1: Present
Acidophil Bodies
0: None or rare
1: Present
Fibrosis location if ≥ stage 2
Portal Predominant
Central Predominant
No predominance
Steatosis Zone
Zone 1 predominant
Zone 3 predominant
Azonal
Panacinar
Glycogenosis
None
Focal
Diffuse


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APPENDIX 3
EQ-5D-5L HEALTH QUESTIONNAIRE
UK SAMPLE ONLY, NOT FOR OFFICIAL USE


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22 Mar 2017
Under each heading, please tick the ONE bo-x that best describes your health TODAY. 
MOB ILITY 
I have no problems in walking about 
I have sJight problems in walking about 
I have moderate prob~ms in walking about 
I have severe probJems in watking about 
I am unable to walk about 
SELF-CARE 
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate probtems washing or dressing mysetf 
I ha\'e severe probJems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, house work, famffy or 
leisure activities) 
I have no problems doing my usual activities 
I have sJtght problems doing my usual activiti.es 
I ha\'e moderate problems doing my usual activities 
I have severe probfems doing my usuaJ activities 
I am unable to do my usual activities 
PAitJ I DISCOMFORT 
I have no pain or discomfort 
I have sltght pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
ANXIETY I DEPRESSION 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severety anxious or depressed 
I am extremety anxious or depressed 
2 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 


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• 
We would Hke to know how good or bad your heatth is TODAY. 
• 
This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• 
MaJ1t an X on the scale to indicate how your health is TODAY. 
• 
Now, please write the number you marked on the scale in the box 
betow. 
YOUR HEALTH TODAY = D 
3 
1M {En<foh) ., 'iYXJ9 E:W>Qol G/"'f' E:~N 
;sa .. de""'*ofif>e E:WJQol Gl"'f' 
The best l"ealth 
you ron imagine 
100 
T 
95 
go 
85 
80 
75 
70 
t 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 
The worst heslth 
yot.J c.m imagine 


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APPENDIX 4
CRITERIA TO ASSESS SEVERITY OF LIVER-
RELATED ADVERSE EVENTS
Parameter
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
ALT
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
AST
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
Alkaline 
Phosphatase
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
GGT
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
Bilirubin
Normal
>1.0-1.5
>1.5-2.5
>2.5-5
>5
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = 
gamma glutamyl transferase. 
Note: Values expressed as multiples of the upper limit of the normal range (ULN).


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APPENDIX 5
STOPPING RULES FOR LIVER-RELATED BLOOD 
TESTS
Table 1. Suggested Algorithm for Monitoring and Management of Drug-induced Liver Injury in Phase 2 and 
Phase 3 Nonalcoholic Steatohepatitis Studies in Patients With Normal or Elevated Baseline ALTa
Treatment-Emergent ALT
Treatment-Emergent TBL
Liver Symptoms
Action
Normal baseline: ALT >5 × 
ULN
Elevated baseline: ALT >3 × 
baseline
or >300 U/L (whichever 
occurs first)
Normal
For patients with Gilbert’s 
syndrome:
No change in baseline TBL
None
Repeat ALT, AST, 
ALP, TBL,  in 2–5 days
Follow-up for 
symptoms.
Normal baseline: ALT >8 × 
ULN
Elevated baseline: ALT >8 ×
baseline
or >500 U/L (whichever 
occurs first)
Normal
Patients with Gilbert’s 
syndrome:
No change in baseline TBL
None
Interrupt study drug.
Initiate close 
monitoring and workup 
for competing 
etiologies.
Study drug can be 
restarted only if another 
etiology is identified 
and liver enzymes 
return to baseline.
Normal baseline: ALT >5 ×
ULN
Elevated baseline: ALT >3 ×
baseline
or >300 U/L (whichever 
occurs first)
TBL >2 × ULN
For patients with Gilbert’s 
syndrome:
Doubling of direct bilirubin
None
Interrupt study drug.
Initiate close 
monitoring and workup 
for competing
etiologies.
Study drug can be 
restarted only if another 
etiology is identified 
and liver enzymes
return to baseline.
Normal baseline: ALT >5 x 
ULN
Elevated baseline: ALT >3 x 
baseline or >300 U/L 
(whichever occurs first)
Normal or elevated
Severe fatigue, nausea, 
vomiting, right upper 
quadrant pain
Interrupt study drug.
Initiate close 
monitoring and workup 
for completing 
etiologies.
Study drug can be 
restarted only if another 
etiology is identified 
and liver enzymes
return to baseline.
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; TBL=total bilirubin; ULN=upper 
limit of normal.
aBaseline is the average of 2 screening ALT measurements.
Source: Chalasani and Regev 2016.


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APPENDIX 6
BRISTOL STOOL CHART


PROTOCOL: SHP626-201
TITLE:
A Phase 2 Double-blind, Randomized, Placebo-controlled, Dose-finding 
Study to Evaluate the Safety, Tolerability and Efficacy of Volixibat 
Potassium, an Apical Sodium-Dependent Bile Acid Transporter 
Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
DRUG:
Volixibat potassium  (SHP626)
IND:
123,847
EUDRACT NO.:
2016-000203-82
SPONSOR: 
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
Philip Newsome MD
Director of Centre for Liver Research 
University of Birmingham
Edgbaston, Birmingham B15 2TT UK
NATIONAL/
COORDINATING
INVESTIGATOR/UK
Guruprasad P Aithal MBBS, MD, FRCP, PhD
Head of the Division, Nottingham Digestive Diseases Centre
Director, NIHR Nottingham Digestive Diseases Biomedical Research 
Unit 
Nottingham University Hospitals and University of Nottingham
Queen's Medical Centre
Nottingham NG7 2UH
PROTOCOL 
HISTORY:
Amendment 2: 19 July 2016
Amendment 1: 8 April 2016
Original Protocol:  24 February 2016 
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations.  This information should be used solely for the purposes for which it was provided
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.


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Protocol SHP626-201 Amendment 2
19 July 2016
PROTOCOL SIGNATURE PAGE 
I have read this protocol for Shire Study SHP626-201. 
Title: A Phase 2 Double-Blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate the 
Safety, Tolerability and Efficacy ofVolixibat Potassium, an Apical Sodium-Dependent Bile Acid 
Transporter Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
I have fully discussed the objective(s) ofthis study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my patiicipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: --------------------------------- Date: 


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Protocol SHP626-201 Amendment 2
19 July 2016
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
19 July 2016
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
General 
Minor editorial changes

Improved clarity, or 
correction
Study Synopsis
Inclusion and Exclusion criteria 
were revised. Endpoints and 
Statistical Analysis were revised. 

To improve clarity

To align with changes in 
the study protocol.
Table 1: Schedule of Assessments
Alcohol Test revised from Serum to 
Blood, Vitamins A and E were 
added, MRI time points were 
clarified, and window for Visit 10 
was added.

Improved clarity
Section  3.1 Study Design and 
Flow Chart
Specified that the interim analysis 
will be conducted after at least 80 
subjects have completed 24 weeks 
of treatment.

Improved clarity
Section 4.1 Inclusion Criteria
Inclusion criterion #4 regarding 
compliance with contraceptive 
requirements were revised.

Improved clarity
Section 4.2  Exclusion Criteria
Acceptability of gastric sleeve was 
added to exclusion criterion #3.

New text added, to provide 
clarity
Section 4.2  Exclusion Criteria
Exclusion #4 added text to include 
MRI in addition to liver biopsy for 
the weight change consideration.

New text added, to provide 
clarity
Section 4.2  Exclusion Criteria
Typographical errors in criterion #7 
regarding treatment with TZD or 
GLP-1 RA were corrected.

Corrections to both terms
Section 4.2 Exclusion Criteria
Criterion #17 regarding use of 
anticoagulants was revised.

Clarified that use of 
antiplatelet medications, 
including clopidogrel, will 
be allowed.
Section 4.2  Exclusion Criteria
Exclusion criterion #24 regarding 
pregnant women, women who plan 
to become pregnant, or men who 
plan to father a child during the 
study, was added.

New text added, to provide 
clarity and supplement 
requirements for inclusion, 
stated in Section 4.1.
Section 4.4.1 Female 
Contraception
The list of acceptable methods of 
contraception was revised.

Ensures alignment with 
methods considered to be 
“highly effective,” ie, <1% 
failure rate per year.
Section 4.4.2 Male Contraception
Added that use of hormonal 
contraception by a female partner 

Ensures alignment with 
methods considered to be 


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Protocol SHP626-201 Amendment 2
19 July 2016
must be accompanied by a barrier 
method; also stipulated that male 
subjects must agree to use 
acceptable contraception for 30
days following the last dose of IP.
“highly effective,” ie, <1% 
failure rate per year and 
addresses the issue of 
potential interaction of 
volixibat with hormones.

Further ensures safety for 
subjects and their partners.
Section 4.5.1 Subject Withdrawal 
Criteria
Revised criteria to clarify that 
subjects who become pregnant or 
demonstrate disease progression 
will be withdrawn;defined disease 
progression for this study.

Improved clarity
Section 4.5.4 Safety-related 
Stopping Rules
Clarified sponsor consultation with 
DMC.

Improved clarity
Section 5.2.1 Permitted treatment
Revised to clarify that use of 
antiplatelet medication is allowed.

Improved clarity
Section 7.1.1 Screening (Visit 1)
Clarified that abnormal screening 
labs may be repeated before 
determining screen failure.

Improved clarity
Sections 7.1.2 and 7.1.4
Added mention of stool assessment, 
to be consistent with Table 1.

Improved clarity
Section 7.2.2.2 MRI
Clarified that the Week 24 MRI 
will be conducted for subjects in the 
IA set only, and deleted mention of 
Week 48, ie, all subjects will have 
EOS MRI.

Change in analysis plan
Section 7.2.3.6 Additional 
Laboratory Assessments
Added Vitamins A & E, and 
clarified derivation of Vitamin K

Additional assessments and 
clarity
Section 7.2.3.11 Volume of Blood 
to be Drawn from Each Subject
Revised blood volumes due to 
additional vitamin testing

Additional assessments and 
clarity
Section 9.5.1 Planned Interim 
Analysis
This section heading was added and 
details regarding the planned 
interim analyses were added in this 
section. The specific rules for dose 
selection (and Appendix 6 
information) were moved to Data 
Monitoring Committee (DMC)
charter.

This revised information 
improves clarity/ accuracy 
of the description of the 
interim analysis.

Appropriate reorganization 
of information.
Section 9.5.2 Data Monitoring 
Committee
This section heading was added and 
section was revised to improve 
clarity of processes.

Improved clarity
Section 9.7 Study Population
This section was revised to improve 
clarity about the definition(s) of 
analysis sets.

Improved clarity
Section 9.8.1 Primary Efficacy 
Endpoint
Removed the restriction that the 
impact of missing data will only be 
investigated if 10% or more of the 
data are missing. Added additional 
methods that may be used.

Alignment with analysis 
plan
Section 9.8.2 Secondary Efficacy 
This section was revised to provide 

Improved clarity


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Protocol SHP626-201 Amendment 2
19 July 2016
Endpoints
additional clarity about efficacy 
endpoints and associated analysis
methods.
Section 9.8.3 Exploratory 
Efficacy Endpoints
This section was revised to provide 
additional clarity about efficacy 
endpoints and associated analysis 
methods considered to be 
exploratory.

Improved clarity
Section 9.9 Safety Analyses
This section was revised / 
reorganized to provide additional 
clarity.

Improved clarity
Section 9.10.2 Stool Assessment
This section was revised to provide  
clarity about the analysis methods 
for these data.

Improved clarity
Former Appendix 6: GENERAL 
PRINCIPLES AND SPECIFIC 
RULES FOR DOSE 
DISCONTINUATION AT 24 
WEEK INTERIM ANALYSIS –
GUIDANCE FOR DATA 
MONITORING COMMITTEE 
ONLY
This section was removed and all 
relevant information was placed in 
the DMC charter.

Appropriate reorganization 
of information


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Protocol SHP626-201 Amendment 2
19 July 2016
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to:
Shire Global Pharmacovigilance and Risk Management Department
Preferred method: scan and e-mail to globalpharmacovigilance@shire.com
OR fax to +44(0) 1256 89 4715 (Global); or +1 866 557 4473 (North America)
AND
A copy of this form must also be sent to the Shire GCDL by fax or e-mail using the details 
below:
Melissa Palmer, MD, FAASLD, GCDL-Hepatology
fax number: +1 781 482 1822
e-mail: mpalmer@shire.com 
For protocol- or safety-related issues during normal business hours 9:00 a.m. to 5:00 p.m. 
(Eastern Time), the investigator must contact the Contract Research Organization (CRO) 
Medical Monitor:
ICON Medical Monitor: Anthony Japour, MD
Telephone number: +1 215 616 6439
Fax number: +1 215 616 3096
Mobile number: +1 267 429 6601
E-mail address: Anthony.Japour@iconplc.com
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact ICON’s 24/7 Medical Emergency Coverage:
Chargeable global telephone number: +1 919 674 5468
NOTE: Investigative sites will be provided country-specific toll-free telephone numbers. Please 
refer to this document, as applicable. Countries without a toll-free number will need to dial the 
chargeable number noted above.


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Protocol SHP626-201 Amendment 2
19 July 2016
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product (IP) quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products).  For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
PQC@shire.com
European Union and Rest of World
PQCROW@shire.com
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA) 
1-888-300-6414 or 1-800-828-2088


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Protocol SHP626-201 Amendment 2
19 July 2016
TABLE OF CONTENTS
1.
BACKGROUND INFORMATION.......................................................................................24
1.1
Indication and Current Treatment Options...............................................................24
1.2
Product Background and Clinical Information ........................................................24
1.3
Benefits and Risks....................................................................................................27
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................29
2.1
Rationale for the Study.............................................................................................29
2.2
Study Objectives ......................................................................................................29
2.2.1
Primary Objective..................................................................................................29
2.2.2
Secondary Objectives.............................................................................................29
2.2.3
Exploratory Objectives ..........................................................................................29
3.
STUDY DESIGN ...................................................................................................................31
3.1
Study Design and Flow Chart ..................................................................................31
3.2
Duration and Study Completion Definition .............................................................32
3.3
Sites and Regions .....................................................................................................32
4.
STUDY POPULATION.........................................................................................................33
4.1
Inclusion Criteria......................................................................................................33
4.2
Exclusion Criteria.....................................................................................................33
4.3
Restrictions...............................................................................................................35
4.4
Reproductive Potential .............................................................................................36
4.4.1
Female Contraception............................................................................................36
4.4.2
Male Contraception................................................................................................37
4.5
Discontinuation of Subjects .....................................................................................37
4.5.1
Subject Withdrawal Criteria ..................................................................................37
4.5.2
Reasons for Discontinuation..................................................................................38
4.5.3
Subjects Lost to Follow-up Prior to Last Scheduled Visit.....................................38
4.5.4
Safety-related Stopping Rules................................................................................39
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................40
5.1
Prior Treatment ........................................................................................................40
5.2
Concomitant Treatment............................................................................................40
5.2.1
Permitted Treatment...............................................................................................40
5.2.2
Prohibited Treatment .............................................................................................40
6.
INVESTIGATIONAL PRODUCT ........................................................................................42
6.1
Identity of Investigational Product...........................................................................42
6.1.1
Blinding the Treatment Assignment......................................................................42
6.2
Administration of Investigational Product(s)...........................................................42
6.2.1
Interactive Response Technology for Investigational Product Management ........42


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Protocol SHP626-201 Amendment 2
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6.2.2
Allocation of Subjects to Treatment ......................................................................42
6.2.3
Dosing....................................................................................................................43
6.2.4
Unblinding the Treatment Assignment..................................................................43
6.3
Labeling, Packaging, Storage, and Handling ...........................................................44
6.3.1
Labeling .................................................................................................................44
6.3.2
Packaging...............................................................................................................44
6.3.3
Storage ...................................................................................................................44
6.4
Drug Accountability.................................................................................................45
6.5
Subject Compliance..................................................................................................46
7.
STUDY PROCEDURES........................................................................................................47
7.1
Study Schedule.........................................................................................................47
7.1.1
Screening (Visit 1).................................................................................................47
7.1.2
Baseline (Visit 2) ...................................................................................................48
7.1.3
Treatment and Assessment Period (Visits 3 through 9/EOS)................................48
7.1.4
Follow-up (Visit 10) ..............................................................................................49
7.1.5
Additional Care of Subjects after the Study ..........................................................49
7.2
Study Evaluations and Procedures ...........................................................................49
7.2.1
Demographic and Other Baseline Characteristics .................................................49
7.2.2
Efficacy..................................................................................................................49
7.2.2.1
Liver Biopsy...........................................................................................49
7.2.2.2
MRI ........................................................................................................49
7.2.3
Safety .....................................................................................................................50
7.2.3.1
Medical History and Medications ..........................................................50
7.2.3.2
Physical Examination.............................................................................50
7.2.3.3
Adverse Event Collection.......................................................................50
7.2.3.4
Vital Signs..............................................................................................50
7.2.3.5
Clinical Laboratory Evaluations.............................................................51
7.2.3.6
Additional Laboratory Assessments.......................................................52
7.2.3.7
Pregnancy Test .......................................................................................53
7.2.3.8
Drug and Alcohol Testing......................................................................53
7.2.3.9
Electrocardiogram ..................................................................................53
7.2.3.10
Health-related Quality of Life Assessments...........................................53
7.2.3.11
Volume of Blood to be Drawn from Each Subject ................................54
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................55
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................55
8.1.1
Severity Categorization..........................................................................................55
8.1.2
Relationship Categorization...................................................................................56


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Protocol SHP626-201 Amendment 2
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8.1.3
Outcome Categorization ........................................................................................56
8.1.4
Symptoms of the Disease Under Study .................................................................57
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................57
8.1.6
Criteria for Discontinuation of Treatment .............................................................57
8.1.7
Pregnancy...............................................................................................................57
8.1.8
Abuse, Misuse, Overdose, and Medication Error..................................................58
8.2
Serious Adverse Event Procedures ..........................................................................59
8.2.1
Reference Safety Information................................................................................59
8.2.2
Reporting Procedures.............................................................................................59
8.2.3
Serious Adverse Event Definition .........................................................................59
8.2.4
Serious Adverse Event Onset and Resolution Dates .............................................60
8.2.5
Fatal Outcome........................................................................................................60
8.2.6
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................60
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................62
9.1
Data Collection.........................................................................................................62
9.2
Clinical Data Management.......................................................................................62
9.3
Data Handling Considerations..................................................................................62
9.4
Statistical Analysis Process......................................................................................62
9.5
Planned Interim Analysis and Data Monitoring Committee....................................63
9.5.1
Planned Interim Analysis.......................................................................................63
9.5.2
Data Monitoring Committee..................................................................................63
9.6
Sample Size Calculation and Power Considerations................................................64
9.7
Study Population ......................................................................................................65
9.8
Efficacy Analyses.....................................................................................................65
9.8.1
Primary Efficacy Endpoint ....................................................................................65
9.8.2
Secondary Efficacy Endpoints...............................................................................66
9.8.3
Exploratory Efficacy Endpoints.............................................................................67
9.9
Safety Analyses........................................................................................................67
9.10
Other Analyses .........................................................................................................68
9.10.1 Health-related Quality of Life Analyses................................................................68
9.10.2 Stool Assessment ...................................................................................................68
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................69
10.1
Sponsor’s Responsibilities .......................................................................................69
10.1.1 Good Clinical Practice Compliance.......................................................................69
10.1.2 Indemnity/Liability and Insurance.........................................................................69
10.1.3 Public Posting of Study Information......................................................................69
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................69


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Protocol SHP626-201 Amendment 2
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10.1.5 Study Suspension, Termination, and Completion..................................................70
10.2
Investigator’s Responsibilities .................................................................................70
10.2.1 Good Clinical Practice Compliance.......................................................................70
10.2.2 Protocol Adherence and Investigator Agreement..................................................70
10.2.3 Documentation and Retention of Records.............................................................71
10.2.3.1
Electronic Case Report Forms................................................................71
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................71
10.2.3.3
Audit/Inspection.....................................................................................72
10.2.3.4
Financial Disclosure...............................................................................72
10.3
Ethical Considerations..............................................................................................72
10.3.1 Informed Consent...................................................................................................72
10.3.2 Institutional Review Board or Ethics Committee..................................................73
10.4
Privacy and Confidentiality......................................................................................73
10.5
Study Results / Publication Policy ...........................................................................74
11. REFERENCES .......................................................................................................................76
12. APPENDICES ........................................................................................................................80


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Protocol SHP626-201 Amendment 2
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LIST OF TABLES
Table 1:
Schedule of Assessments...............................................................................21
LIST OF FIGURES
Figure 1:
Study Design Flow Chart ..............................................................................32
LIST OF APPENDICES
APPENDIX 1
Protocol History.............................................................................................81
APPENDIX 2
Fatty Liver Disease Histology Scoring..........................................................82
APPENDIX 3
EQ-5D-5L Health Questionnaire UK Sample Only, Not for Official 
Use 84
APPENDIX 4
Criteria to Assess Severity of Liver-Related Adverse Events.......................87
APPENDIX 5
Stopping Rules for Liver-related Blood Tests...............................................88
APPENDIX 6
Bristol Stool Chart.........................................................................................89


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ABBREVIATIONS
AE
adverse event
ALP 
alkaline phosphatase
ALT 
alanine aminotransferase
aPPT
activated partial thromboplastin time
ASBT
apical sodium-dependent bile acid transporter
ASBTi 
ASBT inhibitor
AST 
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BA 
bile acid
BMI
body mass index
C4
7-alpha-hydroxy-4-cholesten-3-one
CRA
clinical research associate
CRC 
clinical research center
CRO
contract research organization
DMC 
data monitoring committee
eCRF
electronic case report form
EQ-5D-5L 
EuroQol-5 Dimension-5 Level Questionnaire
ECG
electrocardiogram
EOS
end of study
EU
European Union
FAS
full analysis set
FBA 
fecal bile acid
FDA
Food and Drug Administration
FXR
GCDL 
farnesoid X receptor
Global Clinical Development Lead
GCP
Good Clinical Practice
GGT 
gamma glutamyl transferase
GLP-1 RA
glucagon-like peptide-1 receptor agonists
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HBVDNA
hepatitis B virus deoxyribonucleic acid
HCV
hepatitis C virus


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HCVAb
hepatitis C virus antibody
HCVRNA
hepatitis C virus ribonucleic acid
HDL-C
high-density lipoprotein-cholesterol
HFD
high fat diet
HFF
hepatic fat fraction
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HOMA-%B 
homeostasis model assessment in β-cell function
HOMA-IR 
homeostasis model assessment insulin resistance
HRQoL 
health-related quality of life
IA 
interim analysis
IAS
interim analysis set
ICH
International Conference on Harmonisation
IND 
investigational new drug
INR
international normalized ratio
IP
investigational product
IR
insulin resistance
IRB
Institutional Review Board
IRT
interactive response technology
LDL-C 
low-density lipoprotein-cholesterol
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MR
magnetic resonance
MRI 
magnetic resonance imaging
MRS
magnetic resonance spectroscopy
MOA
mechanism of action
NAFLD 
nonalcoholic fatty liver disease
NAS 
NAFLD Activity Score
NASH 
nonalcoholic steatohepatitis
NASH CRN
NASH Clinical Research Network
NOAEL 
no observed adverse effect level
PBC
primary biliary cirrhosis
PBO
placebo
PDFF
proton density fat-fraction
PO
by mouth


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POC
proof of concept
PRO 
patient-reported outcome
PSC
primary sclerosing cholangitis
PT
prothrombin time
PVRM
Pharmacovigilance and Risk Management
QD 
once daily
RBC
red blood cell 
SAE 
serious adverse event
SAF
steatosis, activity, and fibrosis score
SAP 
statistical analysis plan
T2DM
type 2 diabetes mellitus
T3
triiodothyronine
TA
therapeutic area
TB
total bilirubin
TEAE
treatment-emergent adverse event
TGR5 
transmembrane G protein-coupled receptor
TPN
total parenteral nutrition
TSH
thyroid-stimulating hormone
TZD
thiazolidinediones
ULN
upper limit of normal
USA 
United States of America
VAS
visual analogue scale


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STUDY SYNOPSIS
Protocol number: SHP626-201
Drug: Volixibat potassium (SHP626)
Title of the study: A Phase 2 Double-Blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate 
the Safety, Tolerability and Efficacy of Volixibat Potassium, an Apical Sodium-Dependent Bile Acid 
Transporter Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
Number of subjects (total and for each treatment arm): Approximately 334 subjects will be screened to 
enroll 266 subjects to achieve 201 completers. After enrollment of at least 80 subjects (20/treatment arm – 3 
active and 1 placebo [PBO]) a 24-week interim analysis (IA) will eliminate at least one dose group based on the 
criteria provided to the Data Monitoring Committee; enrollment will continue to include approximately 67 
subjects in each of the remaining arms. The sample size target for this study is 67 completers in each of the 
treatment groups (201 total if 3 arms continue).  Including an additional 20 subjects to account for one dose 
dropped at the IA, 221 subjects are needed.   Therefore, approximately 266 (accounts for 20% of 221 dropping 
out) subjects will be randomized if three arms (2 SHP626 and 1 PBO) continue.  Fewer subjects are needed if 
more than one SHP626 dose is dropped.
Investigator(s):  Multicenter study
Site(s) and Region(s): 
Anticipated regions -US, Canada, and EU 
Estimated number of sites planned – 60 to 80
Study period (planned):
July 2016 to July 2019
Clinical phase:
2
Objectives:
Primary:  To evaluate the effect of volixibat compared to PBO on liver histology 
Secondary:  
•
To evaluate the safety and tolerability of volixibat compared to PBO
•
To evaluate the effect of volixibat compared to PBO on hepatic steatosis  (measured by MRI)
•
To evaluate the effect of volixibat compared to PBO on liver histology (measured by individual 
nonalcoholic fatty liver disease (NAFLD) activity score (NAS) components and fibrosis stage)
•
To evaluate the effect of volixibat compared to PBO on liver histology (measured by NASH resolution 
without worsening fibrosis)
•
To evaluate the effect of volixibat compared to PBO on serum liver-related biochemistry 
•
To evaluate the effect of volixibat compared to PBO on metabolic indicators (glucose, insulin, 
hemoglobin A1c [HbA1c]) 
•
To evaluate the effect of volixibat compared to PBO on serum lipids (cholesterol, HDL-C, LDL-C, 
triglycerides) 
Rationale: Currently, there is no approved medication for the treatment of NASH. Volixibat is under 
development for the treatment of NASH based on its mechanism of action (MOA) and is supported by 
nonclinical and Phase 1 data.  This is a Phase 2, 48-week, dose-finding study to examine the efficacy, 
tolerability, and safety of volixibat in adults with NASH.
Investigational product, dose, and mode of administration:

Volixibat 5, 10, and 20 mg and matched PBO capsules by mouth (PO) once daily (QD). Investigational 
product (IP) should be given 30 minutes prior to the first meal of the day containing approximately 10-20 


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grams of fat. Also see Section 6.2.3 (Dosing).

Identical PBO will be used as comparator 

Subjects should take the IP at the same time each day and should not take more than one dose in a day if 
they miss a dose
Methodology:
This study will be a Phase 2, 48-week, multicenter, double-blind, randomized, PBO-controlled, parallel group, 
proof of concept, dose-finding study, with one IA after at least 80 subjects have received 24 weeks of treatment.  
There will be 3 active arms of volixibat (5, 10 and 20 mg) and a PBO arm.  Subjects will be randomized to 
receive one of three doses of volixibat (5, 10, or 20 mg once daily (QD) or PBO in a 1:1:1:1 ratio.  Depending 
on the results of the IA, the study may be terminated or the randomization to one or more doses will be stopped.  
The follow-up period will be 4 weeks after last dose. Subjects will be expected to visit the study center at least 
10 times. 
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions.
2.
Ability to voluntarily provide written, signed, and dated (personally or via a legally-authorized 
representative, as applicable) informed consent to participate in the study.
3.
Age 18-80 years inclusive.  This inclusion criterion will only be assessed at the first screening visit.
4.
Male, or non-pregnant, non-lactating female, who is sexually active and who agrees to comply with the 
contraceptive requirements of the protocol, or females of non-childbearing potential.  Males and 
females of child-bearing potential who are sexually active must agree to use acceptable contraception 
during the study and 30 days following the last dose of the IP.
5.
Presence of ≥5% steatosis on screening MRI from a centrally read radiologist performed either during 
the screening period or within 6 months prior to the first visit.
6.
Histologic confirmation of NASH without cirrhosis (F1-F3) from a centrally read liver biopsy 
performed either during the screening period or within 6 months prior to the first visit with a NAS of 
≥4 with a score of at least 1 in each component (steatosis, lobular inflammation, and hepatocyte 
ballooning).
Exclusion Criteria:
1.
Presence of or history of cirrhosis or evidence of decompensated liver disease (ie, ascites, variceal 
bleeding, etc.) or hepatocellular carcinoma.
2.
History or presence of other concomitant liver disease as assessed by the investigator or determined by 
laboratory findings including, but not limited to: active hepatitis B virus (HBV) infection (hepatitis B 
surface antigen (HBsAg) positive and/or HBVDNA positive; subjects who are hepatitis B core 
antibody (HBcAb) positive may be eligible as long as HBsAg is negative and HBVDNA is
nondetectable), active hepatitis C virus (HCV) infection (prior exposure to HCV (defined as HCVAb 
positive without a current or prior history of a detectable HCVRNA) will be eligible, alcoholic liver 
disease, proven autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis 
(PSC), hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, bile duct obstruction, liver 
primary or metastatic cancer.
3.
Current or recurrent disease that could affect the action, absorption, disposition, or laboratory 
assessment of the IP (including bile salt metabolism in the intestine) eg, uncontrolled inflammatory 
bowel disease, uncontrolled celiac disease, gastric bypass procedures (gastric lap band or gastric sleeve 
is acceptable), ileal or ileocecal resection, uncontrolled irritable bowel syndrome with predominant 
diarrhea, or history of chronic diarrhea or loose stools of any etiology.
4.
Weight change ≥5% after qualifying liver biopsy and/or MRI performed. If the subject had a liver 


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biopsy and/or MRI within 6 months of screening, but experienced a weight change ≥5% since the date 
of liver biopsy and/or MRI, the liver biopsy and/or MRI must be repeated at screening.
5.
Contraindications to MRI (ie, claustrophobia, coronary stents, coronary implantable devices, girth, 
etc.).
6.
Current or relevant history of physical or psychiatric illness, any medical disorder that may require 
treatment or make the subject unlikely to complete the study.
7.
Treatment with Vitamin E, thiazolidinediones (TZD), or glucagon-like peptide-1 receptor agonists 
(GLP-1 RA) unless subject on a stable dose for 6 months prior to qualifying liver biopsy and not 
initiated after qualifying liver biopsy and will continue the same dosing regimen throughout study 
participation. 
8.
Uncontrolled diabetes defined as HbA1c of ≥9.0% within 60 days prior to enrollment. 
9.
Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) that 
could affect the action, absorption, or disposition of the IP, or clinical or laboratory assessment.  
(Current use is defined as use within 14 days of screening). Patients currently taking insulin will not be 
excluded; however, they must be on a stable dose for at least 30 days prior to screening. 
10. Use of drugs, herbs or supplements historically associated with causing or worsening NAFLD/NASH 
for less than 6 months prior to qualifying liver biopsy, or initiated any time after qualifying liver biopsy 
performed, including the use of total parenteral nutrition (TPN). 
11. Serum AST >5 times upper limit of normal (ULN) at screening.
12. Serum ALT >5 times ULN at screening.
13. Elevated serum creatinine ≥2.0 mg/dL.
14. International normalized ratio (INR) >1.3.
15. Total bilirubin (TB) ≥2.0 x ULN at screening (Except for documented Gilbert’s syndrome with 
bilirubin levels 20 µmol/L to 90 µmol/L (1.2 to 5.3 mg/dL) and with a ratio of 
unconjugated/conjugated bilirubin that is commensurately higher).
16. Platelet count <130 × 109L
17. Medical history of impaired hemostasis or current use of anticoagulant medication (use of antiplatelet 
medications, such as low-dose, ie, 81mg, aspirin (ASA) or clopidogrel (Plavix), will be allowed).
18. Uncontrolled thyroid disease.
19. Type 1 diabetes mellitus.
20. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or any of the 
stated ingredients.
21. Known history of alcohol or other substance abuse within the last year or at any time during the study 
based on investigator’s discretion.  Weekly alcohol intake greater than 21 grams/day for males and 14 
grams/day for females on average or inability to reliably quantify alcohol consumption based on 
investigator’s judgment.
22. Within 6 months of MRI and liver biopsy:

Have used any IP

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study
23. Inability to safely obtain a liver biopsy.
24. Females who are pregnant, planning to become pregnant, or are breastfeeding, or males who are 
planning to father a child during study participation.


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25. The anticipated need for a surgical procedure during the study that could interfere with the treatment. 
26. Known positivity for human immunodeficiency virus (HIV) infection.
27. Cancer within 5 years of screening, except for basal or squamous cell carcinoma of the skin or in situ 
cervical carcinoma that has been treated with no evidence of recurrence.
28. History of noncompliance with medical regimens, unreliability, mental instability or incompetence that 
could compromise the validity of informed consent or lead to noncompliance with the study protocol.
29. Any other conditions or abnormalities which, in the opinion of the investigator, may compromise the 
safety of the subject, or interfere with the subject participating.
30. Subject has failed screening or was previously enrolled in this study or is currently enrolled in this 
study at any study site (unless the subject is transferring to another qualified study site with prior 
Sponsor approval).
31. Subjects who are employees at the investigational site.
Maximum duration of subject involvement in the study:

Planned duration of screening period:  56 days 

Planned duration of enrollment period: 364 days

Planned duration of treatment period: 336 days 

Planned duration of follow-up: 28 days 
Endpoints and statistical analysis:
Safety Analysis Set will consist of all subjects who take at least 1 dose of randomized IP, and have at least 1 
post-baseline safety assessment (eg, coming back for any visit, reporting of an adverse event (AE) or reporting 
the absence of AEs).
Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have at least 1 post-baseline
efficacy assessment (eg, MRI, liver biopsy, serum liver-related biochemistry measurement).
Interim Analysis Set (IAS) will consist of all subjects in the Safety Analysis Set who have at least 1 post-
baseline efficacy assessment (eg, MRI, ALT biochemistry measurement) on or before the Week 24 visit at the 
time of the data cut for the IA.  
Screened Set will consist of all subjects who have signed an informed consent. 
Efficacy Endpoints:

Primary: Binary response indicating (yes/no) whether a subject responded at Week 48 with a reduction 
of at least 2 points without worsening of fibrosis from baseline NAS.

Secondary: 

Change from baseline to Week 48 on liver histology as measured by the individual NAS 
components (ballooning, inflammation, steatosis).  

Change from baseline to Week 48 on hepatic steatosis as measured by MRI-HFF.

Change from baseline to Week 48 on liver histology as measured by fibrosis stage. (NASH 
Clinical Research Network (CRN))

Resolution of NASH (defined as an overall histologic interpretation of no fatty liver disease or 
simple steatosis without steatohepatitis or isolated steatosis without steatohepatitis) without 
worsening of fibrosis as assessed by liver histology at week 48.

Change from baseline to Week 48 on serum liver-related biochemistry as measured by:

alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

alkaline phosphatase (ALP)

gamma glutamyl transferase (GGT)


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
total bilirubin (TB)

Change from baseline to Week 48 on metabolic indicators as measured by:

fasting serum glucose levels

insulin levels

HbA1c 

Change from baseline to Week 48 on serum lipids measured by: 

fasting total cholesterol

HDL-C

LDL-C

triglycerides 
Primary hypotheses:

Null: The proportion of subjects at Week 48 with a reduction of at least 2 points without worsening of 
fibrosis from baseline NAS does not differ between any of the volixibat doses and PBO.

Alternative: The proportion of subjects at Week 48 with a reduction of at least 2 points without 
worsening of fibrosis from baseline NAS does differ between at least one volixibat dose and PBO.
The FAS will be used to assess the primary efficacy endpoint. The difference between a volixibat dose and PBO 
will be tested with a stratified Cochran-Mantel-Haenzel test. The test will be stratified by presence or absence of 
Type 2 diabetes mellitus (T2DM) at baseline, and baseline NAS separated into two groups (NAS={4,5} or 
NAS={6,7,8}). Holm multiplicity adjustment will be applied prior to determining statistical significance at the 
0.1 level. Histology will be read by one central hepatohistopathologist who will use the NASH CRN standard 
scoring system – NAS. The SAF Steatosis (S), Activity (A), and Fibrosis (F) scoring system will be determined 
for exploratory purposes.
The Safety Analysis Set will be used to assess the safety endpoints including AEs (including changes from 
baseline in physical examination findings), vital signs, ECGs, and clinical laboratory tests (chemistry, 
hematology, coagulation and urinalysis).
AEs will be coded using the agreed upon version of the Medical Dictionary for Regulatory Activities 
(MedDRA). TEAEs are defined as AEs that started or worsened on or after the date of the first dose of IP, and 
no later than the follow-up visit. The number of events, incidence, and percentage of TEAEs will be presented 
by system organ class, preferred term, and by treatment group. TEAEs will be further summarized by severity 
and the relationship to the IP. AEs related to the IP, AEs leading to withdrawal, SAEs, and death will be 
similarly summarized/listed.
Vital signs, ECG findings, and clinical laboratory tests will be summarized by treatment group and visit. 
Potentially clinically important findings will be summarized. Graphical presentation may be used when deemed 
necessary.
For safety parameters, baseline is defined as the last assessment prior to the first dose of the IP.
Planned Interim Analysis:
An IA will be conducted by an independent data monitoring committee (DMC) after at least 80 subjects have 
received 24 weeks of treatment. The IA will evaluate the safety, tolerability and efficacy of 3 doses of volixibat 
each compared to PBO. 
Tolerability will be assessed by the number of discontinuations due to any one TEAE, presumably 
gastrointestinal events, most notably, diarrhea, loose stools, increased evacuations, and abdominal pain. Efficacy 
at the IA will be based on reduction of steatosis or ALT. Steatosis is assessed by MRI-HFF. Depending on the 
results from the IA, one or more doses of volixibat may be discontinued or the study may be terminated.  If the 
study is not terminated, subjects will receive a total of 48 weeks of the IP.


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Table 1:
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9
EOS
10
In-Clinic
Week
-8 to 0
0
2
4
8
12
24
36
48
52
Study Day
-56 to -1
0
14
28
56
84
168
252
336
364
Informed consent
X
Inclusion/exclusion criteria
X
X (review)
Demography, medical & medication 
history 
X
Physical examination
X
X
X
X
X
Heightc, weightd, waist circumference 
and waist:hip ratio
X
X
X
X
X
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
X
X
X
PRO (EQ-5D-5L)
X
X
X
Liver biopsyf
X
X
MRIg
X
Xh
X
ECG (12-lead)
X
X
X
X
Biochemistry and Hematologyi
X
X
X
X
X
X
X
X
X
X
Serum Glucose i,j
X
X
X
X
X
X
X
X
X
X
Urinalysisk
X
X
X
Urine Drug and Blood Alcohol Tests
X
X
Urine Pregnancy Testl
X
X
X
X
X
X
X
X
X
X
Lipid Paneli,m
X
X
X
X
X
X
X
X
X
X
Coagulation Paneli,n
X
X
X
X
X
Vitamins A, D, and E i
X
X
X
X
X


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Table 1:
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9
EOS
10
In-Clinic
Week
-8 to 0
0
2
4
8
12
24
36
48
52
Study Day
-56 to -1
0
14
28
56
84
168
252
336
364
HbA1ci
X
X
X
X
X
X
X
X
X
X
Serum Liver-Related Blood Testsi,o
X
X
X
X
X
X
X
X
X
X
Insulini
X
X
X
X
X
X
X
X
HIV, Hepatitis B/Ci,p
X
Thyroid testingi,q
X
X
X
X
X
X
X
C4 Sampling
X
X
X
X
X
IRT Accessed
X
X
X
X
X
X
X
X
X
X
Randomization
X
IP Dispensedr
X
X
X
X
X
X
X
IP Returned/Accountability & 
Compliance Assessed 
X
X
X
X
X
X
X
Stool Assessments
X
X
X
X
X
X
Adverse Eventst
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
ECG=electrocardiogram; EOS=end of study; HOMA=Homeostasis Model Assessment; IA=interim analysis; IP=investigational product; IRT=Interactive Response Technology; 
MRI=magnetic resonance imaging; PRO=patient-reported outcome.
a Visit Windows (calculated from Visit 2): Bi-weekly (Visits 3-4): +/- 3 days; Monthly (Visits 5-6, Visit 10): +/-5 days; Tri-monthly (Visits 7-9/DC): +/- 7 days. 
b Subjects will be reminded not to eat prior to their scheduled visit.  Additionally, during the double-blind treatment period, they should not take their study drug prior to the visit. 
They should bring their study drug with them to the visit to take 30 minutes prior to their first meal of the day containing approximately 10-20 grams of fat. Also see Section 6.2.3
c Height to be measured at screening only.
d BMI to be calculated programmatically by the sponsor or designee for the following visits: screening (Visit 1), baseline (Visit 2), Visits 7 and 9/DC.   


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Table 1:
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9
EOS
10
In-Clinic
Week
-8 to 0
0
2
4
8
12
24
36
48
52
Study Day
-56 to -1
0
14
28
56
84
168
252
336
364
e Vital signs to include oral or tympanic temperature, sitting blood pressure, pulse, and respiratory rate.
f Biopsy performed within 6 months of screening can be used. All biopsies will be centrally read by a hepatic histopathologist.
g MRI from a centrally read radiologist performed either during the screening period or within 6 months prior to the first visit. 
h - MRI at Visit 7 (Week 24) for the Interim Analysis Set only.
i All blood tests are fasting blood tests.
j HOMA-IR and HOMA-%B: will be calculated programmatically by the sponsor or designee for the following visits: screening (Visit 1), baseline (Visit 2), Visits 7, 9/DC, and 10.   
k Urinalysis to include oxalate testing.
lFor all females of child-bearing potential (FOCP).  Positive on-site urine dipstick results must have serum -HCG testing performed by central lab.
Additional testing can be performed at the investigator’s discretion.
m Lipid Panel includes fasting total cholesterol, HDL-C, LDL-C, and triglycerides.
n Full coagulation panel will be done at screening and baseline, but only PT/INR is required at remaining time points to assess vitamin K level. 
o Serum Liver-Related Blood Tests include ALT, AST, ALP, GGT, and total bilirubin.
p Hepatitis B/C testing includes HBcAb, HBsAg, HBVDNA and HCVAb, HCVRNA, respectively.
q Thyroid testing includes thyroid stimulating hormone (TSH) and triiodothyronine (T3).
r Investigational product may be dispensed at an unscheduled visit outside of this schedule as needed to replace lost or damaged product.
s Subjects will be queried about the number of stool evacuations during the 24- hour period before the clinical research center (CRC) visit and asked to describe the consistency of 
the softest stool during that 24- hour period using the Bristol Stool Chart.
t Adverse events will be collected beginning from the signing of informed consent.  All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in the study. Closure indicates that an outcome is reached, stabilization achieved (the 
investigator does not expect any further improvement or worsening of the event), or the event is otherwise explained. When appropriate, medical tests and examinations are 
performed so that resolution of event(s) can be documented.


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1.
BACKGROUND INFORMATION
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease 
worldwide (Vernon et al. 2011), and is estimated to occur in 30-40% of adults in the United 
States and up to 30% of European adults.  These numbers approach 95% in those with morbid 
obesity (Mathus-Vliegen et al. 2012).  NAFLD ranges from simple steatosis, which is typically 
nonprogressive, to nonalcoholic steatohepatitis (NASH), which has a 20% likelihood of 
progression to advanced disease including fibrosis, cirrhosis and its complications including liver 
failure and the need for a liver transplant (Angulo 2002).  Hepatocellular carcinoma is also a 
complication of NASH that may occur with or without the presence of cirrhosis 
(Torres et al. 2012).  NAFLD is typically associated  with type 2 diabetes mellitus (T2DM) 
(Adibi et al. 2007; Loomba et al. 2012), central or visceral obesity (Souza et al. 2012), 
dyslipidemia (Assy et al. 2000; N.C.E.P. 2002), and hypertension (Donati et al. 2004).  Together 
these conditions comprise the metabolic syndrome, and NASH is considered to be the hepatic 
component of this syndrome (Hamaguchi et al. 2005; Neuschwander-Tetri 2005;
Marchesini et al. 2005). Notably, NAFLD is a clinical condition occurring in individuals who do 
not drink excessive alcohol (>20 grams/day), yet have hepatic histology which is 
indistinguishable from that seen with alcoholic excess.  The pathophysiology of NASH is likely 
multifactorial and may include combinations of metabolic, genetic, environmental, and gut 
microbial factors.       
Most individuals with NASH are asymptomatic or have nonspecific symptoms such as fatigue. 
They typically first come to medical attention incidentally following routine blood testing or on 
imaging studies performed routinely or during the evaluation of an unrelated condition. While 
ultrasound and magnetic resonance imaging (MRI) can detect the presence of steatosis 
(Reeder et al. 2011), a liver biopsy is required to diagnose NASH and the extent of liver fibrosis. 
1.1
Indication and Current Treatment Options 
There are currently no drugs approved for the treatment of NASH and it is estimated that there 
are between 6-16 million people in the United States with NASH, of which 600,000 have severe 
disease (Williams et al. 2011 and Torres and Harrison 2008), with similar percentages reported 
throughout most areas of the world (World Gastroenterology Organisation 2012). Treatment of 
associated metabolic comorbidities, weight reduction, and incorporation of an exercise routine 
remain the cornerstone of management.  However, lifestyle changes are seldom successful. Thus, 
NASH represents a disease with an unmet medical need that is growing at an epidemic rate, and 
that if untreated, carries a risk of significant morbidity and mortality.
1.2
Product Background and Clinical Information
Volixibat potassium (SHP626; formerly LUM002), hereafter referred to as volixibat, is a highly 
selective inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that is being 
evaluated for the treatment of NASH.  
Bile acids (BA) promote bile flow, activation of digestive enzymes, and micellization of fats and 
fat-soluble vitamins, thereby permitting their intestinal absorption.  BAs serve as signaling 


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molecules acting via receptors, such as farnesoid X receptor (FXR) and transmembrane G 
protein-coupled receptor (TGR5), in the intestine, liver and other tissues which play an important 
role in regulating insulin homeostasis. (Halilbasic et al. 2013).  Lipid peroxidation and oxidant 
stress have been proposed as one link between the accumulation of fat and subsequent injury 
(Day and James 1998).  All of these metabolic actions have important effects to prevent the 
ongoing liver damage in NASH. 
High fat diet (HFD) fed mice treated with an ASBT inhibitor (ASBTi) (SC-435 a surrogate 
SHP626) normalized hepatic triglycerides and serum cholesterol, significantly improved insulin 
resistance (IR), and decreased NAS, predominantly steatosis.  In addition the BA pool reflected 
increases in BA that were agonists to FXR and decreases in levels that were antagonist to the 
FXR (Karpen et al. oral presentation AASLD 2015; Rao et al. 2015). Miethke and colleagues
(2016) found that pharmacological inhibition of the ileal, ASBT (SC-435 the surrogate molecule 
of volixibat), blocked progression of sclerosing cholangitis in mdr2–/– mice. Beneficial effects in 
liver histology in these mice included a reduction in the severity of hepatic fibrosis, a decrease 
which correlated with a reduction of hepatic profibrogenic gene expression. While very 
encouraging, whether or not the findings in this mouse sclerosing cholangitis model can translate 
to histologic improvements in patients with NASH is unknown.
Volixibat, as a potent inhibitor of ASBT, increases BA excretion and facilitates signaling in the 
intestine that regulates serum and hepatic BA concentrations, glucose metabolism, serum 
cholesterol and fatty acid metabolism in the liver.  The combined events resulting from inhibiting 
BA reuptake are hypothesized to have a positive metabolic, anti-inflammatory, anti-steatotic, and 
potentially antifibrotic effect that will lead to a therapeutic benefit for patients with NASH. 
One of the factors contributing to the pathogenesis of NASH is abnormal cholesterol metabolism 
and the accumulation of free cholesterol in the liver. The free cholesterol is directly toxic to 
hepatocytes, which leads to inflammation and fibrosis (Musso et al. 2013). One treatment 
approach is to remove the cholesterol from the liver to decrease and possibly reverse the damage 
to the hepatocytes. This is one of the mechanisms by which SHP626 will treat NASH.
Due to the mechanism of action (MOA), volixibat is under development for the treatment of 
NASH and may also be able to improve the metabolic syndrome that is associated with NASH. 
Volixibat inhibits ASBT therefore BAs are excreted in the feces and this loss forces the liver to 
synthesize new BA which utilizes cholesterol in the liver and serum. Volixibat also has the 
potential to reduce IR, which is considered to be the most common underlying risk factor for the 
development of NASH (Pagano et al. 2002; Sanyal et al. 2001). 
Volixibat was initially being evaluated for its use as an intervention for dyslipidemia.  As a result 
of initial observations in animals that serum low-density lipoprotein cholesterol (LDL-C) and 
total liver cholesterol content could be decreased after administration of volixibat, additional 
work was undertaken to support the safety and tolerability of the drug in healthy volunteers. 
Clinical and non-clinical studies have demonstrated very low systemic exposure across species. 
Oral administration of volixibat at doses up to 300 mg once daily and 50 mg administered daily 
for 14 days to healthy male subjects was generally safe.  A Phase 1 study revealed that volixibat 
is tolerated at the 10 mg dose for 28 days and that there were trends towards increasing high-


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density lipoprotein cholesterol (HDL-C), decreasing LDL-C, and decreasing fasting glucose in 
patients with T2DM (LUM002-101 trial). 
A healthy volunteer study investigating 12 days of varying levels of repeat doses of volixibat has 
provided key pharmacodynamic information for dose selection as measured by the effect of 
volixibat on excreted fecal bile acid (FBA) levels (SHP626-101).  In addition, the study 
investigated safety and tolerability over the dose range that was considered for this Phase 2 
study.
Data from Phase 1 studies support the position that volixibat is basically a non-absorbed drug 
that works locally in the GI tract and results in virtually no systemic exposure. Thus 
pharmacokinetic sampling will not be done in this study.
The current proof of concept (POC) Phase 2 trial will evaluate the safety, tolerability, and 
efficacy of three doses of volixibat  (5, 10, and 20 mg) in adult subjects with NASH. Due to the 
MOA of volixibat, efficacy will be assessed at an interim analysis (IA) by a change of steatosis 
from baseline to Week 24 compared to placebo (PBO).  While the gold standard for 
quantification of steatosis has historically been an invasive liver biopsy, quantitative magnetic 
resonance (MR) imaging–based biomarkers for liver fat have evolved rapidly over the last 
decade, and are increasingly being incorporated into NASH clinical trials.  Both MR 
spectroscopy (S) and MR imaging (I) proton density fat-fraction (PDFF) provide non-invasive 
means of quantifying intrahepatic lipid content (Reeder et al. 2012).  Both techniques have been 
shown to be accurate, reproducible with a low degree of variability in interpretation, cost-
effective and reliable biomarkers of quantitative hepatic fat (Roldan-Valadez et al. 2010; 
Urdzik et al. 2012;  Raptis et al. 2012).  Importantly, studies demonstrate a close correlation with 
steatosis grade histologically (Qayyum et al. 2005; Schwenzer et al. 2009).  
In a study of 51 adult subjects with NAFLD, PDFF correlated well with the grade of histologic 
steatosis, as the mean fat-fraction values of 8.9%, 16.3%, and 25.0% corresponded to histologic 
steatosis grades 1, 2, and 3, respectively (P < .0001) (Permutt et al. 2012). Thus, MRI will be 
utilized to evaluate the degree of steatosis change from baseline in this study during the IA. The 
Mozart trial was a randomized, double-blind, PBO-controlled trial of 50 patients with NASH 
who were randomized to 24 weeks of either ezetimibe or PBO, evaluating the reduction of liver 
fat by MRI-PDFF as well as by histology. Results revealed that compared to histologic non-
responders, histologic responders, defined as a two-point reduction in NAFLD activity score 
(NAS) without worsening fibrosis, had a statistically significant reduction in net MRI-PDFF of 
-4.1% ± 4.9 vs. +0.6% ± 4.1 (P <0.036) with a mean percent change of -29.3% ± 33.0 vs. 
+2.0% ± 24.0 (P < 0.004), respectively (Loomba et al. 2015). Thus, in the current trial during the 
IA, a ≥5% steatosis reduction for an active dose compared to PBO will be a clinically 
meaningful change after 24 weeks of therapy.
Intrahepatic lipid content of less than 1% is considered to be within the normal range 
(Springer et al. 2015), however, from a study of 2349 people in a general population undergoing 
MRS, it was concluded that a PDFF value of 5.56% represented the upper limit of the normal 
range, as determined from the 95th percentile of PDFF in 345 individuals who were not at 
increased risk for hepatic steatosis (Szczepaniak et al. 2005).  Thus, in the current trial, similar to 


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other NASH trials utilizing MR for evaluation, an MRI ≥5% steatosis will be used as an 
inclusion criterion (Loomba et al. 2015).  
1.3
Benefits and Risks
By virtue of volixibat’s ability to inhibit ASBT bile acid reabsorption, there is an increase in BA 
excretion and signaling in the intestine that results in improvements in glucose metabolism and 
changes in cholesterol and fatty acid synthesis in the liver. Recently, HFD fed mice treated with 
an ASBTi (SC-435 a surrogate of SHP626) normalized hepatic triglycerides and serum 
cholesterol, significantly improved IR, and decreased NAS (predominantly steatosis). In 
addition, these HFD-fed mice did not gain weight when treated with SC-435, in spite of 
consuming increased calories. Finally, the BA pool in these mice changed to predominantly FXR 
agonist (Karpen et al. oral presentation AASLD 2015; Rao et al. 2015).
These metabolic actions and preclinical results may prove to be clinically relevant to subjects 
with NASH.
NASH has recently received considerable attention as awareness of the problem of liver damage 
and prevalence of the disorder has increased, paralleling the obesity epidemic.  Consequences of 
liver damage are detrimental and can lead to liver failure, hepatocellular carcinoma, and the need 
for liver transplantation. There is no currently approved medical therapy for NASH. The large 
unmet medical need and the increased medical resource burden have led to the search for 
potential therapies to treat NASH.
Nonclinical testing established that the no observed adverse effect level (NOAEL) for volixibat 
in rats and dogs following 13 weeks of once-daily administration were 1000 and 500 mg/kg/day, 
respectively. Similarly, testing confirmed that the NOAEL for volixibat in a 6-month study in 
rats and a 9-month study in dogs were 1000 and 500 mg/kg/day, respectively. In both cases, 
these were the highest doses tested. Genotoxicity testing has yielded negative findings. 
Volixibat is minimally absorbed. The pharmacokinetic profiles performed in clinical studies 
completed to date repeatedly suggest negligible systemic exposure. Furthermore, there has been 
no observation of clinically relevant changes in fat absorption parameters such as those related to 
fat-soluble vitamins.
The most frequent TEAEs in the Phase 1 studies were GI and were considered mechanism-based 
due to elevated BA concentrations in the colon. The percentage of subjects reporting at least 1 
TEAE in the GI disorders SOC generally increased with an increasing volixibat dose level (Part 
1 Study TDU10632 and Study LUM002-101). Most TEAEs were mild in intensity, and none 
were assessed as severe.
In the multiple dose studies, the most commonly reported TEAEs in subjects (both healthy and 
with T2DM) who received volixibat for the longest duration of 28 days in Study LUM002-101 
included diarrhea and abdominal pain. The most commonly reported TEAEs in subjects 
receiving 50 mg volixibat for 14 days (part 3 Study TDR10633) were diarrhea and GI pain.


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Overall, there were 2 SAEs (ALT increased and retinal detachment), both of which led to the 
discontinuation of volixibat. In part 3 of the initial Phase 1 study (TDU10633), 1 subject dosed 
with 50 mg volixibat  for 13 days was withdrawn from the study due to a mild TEAE (which 
became a SAE due to prolonged hospitalization) of ALT increased that was considered related to 
volixibat . The subject’s ALT level returned to normal after discontinuation of volixibat. A 
second subject dosed with 10 mg volixibat for 12 days in Study LUM002-101 reported a 
moderate SAE of ablation of the retina with a bleed in the vitreous body of the right eye that was 
considered not related to volixibat.
Overall, 3 subjects, all dosed with 5 mg volixibat in Study LUM002-101, discontinued volixibat 
due to non-serious TEAEs: 1 due to a related TEAE of mild hemorrhagic diarrhea, 1 due to an 
unrelated TEAE of moderate Epstein-Barr virus infection, and 1 due to mild related TEAEs of 
diarrhea and anal erosion.
Overall, the observed AEs attributable to volixibat have been self-limited as would be expected 
given the local MOA of ASBT inhibition in the terminal ileum. Generally, among subjects who 
experienced GI TEAEs, the events have been mild and diminished over the course of treatment. 
Please refer to the investigator’s brochure for additional information.
Volixibat is a novel drug candidate, demonstrating limited systemic exposure across species with 
the potential to affect important metabolic pathways associated with NASH. The overall safety, 
tolerability, and preliminary activity of volixibat in available clinical trials suggest that further 
investigation is warranted and that there is a positive benefit to risk profile.
Always refer to the latest version of the Volixibat Potassium (SHP626) Investigator’s Brochure 
for the overall risk/benefit assessment and the most accurate and current information regarding 
the drug metabolism, pharmacokinetics, efficacy, and safety of volixibat. 
See Appendix 1 for protocol history, including all amendments.


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Currently there is no approved medication for the treatment of NASH. Volixibat is under 
development for the treatment of NASH based on its MOA and is supported by nonclinical and 
Phase 1 data.  This is a Phase 2, 48-week, dose-finding study to examine the efficacy,
tolerability, and safety of volixibat in adults with NASH.
2.2
Study Objectives
2.2.1
Primary Objective
To evaluate the effect of volixibat compared to PBO on liver histology 
2.2.2
Secondary Objectives

To evaluate the safety and tolerability of volixibat  compared to PBO 

To evaluate the effect of volixibat compared to PBO on hepatic steatosis  (measured by 
MRI)

To evaluate the effect of volixibat  compared to PBO on liver histology (measured by 
individual NAS components and fibrosis stage)

To evaluate the effect of volixibat compared to PBO on liver histology (measured by 
NASH resolution without worsening fibrosis)

To evaluate the effect of volixibat compared to PBO on serum liver-related biochemistry 

To evaluate the effect of volixibat compared to PBO on metabolic indicators (glucose, 
insulin, hemoglobin A1c [HbA1c]) 

To evaluate the effect of volixibat compared to PBO on serum lipids (cholesterol, HDL-
C, LDL-C, triglycerides) 
2.2.3
Exploratory Objectives

To explore the effect of volixibat compared to PBO on liver histology (measured by 
individual SAF scoring components: Steatosis (S), Activity (A), and Fibrosis (F)) 

To explore the effect of volixibat compared to PBO on anthropometric measures (body 
weight, body mass index (BMI), waist circumference and waist-hip ratio) 

To explore the effect of volixibat compared to PBO on homeostasis model assessment-IR 
(HOMA-IR) and HOMA-beta cell function (HOMA-%B) in subjects with T2DM 

To explore the effect of volixibat compared to PBO on BA synthesis (7-alpha-hydroxy-4-
cholesten-3-one [C4])


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
To explore the effect of volixibat on patient-reported health-related quality of life 
(HRQoL) and overall health status.


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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This study will be a Phase 2, 48-week, multicenter, double-blind, randomized, PBO-controlled, 
parallel group, proof of concept, dose-finding study, with one IA after at least 80 subjects have 
24 weeks of treatment.  There will be 3 active arms of volixibat (5, 10 and 20 mg) and a PBO 
arm. Subjects will be randomized to receive one of three doses of volixibat (5, 10, or 20 mg once 
daily (QD) or PBO in a 1:1:1:1 ratio such that a target of 266 subjects is achieved (221x1.2 is 
approximately 266).  The 221 subjects include 201 subjects for the three arms analyzed at 48 
weeks plus an additional 20 subjects to account for one dose dropped at the IA). Attempt will be 
made to perform the IA before any subject has had their 48-week post-treatment liver biopsy, 
although this will be dependent upon the rate of enrollment and dropout.
There will be up to 3 periods (screening, treatment, and follow-up) and an IA. The duration of 
the Treatment period will be 48 weeks, with an IA at Week 24.  Depending on the results of the 
IA, the study may be terminated or the randomization to one or more doses will be stopped.  The 
follow-up period will be 4 weeks after last dose.  Subjects will be expected to visit the study 
center at least 10 times.
The IA will be conducted by an independent data monitoring committee (DMC) after at least 
80 subjects have received 24 weeks of treatment. Study enrollment will be paused after 
92 subjects have been randomized. The IA will evaluate the safety, tolerability and efficacy of 3 
doses of volixibat each compared to PBO. 
Once decisions as to dose elimination are made, study enrollment will be reopened and 
additional sites may be added. Subjects recruited into the study prior to the IA will continue with 
the same dosing regimen for the duration of the planned study participation. Subjects recruited 
into the study after completion of the IA will be randomized evenly to the remaining dose groups
(noted by “[1 or 2]… Dose TBD” in Figure 1) or PBO group by IRT. Thus, depending on the 
results from the IA, the study may be terminated, or one or more doses of volixibat will be 
discontinued. If the study is not terminated, subjects will receive a total of 48 weeks of 
investigational product (IP).
The study will be conducted over 3 periods: screening (8 weeks), treatment (48 weeks), and 
follow-up (4 weeks), with an IA at 24 weeks as outlined in Figure 1.  


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Figure 1:
Study Design Flow Chart
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 364 days.  The 
last visit is an in-clinic safety follow-up visit. The study will be completed in approximately 3 
years.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment.  Please note that this includes the follow-up visit.  The 
Study Completion Date is used to ascertain timing for study results posting and reporting.
3.3
Sites and Regions
This study will be conducted at approximately 60 to 80 clinical sites in the USA, Canada, and 
EU.


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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.
2. Ability to voluntarily provide written, signed, and dated (personally or via a legally 
authorized representative, as applicable) informed consent to participate in the study.
3. Age 18-80 years inclusive. This inclusion criterion will only be assessed at the first screening
visit.
4. Male, or non-pregnant, non-lactating female, who is sexually active and who agrees to 
comply with the contraceptive requirements of the protocol, or females of non-childbearing 
potential.  Males and females of child-bearing potential who are sexually active must agree to 
use acceptable contraception during the study and for 30 days following the last dose of the 
IP as described in Section 4.4.
5. Presence of ≥5% steatosis on screening MRI from a centrally read radiologist performed 
either during the screening period or within 6 months prior to the first visit.
6. Histologic confirmation of NASH without cirrhosis (F1-F3) from a centrally read liver 
biopsy performed either during the screening period or within 6 months prior to the first  visit 
with a NAS of ≥4 with a score of at least 1 in each component (steatosis, lobular 
inflammation, and hepatocyte ballooning).
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Presence of or history of cirrhosis or evidence of decompensated liver disease (ie, ascites, 
variceal bleeding, etc.) or hepatocellular carcinoma.
2. History or presence of other concomitant liver disease as assessed by the investigator or 
determined by laboratory findings including, but not limited to: active hepatitis B virus 
(HBV) infection (hepatitis B surface antigen [HBsAg] positive and/or HBVDNA positive; 
subjects who are hepatitis B core antibody [HBcAb] positive may be eligible as long as 
HBsAg is negative and HBVDNA is nondetectable), active hepatitis C virus (HCV) infection 
(prior exposure to HCV [defined as HCVAb positive] without a current or prior history of a 
detectable HCVRNA) may be eligible, alcoholic liver disease, proven autoimmune hepatitis, 
primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, 
Wilson’s disease, alpha-1 antitrypsin deficiency, bile duct obstruction, liver primary or 
metastatic cancer.


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3. Current or recurrent disease that could affect the action, absorption, disposition, or laboratory 
assessment of the investigational product (IP) (including bile salt metabolism in the intestine) 
eg, uncontrolled inflammatory bowel disease, uncontrolled celiac disease, gastric bypass 
procedures (gastric lap band or gastric sleeve is acceptable), ileal or ileocecal resection, 
uncontrolled irritable bowel syndrome with predominant diarrhea, or history of chronic 
diarrhea or loose stools of any etiology.
4. Weight change ≥5% after qualifying liver biopsy and/or MRI performed. If the subject had a 
liver biopsy and/or MRI within 6 months of screening, but experienced a weight change of
≥5% since the date of liver biopsy and/or MRI, the liver biopsy and/or MRI must be repeated 
at screening.
5. Contraindications to MRI (eg, claustrophobia, coronary stents, coronary implantable devices, 
girth, etc.).
6. Current or relevant history of physical or psychiatric illness, any medical disorder that may 
require treatment or make the subject unlikely to complete the study.
7. Treatment with Vitamin E, thiazolidinediones (TZD), or glucagon-like peptide-1 receptor 
agonists (GLP-1 RA) unless subject on a stable dose for 6 months prior to qualifying liver 
biopsy and not initiated after qualifying liver biopsy and will continue the same dosing 
regimen throughout study participation (refer to Section 5.2.1, Permitted Treatment). 
8. Uncontrolled diabetes defined as HbA1c of ≥9.0% within 60 days prior to enrollment. 
9. Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations) that could affect the action, absorption, or disposition of the IP, or clinical or 
laboratory assessment.  (Current use is defined as use within 14 days of screening).  Patients 
currently taking insulin will not be excluded; however, they must be on a stable dose for at 
least 30 days prior to screening. Also refer to Section 5.2.2, Prohibited Treatment.
10. Use of drugs, herbs or supplements historically associated with causing or worsening 
NAFLD/NASH for less than 6 months prior to liver biopsy, or initiated any time after liver 
biopsy performed, including the use of total parenteral nutrition (TPN). Also refer to Section 
5.2.2, Prohibited Treatment.
11. Serum AST > 5 times upper limit of normal (ULN) at screening.
12. Serum ALT > 5 times ULN at screening.
13. Elevated serum creatinine ≥2.0 mg/dL.
14. International normalized ratio (INR) >1.3
15. TB ≥2.0 x ULN at screening (Except for documented Gilbert’s syndrome with bilirubin 
levels 20 µmol/L to 90 µmol/L (1.2 to 5.3 mg/dL) and with a ratio of 
unconjugated/conjugated bilirubin that is commensurately higher).
16. Platelet count <130 × 109/L
17. Medical history of impaired hemostasis or use of anticoagulant medication (use of 
antiplatelet medications, such as low-dose, ie 81 mg, aspirin (ASA) or clopidogrel (Plavix) 
will be allowed).
18. Uncontrolled thyroid disease.


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19. Type 1 diabetes mellitus.
20. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or 
any of the stated ingredients.
21. Known history of alcohol or other substance abuse within the last year or at any time during 
the study based on investigator’s discretion.  Refer to Section 7.2.3.8, Drug and Alcohol 
screening. Weekly alcohol intake greater than 21 grams/day for males and 14 grams/day for 
females on average or inability to reliably quantify alcohol consumption based on 
investigator’s judgment.
22. Within 6 months of MRI and liver biopsy:

Have used any IP

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study
23. Inability to safely obtain a liver biopsy.
24. Females who are pregnant, planning to become pregnant, or are breastfeeding, or males who 
are planning to father a child during study participation.
25. The anticipated need for a surgical procedure during the study that could interfere with the 
treatment. 
26. Known positivity for human immunodeficiency virus (HIV) infection.
27. Cancer within 5 years of screening, except for basal or squamous cell carcinoma of the skin 
or in situ cervical carcinoma that has been treated with no evidence of recurrence.
28. History of noncompliance with medical regimens, unreliability, mental instability or 
incompetence that could compromise the validity of informed consent or lead to 
noncompliance with the study protocol.
29. Any other conditions or abnormalities which, in the opinion of the investigator, may 
compromise the safety of the subject, or interfere with the subject participating.
30. Subject has failed screening or was previously enrolled in this study or is currently enrolled 
in this study at any study site (unless the subject is transferring to another qualified study site 
with prior Sponsor approval).
31. Subjects who are employees at the investigational site.
4.3
Restrictions 
Subjects must adhere to the following restrictions for the duration of the study:

Subjects must remain compliant with inclusion/exclusion criteria.

Subjects should not become pregnant, father a child, or nurse/breastfeed a baby. 

Subjects should be encouraged to adhere to the same exercise routine and a healthy diet 
throughout the study.


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4.4
Reproductive Potential
4.4.1
Female Contraception
Sexually active females of child-bearing potential should use an acceptable form of 
contraception. Females of child-bearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 30 days following the last dose of the IP. If 
hormonal contraceptives are used they should be administered according to the package insert. 
Female subjects should be either:

Post-menopausal (12 consecutive months of spontaneous amenorrhea and age 51 years)

Surgically sterile (having undergone one of the following surgical acts:  hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of child-bearing potential with a negative urine and/or serum -human chorionic 
gonadotropin (-HCG) pregnancy test each study visit. Females of child-bearing 
potential must agree to abstain from sexual activity that could result in pregnancy or 
agree to use acceptable methods of highly-effective contraception.
Acceptable methods of highly-effective contraception (ie, methods that result in a failure rate of 
<1% per year) are:

Combined (estrogen and progestogen containing) hormonal contraceptives associated 
with inhibition of ovulation (oral, intravaginal, transdermal) stabilized for at least 30 days 
prior to the screening visit (Visit 1) plus a barrier method (eg, condoms or diaphragms 
with spermicidal gel or foam)

Progestogen-only hormonal contraception associated with inhibition of ovulation plus a 
barrier method 

Intrauterine device (IUD) 

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Male sterilization/vasectomized partner

True abstinence: When this is in line with the preferred and usual lifestyle of the subject 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], 
declaration of abstinence for the duration of exposure to IMP, and withdrawal are not 
acceptable methods of contraception.)


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4.4.2
Male Contraception
Contraception is required for all sexually-active male subjects and their partners. All male 
subjects (including those who are sterile) agree not to donate sperm, and to use 1 of the following 
approved methods of contraception from the baseline visit on Day 0 until 30 days following 
study discharge:

Male condom with spermicide

Sterile sexual partner

Intrauterine device with spermicide (use by female sexual partner)

Female condom with spermicide (use by female sexual partner)

Contraceptive sponge with spermicide (use by female sexual partner)

Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with spermicide, or a 
cervical cap with spermicide) (use by female sexual partner)

Oral, implantable, transdermal, or injectable hormonal contraceptive (use by female 
sexual partner) plus a barrier method
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety).  The investigator is 
encouraged to discuss withdrawal of a subject from the IP with the CRO Medical Monitor when 
possible.
If the IP is discontinued, regardless of the reason, the evaluations listed for both Visit 9/end of 
study (EOS) and Visit 10/Follow-up, are to be performed as completely as possible; however, the 
EOS liver biopsy will not be required for patients discontinuing prior to Week 44. 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
source documents.  The reason for termination, date of stopping the IP, and the total amount of 
the IP taken must be recorded in the electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Medically important events that in the opinion of the investigator, medical monitor or sponsor 
would compromise the subject’s ability to safely continue in the study may result in withdrawal 
of the subject from the study.  Subjects who become pregnant or demonstrate disease 
progression, defined as the development of signs or symptoms of hepatic decompensation (ie,


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esophageal variceal hemorrhage, hepatic encephalopathy, ascites, or hepatocellular carcinoma), 
will be withdrawn from the study and followed as set forth in the protocol.
4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the eCRF.  If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the eCRF.  
Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol violation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Death

Screen failure 

Noncompliance with study drug

Physician decision

Pregnancy

Progressive disease (refer to Section 4.5.1)

Study terminated by sponsor

Other - If “Other” is selected, the investigator must specify on the eCRF 
4.5.3
Subjects Lost to Follow-up Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact clinic visit.  At least 1 of these documented 
attempts must include a written communication sent to the subject’s last known address via 
courier or mail (with an acknowledgement of receipt request) asking that they return to the site 
for final safety evaluations and return any unused IP.


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4.5.4
Safety-related Stopping Rules
Refer to Appendix 4 and Appendix 5 for criteria to assess severity of liver-related AEs and 
stopping rules for liver-related blood tests, respectively.
An urgent safety review will be conducted within 7 days by the sponsor and in consultation with 
the DMC if 1 or more of the following criteria are met:

Death that is considered related to the study drug

Two SAEs of similar type (defined as same or similar Medical Dictionary for Regulatory 
Activities (MedDRA) higher level group code), and considered related to the study drug.
The urgent review will be performed by a sponsor safety review group, which will include the 
study Pharmacovigilance and Risk Management (PVRM) Medical Lead and the PVRM 
therapeutic area (TA) Head, and in consultation with the DMC. The PVRM TA Head, not the 
PVRM Medical Lead involved in the study, may be unblinded as part of this urgent safety 
review, if required. Following the sponsor’s review of safety data and consultation with the 
DMC, one of the following actions will be taken with respect to study status:

Continue study with protocol unchanged

Continue study with modifications to the protocol

Terminate study
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment.


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5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to signing informed consent at the screening visit (Visit 1) and through the 
final study contact (including protocol-defined follow-up period) must be recorded on the 
appropriate eCRF page.
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
and behavioral treatment, non-pharmacological treatment, such as psychotherapy, as 
appropriate), received within 30 days of the date of first dose of the IP. Prior treatment 
information must be recorded on the appropriate eCRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of the IP 
and the end of the follow-up period, inclusive.  Concomitant treatment information must be 
recorded on the appropriate eCRF page.
5.2.1
Permitted Treatment
Medications and supplements including but not limited to vitamin E, betaine, s-adenosyl-l-
methionine, ursodeoxycholic acid, milk thistle, gemfibrozil, anti-TNF therapies, probiotics 
biguanides (metformin), thiazolidinediones (TZDs) and GLP-1 RAs that have been used to treat 
NAFLD/NASH are allowed during the course of the study if the subject has been on a stable 
dosing regimen (ie, same dose and frequency in the previous 6 months prior to the qualifying 
liver biopsy and not initiated after qualifying liver biopsy) and will continue this dosing regimen 
throughout study participation. Use of antiplatelet medications is also allowed.  The investigator 
must contact the CRO medical monitor then the Shire GCDL to discuss any changes to 
concomitant medications that may impact the study.
5.2.2
Prohibited Treatment
The following list of prohibited drugs cannot have been taken for more than 2 weeks within the 
year prior to randomization and are excluded while on study.

Systemic Glucocorticoids

Tamoxifen

Amiodarone

Methotrexate

Alcohol (see Section 4.2)

Griseofulvin

Valproate

Nucleoside Analogues

Tetracycline (high dose)

Estrogens at doses greater than 
used for hormone replacement

Anabolic steroids

Bile acid sequestrants such as 


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
Total parenteral nutrition
cholestyramine or colestipol

Any other known hepatotoxins 
including over-the counter 
therapies and herbal therapies 
such as germander, chaparral and 
ma-huang.
This is not a comprehensive list.  Treatments not listed above are generally considered allowable, 
unless considered a potential hepatotoxin.  Antidiarrheals will be allowed at the discretion of the 
investigator, with the exception of BA sequestrants.


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is volixibat potassium (volixibat), which will be provided in 5, 10 and 20 mg 
capsule form.  Additional information is provided in the current Volixibat Potassium (SHP626) 
Investigator’s Brochure.
The reference/comparator product is an identical PBO which will be provided in capsule form.  
6.1.1
Blinding the Treatment Assignment
The IP will be supplied as double-blind blister packs. The actual double-blind treatment given to 
individual subjects is determined by a randomization schedule which will be automatically 
assigned by the interactive response technology (IRT). Placebo capsules, which exactly match 
the IP, will be used in the blister packs to provide the same number and size capsules for each of 
the doses within the treatment groups.
6.2
Administration of Investigational Product(s)
All IP and supplies will be provided by Shire or its designee. At each visit, subjects will be 
supplied with enough IP to last until the subsequent visit. Lost or damaged IP will be replaced as 
needed. Volixibat will be supplied to the clinical research center (CRC) as powder in capsule. 
Volixibat will be supplied in identical capsules in strengths of 5, 10, and 20 mg (with matched 
PBO). 
6.2.1
Interactive Response Technology for Investigational Product Management
IRT will be used for the following investigational tasks:

Randomization

Supply management

Inventory management and supply ordering

Expiration tracking

Returns

Emergency unblinding
6.2.2
Allocation of Subjects to Treatment 
This is a double-blind, PBO-controlled study. The actual treatment given to individual subjects is 
determined by a randomization schedule.


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Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to the IP allocated to the 
subject, once eligibility has been determined.  
Individual subject treatment is automatically assigned by the IRT.
Once a randomization number/unique identifier has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study.  If a randomization number/unique 
identifier is allocated incorrectly, the clinical research associate (CRA)/study monitor must be 
notified as soon as the error is discovered. 
IP packaging identification numbers, separate from randomization numbers/unique identifiers, 
may also be assigned to subjects for specific treatment assignment as dictated by the study.  In 
these cases, the same IP packing identification number may not be assigned to more than 1 
subject.
Subjects will be equally allocated to all volixibat doses and PBO if their randomization precedes 
the 24 week IA. If a subject’s randomization occurs after the 24 week IA, subjects will be 
equally allocated to all remaining volixibat doses (determined based on the results of the IA) and 
PBO. The randomization will be stratified by baseline T2DM and NAS ≥6 or NAS = {4, 5}. 
6.2.3
Dosing
All doses of volixibat or matching PBO will be administered orally as a capsule in a double-
blinded fashion.  The first dose of IP for each subject will be administered in the clinic. The dose 
will be administered with 240 mL of water and should be given 30 minutes prior to the first meal 
of the day containing approximately 10-20 grams of fat. All assessments should be completed at 
least 30 minutes prior to administration of the IP. The subject should make all attempts to 
consistently take the IP around the same time each day.  If a dose is missed at the normally 
scheduled time, the subject can make up the dose that day; however, they should not take two 
doses in any 24-hour period.  
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the IP is required for further treatment of the subject. The investigator 
should contact the CRO medical monitor and the Shire GCDL at the same time and as soon as 
possible after the investigator has been unblinded.  
In the event that the treatment assignment is broken, the date and the signature of the person who 
broke the code are to be recorded in the source documents and the IRT, and the reason for 
breaking the code will be recorded in the source documents and the clinical database.  Upon 


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breaking the blind, the subject is withdrawn from the study, but should be followed up for safety 
purposes. Any code-breaks that occur must be reported to the CRO medical monitor.  Code-
break information is held by the pharmacist/designated person at the site and by the CRO 
medical monitor for the study or designee.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the IP container. 
All IP is labeled with a minimum of the protocol number, medication identification number, 
dosage form (including product name and quantity in pack), directions for use, storage 
conditions, expiry date (if applicable), batch number and/or packaging reference, the statements 
‘For clinical trial use only’, and/or ‘CAUTION: New Drug - Limited by Federal (or USA) Law 
to Investigational Use’, ‘Keep out of reach of children’, and the sponsor's name and address. Any 
additional labeling requirements for participating countries will also be included on the label.
Additional labels may, on a case-by-case basis, be applied to the IP in order to satisfy local or 
institutional requirements, but must not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
The sponsor or designee will provide the IP for this study. The IP is packaged in the following 
labeled containers:

Volixibat 5 mg capsules

Volixibat 10 mg capsules

Volixibat 20 mg capsules

Volixibat PBO capsules
6.3.3
Storage
The investigator has overall responsibility for ensuring that the IP is stored in a secure, limited-
access location.  Limited responsibility may be delegated to the pharmacy or member of the 
study team, but this delegation must be documented.  


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IPs are distributed by the pharmacy or nominated member of the study team. The 
pharmacist/nominated team member will enter the unique subject identifier on the IP labels as 
they are distributed. 
All IP must be stored at the clinic at 20 - 25oC (68 - 77oF); excursions are allowed between 15 -
30oC (59 - 86oF).
IPs must be stored in accordance with labeled storage conditions.  Temperature monitoring is 
required at the storage location to ensure that the IP is maintained within an established 
temperature range. The investigator is responsible for ensuring that the temperature is monitored 
throughout the duration of the study and that records are maintained; the temperature should be 
monitored continuously by using either an in-house system, a mechanical recording device such 
as a calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.  Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording.  The sponsor must be notified immediately upon discovery of any excursion below 
15oC (59oF) or above 30oC (86oF); these excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the IP and will 
provide supportive documentation as necessary.  Under no circumstances should the product be 
dispensed to subjects until the impact has been determined and the product is deemed appropriate 
for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the IP 
that could affect the integrity of the product(s), eg, fumigation of a storage room or a change in 
storage location.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the IP to carry out this protocol for the 
agreed number of subjects.  The investigator or designee will acknowledge receipt of the IP, 
documenting shipment content and condition.  Accurate records of all IP dispensed, used, 
returned, and/or destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing the IP.  Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator.  This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the IP only to subjects included in this study 
following the procedures set out in the study protocol.  Each subject will be given only the IP 
carrying his/her treatment assignment. All dispensed IP will be documented on the eCRFs and/or 
other IP record. The investigator is responsible to ensure the retrieval of all study supplies from 
subjects.


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No IP stock or returned inventory from a Shire-sponsored study may be removed from the site 
where originally shipped without prior knowledge and consent by the sponsor.  If such transfer is 
authorized by the sponsor, all applicable local, state, and national laws must be adhered to for the 
transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.  The site must ensure that the accountability and destruction 
records are complete, accurate, and ready for verification at each monitoring visit.
The process for return and destruction of IP must be determined and documented during the 
study start-up phase.
With the written agreement by the sponsor of the site’s IP destruction procedures, all unused 
stock, subject returned IP, and empty/used IP packaging may be destroyed at the site or a local 
facility on an ongoing basis throughout the study and at the end of the study following 
verification of accountability by the CRA/study monitor. In this case, destruction records 
identifying what was destroyed, when, how, and by whom, must be obtained with copies 
provided to the sponsor. Destruction of IP must be in accordance with local, state, and national 
laws.
Alternatively, in the absence of written agreement by the sponsor of the site’s IP destruction 
procedures, all unused stock, subject-returned IP, and empty/used IP packaging may be required 
to be sent to a nominated contractor on behalf of the sponsor for IP destruction on an ongoing 
basis throughout the study and at the end of the study. IP being returned to the sponsor’s 
designated contractors also must be counted and verified by clinical site personnel and the 
CRA/study monitor. For unused supplies where the original supplied tamper-evident feature is 
verified as intact, the tamper-evident feature must not be broken and the labeled amount is to be 
documented in lieu of counting. Shipment return forms, when used, must be signed prior to 
shipment from the site. Validated electronic return systems (ie, IRT) do not require a shipment 
form. Returned IP must be packed in a tamper-evident manner to ensure product integrity. 
Contact the sponsor for authorization to return any IP prior to shipment. Shipment of all returned 
IP must comply with local, state, and national laws.
6.5
Subject Compliance
Subjects must be instructed to bring their unused IP and empty/used IP packaging to every visit. 
Drug accountability must be assessed at the container/packaging level for unused IP that is 
contained within the original tamper-evident sealed container (eg, blister pack) or at the 
individual count level for opened containers/packaging. The pharmacist/nominated person will 
record details on the drug accountability form.


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7.
STUDY PROCEDURES
7.1
Study Schedule
This study will consist of a screening period of up to 56 days (the screening period may be 
minimally extended under special circumstances only with the explicit approval of the medical 
monitor), a 48-week Treatment period, and a Follow-up visit 4 weeks after treatment ends. A 
detailed display of all study procedures is provided in Table 1. 
Patients will be assessed according to the following schedule:

Screening – Visit 1  (Weeks -8 to 0 [Day -56 to Day -1])

Baseline – Visit 2  (Week 0 [Day 0])

Treatment and Assessments – Visits 3 through 9 (Week 2 through Week 48)

Follow-up – Visit 10 (Week 52, 4 weeks after completion of dosing) 
7.1.1
Screening (Visit 1) 
Screening procedures must be completed within 56 days prior to randomization for the first dose 
of the IP. The screening period may be minimally extended under special circumstances only 
with the explicit approval of the medical monitor. At the screening visit, considered Visit 1 
(Week -8 to 0, Day -56 to -1), all screening assessments and procedures are to be performed by 
the principal investigator or a qualified designee. See Table 1 for a complete list of screening 
procedures to be performed.
Written, signed, and dated informed consent from the subject prior to the performance of any 
study-related procedures must be obtained by the principal investigator or a designee. A copy of 
the signed informed consent form must be given to the subject for their records.
The following screening procedures should be assessed at the beginning of the visit window, 
preferably between Day -56 and Day -49: inclusion/exclusion criteria, collection of subject 
information (demographics, medical and medication history AEs, and concomitant medications), 
a physical examination including vital signs, height, weight, and waist/hip measurements; 
collection of blood and urine samples for screening and safety assessments, performance of an 
electrocardiogram (ECG), and scheduling of MRI and liver biopsy. MRI and liver biopsy (if one 
has not been completed in the previous 6 months) should be performed with sufficient time to 
ensure results are received prior to the baseline visit. 
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered the 
IP. Subjects cannot be rescreened once they have been designated as a screen failure.  However, 
a subject’s abnormal screening lab results may be repeated for confirmation before designating a 
subject as a screen failure.


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7.1.2
Baseline (Visit 2)
Following the screening visit, subjects will return to the clinic within 56 days for Visit 2, 
(considered Week 0, Day 0), for baseline assessments including review of the 
inclusion/exclusion criteria, adverse events, and concomitant medications; physical examination 
with vital signs, weight, and waist/hip measurements; ECG; collection of blood and urine 
samples; stool assessment; and completion of the patient-reported outcome (PRO) EuroQol-5 
Dimension-5 Level Questionnaire (EQ-5D-5L) survey. After completion of these assessments, 
subjects are randomized using Interactive Response Technology (IRT) to 1 of 4 treatment arms 
receiving volixibat 5 mg, 10 mg, or 20 mg, or PBO. The initial supply of study drug is dispensed 
to ensure adequate daily dosing until the next scheduled study visit.
7.1.3
Treatment and Assessment Period (Visits 3 through 9/EOS) 
During the 48 weeks of double-blind treatment, 7 clinic visits are scheduled to occur as follows:

Visit 3 - Week 2, Day 14 (+/- 3 days)

Visit 4 - Week 4, Day 28 (+/- 3 days)

Visit 5 - Week 8, Day 56 (+/- 5 days)

Visit 6 - Week 12, Day 84 (+/- 5 days)

Visit 7 - Week 24, Day 168 (+/- 7 days) – Interim Analysis

Visit 8 - Week 36, Day 252 (+/- 7 days)

Visit 9 - Week 48, Day 336 (+/- 7 days) – End of Study
Subjects are reminded not to eat and not to take their study drug on the day of scheduled study 
visits prior to completion of assessments. They should bring their study drug with them to the 
visit. All assessments should be completed at least 30 minutes prior to administration of the IP.
IP should be taken 30 minutes prior to the first meal of the day containing approximately 10-20 
grams of fat. 
The Schedule of Assessments provided in Table 1 details the procedures to be completed at each 
visit. All Treatment visits (3 through 9) will include weight and waist/hip measurements, 
assessment of vital signs, and blood sampling for completion of biochemistry, hematology, 
serum glucose, lipid panel, HbA1c, and serum liver-related blood tests. At all visits, adverse 
events, and concomitant medications will be collected for all subjects, and female subjects of 
childbearing potential will have a urine pregnancy test. Subjects will return containers of unused 
study drug for assessment of accountability and compliance which will be documented in the 
IRT. New supplies of study drug will be dispensed at Visits 3 through 8. 
Additional assessments will also occur less frequently during the Treatment Period for vitamin 
A, vitamin D, vitamin E, vitamin K via PT/INR, insulin, thyroid testing, urinalysis, ECG, 
physical examinations, stool assessment, and completion of the EQ-5D-5L. 


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An MRI will be repeated at Visit 7 for the 24-week IA and at Visit 9 (Week 48) for all subjects. 
A final liver biopsy will be performed at Visit 9 (Week 48) for all subjects unless a subject 
discontinues prior to Week 44, in which case the EOS liver biopsy is not required.
7.1.4
Follow-up (Visit 10)
The follow-up period for this protocol is 4 weeks after the last dose of study drug with a final 
Follow-up visit scheduled for Week 52. Procedures to be completed at this final visit include 
physical examination, weight, waist/hip measurements, vital signs, samples for biochemistry and 
hematology, serum glucose, lipid panel, HbA1c, serum liver-related blood tests, insulin, thyroid 
testing, stool assessment, and urine pregnancy test (for women of childbearing potential). 
Adverse events and concomitant medications will be recorded. All AEs and SAEs that are not 
resolved at the time of this contact will be followed to closure (see Section 8.1).
7.1.5
Additional Care of Subjects after the Study
No after care is planned for this study.
7.2
Study Evaluations and Procedures
All assessments and procedures are to be performed by the Investigator or a qualified designee 
who has been trained in the protocol. Assessments are to be performed according to the 
schedules shown in Table 1. If a subject terminates the study early, the CRC will make 
reasonable effort to perform the EOS and safety follow-up assessments and procedures for the 
subject’s safety and well-being.
7.2.1
Demographic and Other Baseline Characteristics
Demographic details will be obtained at screening and recorded on the eCRF. Data collected will 
include age, gender, ethnicity, height, and weight.
7.2.2
Efficacy
7.2.2.1
Liver Biopsy
Liver biopsies will provide histologic data for confirmation of the diagnosis of NASH, 
assessment and grading of NASH activity, and scoring of steatosis, lobular inflammation, 
ballooning, as well as fibrosis and additional features (see Appendix 2 and Laboratory Manual 
for additional information). 
7.2.2.2
MRI
The presence of ≥5% steatosis on screening MRI from a centrally read radiologist will be 
performed either during the screening period or within 6 months prior to the first visit. Steatosis 
is assessed by MRI hepatic fat fraction. The Week 24 MRI will be conducted for subjects in the 
IA set only.


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7.2.3
Safety
7.2.3.1
Medical History and Medications 
Medical history including important medical events and concomitant medication and illnesses 
will be obtained at screening and will be recorded on the eCRF. Any existing medical condition 
present prior to the time of randomization should be reported as medical history
7.2.3.2
Physical Examination 
A complete physical examination will be performed with a thorough review of body systems at 
screening, baseline prior to randomization, and at study visits specified in Table 1.  Physical 
examinations will include a review of the subject’s general appearance, as well as evaluation of 
the body systems including:

Eyes, ears, nose, throat

Lymph nodes

Cardiovascular

Skin

Abdomen

Neurological

Spine and extremities
Abnormalities identified at the screening visit (Visit 1) will be documented in the subject’s 
source documents and on the medical history eCRF. Changes after the screening visit (Visit 1) 
will be captured as AEs on the AE eCRF page, if deemed clinically significant by the 
investigator.
Height will be measured at the screening visit only while weight and waist and hip 
circumference will be recorded at all study visits. BMI will be calculated programmatically.   
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”).  
Adverse events are collected from the time informed consent is signed.  (Please refer to Section 
8, Adverse and Serious Adverse Events Assessment.)
7.2.3.4
Vital Signs
Vital signs include oral or tympanic temperature, sitting blood pressure, pulse, and respiratory 
rate. Blood pressure should be determined by cuff (using the same method, the same arm, and in 


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the same position throughout the study). Any deviations from baseline (Visit 2) vital signs which 
are deemed clinically significant in the opinion of the investigator are to be recorded as an AE.
7.2.3.5
Clinical Laboratory Evaluations 
All clinical laboratory assays will be performed according to the central laboratory’s normal 
procedures.  Reference ranges supplied by the central laboratory will be used to assess the 
clinical laboratory data for clinical significance and out-of-range pathological changes.  The 
investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Clinically 
significant findings should be evaluated for recording as adverse events on the eCRF. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry
Albumin (ALB)
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT; SGPT)
Aspartate aminotransferase (AST; SGOT)
Blood urea nitrogen (BUN)
C4
Calcium (Ca)
Bicarbonate (CO2)
Chloride (Cl)
Creatinine
Creatine kinase
Gamma glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
Magnesium (Mg)
Phosphate (P)
Potassium (K)
Sodium (Na)
Total and direct bilirubin
Total cholesterol
Protein
Triiodothyronine (T3)
Thyroid-stimulating hormone 
(TSH)
Triglycerides
Uric acid


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Hematology
Hemoglobin 
Hematocrit
Mean corpuscular hemoglobin (MCH)
Mean corpuscular volume (MCV)
Platelets
Red blood cell (RBC) 
White blood cell (WBC) count with 
differential
Prothrombin time (PT)
Activated partial thromboplastin time 
(aPTT)
International normalized ratio (INR)
Urinalysis
Appearance (clarity and color)
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Microscopic examination of sediment
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Oxalate
7.2.3.6
Additional Laboratory Assessments
Laboratory samples will be collected and assessed for:

HIV testing and assessment of Hepatitis B/C including HBcAb, HBsAg, HBVDNA, and 
HCVAb, and HCVRNA will occur at the screening visit only

Lipid panel including fasting total cholesterol, HDL-C, LDL-C, and triglycerides at each 
scheduled study visit (Visits 1 through 10)

HbA1c will be tested at every scheduled visit (Visits 1 through 10)

Full coagulation panel will be done at screening and baseline, but only PT/INR is 
required at remaining time points at Visits 4, 7, and 9

Insulin will be tested at screening, baseline, at Visit 4 and Visits 6 through 10

HOMA-IR and HOMA-%B: will be calculated programmatically from serum glucose 
tested at screening, baseline, Visits 7, 9, and 10


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
Vitamin A, Vitamin D, Vitamin E, and Vitamin K (via PT/INR) will be tested at 
screening, baseline, and Visits 4, 7, and 9

Thyroid testing including TSH and T3 will be tested at screening, baseline, and Visits 4, 
6, 7, 9, and 10

C4 samples will be collected at baseline and Visits 6, 7, 9, and 10
7.2.3.7
Pregnancy Test 
A urine pregnancy test is performed on all females of child-bearing potential at the screening
visit (Visit 1), baseline visit (Visit 2), at each Treatment visit (Visits 3 through 9) and at the Final 
visit (Visit 10), or if pregnancy is suspected, or on withdrawal of the subject from the study. A 
positive urine pregnancy test must be followed with a serum pregnancy test performed by the 
central laboratory. Additional testing can be performed at the investigator’s discretion. Also, 
refer to Section 8.1.7.
7.2.3.8
Drug and Alcohol Testing 
A urine screen for drugs of abuse and blood test for alcohol will be performed at screening and 
baseline as described in Table 1. Additional drug and alcohol screens may be performed at the 
investigator’s discretion.
Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiate metabolite, and phencyclidine. 
Results of drug and alcohol screens will be reviewed and verified by the study monitor, but will 
not be collected in the eCRF database.
Any positive result for drugs of abuse at the screening or baseline visits may exclude the subject 
from further participation in the study. A positive test for drugs of abuse or alcohol done at the 
investigator’s discretion discovered at any time during the study will be grounds for study 
discontinuation.
7.2.3.9
Electrocardiogram 
An ECG (12-lead) will be performed at the times specified in Table 1 in accordance with the 
clinical site’s standard practice(s) and equipment supplied by the CRC.  Recordings of ECGs 
will be read locally at the clinical site by the investigator or designee. The ECG will include 
assessments of heart rate and PR, RR, QRS, and QT intervals. Identification of any clinically 
significant findings and/or abnormalities will be recorded on the eCRF. 
7.2.3.10
Health-related Quality of Life Assessments
The EuroQol (EuroQol. 2016. Available at: http://www.euroqol.org. [Accessed 17 February 
2016]) EQ-5D-5L (“EQ-5D”) is a widely used standardized questionnaire that assesses generic 
HRQoL and is also recommended for health-economic evaluations.  The EQ-5D includes two 
components: a descriptive profile and a visual analogue scale (VAS).  The descriptive profile 


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includes five dimensions (ie, pain/discomfort, mobility, usual activities, self-care and 
anxiety/depression), each with five levels (ie, no problems, slight problems, moderate problems, 
severe problems, extreme problems). An EQ-5D index can also be derived from the data which 
summarizes health status using a single value (ie, health-state utility).  The psychometric 
properties of the EQ-5D-5L have been established and well documented (see Appendix 3).
7.2.3.11
Volume of Blood to be Drawn from Each Subject
During this study, it is expected that approximately 146 mL of blood will be drawn from all 
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 146 mL. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments may be combined. 


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4.  This includes events occurring during the screening phase of the 
study, regardless of whether or not the IP is administered.  Where possible, a diagnosis rather 
than a list of symptoms should be recorded.  If a diagnosis has not been made, then each 
symptom should be listed individually.  All AEs should be captured on the appropriate AE pages 
in the eCRF and in source documents.  In addition to untoward AEs, unexpected benefits outside 
the IP indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study.  Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained.  When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity.  An event that changes in severity should be captured as a new 
event.  Worsening of pre-treatment events, after initiation of the IP, must be recorded as new 
AEs (for example, if a subject experiences mild intermittent dyspepsia prior to dosing of the IP, 
but the dyspepsia becomes severe and more frequent after first dose of the IP has been 
administered, a new AE of severe dyspepsia (with the appropriate date of onset) is recorded on 
the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of daily 
living.
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.


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Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Appendix 4 provides criteria to assess the severity of liver-related adverse events.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to the IP for each AE.  The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the IP.  If there is no valid reason for 
suggesting a relationship, then the AE should be classified as “not related”.  Otherwise, if there is 
any valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect 
relationship between the IP and the occurrence of the AE, then the AE should be considered 
“related”.  The causality assessment must be documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the IP is 
compelling and/or follows a known or suspected response pattern to that product, and 
the event cannot be explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the IP and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF.  Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown.


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8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation of the disease and are part of the efficacy data to be collected in 
the study; however, significant worsening of the symptoms should be recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the IP, a shift of a parameter is 
observed from a normal value to an abnormal value, or a further worsening of an already 
abnormal value.  When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range, either while continuing treatment or after 
the end of treatment with the IP, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Criteria for Discontinuation of Treatment
Appendix 5 provides guidelines for discontinuation of treatment based on elevated ALT, AST, 
TB, and associated signs and symptoms.  
8.1.7
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.
Any report of pregnancy for any female study participant (or the female partner of a male 
participant) must be reported within 24 hours to the Shire Global Pharmacovigilance and Risk 
Management Department using the Shire Investigational and Marketed Products Pregnancy 
Report Form.  A copy of the Shire Investigational and Marketed Products Pregnancy Report 
Form (and any applicable follow-up reports) must also be sent to the CRO medical monitor and 
the Shire clinical physician using the details specified in the Emergency Contact Information 
section of the protocol. The pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days post 
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Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form.  Note:  An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and Non-
serious AEs Required by the Protocol Form as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form.  The test date of the first positive serum/urine -HCG test or 
ultrasound result will determine the pregnancy onset date.
8.1.8
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2.  Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of the IP when used for a non-medical 
purpose (eg, to alter one’s state of consciousness or get high) in a manner that may be 
detrimental to the individual and/or society

Misuse – Intentional use of the IP other than as directed or indicated at any dose (Note: 
this includes a situation where the IP is not used as directed at the dose prescribed by the 
protocol)

Overdose – Intentional or unintentional intake of a dose of an IP exceeding a pre-
specified total daily dose of the product.  

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an IP.  For studies, medication errors are reportable to the sponsor only as defined 
below.
Cases of subjects missing doses of the IP are not considered reportable as medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired IP should be considered as a reportable medication 
error.


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8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the Volixibat Potassium (SHP626) 
Investigator’s Brochure which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire GCDL within 24 hours of 
the first awareness of the event.  Note: The 24-hour reporting requirement for SAEs does not 
apply to reports of abuse, misuse, overdose, or medication errors (see Section 8.1.8) unless they 
result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note:  Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the Shire GCDL using the details specified in the Emergency Contact 
Information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to the IP or not) that at any dose:

Results in death

Is life-threatening.  Note: The term ‘life-threatening’ in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization.  Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs.  For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect


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
Is an important medical event.  Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions 
that do not result in inpatient hospitalization; or the development of drug dependency or 
drug abuse.  
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4, and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the Shire GCDL 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the IP and discovered by the investigator at any 
interval after the study has completed must be reported to the Shire Global Pharmacovigilance 
and Risk Management Department within 24 hours of the first awareness of the event.
8.2.4
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic.  In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.5
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date.  
For all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another IP action was previously taken (eg, drug interrupted, reduced, withdrawn), the action 
taken with the IP should be recorded as “dose not changed” or “not applicable” (if the subject 
never received the IP). The IP action of “withdrawn” should not be selected solely as a result of 
the subject’s death. 
8.2.6
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The CRO is responsible for notifying the relevant regulatory authorities as appropriate: USA 
central IRBs/EU central ECs of related, unexpected SAEs.


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In addition the CRO is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the SHP626-201 program.  
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.


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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan.  
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification are 
to be communicated to the site for resolution.  Only authorized personnel will make corrections 
to the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, IP serum concentrations, 
antibiotics to investigation product, treatment allocation, and IP preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available.  If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.  
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, IP exposure, and prior and concomitant medications.  The SAP will also include 
a description of how missing, unused and spurious data will be addressed.


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The SAP will be finalized prior to unblinding to preserve the integrity of the statistical analysis 
and study conclusions.  
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513). 
9.5
Planned Interim Analysis and Data Monitoring Committee 
9.5.1
Planned Interim Analysis
Study enrollment will be paused after 92 subjects have been randomized in order for an IA to be 
conducted after at least 80 subjects have received 24 weeks of treatment.  To protect study 
integrity, the IA will be performed by an independent statistician and statistical reporting group 
who are not involved in the clinical trial conduct and are not responsible for the final analysis of 
clinical trial data.  The IA will be performed to evaluate the safety, tolerability, and efficacy of 3 
doses of volixibat each compared to PBO and be used to drop 1 or more doses of volixibat, or to 
terminate the trial. 
The criteria for deciding whether or not to continue randomizing to a particular volixibat dose 
following the Week 24 IA will be specified in the DMC charter.  In general, randomization to 
any volixibat dose determined to be unsafe, intolerable or ineffective/futile at the IA will be 
discontinued.   If all of the volixibat doses are determined to be intolerable or ineffective/futile 
the clinical trial will be terminated. If none of the volixibat doses are determined to be unsafe, 
intolerable or ineffective/futile then randomization to the volixibat dose that is the least 
promising or least helpful in characterizing the dose-response relationship (as specified in the 
DMC charter) will be discontinued. Tolerability will be assessed by comparing the number of 
discontinuations due to any one TEAE (presumably gastrointestinal events, most notably, 
diarrhea, loose stools, increased evacuations, and abdominal pain) between each volixibat dose 
group and PBO group.  Efficacy will be assessed based on a reduction of steatosis (assessed by 
MRI-HFF) and ALT by comparing the change from baseline in MRI-HFF and percent change 
from baseline in ALT at Week 24 between each volixibat dose group and PBO group.
Subjects recruited into the study prior to the IA will continue with the same dosing regimen for 
the duration of the planned study participation. That is, a subject receiving a dose to which 
randomization is stopped after the IA will continue to receive that same dose throughout the 
course of the study, and complete all required assessments, unless a dose is determined to be 
unsafe, in which case the affected subjects would be discontinued from the study and followed as 
per Section 4.5. Subjects recruited into the study after completion of the IA will be randomized 
evenly to the remaining volixibat dose groups or PBO group by IRT.  Subjects will be 
randomized to 1 or 2 volixibat doses or to PBO.  Thus, depending on the results from the IA, the 
study may be terminated, or one or more doses of volixibat will be discontinued.  If the study is 
not terminated, subjects will receive a total of 48 weeks of IP.
9.5.2
Data Monitoring Committee
An independent DMC will be established to assess safety, tolerability, and efficacy during the 
study, as well as to ensure the validity and scientific merit of the trial.  The DMC will monitor 
ongoing data generated by the study at regular intervals for the duration of the study. Their role 


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is to protect the interests of the subjects in the study and of those still to be entered, by review of 
accumulating data generated in the study. If a safety concern is identified (eg, if either of the 
criteria are met in Section 4.5.4, Safety-related Stopping Rules), the DMC may recommend an 
action to the sponsor on further study conduct, including stopping the study at any time.
In addition, the DMC will review the results of the Week 24 IA and make recommendations 
concerning study discontinuation due to intolerability or futility, or the continued randomization 
of 1 or more volixibat dose groups and PBO.  
The roles, responsibilities, and rules governing operation of the DMC will be discussed in full in 
a DMC charter. The DMC charter will define the primary responsibilities of the DMC; guide its 
activities, its relationship with other study components, its membership, and the purpose and 
timings of its meetings. It will provide the procedures for ensuring confidentiality, formal 
communication, and outline of the content of reports that will be provided by the DMC. 
Appropriate summary statistics and data listings will be provided to the DMC by an independent 
statistician supported by an independent statistical reporting group not otherwise assigned to the 
study.  
The recommendations made by the DMC to alter the conduct of the study or to stop the study 
will be forwarded to Shire for final decision.  The implementation of any DMC recommendation 
is solely the responsibility of the sponsor.  Shire will forward such decisions to regulatory 
authorities, as appropriate.
9.6
Sample Size Calculation and Power Considerations 
These are the primary hypotheses that are being tested in this study:

Null: The proportion of subjects at Week 48 with a reduction of at least 2 points without 
worsening of fibrosis from baseline NAS does not differ between any of the volixibat
doses and PBO.

Alternative: The proportion of subjects at Week 48 with a reduction of at least 2 points 
without worsening of fibrosis from baseline NAS does differ between at least one 
volixibat dose and PBO.
Response rates of 21% (PBO) and 45% (active) were reported in the FLINT trial 
(Neuschwander-Tetri et al. 2015) using the same primary end-point of reduction of NAS by at 
least two points (without worsening of fibrosis).   Based on those response rates, 67 subjects per 
group completing the trial are needed for 80% power with a 10% type I error for a study 
comparing two volixibat doses to PBO.  Holm multiplicity adjustment was included in the 
sample size estimate.
Approximately 334 subjects will be screened to enroll 266 subjects to achieve 201 completers. 
After enrollment of at least 80 subjects (20/treatment arm – 3 active and 1 PBO) a 24-week IA 
will eliminate at least one dose group based on the criteria provided to the DMC; enrollment will 


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continue to include approximately 67 subjects in each of the remaining arms. The sample size 
target for this study is 67 completers in each of the treatment groups (201 total if 3 arms 
continue). Including an additional 20 subjects to account for one dose dropped at the IA, 221 
subjects are needed. Therefore, approximately 266 (accounts for 20% of 221 dropping out) 
subjects will be randomized if three arms (2 active and 1 PBO) continue. Fewer subjects are 
needed if more than one active dose is dropped.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Safety Analysis Set will consist of all subjects who take at least 1 dose of randomized IP, 
and have at least 1 post-baseline safety assessment (eg, coming back for any visit, reporting of an 
AE or reporting the absence of AEs).
The Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have at 
least 1 post-baseline efficacy assessment (eg, MRI, liver biopsy, serum liver-related biochemistry 
measurement).
The Interim Analysis Set (IAS) will consist of all subjects in the Safety Analysis Set who have at 
least 1 post-baseline efficacy assessment (eg, MRI, ALT biochemistry measurement) on or 
before the Week 24 visit at the data cut time of the IA. 
9.8
Efficacy Analyses
All efficacy analyses will be based on the FAS and all statistical tests will be 2-sided hypothesis 
tests performed at the 10% level of significance. Also, all confidence intervals will be 2-sided 
confidence intervals, unless otherwise stated.
9.8.1
Primary Efficacy Endpoint
The primary endpoint is the binary response indicating (yes/no) whether a subject responded at 
Week 48 with a reduction of at least 2 points, without worsening of fibrosis, from baseline NAS. 
The FAS will be used to assess the primary efficacy endpoint. The proportion of subjects at 
Week 48 with a reduction of at least 2 points without worsening of fibrosis from baseline NAS 
will be analyzed. The difference between a volixibat dose and PBO will be tested with a 
stratified Cochran-Mantel-Haenzel test. The test will be stratified by presence or absence of 
T2DM at baseline and baseline NAS separated into two groups (NAS={4, 5} or NAS={6,7,8}). 
Holm multiplicity adjustment will be applied prior to determining statistical significance at the 
0.1 level.
Analyses which explore the impact of the missing data on the primary efficacy endpoint will be 
conducted. These analyses may compare imputations of the missing values which favor the PBO 
and/or imputations which favor the active.  In addition, analyses utilizing existing HFF and/or 
ALT data may be performed.  Further, if the pattern of missing values does not appear uniformly 
distributed among the treatment arms, imputation method(s) based on informative missingness 


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may also be performed.  Analyses investigating the impact of missing data will be detailed in the 
Statistical Analysis Plan.
9.8.2
Secondary Efficacy Endpoints
Descriptive statistics will be presented for each time point at which the variable is measured (see 
Table 1) for the secondary efficacy endpoints.  Binary secondary efficacy endpoints will be 
analyzed with the same method (stratified Cochran-Mantel-Haenzel test) as the primary efficacy 
endpoint.  Continuous secondary efficacy endpoints will be analyzed with an ANCOVA model 
with change from baseline as the outcome variable; treatment group, presence or absence of 
T2DM at baseline, and baseline NAS separated into 2 groups (NAS={4,5} or NAS={6,7,8}) as 
factors and baseline values as a covariate.  Endpoints include:

Change from baseline to Week 48 on liver histology as measured by the individual NAS 
components (ballooning, inflammation, steatosis).

Change from baseline to Week 48 on hepatic steatosis as measured by MRI-HFF.

Change from baseline to Week 48 on liver histology as measured by fibrosis stage.
(NASH CRN) 

Resolution of NASH (defined as an overall histologic interpretation of no fatty liver 
disease or simple steatosis without steatohepatitis or isolated steatosis without 
steatohepatitis) without worsening of fibrosis as assessed by liver histology at Week 48.

Change from baseline to Week 48 on serum liver-related biochemistry as measured by:

alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

alkaline phosphatase (ALP)

gamma glutamyl transferase (GGT)

total bilirubin (TB)

Change from baseline to Week 48 on metabolic indicators as measured by:

fasting serum glucose levels

insulin levels

HbA1c

Change from baseline to Week 48 on serum lipids measured by:

fasting total cholesterol


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
HDL-C

LDL-C

triglycerides
9.8.3
Exploratory Efficacy Endpoints
Descriptive statistics will be presented for each time point at which the variable is measured (see 
Table 1) for the exploratory efficacy endpoints.  Binary exploratory efficacy endpoints will be 
analyzed with the same method (stratified Cochran-Mantel-Haenzel test) as the primary efficacy 
endpoint.  Continuous exploratory efficacy endpoints will be analyzed with an ANCOVA model 
with change from baseline as the outcome variable; treatment group, presence or absence of 
T2DM at baseline, and baseline NAS separated into 2 groups (NAS={4,5} or NAS={6,7,8}) as 
factors and baseline values as a covariate.  Endpoints include:

Change from baseline to Week 48 on liver histology as measured by the SAF scoring 
components: Steatosis (S), Activity (A), and Fibrosis (F)

Change from baseline to Week 48 on anthropomorphic measures: 

body weight

BMI 

waist circumference 

waist-hip ratio 

Change from baseline to Week 48 in subjects with T2DM on homeostasis measured by: 

Homeostasis model assessment -IR (HOMA-IR) 

HOMA-beta cell function (HOMA-%B) 
9.9
Safety Analyses
The Safety Analysis Set will be used to assess the safety endpoints. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  
Treatment-emergent AEs are defined as AEs that start or worsen on or after the date of the first 
dose of IP, and no later than the follow-up visit. The number of events, incidence, and percentage 
of TEAEs will be calculated by SOC, by preferred term, and by treatment group. 
Treatment-emergent AEs will be further summarized by severity and relationship to the IP. 
Adverse events related to the IP, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized/listed.


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Vital signs, ECG findings, and clinical laboratory tests will be summarized by treatment group 
and visit. Potentially clinically important findings will be summarized. Graphical presentation 
may be used when deemed necessary.
9.10 Other Analyses
9.10.1
Health-related Quality of Life Analyses

Change from baseline to Week 48 on the EQ-5D index (Appendix 3). The EQ-5D index 
will be derived using published UK-based preference weights. Univariate descriptive 
statistics and multivariate regression analyses adjusting for selected baseline covariates 
will be undertaken.

Change from baseline to Week 48 on the EQ-5D VAS score. Univariate descriptive 
statistics and multivariate regression analyses adjusting for selected baseline covariates 
will be undertaken.

Change from baseline to Week 48 in the proportion of subjects reporting having 
problems (none, slight, moderate, severe, extreme) with pain/discomfort, mobility, usual-
activities, self-care, anxiety/depression in the EQ-5D questionnaire.  Proportions and 
95% confidence intervals will also be generated for the baseline and Week 48 values as 
well as for change from baseline.
9.10.2
Stool Assessment
Stool hardness and number of evacuations will be assessed throughout the study. Stool hardness 
will be assessed for the softest evacuation within 24 hours of each clinic visit using the Bristol 
Stool Chart, a medical aid designed to classify the form of human feces into 7 categories where 
Type 1 is the hardest and Type 7 is the softest. Appendix 6 provides a sample of the Bristol Stool 
Chart.  Number of evacuations within the past 24 hours prior to the clinic visit will be recorded 
at specified times as per Table 1. Descriptive statistics by treatment group will be presented for 
each time point at which the variable is measured.


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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study.  The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of the IP 
for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites.  
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 


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Community guideline on GCP.  This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason.  
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.do
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification.  Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies.  Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.


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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation.  The 
investigator will also return all the IP, containers, and other study materials to the sponsor.  Upon 
study completion, the investigator will provide the sponsor, IRB/EC, and regulatory agency with 
final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
eCRFs are supplied by the sponsor and should be handled in accordance with instructions from 
the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. eCRFs must be completed by 
the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
All eCRF data must be endorsed by the investigator.
The CRA/study monitor will verify the contents of the eCRF against the source data per the 
monitoring plan. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents.  The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 


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regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, images, etc.).  Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other 
USA national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor.  The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in the IP; any significant equity 
interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments.  All consent 
documentation must be in accordance with applicable regulations and GCP.  Each subject or the 
subject’s legally-authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally-authorized representative, as applicable. This document may 
require translation into the local language.  Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form which was 
reviewed by the IRB/EC and which received their favorable opinion/approval.  A copy of the 


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IRB/EC’s written favorable opinion/approval of these documents must be provided to the 
sponsor, prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to study start that another party (ie, sponsor 
or coordinating principal investigator) is responsible for this action.  Additionally, if the IRB/EC 
requires modification of the sample subject information and consent document provided by the 
sponsor, the documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
IP supplies will not be released until the sponsor or its designee has received written IRB/EC 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions.  The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All USA-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996.  A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the sponsor or its designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study.  These records and data may, 
in addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 


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market volixibat; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed.  The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded.  They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted.  The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative.  Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire.  The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.  The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study.  To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications.  To the extent that the principal investigator has such sole, 
joint or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 


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agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results.  If such a multicenter publication is not submitted to 
a journal for publication by the sponsor within an 18-month period after conclusion, 
abandonment, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section.  The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards.  Participation as an investigator does not confer any rights to 
authorship of publications.


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11.
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Rao, A., Kosters, A., Mells, J., Keller, B., Yin, H., Banton, S., Li, S., Jones, D. P., Wu, H., 
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transporter inhibitor protects against non-alcoholic fatty liver disease in high fat diet-fed mice. 
Hepatology, 62, 217A.
Raptis, D. A., Fischer, M. A., Graf, R., Nanz, D., Weber, A., Moritz, W., Tian, Y., Oberkofler, 
C. E. & Clavien, P. A. 2012. MRI: the new reference standard in quantifying hepatic steatosis? 
Gut, 61, 117-27.
Reeder, S. B., Cruite, I., Hamilton, G. & Sirlin, C. B. 2011. Quantitative Assessment of Liver Fat 
with Magnetic Resonance Imaging and Spectroscopy. J Magn Reson Imaging, 34, 1011-1014.
Reeder, S. B., Hu, H. H. & Sirlin, C. B. 2012. Proton density fat-fraction: a standardized MR-
based biomarker of tissue fat concentration. J Magn Reson Imaging, 36, 1011-4.
Roldan-Valadez, E., Favila, R., Martinez-Lopez, M., Uribe, M., Rios, C. & Mendez-Sanchez, N. 
2010. In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty liver 
disease: Correlation with biochemical method and morphometry. J Hepatol, 53, 732-7.
Sanyal, A. J., Campbell-Sargent, C., Mirshahi, F., Rizzo, W. B., Contos, M. J., Sterling, R. K., 
Luketic, V. A., Shiffman, M. L. & Clore, J. N. 2001. Nonalcoholic steatohepatitis: association of 
insulin resistance and mitochondrial abnormalities. Gastroenterology, 120, 1183-92.
Schwenzer, N. F., Springer, F., Schraml, C., Stefan, N., Machann, J. & Schick, F. 2009. Non-
invasive assessment and quantification of liver steatosis by ultrasound, computed tomography 
and magnetic resonance. J Hepatol, 51, 433-45.
Souza, M. R., Diniz Mde, F., Medeiros-Filho, J. E. & Araujo, M. S. 2012. Metabolic syndrome 
and risk factors for non-alcoholic fatty liver disease. Arq Gastroenterol, 49, 89-96.
Springer, F., Ballweg, V., Schweizer, R., Schick, F., Ranke, M. B., Binder, G. & Ehehalt, S. 
2015. Changes in whole-body fat distribution, intrahepatic lipids, and insulin resistance of obese 
adolescents during a low-level lifestyle intervention. Eur J Pediatr, 174, 1603-12.
Szczepaniak, L. S., Nurenberg, P., Leonard, D., Browning, J. D., Reingold, J. S., Grundy, S., 
Hobbs, H. H. & Dobbins, R. L. 2005. Magnetic resonance spectroscopy to measure hepatic 
triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol 
Endocrinol Metab, 288, E462-8.
Torres, D. M. & Harrison, S. A. 2008. Diagnosis and therapy of nonalcoholic steatohepatitis. 
Gastroenterology, 134, 1682-98.
Torres, D. M., Williams, C. D. & Harrison, S. A. 2012. Features, diagnosis, and treatment of 
nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol, 10, 837-58.


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Urdzik, J., Bjerner, T., Wanders, A., Weis, J., Duraj, F., Haglund, U. & Noren, A. 2012. The 
value of pre-operative magnetic resonance spectroscopy in the assessment of steatohepatitis in 
patients with colorectal liver metastasis. J Hepatol, 56, 640-6.
Vernon, G., Baranova, A. & Younossi, Z. M. 2011. Systematic review: the epidemiology and 
natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. 
Aliment Pharmacol Ther, 34, 274-85.
Williams, C. D., Stengel, J., Asike, M. I., Torres, D. M., Shaw, J., Contreras, M., Landt, C. L. & 
Harrison, S. A. 2011. Prevalence of nonalcoholic fatty liver disease and nonalcoholic 
steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a 
prospective study. Gastroenterology, 140, 124-31.
World Gastroenterology Organisation 2012. World Gastroenterology Organisation Global 
Guidelines: Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis.


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12.
APPENDICES


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APPENDIX 1
PROTOCOL HISTORY 
Document
Date
Global/Country/Site Specific
Original Protocol
24 February 2016
Global
Amendment 1
8 April 2016
Global
Amendment 2
19 July 2016
Global


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APPENDIX 2
FATTY LIVER DISEASE HISTOLOGY SCORING
Diagnosis: NASH, Suspicious/Borderline NASH (type a or b), NAFLD, Not NAFLD
NAS SCORING
Steatosis
0       <5%
1        5-33%
2        34-66%
3        67-100%
Lobular Inflammation
0        no foci
1        < 2 foci per 200x field
2        2-4 foci per 200x field
3        > 4 foci per 200 x field
Ballooning
0       None
1       Rare or diagnostically borderline
2       Many or Prominent ballooned hepatocytes
            SAF SCORING
Steatosis
0         <5%
1        5-33%
2        34-66%
3        67-100%
Ballooning
0        normal hepatocytes with  cuboidal shape and pink cytoplasm
1       clusters of hepatocytes with rounded shape and pale cytoplasm usually  reticulated      
2       grade 1 plus enlarged hepatocytes, 2 x bigger than normal cells. 
Lobular Inflammation
0       none
1       < 2 foci per 200x field
2       >2 foci per 200x field
Steatosis 1,2,3 + Ballooning 1,2 + Lobular Inflammation  1,2 = NASH
Steatosis 1,2,3 +Ballooning 0 + Lobular Inflammation 0,1,2 = NAFLD
Steatosis 1,2,3 + Ballooning 1,2 + Lobular 0 = NAFLD
Steatosis 0 = no NAFLD
FIBROSIS SCORE
None
0
Mild zone 3 perisinusoidal (requires trichrome)
1a
Moderate Zone 3 perisinusoidal (visible on H&E)
1b
Portal/periportal only
1c
Portal, periportal and perisinusoidal
2
Bridging
3
Cirrhosis
4
References: Kleiner et al. 2005; Bedossa 2012


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ADDITIONAL SCORING FEATURES
Expanded Balloon Score
0: None
1: Few Non classic
2: Few Classic
3. Many Classic
4: Severe Classic
Portal Inflammation
0: None
1: Minimal
2: Mild
3: More than Mild
Megamitochondria
0: None
1: Present
Acidophil Bodies
0: None or rare
1: Present
For stage 2 or greater fibrosis
Portal Predominant
Central Predominant
No predominance
Steatosis Zone
Zone 1 predominant
Zone 3 predominant
Azonal
Panacinar
Glycogenosis
None
Focal
Diffuse


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APPENDIX 3
EQ-5D-5L HEALTH QUESTIONNAIRE
UK SAMPLE ONLY, NOT FOR OFFICIAL USE


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Under each heading, piease tick the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems in walking about 
I have sJight problems in walking about 
I have moderate problems in walking about 
I have severe problems in walking about 
I am unable to walk about 
SELF-CARE 
I have no problems washing or dressing mys.elf 
I have slight problems washing or dressing myself 
I have moderate probtems washing or dressing mysetf 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, housework, famHy or 
leisure activities) 
I have no problems doing my usual activities 
I have sJtght problems doing my usual activities 
I have moderate problems doing my usual activities 
I have severe probtems doing my usuaJ activities 
I am unable to do my usual activities 
PAIN I DISCOMFORT 
I have no pain or discomfort 
I have sHght pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
ANXIETY I DEPRESSION 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderatety anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
2 
to< (Engish) (> 2C09 Eun>Qol Grocf> E~N 
Gallade"""* dille Eun>Qol Grocf> 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 


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• 
We would like to know how good or bad your heotth is TODAY. 
• 
This seate is numbered from 0 to 100. 
• 
100 means the best heatth you can imagine. 
o means me worst heanh you can 1mag1ne. 
• 
Martt an X on the scale to indicate how your health is TODAY. 
• 
Now, please write the number you marked on the seale in the box 
below. 
YOURHEALTHTODAY• D 
3 
(A( (&ogi$Jt) 40 2009 E..oQoi G"'f' eo,so~ is • a.o. -of flit &oOol G"'f' 
Thebes<-
)'OUcaf'l~ 
T 
100 
G5 
:£ 
go 
85 
80 
-t-
75 t 
70 
115 
-!-
eo 
:t: 
± ± 
~ 
55 
50 
•5 
•o 
35 
30 
25 
20 
15 
__±__ 
10 
1 
5 
0 
The worst heahh 
you can imagin@ 


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APPENDIX 4
CRITERIA TO ASSESS SEVERITY OF LIVER-
RELATED ADVERSE EVENTS
Parameter
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
ALT
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
AST
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
Alkaline 
Phosphatase
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
GGT
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
Bilirubin
Normal
>1.0-1.5
>1.5-2.5
>2.5-5
>5
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = 
gamma glutamyl transferase. 
NOTE: Values expressed as multiples of the upper limit of the normal range (ULN).


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APPENDIX 5
STOPPING RULES FOR LIVER-RELATED BLOOD 
TESTS 

ALT or AST >6xULN (confirmed with repeat within 24hrs)

ALT or AST >5xULN for more than 2 weeks 

ALT or AST >3xULN and (TBL >2xULN or INR >1.5) 

ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
If ALT or AST elevations do not fall within the above parameters, but are > 4 ×ULN 
subject should remain on study drug with close observation which includes: 
1. Immediately contacting the CRO medical monitor. 
2. Repeating liver enzyme and serum bilirubin tests two or three times weekly. 
Frequency of retesting can decrease to once a week or less if abnormalities stabilize or 
the trial drug has been discontinued and the subject is asymptomatic. 
3. Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
4. Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets. 
5. Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease., or other disease at the 
discretion of the investigator
6. Obtaining a history of exposure to environmental chemical agents. 
7. Obtaining additional tests to evaluate liver function, as appropriate (eg, INR, direct 
bilirubin). 


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APPENDIX 6
BRISTOL STOOL CHART


PROTOCOL: SHP626-201
TITLE:
A Phase 2 Double-Blind, Randomized, Placebo-controlled, Dose-finding 
Study to Evaluate the Safety, Tolerability and Efficacy of Volixibat 
Potassium, an Apical Sodium-Dependent Bile Acid Transporter 
Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
DRUG:
Volixibat potassium  (SHP626)
IND:
123,847
EUDRACT NO.:
2016-000203-82
SPONSOR: 
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
Philip Newsome MD
Director of Centre for Liver Research 
University of Birmingham
Edgbaston, Birmingham B15 2TT UK
NATIONAL/
COORDINATING
INVESTIGATOR/UK
Guruprasad P Aithal MBBS, MD, FRCP, PhD
Head of the Division, Nottingham Digestive Diseases Centre
Director, NIHR Nottingham Digestive Diseases Biomedical Research 
Unit 
Nottingham University Hospitals and University of Nottingham
Queen's Medical Centre
Nottingham NG7 2UH
PROTOCOL 
HISTORY:
Amendment 1: 8 April 2016
Original Protocol:  24 February 2016 
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations.  This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.


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8 April 2016
PROTOCOL SIGNATURE PAGE 
I have read this protocol for Shire Study SHP626-20 I. 
Title: A Phase 2 Double-Blind, Randomized, Placebo-controlled, Do&e-finding Study to Evaluate the 
Safety, Tolerability and Efficacy of V olixibat Potassium, an Apical Sodium-Dependent Bile Acid 
Transporter Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the infon:nation in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely ten:ninate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from e:;;ecution ofthe study I will communicate my intention 
immediately \n writing to the sponsor. 


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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
8 April 2016
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Emergency Contact Information updated
Emergency Contact Information
Abbreviations list updated
Abbreviations
Requirement for meal fat content of 10-20 grams before daily dose of 
investigational product added
Synopsis
Table 1 Schedule of Assessments
Sections 6.2.3, 7.1.3
Inclusion Criterion #6 clarified fibrosis stage F1-F3
Synopsis
Section 4.1
Exclusion Criterion #6 shortened sentence for clarity
Synopsis
Section 4.2
Exclusion Criterion #7 cross referenced to Section 5.2.1 Permitted 
Treatment
Synopsis
Section 4.2
Exclusion Criterion #9  referred to Section 5.2.2 Prohibited Treatment
Synopsis
Section 4.2
Exclusion Criterion #17 dose for current use of low-dose aspirin (81 mg) 
allowed
Synopsis
Section 4.2
Exclusion Criterion #21 clarified weekly alcohol intake measurement 
from units to grams/day; added statement that subjects could be excluded 
at any time during the study based on investigator discretion due to 
alcohol or substance abuse
Synopsis
Section 4.2
Planned duration of screening period increased from 42 to 56 days
Synopsis
Table 1 Schedule of Assessments
Sections 7.1, 7.1.1, 7.1.2
Secondary endpoint of MRI-HFF clarified for subjects included in the IA
Synopsis
Primary hypothesis was clarified to Null and Alternative hypotheses 
Synopsis
Section 9.6
Clarified that NAS ≥ 6 is 6, 7, 8
Synopsis
Sections 6.2.2
Screening period changed from -6 to -8 weeks 
Table 1 Schedule of Assessments
Section 3.1
Figure 1
Sections 7.1, 7.1.1
Footnote deleted for ECG; all subsequent footnotes revised
Table 1 Schedule of Assessments
Footnote l revised serum pregnancy test from reflex to serum β-HCG
Table 1 Schedule of Assessments
Reference to Karpen oral presentation at AASLD added
Sections 1.2, 1.3


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Inclusion Criterion #4 added cross reference to Section 4.4 Reproductive 
Potential
Section 4.1
Exclusion Criteria #9 and #10 added cross reference to Section 5.2.2 
Prohibited Treatment
Section 4.2
Exclusion Criterion #21 added cross reference to Section 7.2.3.8 Drug 
and Alcohol Screening
Section 4.2
Acceptable methods of contraception were modified to delete the use of 
double-barrier methods and clarify barrier methods, add male 
sterilization, add and define abstinence
Section 4.4.1
Section 4.4.2
Deleted statement regarding withdrawal of subjects for missing >3 
consecutive days of dosing
Section 4.5
Redefined PVRM physician as PVRM Medical Lead
Section 4.5.4
Additional permitted medications and supplements were further defined 
and sponsor medical monitor was redefined as Shire GCDL
Section 5.2.1
Additional prohibited over-the-counter and herbal therapies were 
specified and a note was added that the list is not comprehensive
Section 5.2.2
Dosing statement deleted from Section 6.2 and moved to Section 6.2.3
Sections 6.2, 6.2.3
Clarified that NAS ≥ 6 is 6, 7, 8; text modified to specify randomization 
after the Week 24 IA would be equally allocated to all remaining doses. 
Section 6.2.2
Text deleted “For blinded studies, there will be a provision for 
unblinding to ensure adequate treatment of the subject in the case of an 
emergency.”
Section 6.2.4
Process for drug return or destruction was further clarified
Section 6.4
Added that the screening period may be minimally extended under 
special circumstances only with the explicit approval of the medical 
monitor.
Sections 7.1, 7.1.1
Clarified that the Week 24 and Week 48 MRIs will be conducted for 
subjects in the IA set only
Section 7.2.2.2
Serum liver-related tests deleted from list of Additional Laboratory 
Assessment; calculation of HOMA1-IR and HOMA2-%B added
Section 7.2.3.6
ECG section modified
Section 7.2.3.9
Text related to paper capture (rather than electronic) was deleted
Section 10.2.3.1
Minor typographic and editing corrections where made 
Throughout amendment


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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to:
Shire Global Pharmacovigilance and Risk Management Department
Preferred method: scan and e-mail to globalpharmacovigilance@shire.com
OR fax to +44(0) 1256 89 4715 (Global); or +1 866 557 4473 (North America)
AND
A copy of this form must also be sent to the Shire GCDL by fax or e-mail using the details 
below:
Melissa Palmer, MD, FAASLD, GCDL-Hepatology
fax number: +1 781 482 1822
e-mail: mpalmer@shire.com 
For protocol- or safety-related issues during normal business hours 9:00 a.m. to 5:00 p.m. 
(Eastern Time), the investigator must contact the Contract Research Organization (CRO) 
Medical Monitor:
ICON Medical Monitor: Anthony Japour, MD
Telephone number: +1 215 616 6439
Fax number: +1 215 616 3096
Mobile number: +1 267 429 6601
E-mail address: Anthony.Japour@iconplc.com
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact ICON’s 24/7 Medical Emergency Coverage:
Chargeable global telephone number: +1 919 674 5468
NOTE: Investigative sites will be provided country-specific toll-free telephone numbers. Please 
refer to this document, as applicable. Countries without a toll-free number will need to dial the 
chargeable number noted above.


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product (IP) quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products).  For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
PQC@shire.com
European Union and Rest of World
PQCROW@shire.com
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA) 
1-888-300-6414 or 1-800-828-2088


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TABLE OF CONTENTS
1.
BACKGROUND INFORMATION.......................................................................................23
1.1
Indication and Current Treatment Options...............................................................23
1.2
Product Background and Clinical Information ........................................................23
1.3
Benefits and Risks....................................................................................................26
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................28
2.1
Rationale for the Study.............................................................................................28
2.2
Study Objectives ......................................................................................................28
2.2.1
Primary Objective..................................................................................................28
2.2.2
Secondary Objectives.............................................................................................28
2.2.3
Exploratory Objectives ..........................................................................................28
3.
STUDY DESIGN ...................................................................................................................30
3.1
Study Design and Flow Chart ..................................................................................30
3.2
Duration and Study Completion Definition .............................................................31
3.3
Sites and Regions .....................................................................................................31
4.
STUDY POPULATION.........................................................................................................32
4.1
Inclusion Criteria......................................................................................................32
4.2
Exclusion Criteria.....................................................................................................32
4.3
Restrictions...............................................................................................................34
4.4
Reproductive Potential .............................................................................................35
4.4.1
Female Contraception............................................................................................35
4.4.2
Male Contraception................................................................................................35
4.5
Discontinuation of Subjects .....................................................................................36
4.5.1
Subject Withdrawal Criteria ..................................................................................36
4.5.2
Reasons for Discontinuation..................................................................................36
4.5.3
Subjects Lost to Follow-up Prior to Last Scheduled Visit.....................................37
4.5.4
Safety-related Stopping Rules................................................................................37
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................39
5.1
Prior Treatment ........................................................................................................39
5.2
Concomitant Treatment............................................................................................39
5.2.1
Permitted Treatment...............................................................................................39
5.2.2
Prohibited Treatment .............................................................................................39
6.
INVESTIGATIONAL PRODUCT ........................................................................................41
6.1
Identity of Investigational Product...........................................................................41
6.1.1
Blinding the Treatment Assignment......................................................................41
6.2
Administration of Investigational Product(s)...........................................................41
6.2.1
Interactive Response Technology for Investigational Product Management ........41


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6.2.2
Allocation of Subjects to Treatment ......................................................................41
6.2.3
Dosing....................................................................................................................42
6.2.4
Unblinding the Treatment Assignment..................................................................42
6.3
Labeling, Packaging, Storage, and Handling ...........................................................43
6.3.1
Labeling .................................................................................................................43
6.3.2
Packaging...............................................................................................................43
6.3.3
Storage ...................................................................................................................43
6.4
Drug Accountability.................................................................................................44
6.5
Subject Compliance..................................................................................................45
7.
STUDY PROCEDURES........................................................................................................46
7.1
Study Schedule.........................................................................................................46
7.1.1
Screening (Visit 1).................................................................................................46
7.1.2
Baseline (Visit 2) ...................................................................................................47
7.1.3
Treatment and Assessment Period (Visits 3 through 9/EOS)................................47
7.1.4
Follow-up (Visit 10) ..............................................................................................48
7.1.5
Additional Care of Subjects after the Study ..........................................................48
7.2
Study Evaluations and Procedures ...........................................................................48
7.2.1
Demographic and Other Baseline Characteristics .................................................48
7.2.2
Efficacy..................................................................................................................48
7.2.2.1
Liver Biopsy...........................................................................................48
7.2.2.2
MRI ........................................................................................................48
7.2.3
Safety .....................................................................................................................49
7.2.3.1
Medical History and Medications ..........................................................49
7.2.3.2
Physical Examination.............................................................................49
7.2.3.3
Adverse Event Collection.......................................................................49
7.2.3.4
Vital Signs..............................................................................................49
7.2.3.5
Clinical Laboratory Evaluations.............................................................50
7.2.3.6
Additional Laboratory Assessments.......................................................51
7.2.3.7
Pregnancy Test .......................................................................................52
7.2.3.8
Drug and Alcohol Testing......................................................................52
7.2.3.9
Electrocardiogram ..................................................................................52
7.2.3.10
Health-related Quality of Life Assessments...........................................52
7.2.3.11
Volume of Blood to be Drawn from Each Subject ................................53
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................54
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................54
8.1.1
Severity Categorization..........................................................................................54
8.1.2
Relationship Categorization...................................................................................55


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8.1.3
Outcome Categorization ........................................................................................55
8.1.4
Symptoms of the Disease Under Study .................................................................55
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................56
8.1.6
Criteria for Discontinuation of Treatment .............................................................56
8.1.7
Pregnancy...............................................................................................................56
8.1.8
Abuse, Misuse, Overdose, and Medication Error..................................................57
8.2
Serious Adverse Event Procedures ..........................................................................58
8.2.1
Reference Safety Information................................................................................58
8.2.2
Reporting Procedures.............................................................................................58
8.2.3
Serious Adverse Event Definition .........................................................................58
8.2.4
Serious Adverse Event Onset and Resolution Dates .............................................59
8.2.5
Fatal Outcome........................................................................................................59
8.2.6
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................59
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................61
9.1
Data Collection.........................................................................................................61
9.2
Clinical Data Management.......................................................................................61
9.3
Data Handling Considerations..................................................................................61
9.4
Statistical Analysis Process......................................................................................61
9.5
Planned Interim Analysis .........................................................................................62
9.5.1
Tolerability.............................................................................................................64
9.5.2
Efficacy..................................................................................................................64
9.6
Sample Size Calculation and Power Considerations................................................65
9.7
Study Population ......................................................................................................66
9.8
Efficacy Analyses.....................................................................................................66
9.8.1
Primary Efficacy Endpoint ....................................................................................66
9.8.2
Secondary Efficacy Endpoints...............................................................................67
9.8.3
Exploratory Efficacy Endpoints.............................................................................68
9.9
Safety Analyses........................................................................................................69
9.10
Other Analyses .........................................................................................................69
9.10.1 Health-related Quality of Life Analyses................................................................69
9.10.2 Stool Assessment ...................................................................................................70
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................71
10.1
Sponsor’s Responsibilities .......................................................................................71
10.1.1 Good Clinical Practice Compliance.......................................................................71
10.1.2 Indemnity/Liability and Insurance.........................................................................71
10.1.3 Public Posting of Study Information......................................................................71
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................71


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10.1.5 Study Suspension, Termination, and Completion..................................................72
10.2
Investigator’s Responsibilities .................................................................................72
10.2.1 Good Clinical Practice Compliance.......................................................................72
10.2.2 Protocol Adherence and Investigator Agreement..................................................72
10.2.3 Documentation and Retention of Records.............................................................73
10.2.3.1
Electronic Case Report Forms................................................................73
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................73
10.2.3.3
Audit/Inspection.....................................................................................74
10.2.3.4
Financial Disclosure...............................................................................74
10.3
Ethical Considerations..............................................................................................74
10.3.1 Informed Consent...................................................................................................74
10.3.2 Institutional Review Board or Ethics Committee..................................................75
10.4
Privacy and Confidentiality......................................................................................75
10.5
Study Results / Publication Policy ...........................................................................76
11. REFERENCES .......................................................................................................................78
12. APPENDICES ........................................................................................................................82


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LIST OF TABLES
Table 1:
Schedule of Assessments...............................................................................20
LIST OF FIGURES
Figure 1:
Study Design Flow Chart ..............................................................................31
Figure 2:
Process Flow for Volixibat Dose Decisions at 24 Week IA .........................63
LIST OF APPENDICES
APPENDIX 1
Protocol History.............................................................................................83
APPENDIX 2
Fatty Liver Disease Histology Scoring..........................................................84
APPENDIX 3
EQ-5D-5L Health Questionnaire UK Sample Only, Not for Official 
Use ................................................................................................................86
APPENDIX 4
Criteria to Assess Severity of Liver-Related Adverse Events.......................89
APPENDIX 5
Stopping Rules for Liver-related Blood Tests...............................................90
APPENDIX 6
General Principles and Specific Rules for Dose Discontinuation at 24 
Week Interim Analysis – Guidance for Data Monitoring Committee 
Only...............................................................................................................91
APPENDIX 7
Bristol Stool Chart.........................................................................................94


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ABBREVIATIONS
AE
adverse event
ALP 
alkaline phosphatase
ALT 
alanine aminotransferase
aPPT
activated partial thromboplastin time
ASBT
apical sodium-dependent bile acid transporter
ASBTi 
ASBT inhibitor
AST 
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BA 
bile acid
BMI
body mass index
C4
7-alpha-hydroxy-4-cholesten-3-one
CRA
clinical research associate
CRC 
clinical research center
CRO
contract research organization
DMC 
data monitoring committee
eCRF
electronic case report form
EQ-5D-5L 
EuroQol-5 Dimension-5 Level Questionnaire
ECG
electrocardiogram
EOS
end of study
EU
European Union
FAS
full analysis set
FBA 
fecal bile acid
FDA
Food and Drug Administration
FXR
GCDL 
farnesoid X receptor
Global Clinical Development Lead
GCP
Good Clinical Practice
GGT 
gamma glutamyl transferase
GLP1 RA
glucagon-like peptide-1 receptors agonists
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HBVDNA
hepatitis B virus deoxyribonucleic acid
HCV
hepatitis C virus


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HCVAb
hepatitis C virus antibody
HCVRNA
hepatitis C virus ribonucleic acid
HDL-C
high-density lipoprotein-cholesterol
HFD
high fat diet
HFF
hepatic fat fraction
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HOMA2-%B 
homeostatic model assessment in β-cell function
HOMA2-IR 
homeostatic model assessment insulin resistance
HRQoL 
health-related quality of life
IA 
interim analysis
IAS
interim analysis set
ICH
International Conference on Harmonisation
IND 
investigational new drug
INR
international normalized ratio
IP
investigational product
IR
insulin resistance
IRB
Institutional Review Board
IRT
interactive response technology
LDL-C 
low-density lipoprotein-cholesterol
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MedDRA
Medical Dictionary for Regulatory Activities
MR
magnetic resonance
MRI 
magnetic resonance imaging
MRS
magnetic resonance spectroscopy
MOA
mechanism of action
NAFLD 
nonalcoholic fatty liver disease
NAS 
NAFLD Activity Score
NASH 
nonalcoholic steatohepatitis
NASH CRN
NASH Clinical Research Network
NOAEL 
no observed adverse effect level
PBC
primary biliary cirrhosis
PBO
placebo
PDFF
proton density fat-fraction
PO
by mouth


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POC
proof of concept
PRO
patient-reported outcome
PSC
primary sclerosing cholangitis
PTT
prothrombin time
PVRM
Pharmacovigilance and Risk Management
QD 
once daily
RBC
red blood cell 
SAE 
serious adverse event
SAF
steatosis, activity, and fibrosis score
SAP 
statistical analysis plan
T2DM
type 2 diabetes mellitus
T3
triiodothyronine
TA
therapeutic area
TB
total bilirubin
TEAE
treatment-emergent adverse event
TGR5 
transmembrane G protein-coupled receptor
TPN
total parenteral nutrition
TSH
thyroid-stimulating hormone
TZD
thiazolidinediones
ULN
upper limit of normal
USA 
United States of America
VAS
visual analogue scale


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STUDY SYNOPSIS
Protocol number: SHP626-201
Drug: Volixibat potassium (SHP626)
Title of the study: A Phase 2 Double-Blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate 
the Safety, Tolerability and Efficacy of Volixibat Potassium, an Apical Sodium-Dependent Bile Acid 
Transporter Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
Number of subjects (total and for each treatment arm): Approximately 334 subjects will be screened to 
enroll 266 subjects to achieve 201 completers. After enrollment of at least 80 subjects (20/treatment arm – 3 
active and 1 placebo [PBO]) a 24-week interim analysis (IA) will eliminate at least one dose group based on the 
criteria provided to the Data Monitoring Committee; enrollment will continue to include approximately 67 
subjects in each of the remaining arms. The sample size target for this study is 67 completers in each of the 
treatment groups (201 total if 3 arms continue).  Including an additional 20 subjects to account for one dose 
dropped at the IA, 221 subjects are needed.   Therefore, approximately 266 (accounts for 20% of 221 dropping 
out) subjects will be randomized if three arms (2 SHP626 and 1 PBO) continue.  Fewer subjects are needed if 
more than one SHP626 dose is dropped.
Investigator(s):  Multicenter study
Site(s) and Region(s): 
Anticipated regions -US, Canada, and EU 
Estimated number of sites planned – 60 to 80
Study period (planned):
July 2016 to July 2019
Clinical phase:
2
Objectives:
Primary:  To evaluate the effect of volixibat compared to PBO on liver histology 
Secondary:  
•
To evaluate the safety and tolerability of volixibat compared to PBO
•
To evaluate the effect of volixibat compared to PBO on hepatic steatosis  (measured by MRI)
•
To evaluate the effect of volixibat compared to PBO on liver histology (measured by individual 
nonalcoholic fatty liver disease (NAFLD) activity score (NAS) components and fibrosis stage)
•
To evaluate the effect of volixibat compared to PBO on liver histology (measured by NASH resolution 
without worsening fibrosis)
•
To evaluate the effect of volixibat compared to PBO on serum liver-related biochemistry 
•
To evaluate the effect of volixibat compared to PBO on metabolic indicators (glucose, insulin, 
hemoglobin A1c [HbA1c]) 
•
To evaluate the effect of volixibat compared to PBO on serum lipids (cholesterol, HDL-C, LDL-C, 
triglycerides) 
Rationale: Currently, there is no approved medication for the treatment of NASH. Volixibat is under 
development for the treatment of NASH based on its mechanism of action (MOA) and is supported by 
nonclinical and Phase 1 data.  This is a Phase 2, 48-week, dose-finding study to examine the efficacy, 
tolerability, and safety of volixibat in adults with NASH.
Investigational product, dose, and mode of administration:

Volixibat 5, 10, and 20 mg and matched PBO capsules by mouth (PO) once daily (QD). Investigational 
product (IP) should be given 30 minutes prior to the first meal of the day containing approximately 10-20 


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grams of fat Also see Section 6.2.3 (Dosing).

Identical PBO will be used as comparator 

Subjects should take the IP at the same time each day and should not take more than one dose in a day if 
they miss a dose
Methodology:
This study will be a Phase 2, 48-week, multicenter, double-blind, randomized, PBO-controlled, parallel group, 
proof of concept, dose-finding study, with one IA after 24 weeks of treatment.  There will be 3 active arms of 
volixibat (5, 10 and 20 mg) and a PBO arm.  Subjects will be randomized to receive one of three doses of 
volixibat (5, 10, or 20 mg once daily (QD) or PBO in a 1:1:1:1 ratio.  Depending on the results of the IA, the 
study may be terminated or the randomization to one or more doses will be stopped.  The follow-up period will 
be 4 weeks after last dose. Subjects will be expected to visit the study center at least 10 times. 
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions.
2.
Ability to voluntarily provide written, signed, and dated (personally or via a legally-authorized 
representative, as applicable) informed consent to participate in the study.
3.
Age 18-80 years inclusive.  This inclusion criterion will only be assessed at the first Screening visit.
4.
Male, or non-pregnant, non-lactating female who is sexually active and who agrees to comply with any 
applicable contraceptive requirements of the protocol or females of non-childbearing potential.
Males and females of child-bearing potential who are sexually active, or are not currently sexually 
active during the period of the study, but become sexually active during the study and 30 days 
following the last dose of the IP, must agree to use acceptable contraception.
5.
Presence of ≥ 5% steatosis on screening MRI from a centrally read radiologist performed either during 
the Screening period or within 6 months prior to the first visit.
6.
Histologic confirmation of NASH without cirrhosis (F1-F3) from a centrally read liver biopsy 
performed either during the Screening period or within 6 months prior to the first visit with a NAS of ≥ 
4 with a score of at least 1 in each component (steatosis, lobular inflammation, and hepatocyte 
ballooning).
Exclusion Criteria:
1.
Presence of or history of cirrhosis or evidence of decompensated liver disease (ie, ascites, variceal 
bleeding, etc.) or hepatocellular carcinoma.
2.
History or presence of other concomitant liver disease as assessed by the investigator or determined by 
laboratory findings including, but not limited to: active hepatitis B virus (HBV) infection (hepatitis B 
surface antigen (HBsAg) positive and/or HBVDNA positive; subjects who are hepatitis B core 
antibody (HBcAb) positive may be eligible as long as HBsAg is negative and HBVDNA is 
nondetectable), active hepatitis C virus (HCV) infection (prior exposure to HCV (defined as HCVAb 
positive without a current or prior history of a detectable HCVRNA) will be eligible, alcoholic liver 
disease, proven autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis 
(PSC), hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, bile duct obstruction, liver 
primary or metastatic cancer.
3.
Current or recurrent disease that could affect the action, absorption, disposition, or laboratory 
assessment of the IP (including bile salt metabolism in the intestine) eg, uncontrolled inflammatory 
bowel disease, uncontrolled celiac disease, gastric bypass procedures (gastric lap band is acceptable), 
ileal or ileocecal resection, uncontrolled irritable bowel syndrome with predominant diarrhea, or 
history of chronic diarrhea or loose stools of any etiology.


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4.
Weight change ≥ 5% after qualifying liver biopsy performed.
5.
Contraindications to MRI (ie, claustrophobia, coronary stents, coronary implantable devices, girth, 
etc.).
6.
Current or relevant history of physical or psychiatric illness, any medical disorder that may require 
treatment or make the subject unlikely to complete the study.
7.
Treatment with Vitamin E, thiazolidinediones (TZD), or glucagon-like peptide-1 receptors agonists 
(GLP1 RA) unless subject on a stable dose for 6 months prior to qualifying liver biopsy and not 
initiated after qualifying liver biopsy and will continue the same dosing regimen throughout study 
participation. Also refer to Section 5.2.1, Permitted Treatment.
8.
Uncontrolled diabetes defined as HbA1c of ≥ 9.0% within 60 days prior to enrollment. 
9.
Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) that 
could affect the action, absorption, or disposition of the IP, or clinical or laboratory assessment.  
(Current use is defined as use within 14 days of Screening). Patients currently taking insulin will not be 
excluded; however, they must be on a stable dose for at least 30 days prior to Screening. Also refer to 
Section 5.2.2, Prohibited Treatment.
10. Use of drugs, herbs or supplements historically associated with causing or worsening NAFLD/NASH 
for less than 6 months prior to qualifying liver biopsy, or initiated any time after qualifying liver biopsy 
performed, including the use of total parenteral nutrition (TPN). 
11. Serum AST > 5 times upper limit of normal (ULN) at Screening.
12. Serum ALT > 5 times ULN at Screening.
13. Elevated serum creatinine ≥ 2.0 mg/dL.
14. International normalized ratio (INR) >1.3.
15. Total bilirubin (TB) ≥ 2.0 x ULN at Screening (Except for documented Gilbert’s syndrome with 
bilirubin levels 20 µmol/L to 90 µmol/L (1.2 to 5.3 mg/dL) and with a ratio of 
unconjugated/conjugated bilirubin that is commensurately higher).
16. Platelet count < 130 × 109L
17. Medical history of impaired hemostasis or current use of anticoagulant medication (low-dose, ie 81mg, 
aspirin (ASA) will be allowed).
18. Uncontrolled thyroid disease.
19. Type 1 diabetes mellitus.
20. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or any of the 
stated ingredients.
21. Known history of alcohol or other substance abuse within the last year or at any time during the study 
based on investigator’s discretion.  Weekly alcohol intake greater than 21 grams/day for males and 14 
grams/day for females on average or inability to reliably quantify alcohol consumption based on 
investigator’s judgment.
22. Within 6 months of MRI and liver biopsy:

Have used any IP

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study
23. Inability to safely obtain a liver biopsy.
24. The anticipated need for a surgical procedure during the study that could interfere with the treatment. 
25. Known positivity for human immunodeficiency virus (HIV) infection.


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26. Cancer within 5 years of Screening, except for basal or squamous cell carcinoma of the skin or in situ 
cervical carcinoma that has been treated with no evidence of recurrence.
27. History of noncompliance with medical regimens, unreliability, mental instability or incompetence that 
could compromise the validity of informed consent or lead to noncompliance with the study protocol.
28. Any other conditions or abnormalities which, in the opinion of the investigator, may compromise the 
safety of the subject, or interfere with the subject participating.
29. Subject has failed Screening or was previously enrolled in this study or is currently enrolled in this 
study at any study site (unless the subject is transferring to another qualified study site with prior 
Sponsor approval).
30. Subjects who are employees at the investigational site.
Maximum duration of subject involvement in the study:

Planned duration of screening period:  56 days 

Planned duration of enrollment period: 364 days

Planned duration of treatment period: 336 days 

Planned duration of follow-up: 28 days 
Endpoints and statistical analysis:
Safety Analysis Set will consist of all subjects who take at least 1 dose of randomized IP, and have at least 1 
post-Baseline safety assessment (eg, coming back for any visit, reporting of an adverse event (AE) or reporting 
the absence of AEs).
Full Analysis Set (FAS) will consist of all subjects in the Safety Set who have a valid scored liver biopsy.
Interim Analysis Set (IAS) will consist of all subjects in the Safety Set who have a valid post-baseline hepatic 
fat fraction (HFF) assessed by MRI and a valid post-baseline ALT at Week 24. 
Screened Set will consist of all subjects who have signed an informed consent.
Endpoints:

Primary: Binary response indicating (yes/no) whether a subject responded at Week 48 with a reduction 
of at least 2 points without worsening of fibrosis from Baseline NAS.

Secondary: 

Change from Baseline to Week 48 in safety and tolerability of volixibat as measured by the 
number of subjects discontinuing treatment due to any one treatment-emergent adverse event 
(TEAE). 

Change from Baseline to Week 48 on liver histology as measured by the individual NAS 
components (ballooning, inflammation, steatosis).  

Change from Baseline to Week 48 on hepatic steatosis as measured by MRI-HFF for subjects 
included in the IA.

Change from Baseline to Week 48 on liver histology as measured by fibrosis stage. (NASH 
Clinical Research Network (CRN)

Resolution of NASH (defined as an overall histologic interpretation of no fatty liver disease or 
simple steatosis without steatohepatitis or isolated steatosis without steatohepatitis) without 
worsening of fibrosis as assessed by liver histology at week 48.

Change from Baseline to Week 48 on serum liver-related biochemistry as measured by:

alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

alkaline phosphatase (ALP)

gamma glutamyl transferase (GGT)

total bilirubin (TB)

Change from Baseline to Week 48 on metabolic indicators as measured by


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
fasting serum glucose levels

insulin levels

HbA1c 

Change from Baseline to Week 48  on serum lipids measured by 

fasting total cholesterol

HDL-C

LDL-C

triglycerides 
Primary hypotheses:

Null: The proportion of subjects at Week 48 with a reduction of at least 2 points without worsening of 
fibrosis from Baseline NAS does not differ between any of the volixbat doses and PBO.

Alternative: The proportion of subjects at Week 48 with a reduction of at least 2 points without 
worsening of fibrosis from Baseline NAS does differ between at least one volixbat dose and PBO.
The FAS will be used to assess the primary efficacy endpoint. The difference between a volixibat dose and PBO 
will be tested with a stratified Cochran-Mantel-Haenzel test. The test will be stratified by presence or absence of 
Type 2 diabetes mellitus (T2DM) at Baseline, and baseline NAS separated into two groups (NAS={4,5} or 
NAS={6,7,8}). Holm multiplicity adjustment will be applied prior to determining statistical significance at the 
0.1 level. Histology will be read by one central hepatohistopathologist who will use the NASH CRN standard 
scoring system – NAS. The SAF Steatosis (S), Activity (A), and Fibrosis (F) scoring system will be determined 
for exploratory purposes.
The Safety Set will be used to assess the safety endpoints including AEs (including changes from Baseline in 
physical examination findings), vital signs, ECGs, and clinical laboratory tests (chemistry, hematology, 
coagulation and urinalysis).
AEs will be coded using the agreed upon version of the Medical Dictionary for Regulatory Activities 
(MedDRA). TEAEs are defined as AEs that started or worsened on or after the date of the dose of IP, and no 
later than the study completion visit (or follow-up visit for subjects who terminate the study early). The number 
of events, incidence, and percentage of TEAEs will be presented by system organ class and preferred term. 
TEAEs will be further summarized by severity and the relationship to the IP. AEs related to the IP, AEs leading 
to withdrawal, SAEs, and death will be listed. The number of discontinuations due to any 1 TEAE will be 
summarized for each treatment group.
Vital signs, ECG findings, and clinical laboratory tests will be listed for each subject and summarized for each 
treatment arm, including a flag for any potentially clinically important findings. Graphical presentation may be 
used when deemed necessary.
For safety parameters, baseline is defined as the last assessment prior to the first dose of the IP.
Planned Interim Analysis:
An IA will be conducted by an independent data monitoring committee (DMC) after at least 80 subjects have 
received 24 weeks of treatment. The IA will evaluate the safety, tolerability and efficacy of 3 doses of volixibat 
each compared to PBO, on reduction of steatosis as measured by HFF by MRI and ALT. 
Tolerability will be assessed by the number of discontinuations due to any one TEAE, presumably 
gastrointestinal events, most notably, diarrhea, loose stools, increased evacuations, and abdominal pain. Efficacy 
at the IA will be based on reduction of steatosis or ALT. Steatosis is assessed by MRI-HFF. Depending on the 
results from the IA, one or more doses of volixibat may be discontinued or the study may be terminated.  If the 
study is not terminated, subjects will receive a total of 48 weeks of the IP.


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Table 1:
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9
EOS
10
In-Clinic
Week
-8 to 0
0
2
4
8
12
24
36
48
52
Study Day
-56 to -1
0
14
28
56
84
168
252
336
364
Informed consent
X
Inclusion/exclusion criteria
X
X (review)
Demography, medical & medication 
history 
X
Physical examination
X
X
X
X
X
Heightc, weightd, waist circumference 
and waist:hip ratio
X
X
X
X
X
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
X
X
X
PRO (EQ-5D-5L)
X
X
X
Liver biopsyf
X
X
MRIg
X
Xh
Xh
ECG (12-lead)
X
X
X
X
Biochemistry and Hematologyi
X
X
X
X
X
X
X
X
X
X
Serum Glucose i,j
X
X
X
X
X
X
X
X
X
X
Urinalysisk
X
X
X
Urine Drug and Serum Alcohol Tests
X
X
Urine Pregnancy Testl
X
X
X
X
X
X
X
X
X
X
Lipid Paneli,m
X
X
X
X
X
X
X
X
X
X
Coagulation Paneli,n
X
X
X
X
X
Vitamin D i
X
X
X
X
X


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Table 1:
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9
EOS
10
In-Clinic
Week
-8 to 0
0
2
4
8
12
24
36
48
52
Study Day
-56 to -1
0
14
28
56
84
168
252
336
364
HbA1ci
X
X
X
X
X
X
X
X
X
X
Serum Liver-Related Blood Testsi,o
X
X
X
X
X
X
X
X
X
X
Insulini
X
X
X
X
X
X
X
X
HIV, Hepatitis B/Ci,p
X
Thyroid testingi,q
X
X
X
X
X
X
X
C4 Sampling
X
X
X
X
X
IRT Accessed
X
X
X
X
X
X
X
X
X
X
Randomization
X
IP Dispensedr
X
X
X
X
X
X
X
IP Returned/Accountability & 
Compliance Assessed 
X
X
X
X
X
X
X
Stool Assessmentt
X
X
X
X
X
X
Adverse Eventst
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
ECG=electrocardiogram; EOS=end of study; HOMA=Homeostasis Model Assessment; IA=interim analysis; IP=investigational product; IRT=Interactive Response Technology; 
MRI=magnetic resonance imaging; PRO=patient-reported outcome.
a Visit Windows (calculated from Visit 2): Bi-weekly (Visits 3-4): +/- 3 days; Monthly (Visits 5-6): +/-5 days; Tri-monthly (Visits 7-9/DC): +/- 7 days.   
b Subjects will be reminded not to eat prior to their scheduled visit.  Additionally, during the double-blind treatment period, they should not take their study drug prior to the visit. 
They should bring their study drug with them to the visit to take 30 minutes prior to their first meal of the day containing approximately 10-20 grams of fat. Also see Section 6.2.3
c Height to be measured at Screening only.
d BMI to be calculated programmatically by the Sponsor or designee for the following visits: Screening (Visit 1), Baseline (Visit 2), Visits 7 and 9/DC.   


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Table 1:
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9
EOS
10
In-Clinic
Week
-8 to 0
0
2
4
8
12
24
36
48
52
Study Day
-56 to -1
0
14
28
56
84
168
252
336
364
e Vital signs to include oral or tympanic temperature, sitting blood pressure, pulse, and respiratory rate.
f Biopsy performed within 6 months of Screening can be used. All biopsies will be centrally read by a hepatic histopathologist.
g MRI from a centrally read radiologist performed either during the Screening period or within 6 months prior to the first visit. 
h MRI at Visit 7 (Week 24) and at Visit 9 (Week 48) for the Interim Analysis Set only.
i All blood tests are fasting blood tests.
j HOMA2-IR and HOMA2-%B: will be calculated programmatically by the Sponsor or designee for the following visits: Screening (Visit 1), Baseline (Visit 2), Visits 7, 9/DC, and 
10.   
k Urinalysis to include oxalate testing.
l For all females of child-bearing potential (FOCP).  Positive on-site urine dipstick results must have serum -HCG testing performed by central lab.
Additional testing can be performed at the investigator’s discretion.
m Lipid Panel includes fasting total cholesterol, HDL-C, LDL-C, and triglycerides.
n Full coagulation panel will be done at Screening and Baseline, but only INR and PT are required at remaining time points. 
o Serum Liver-Related Blood Tests include ALT, AST, ALP, GGT, and total bilirubin.
p Hepatitis B/C testing includes HBcAb, HBsAg, HBVDNA and HCVAb, HCVRNA, respectively.
q Thyroid testing includes thyroid stimulating hormone (TSH) and triiodothyronine (T3).
r Investigational product may be dispensed at an unscheduled visit outside of this schedule as needed to replace lost or damaged product.
s Subjects will be queried about the number of stool evacuations during the 24- hour period before the clinical research center (CRC) visit and asked to describe the consistency of 
the softest stool during that 24- hour period using the Bristol Stool Chart.
t Adverse events will be collected beginning from the signing of informed consent.  All AEs must be followed to closure (the subject’s health has returned to his/her Baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in the study. Closure indicates that an outcome is reached, stabilization achieved (the 
investigator does not expect any further improvement or worsening of the event), or the event is otherwise explained. When appropriate, medical tests and examinations are 
performed so that resolution of event(s) can be documented.


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1.
BACKGROUND INFORMATION
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease 
worldwide (Vernon et al. 2011), and is estimated to occur in 30-40% of adults in the United 
States and up to 30% of European adults.  These numbers approach 95% in those with morbid 
obesity (Mathus-Vliegen et al. 2012).  NAFLD ranges from simple steatosis, which is typically 
nonprogressive, to nonalcoholic steatohepatitis (NASH), which has a 20% likelihood of 
progression to advanced disease including fibrosis, cirrhosis and its complications including liver 
failure and the need for a liver transplant (Angulo 2002).  Hepatocellular carcinoma is also a 
complication of NASH that may occur with or without the presence of cirrhosis (Torres et al. 
2012).  NAFLD is typically associated  with type 2 diabetes mellitus (T2DM) (Adibi et al. 2007; 
Loomba et al. 2012), central or visceral obesity (Souza et al. 2012), dyslipidemia (Assy et al. 
2000; N.C.E.P. 2002), and hypertension (Donati et al. 2004).  Together these conditions 
comprise the metabolic syndrome, and NASH is considered to be the hepatic component of this 
syndrome (Hamaguchi et al. 2005, Neuschwander-Tetri 2005, Marchesini et al. 2005). Notably, 
NAFLD is a clinical condition occurring in individuals who do not drink excessive alcohol (>20 
grams/day), yet have hepatic histology which is indistinguishable from that seen with alcoholic 
excess.  The pathophysiology of NASH is likely multifactorial and may include combinations of 
metabolic, genetic, environmental, and gut microbial factors.       
Most individuals with NASH are asymptomatic or have nonspecific symptoms such as fatigue. 
They typically first come to medical attention incidentally following routine blood testing or on 
imaging studies performed routinely or during the evaluation of an unrelated condition. While 
ultrasound and magnetic resonance imaging (MRI) can detect the presence of steatosis (Reeder 
et al. 2011), a liver biopsy is required to diagnose NASH and the extent of liver fibrosis. 
1.1
Indication and Current Treatment Options 
There are currently no drugs approved for the treatment of NASH and it is estimated that there 
are between 6-16 million people in the United States with NASH, of which 600,000 have severe 
disease (Williams et al. 2011 and Torres and Harrison 2008), with similar percentages reported 
throughout most areas of the world (World Gastroenterology Organisation 2012). Treatment of 
associated metabolic comorbidities, weight reduction, and incorporation of an exercise routine 
remain the cornerstone of management.  However, lifestyle changes are seldom successful. Thus, 
NASH represents a disease with an unmet medical need that is growing at an epidemic rate, and 
that if untreated, carries a risk of significant morbidity and mortality.
1.2
Product Background and Clinical Information
Volixibat potassium (SHP626; formerly LUM002), hereafter referred to as volixibat, is a highly 
selective inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that is being 
evaluated for the treatment of NASH.  
Bile acids (BA) promote bile flow, activation of digestive enzymes, and micellization of fats and 
fat-soluble vitamins, thereby permitting their intestinal absorption.  BAs serve as signaling 
molecules acting via receptors, such as farnesoid X receptor (FXR) and transmembrane G 


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protein-coupled receptor (TGR5), in the intestine, liver and other tissues which play an important 
role in regulating insulin homeostasis. (Halilbasic et al. 2013).  Lipid peroxidation and oxidant 
stress have been proposed as one link between the accumulation of fat and subsequent injury 
(Day and James 1998).  All of these metabolic actions have important effects to prevent the 
ongoing liver damage in NASH. 
High fat diet (HFD) fed mice treated with an ASBT inhibitor (ASBTi) (SC-435 a surrogate 
SHP626) normalized hepatic triglycerides and serum cholesterol, significantly improved insulin 
resistance (IR), and decreased NAS, predominantly steatosis.  In addition the BA pool reflected 
increases in BA that were agonists to FXR and decreases in levels that were antagonist to the 
FXR (Karpen et al. oral presentation AASLD 2015; Rao et al. 2015). Miethke and colleagues
(2016) found that pharmacological inhibition of the ileal, ASBT (SC-435 the surrogate molecule 
of volixibat), blocked progression of sclerosing cholangitis in mdr2–/– mice. Beneficial effects in 
liver histology in these mice included a reduction in the severity of hepatic fibrosis, a decrease 
which correlated with a reduction of hepatic profibrogenic gene expression. While very 
encouraging, whether or not the findings in this mouse sclerosing cholangitis model can translate 
to histologic improvements in patients with NASH is unknown.
Volixibat, as a potent inhibitor of ASBT, increases BA excretion and facilitates signaling in the 
intestine that regulates serum and hepatic BA concentrations, glucose metabolism, serum 
cholesterol and fatty acid metabolism in the liver.  The combined events resulting from inhibiting 
BA reuptake are hypothesized to have a positive metabolic, anti-inflammatory, anti-steatotic, and 
potentially antifibrotic effect that will lead to a therapeutic benefit for patients with NASH. 
One of the factors contributing to the pathogenesis of NASH is abnormal cholesterol metabolism 
and the accumulation of free cholesterol in the liver. The free cholesterol is directly toxic to 
hepatocytes, which leads to inflammation and fibrosis (Musso et al. 2013). One treatment 
approach is to remove the cholesterol from the liver to decrease and possibly reverse the damage 
to the hepatocytes. This is one of the mechanisms by which SHP626 will treat NASH.
Due to the mechanism of action (MOA), volixibat is under development for the treatment of 
NASH and may also be able to improve the metabolic syndrome that is associated with NASH. 
Volixibat inhibits ASBT therefore BAs are excreted in the feces and this loss forces the liver to 
synthesize new BA which utilizes cholesterol in the liver and serum. Volixibat also has the 
potential to reduce IR, which is considered to be the most common underlying risk factor for the 
development of NASH (Pagano et al. 2002; Sanyal et al. 2001). 
Volixibat was initially being evaluated for its use as an intervention for dyslipidemia.  As a result 
of initial observations in animals that serum low-density lipoprotein cholesterol (LDL-C) and 
total liver cholesterol content could be decreased after administration of volixibat, additional 
work was undertaken to support the safety and tolerability of the drug in healthy volunteers. 
Clinical and non-clinical studies have demonstrated very low systemic exposure across species. 
Oral administration of volixibat at doses up to 300 mg once daily and 50 mg administered daily 
for 14 days to healthy male subjects was generally safe.  A Phase 1 study revealed that volixibat 
is tolerated at the 10 mg dose for 28 days and that there were trends towards increasing high-


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density lipoprotein cholesterol (HDL-C), decreasing LDL-C, and decreasing fasting glucose in 
patients with T2DM (LUM002-101 trial). 
A healthy volunteer study investigating 12 days of varying levels of repeat doses of volixibat has 
provided key pharmacodynamic information for dose selection as measured by the effect of 
volixibat on excreted fecal bile acid (FBA) levels (SHP626-101).  In addition, the study 
investigated safety and tolerability over the dose range that was considered for this Phase 2 
study.
Data from Phase 1 studies support the position that volixibat is basically a non-absorbed drug 
that works locally in the GI tract and results in virtually no systemic exposure. Thus 
pharmacokinetic sampling will not be done in this study.
The current proof of concept (POC) Phase 2 trial will evaluate the safety, tolerability, and 
efficacy of three doses of volixibat  (5, 10, and 20 mg) in adult subjects with NASH. Due to the 
MOA of volixibat, efficacy will be assessed at an interim analysis (IA) by a change of steatosis 
from Baseline to Week 24 compared to placebo (PBO).  While the gold standard for 
quantification of steatosis has historically been an invasive liver biopsy, quantitative magnetic 
resonance (MR) imaging–based biomarkers for liver fat have evolved rapidly over the last 
decade, and are increasingly being incorporated into NASH clinical trials.  Both MR 
spectroscopy (S) and MR imaging (I) proton density fat-fraction (PDFF) provide non-invasive 
means of quantifying intrahepatic lipid content (Reeder et al. 2012).  Both techniques have been 
shown to be accurate, reproducible with a low degree of variability in interpretation, cost-
effective and reliable biomarkers of quantitative hepatic fat (Roldan-Valadez et al. 2010; Urdzik 
et al. 2012;  Raptis et al. 2012).  Importantly, studies demonstrate a close correlation with 
steatosis grade histologically (Qayyum et al. 2005; Schwenzer et al. 2009).  
In a study of 51 adult subjects with NAFLD, PDFF correlated well with the grade of histologic 
steatosis, as the mean fat-fraction values of 8.9%, 16.3%, and 25.0% corresponded to histologic 
steatosis grades 1, 2, and 3, respectively (P < .0001) (Permutt et al. 2012).  Thus, MRI will be 
utilized to evaluate the degree of steatosis change from Baseline in this study during the IA. The 
Mozart trial was a randomized, double-blind, PBO-controlled trial of 50 patients with NASH 
who were randomized to 24 weeks of either ezetimibe or PBO, evaluating the reduction of liver 
fat by MRI-PDFF as well as by histology. Results revealed that compared to histologic non-
responders, histologic responders, defined as a two-point reduction in NAFLD activity score 
(NAS) without worsening fibrosis, had a statistically significant reduction in net MRI-PDFF of -
4.1% ± 4.9 vs. +0.6% ± 4.1 (P < 0.036) with a mean percent change of -29.3% ± 33.0 vs. +2.0% 
± 24.0 (P < 0.004), respectively (Loomba et al. 2015).  Thus, in the current trial during the IA, an 
active dose will be considered to be efficacious if a ≥ 5% steatosis reduction compared to PBO is 
seen after 24 weeks of therapy. 
Intrahepatic lipid content of less than 1% is considered to be within the normal range (Springer et 
al. 2015), however, from a study of 2349 people in a general population undergoing MRS, it was 
concluded that a PDFF value of 5.56% represented the upper limit of the normal range, as 
determined from the 95th percentile of PDFF in 345 individuals who were not at increased risk 
for hepatic steatosis (Szczepaniak et al. 2005).  Thus, in the current trial, similar to other NASH 


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trials utilizing MR for evaluation, an MRI ≥5% steatosis will be used as an inclusion criterion 
(Loomba et al. 2015).  
1.3
Benefits and Risks
By virtue of volixibat’s ability to inhibit ASBT bile acid reabsorption, there is an increase in BA 
excretion and signaling in the intestine that results in improvements in glucose metabolism and 
changes in cholesterol and fatty acid synthesis in the liver. Recently, HFD fed mice treated with 
an ASBTi (SC-435 a surrogate of SHP626) normalized hepatic triglycerides and serum 
cholesterol, significantly improved IR, and decreased NAS (predominantly steatosis). In 
addition, these HFD-fed mice did not gain weight when treated with SC-435, in spite of 
consuming increased calories. Finally, the BA pool in these mice changed to predominantly FXR 
agonist (Karpen et al. oral presentation AASLD 2015; Rao et al. 2015).
These metabolic actions and preclinical results may prove to be clinically relevant to subjects 
with NASH.
NASH has recently received considerable attention as awareness of the problem of liver damage 
and prevalence of the disorder has increased, paralleling the obesity epidemic.  Consequences of 
liver damage are detrimental and can lead to liver failure, hepatocellular carcinoma, and the need 
for liver transplantation. There is no currently approved medical therapy for NASH. The large 
unmet medical need and the increased medical resource burden have led to the search for 
potential therapies to treat NASH.
Nonclinical testing established that the no observed adverse effect level (NOAEL) for volixibat 
in rats and dogs following 13 weeks of once-daily administration were 1000 and 500 mg/kg/day, 
respectively. Similarly, testing confirmed that the NOAEL for volixibat in a 6-month study in 
rats and a 9-month study in dogs were 1000 and 500 mg/kg/day, respectively. In both cases, 
these were the highest doses tested. Genotoxicity testing has yielded negative findings. 
Volixibat is minimally absorbed. The pharmacokinetic profiles performed in clinical studies 
completed to date repeatedly suggest negligible systemic exposure. Furthermore, there has been 
no observation of clinically relevant changes in fat absorption parameters such as those related to 
fat-soluble vitamins.
The most frequent TEAEs in the Phase 1 studies were GI and were considered mechanism-based 
due to elevated BA concentrations in the colon. The percentage of subjects reporting at least 1 
TEAE in the GI disorders SOC generally increased with an increasing volixibat dose level (Part 
1 Study TDU10632 and Study LUM002-101). Most TEAEs were mild in intensity, and none 
were assessed as severe.
In the multiple dose studies, the most commonly reported TEAEs in subjects (both healthy and 
with T2DM) who received volixibat for the longest duration of 28 days in Study LUM002-101 
included diarrhea and abdominal pain. The most commonly reported TEAEs in subjects 
receiving 50 mg volixibat for 14 days (part 3 Study TDR10633) were diarrhea and GI pain.


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Overall, there were 2 SAEs (ALT increased and retinal detachment), both of which led to the 
discontinuation of volixibat. In part 3 of the initial Phase 1 study (TDU10633), 1 subject dosed 
with 50 mg volixibat  for 13 days was withdrawn from the study due to a mild TEAE (which 
became a SAE due to prolonged hospitalization) of ALT increased that was considered related to 
volixibat . The subject’s ALT level returned to normal after discontinuation of volixibat. A 
second subject dosed with 10 mg volixibat for 12 days in Study LUM002-101 reported a 
moderate SAE of ablation of the retina with a bleed in the vitreous body of the right eye that was 
considered not related to volixibat.
Overall, 3 subjects, all dosed with 5 mg volixibat in Study LUM002-101, discontinued volixibat 
due to non-serious TEAEs: 1 due to a related TEAE of mild hemorrhagic diarrhea, 1 due to an 
unrelated TEAE of moderate Epstein-Barr virus infection, and 1 due to mild related TEAEs of 
diarrhea and anal erosion.
Overall, the observed AEs attributable to volixibat have been self-limited as would be expected 
given the local MOA of ASBT inhibition in the terminal ileum. Generally, among subjects who 
experienced GI TEAEs, the events have been mild and diminished over the course of treatment. 
Please refer to the investigator’s brochure for additional information.
Volixibat is a novel drug candidate, demonstrating limited systemic exposure across species with 
the potential to affect important metabolic pathways associated with NASH. The overall safety, 
tolerability, and preliminary activity of volixibat in available clinical trials suggest that further 
investigation is warranted and that there is a positive benefit to risk profile.
Always refer to the latest version of the Volixibat Potassium (SHP626) Investigator’s Brochure 
for the overall risk/benefit assessment and the most accurate and current information regarding 
the drug metabolism, pharmacokinetics, efficacy, and safety of volixibat. 
See Appendix 1 for protocol history, including all amendments.


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Currently there is no approved medication for the treatment of NASH. Volixibat is under 
development for the treatment of NASH based on its MOA and is supported by nonclinical and 
Phase 1 data.  This is a Phase 2, 48-week, dose-finding study to examine the efficacy, 
tolerability, and safety of volixibat in adults with NASH.
2.2
Study Objectives
2.2.1
Primary Objective
To evaluate the effect of volixibat compared to PBO on liver histology 
2.2.2
Secondary Objectives

To evaluate the safety and tolerability of volixibat  compared to PBO 

To evaluate the effect of volixibat compared to PBO on hepatic steatosis  (measured by 
MRI)

To evaluate the effect of volixibat  compared to PBO on liver histology (measured by 
individual NAS components and fibrosis stage)

To evaluate the effect of volixibat compared to PBO on liver histology (measured by 
NASH resolution without worsening fibrosis)

To evaluate the effect of volixibat compared to PBO on serum liver-related biochemistry

To evaluate the effect of volixibat compared to PBO on metabolic indicators (glucose, 
insulin, hemoglobin A1c [HbA1c]) 

To evaluate the effect of volixibat compared to PBO on serum lipids (cholesterol, HDL-
C, LDL-C, triglycerides) 
2.2.3
Exploratory Objectives

To explore the effect of volixibat compared to PBO on liver histology (measured by 
individual SAF scoring components: Steatosis (S), Activity (A), and Fibrosis (F)) 

To explore the effect of volixibat compared to PBO on anthropometric measures (body 
weight, body mass index (BMI), waist circumference and waist-hip ratio) 

To explore the effect of volixibat compared to PBO on homeostasis model assessment 2-
IR (HOMA2-IR) and HOMA2-beta cell function (HOMA2-%B) in subjects with T2DM 

To explore the effect of volixibat compared to PBO on BA synthesis (7-alpha-hydroxy-4-
cholesten-3-one [C4])


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
To explore the effect of volixibat on patient-reported health-related quality of life 
(HRQoL) and overall health status.


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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This study will be a Phase 2, 48-week, multicenter, double-blind, randomized, PBO-controlled, 
parallel group, proof of concept, dose-finding study, with one IA after 24 weeks of treatment.  
There will be 3 active arms of volixibat (5, 10 and 20 mg) and a PBO arm. Subjects will be 
randomized to receive one of three doses of volixibat (5, 10, or 20 mg once daily (QD) or PBO 
in a 1:1:1:1 ratio such that a target of 266 subjects is achieved (221x1.2 is approximately 266).  
The 221 subjects include 201 subjects for the three arms analyzed at 48 weeks plus an additional 
20 subjects to account for one dose dropped at the IA). Attempt will be made to perform the IA 
before any subject has had their 48-week post-treatment liver biopsy, although this will be 
dependent upon the rate of enrollment and dropout.
There will be up to 3 periods (Screening, Treatment and Follow-up) and an IA. The duration of 
the Treatment period will be 48 weeks, with an IA at Week 24.  Depending on the results of the 
IA, the study may be terminated or the randomization to one or more doses will be stopped.  The 
follow-up period will be 4 weeks after last dose.  Subjects will be expected to visit the study 
center at least 10 times.
The IA will be conducted by an independent data monitoring committee (DMC) after at least 
80 subjects have received 24 weeks of treatment. Study enrollment will be paused after 
92 subjects have been randomized. The IA will evaluate the safety, tolerability and efficacy of 3 
doses of volixibat each compared to PBO, on reduction of steatosis as measured by high fat 
fraction (HFF) by MRI and ALT. 
Once decisions as to dose elimination are made, study enrollment will be reopened and 
additional sites may be added. Subjects recruited into the study prior to the IA will continue with 
the same dosing regimen for the duration of the planned study participation. Subjects recruited 
into the study after completion of the IA will be randomized evenly to the remaining dose groups 
or PBO group by IRT. Thus, depending on the results from the IA, the study may be terminated, 
or one or more doses of volixibat will be discontinued. If the study is not terminated, subjects 
will receive a total of 48 weeks of investigational product (IP).
The study will be conducted over 3 periods: Screening (8 weeks), Treatment (48 weeks), and 
Follow-up (4 weeks), with an IA at 24 weeks as outlined in Figure 1.  


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Figure 1:
Study Design Flow Chart
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 364 days.  The 
last visit is an in-clinic safety follow-up visit. The study will be completed in approximately 3 
years.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment.  Please note that this includes the follow-up visit.  The 
Study Completion Date is used to ascertain timing for study results posting and reporting.
3.3
Sites and Regions
This study will be conducted at approximately 60 to 80 clinical sites in the USA, Canada, and 
EU.


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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.
2. Ability to voluntarily provide written, signed, and dated (personally or via a legally 
authorized representative, as applicable) informed consent to participate in the study.
3. Age 18-80 years inclusive. This inclusion criterion will only be assessed at the first 
Screening visit.
4. Males and females of child-bearing potential who are sexually active, or are not currently 
sexually active during the study, but become sexually active during the period of the study 
and 30 days following the last dose of the IP, must agree to use acceptable contraception as 
described in Section 4.4, Reproductive Potential.
Males and females of child-bearing potential who are not currently sexually active must 
agree to use acceptable contraception, if they become sexually active during the period of the 
study and 30 days following the last dose of the IP.
5. Presence of ≥ 5% steatosis on screening MRI from a centrally read radiologist performed 
either during the Screening period or within 6 months prior to the first visit.
6. Histologic confirmation of NASH without cirrhosis (F1-F3) from a centrally read liver 
biopsy performed either during the Screening period or within 6 months prior to the first  
visit with a NAS of ≥ 4 with a score of at least 1 in each component (steatosis, lobular 
inflammation, and hepatocyte ballooning).
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Presence of or history of cirrhosis or evidence of decompensated liver disease (ie, ascites, 
variceal bleeding, etc.) or hepatocellular carcinoma.
2. History or presence of other concomitant liver disease as assessed by the investigator or 
determined by laboratory findings including, but not limited to: active hepatitis B virus 
(HBV) infection (hepatitis B surface antigen (HBsAg) positive and/or HBVDNA positive; 
subjects who are hepatitis B core antibody (HBcAb) positive may be eligible as long as 
HBsAg is negative and HBVDNA is nondetectable), active hepatitis C virus (HCV) infection 
(prior exposure to HCV (defined as HCVAb positive without a current or prior history of a 
detectable HCVRNA) may be eligible alcoholic liver disease, proven autoimmune hepatitis, 
primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, 


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Wilson’s disease, alpha-1 antitrypsin deficiency, bile duct obstruction, liver primary or 
metastatic cancer.
3. Current or recurrent disease that could affect the action, absorption, disposition, or laboratory 
assessment of the investigational product (IP) (including bile salt metabolism in the intestine) 
eg, uncontrolled inflammatory bowel disease, uncontrolled celiac disease, gastric bypass 
procedures (gastric lap band is acceptable), ileal or ileocecal resection, uncontrolled irritable 
bowel syndrome with predominant diarrhea, or history of chronic diarrhea or loose stools of 
any etiology.
4. Weight change ≥ 5% after qualifying liver biopsy performed.
5. Contraindications to MRI (eg, claustrophobia, coronary stents, coronary implantable devices, 
girth, etc.).
6. Current or relevant history of physical or psychiatric illness, any medical disorder that may 
require treatment or make the subject unlikely to complete the study.
7. Treatment with Vitamin E, thioglitazones, or glucagon-like peptide-1 receptors agonists 
(GLP1 RA) unless subject on a stable dose for 6 months prior to qualifying liver biopsy and 
not initiated after qualifying liver biopsy and will continue the same dosing regimen 
throughout study participation (refer to Section 5.2.1, Permitted Treatment). 
8. Uncontrolled diabetes defined as HbA1c of ≥ 9.0% within 60 days prior to enrollment. 
9. Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations) that could affect the action, absorption, or disposition of the IP, or clinical or 
laboratory assessment.  (Current use is defined as use within 14 days of Screening).  Patients 
currently taking insulin will not be excluded; however, they must be on a stable dose for at 
least 30 days prior to Screening. Also refer to Section 5.2.2, Prohibited Treatment.
10. Use of drugs, herbs or supplements historically associated with causing or worsening 
NAFLD/NASH for less than 6 months prior to liver biopsy, or initiated any time after liver 
biopsy performed, including the use of total parenteral nutrition (TPN). Also refer to Section 
5.2.2, Prohibited Treatment.
11. Serum AST > 5 times upper limit of normal (ULN) at Screening.
12. Serum ALT > 5 times ULN at Screening.
13. Elevated serum creatinine ≥ 2.0 mg/dL.
14. International normalized ratio (INR) >1.3
15. TB ≥ 2.0 x ULN at Screening (Except for documented Gilbert’s syndrome with bilirubin 
levels 20 µmol/L to 90 µmol/L (1.2 to 5.3 mg/dL) and with a ratio of 
unconjugated/conjugated bilirubin that is commensurately higher).
16. Platelet count < 130 × 109/L
17. Medical history of impaired hemostasis or use of anticoagulant medication (low-dose, ie 81 
mg, aspirin (ASA) will be allowed).
18. Uncontrolled thyroid disease.
19. Type 1 diabetes mellitus.


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20. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or 
any of the stated ingredients.
21. Known history of alcohol or other substance abuse within the last year or at any time during 
the study based on investigator’s discretion.  Refer to Section 7.2.3.8, Drug and Alcohol 
Screening. Weekly alcohol intake greater than 21 grams/day for males and 14 grams/day for 
females on average or inability to reliably quantify alcohol consumption based on 
investigator’s judgment.
22. Within 6 months of MRI and liver biopsy:

Have used any IP

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study
23. Inability to safely obtain a liver biopsy.
24. The anticipated need for a surgical procedure during the study that could interfere with the 
treatment. 
25. Known positivity for human immunodeficiency virus (HIV) infection.
26. Cancer within 5 years of Screening, except for basal or squamous cell carcinoma of the skin 
or in situ cervical carcinoma that has been treated with no evidence of recurrence.
27. History of noncompliance with medical regimens, unreliability, mental instability or 
incompetence that could compromise the validity of informed consent or lead to 
noncompliance with the study protocol.
28. Any other conditions or abnormalities which, in the opinion of the investigator, may 
compromise the safety of the subject, or interfere with the subject participating.
29. Subject has failed Screening or was previously enrolled in this study or is currently enrolled 
in this study at any study site (unless the subject is transferring to another qualified study site 
with prior Sponsor approval).
30. Subjects who are employees at the investigational site.
4.3
Restrictions 
Subjects must adhere to the following restrictions for the duration of the study:

Subjects must remain compliant with inclusion/exclusion criteria.

Subjects should not become pregnant, father a child, or nurse/breastfeed a baby. 

Subjects should be encouraged to adhere to the same exercise routine and a healthy diet 
throughout the study.


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4.4
Reproductive Potential
4.4.1
Female Contraception
Sexually active females of child-bearing potential should be using an acceptable form of 
contraception. Females of child-bearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 30 days following the last dose of the IP.  If 
hormonal contraceptives are used they should be administered according to the package insert. 
Females of child-bearing potential who are not currently sexually active must agree to use 
acceptable contraception, as defined below, if they become sexually active during the period of 
the study and 30 days following the last dose of the IP. 
Female subjects should be either:

Post-menopausal (12 consecutive months of spontaneous amenorrhea and age 51 years)

Surgically sterile (having undergone one of the following surgical acts:  hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of child-bearing potential with a negative urine and/or serum -human chorionic 
gonadotropin (-HCG) pregnancy test each study visit.  Females of child-bearing 
potential must agree to abstain from sexual activity that could result in pregnancy or 
agree to use acceptable methods of contraception.
Acceptable methods of contraception are:

Intrauterine devices(IUDs) 

Barrier methods (eg, condoms or diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the Screening visit (Visit 1), plus condoms.  Note:  if subject 
becomes sexually active during the study, they should use one of the other acceptable 
methods noted above in addition to the hormonal contraceptive until it has been stabilized 
for 30 days.

Male sterilization

True abstinence (ie, periodic abstinence and withdrawal are not acceptable)
4.4.2
Male Contraception
Contraception is required for all sexually-active male subjects and their partners. All male 
subjects (including those who are sterile) agree not to donate sperm, and to use 1 of the following 
approved methods of contraception from the Baseline visit on Day 0 until 30 days following 
study discharge:


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
Male condom with spermicide

Sterile sexual partner

Intrauterine device with spermicide (use by female sexual partner)

Female condom with spermicide (use by female sexual partner)

Contraceptive sponge with spermicide (use by female sexual partner)

Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with spermicide, or a 
cervical cap with spermicide) (use by female sexual partner)

Oral, implantable, transdermal, or injectable hormonal contraceptive (use by female 
sexual partner).
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety).  The investigator is 
encouraged to discuss withdrawal of a subject from the IP with the CRO Medical Monitor when 
possible.
If the IP is discontinued, regardless of the reason, the evaluations listed for both Visit 9/end of 
study (EOS) and Visit 10/Follow-up, are to be performed as completely as possible; however, the 
EOS liver biopsy will not be required for patients discontinuing prior to Week 44. 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
source documents.  The reason for termination, date of stopping the IP, and the total amount of 
the IP taken must be recorded in the electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Medically important events that in the opinion of the investigator, medical monitor or sponsor 
would compromise the subject’s ability to safely continue in the study may result in withdrawal 
of the subject from the study. 
4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the eCRF.  If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
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Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol violation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Death

Screen failure 

Noncompliance with study drug

Physician decision

Pregnancy

Progressive disease

Study terminated by sponsor

Other - If “Other” is selected, the investigator must specify on the eCRF 
4.5.3
Subjects Lost to Follow-up Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact clinic visit.  At least 1 of these documented 
attempts must include a written communication sent to the subject’s last known address via 
courier or mail (with an acknowledgement of receipt request) asking that they return to the site 
for final safety evaluations and return any unused IP.
4.5.4
Safety-related Stopping Rules
Refer to Appendix 4 and Appendix 5 for criteria to assess severity of liver-related AEs and 
stopping rules for liver-related blood tests, respectively.
An urgent safety review will be conducted within 7 days by the sponsor if one or more of the
following criteria are met:

Death that is considered related to the study drug

Two SAEs of similar type (defined as same or similar Medical Dictionary for Regulatory 
Activities (MedDRA) higher level group code), and considered related to the study drug.


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The urgent review will be performed by a sponsor safety review group, which will include the 
study Pharmacovigilance and Risk Management (PVRM) Medical Lead and the PVRM 
therapeutic area (TA) Head. The PVRM TA Head, not the PVRM Medical Lead involved in the 
study, may be unblinded as part of this urgent safety review, if required. Following the sponsor’s 
review of safety data, one of the following actions will be taken with respect to study status:

Continue study with protocol unchanged

Continue study with modifications to the protocol

Terminate study
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment.


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5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to signing informed consent at the Screening visit (Visit 1) and through the 
final study contact (including protocol-defined follow-up period) must be recorded on the 
appropriate eCRF page.
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
and behavioral treatment, non-pharmacological treatment, such as psychotherapy, as 
appropriate), received within 30 days of the date of first dose of the IP. Prior treatment 
information must be recorded on the appropriate eCRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of the IP 
and the end of the follow-up period, inclusive.  Concomitant treatment information must be 
recorded on the appropriate eCRF page.
5.2.1
Permitted Treatment
Medications and supplements including but not limited to vitamin E, betaine, s-adenosyl-l-
methionine, ursodeoxycholic acid, milk thistle, gemfibrozil, anti-TNF therapies, probiotics 
biguanides (metformin), thiazolidinediones (TZDs) and GLP1 RAs that have been used to treat 
NAFLD/NASH are allowed during the course of the study if the subject has been on a stable 
dosing regimen (ie, same dose and frequency in the previous 6 months prior to the qualifying 
liver biopsy and not initiated after qualifying liver biopsy) and will continue this dosing regimen 
throughout study participation. The investigator must contact the CRO medical monitor then the 
Shire GCDL to discuss any changes to concomitant medications that may impact the study.
5.2.2
Prohibited Treatment
The following list of prohibited drugs cannot have been taken for more than 2 weeks within the 
year prior to randomization and are excluded while on study.

Systemic Glucocorticoids

Tamoxifen

Amiodarone

Methotrexate

Alcohol (see Section 4.2)

Griseofulvin

Total parenteral nutrition

Valproate

Nucleoside Analogues

Tetracycline (high dose)

Estrogens at doses greater than 
used for hormone replacement

Anabolic steroids

Bile acid sequestrants such as 


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cholestyramine or colestipol

Any other known hepatotoxins 
including over-the counter 
therapies and herbal therapies 
such as germander, chaparral and 
ma-huang.
This is not a comprehensive list.  Treatments not listed above are generally considered allowable, 
unless considered a potential hepatotoxin.  Antidiarrheals will be allowed at the discretion of the 
investigator, with the exception of BA sequestrants.


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is volixibat potassium (formerly LUM002, formerly SHP626, hereafter referred 
to as volixibat) which will be provided in 5, 10 and 20 mg capsule form.  Additional information 
is provided in the current Volixibat Potassium (SHP626) Investigator’s Brochure.
The reference/comparator product is an identical PBO which will be provided in capsule form.
6.1.1
Blinding the Treatment Assignment
The IP will be supplied as double-blind blister packs. The actual double-blind treatment given to 
individual subjects is determined by a randomization schedule which will be automatically 
assigned by the interactive response technology (IRT). Placebo capsules, which exactly match 
the IP, will be used in the blister packs to provide the same number and size capsules for each of 
the doses within the treatment groups.
6.2
Administration of Investigational Product(s)
All IP and supplies will be provided by Shire or its designee. At each visit, subjects will be 
supplied with enough IP to last until the subsequent visit. Lost or damaged IP will be replaced as 
needed. Volixibat will be supplied to the clinical research center (CRC) as powder in capsule. 
Volixibat will be supplied in identical capsules in strengths of 5, 10, and 20 mg (with matched 
PBO). 
6.2.1
Interactive Response Technology for Investigational Product Management
IRT will be used for the following investigational tasks:

Randomization

Supply management

Inventory management and supply ordering

Expiration tracking

Returns

Emergency unblinding
6.2.2
Allocation of Subjects to Treatment 
This is a double-blind, PBO-controlled study. The actual treatment given to individual subjects is 
determined by a randomization schedule.


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Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to the IP allocated to the 
subject, once eligibility has been determined.  
Individual subject treatment is automatically assigned by the IRT.
Once a randomization number/unique identifier has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study.  If a randomization number/unique 
identifier is allocated incorrectly, the clinical research associate (CRA)/study monitor must be 
notified as soon as the error is discovered. 
IP packaging identification numbers, separate from randomization numbers/unique identifiers, 
may also be assigned to subjects for specific treatment assignment as dictated by the study.  In 
these cases, the same IP packing identification number may not be assigned to more than 1 
subject.
Subjects will be equally allocated to all volixibat doses and PBO if their randomization precedes 
the 24 week IA. If a subject’s randomization occurs after the 24 week IA, subjects will be 
equally allocated to all remaining volixibat doses (determined based on the results of the IA) and 
PBO.  The randomization will be stratified by treatment arm, baseline T2DM, and NAS ≥ 6 or 
NAS = {4, 5}.  
6.2.3
Dosing
All doses of volixibat or matching PBO will be administered orally as a capsule in a double-
blinded fashion.  The first dose of IP for each subject will be administered in the clinic. The dose 
will be administered with 240 mL of water and should be given 30 minutes prior to the first meal 
of the day containing approximately 10-20 grams of fat. All assessments should be completed at 
least 30 minutes prior to administration of the IP. The subject should make all attempts to 
consistently take the IP around the same time each day.  If a dose is missed at the normally 
scheduled time, the subject can make up the dose that day; however, they should not take two 
doses in any 24-hour period.  
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the IP is required for further treatment of the subject. The investigator 
should contact the CRO medical monitor and the Shire GCDL at the same time and as soon as 
possible after the investigator has been unblinded.  
In the event that the treatment assignment is broken, the date and the signature of the person who 
broke the code are to be recorded in the source documents and the IRT, and the reason for 


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breaking the code will be recorded in the source documents and the clinical database.  Upon 
breaking the blind, the subject is withdrawn from the study, but should be followed up for safety 
purposes. Any code-breaks that occur must be reported to the CRO medical monitor.  Code-
break information is held by the pharmacist/designated person at the site and by the CRO 
medical monitor for the study or designee.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the IP container. 
All IP is labeled with a minimum of the protocol number, medication identification number, 
dosage form (including product name and quantity in pack), directions for use, storage 
conditions, expiry date (if applicable), batch number and/or packaging reference, the statements 
‘For clinical trial use only’, and/or ‘CAUTION: New Drug - Limited by Federal (or USA) Law 
to Investigational Use’, ‘Keep out of reach of children’, and the sponsor's name and address. Any 
additional labeling requirements for participating countries will also be included on the label.
Additional labels may, on a case-by-case basis, be applied to the IP in order to satisfy local or 
institutional requirements, but must not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
The sponsor or designee will provide the IP for this study. The IP is packaged in the following 
labeled containers:

Volixibat 5 mg capsules

Volixibat 10 mg capsules

Volixibat 20 mg capsules

Volixibat PBO capsules
6.3.3
Storage
The investigator has overall responsibility for ensuring that the IP is stored in a secure, limited-
access location.  Limited responsibility may be delegated to the pharmacy or member of the 
study team, but this delegation must be documented.  


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IPs are distributed by the pharmacy or nominated member of the study team. The 
pharmacist/nominated team member will enter the unique subject identifier on the IP labels as 
they are distributed. 
All IP must be stored at the clinic at 20 - 25oC (68 - 77oF); excursions are allowed between 15 -
30oC (59 - 86oF).
IPs must be stored in accordance with labeled storage conditions.  Temperature monitoring is 
required at the storage location to ensure that the IP is maintained within an established 
temperature range. The investigator is responsible for ensuring that the temperature is monitored 
throughout the duration of the study and that records are maintained; the temperature should be 
monitored continuously by using either an in-house system, a mechanical recording device such 
as a calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.  Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording.  The sponsor must be notified immediately upon discovery of any excursion below 
15oC (59oF) or above 30oC (86oF); these excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the IP and will 
provide supportive documentation as necessary.  Under no circumstances should the product be 
dispensed to subjects until the impact has been determined and the product is deemed appropriate 
for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the IP 
that could affect the integrity of the product(s), eg, fumigation of a storage room or a change in 
storage location.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the IP to carry out this protocol for the 
agreed number of subjects.  The investigator or designee will acknowledge receipt of the IP, 
documenting shipment content and condition.  Accurate records of all IP dispensed, used, 
returned, and/or destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing the IP.  Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator.  This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the IP only to subjects included in this study 
following the procedures set out in the study protocol.  Each subject will be given only the IP 
carrying his/her treatment assignment. All dispensed IP will be documented on the eCRFs and/or 
other IP record. The investigator is responsible to ensure the retrieval of all study supplies from 
subjects.


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No IP stock or returned inventory from a Shire-sponsored study may be removed from the site 
where originally shipped without prior knowledge and consent by the sponsor.  If such transfer is 
authorized by the sponsor, all applicable local, state, and national laws must be adhered to for the 
transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.  The site must ensure that the accountability and destruction 
records are complete, accurate, and ready for verification at each monitoring visit.
The process for return and destruction of IP must be determined and documented during the 
study start-up phase.
With the written agreement by the sponsor of the site’s IP destruction procedures, all unused 
stock, subject returned IP, and empty/used IP packaging may be destroyed at the site or a local 
facility on an ongoing basis throughout the study and at the end of the study following 
verification of accountability by the CRA/study monitor. In this case, destruction records 
identifying what was destroyed, when, how, and by whom, must be obtained with copies 
provided to the sponsor. Destruction of IP must be in accordance with local, state, and national 
laws.
Alternatively, in the absence of written agreement by the sponsor of the site’s IP destruction 
procedures, all unused stock, subject-returned IP, and empty/used IP packaging may be required 
to be sent to a nominated contractor on behalf of the sponsor for IP destruction on an ongoing 
basis throughout the study and at the end of the study. IP being returned to the sponsor’s 
designated contractors also must be counted and verified by clinical site personnel and the 
CRA/study monitor. For unused supplies where the original supplied tamper-evident feature is 
verified as intact, the tamper-evident feature must not be broken and the labeled amount is to be 
documented in lieu of counting. Shipment return forms, when used, must be signed prior to 
shipment from the site. Validated electronic return systems (ie, IRT) do not require a shipment 
form. Returned IP must be packed in a tamper-evident manner to ensure product integrity. 
Contact the sponsor for authorization to return any IP prior to shipment. Shipment of all returned 
IP must comply with local, state, and national laws.
6.5
Subject Compliance
Subjects must be instructed to bring their unused IP and empty/used IP packaging to every visit. 
Drug accountability must be assessed at the container/packaging level for unused IP that is 
contained within the original tamper-evident sealed container (eg, blister pack) or at the 
individual count level for opened containers/packaging. The pharmacist/nominated person will 
record details on the drug accountability form.


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7.
STUDY PROCEDURES
7.1
Study Schedule
This study will consist of a Screening period of up to 56 days (the screening period may be 
minimally extended under special circumstances only with the explicit approval of the medical 
monitor), a 48-week Treatment period, and a Follow-up visit 4 weeks after treatment ends. A 
detailed display of all study procedures is provided in Table 1: Schedule of Assessments. 
Patients will be assessed according to the following schedule:

Screening – Visit 1  (Weeks -8 to 0 [Day -56 to Day -1])

Baseline – Visit 2  (Week 0 [Day 0])

Treatment and Assessments – Visits 3 through 9 (Week 2 through Week 48)

Follow-up – Visit 10 (Week 52, 4 weeks after completion of dosing) 
7.1.1
Screening (Visit 1) 
Screening procedures must be completed within 56 days prior to randomization for the first dose 
of the IP. The screening period may be minimally extended under special circumstances only 
with the explicit approval of the medical monitor. At the Screening visit, considered Visit 1 
(Week -8 to 0, Day -56 to -1), all screening assessments and procedures are to be performed by 
the principal investigator or a qualified designee. See Table 1 for a complete list of screening 
procedures to be performed.
Written, signed, and dated informed consent from the subject prior to the performance of any 
study-related procedures must be obtained by the principal investigator or a designee. A copy of 
the signed informed consent form must be given to the subject for their records.
The following Screening procedures should be assessed at the beginning of the visit window, 
preferably between Day -56 and Day -49: inclusion/exclusion criteria, collection of subject 
information (demographics, medical and medication history AEs, and concomitant medications), 
a physical examination including vital signs, height, weight, and waist/hip measurements; 
collection of blood and urine samples for screening and safety assessments, performance of an 
electrocardiogram (ECG), and scheduling of MRI and liver biopsy. MRI and liver biopsy (if one 
has not been completed in the previous 6 months) should be performed with sufficient time to 
ensure results are received prior to the Baseline visit. 
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered the 
IP. Subjects cannot be rescreened once they have been designated as a screen failure. 


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7.1.2
Baseline (Visit 2)
Following the Screening visit, subjects will return to the clinic within 56 days for Visit 2, 
(considered Week 0, Day 0), for Baseline assessments including review of the 
inclusion/exclusion criteria, adverse events, and concomitant medications; physical examination 
with vital signs, weight, and waist/hip measurements; ECG; collection of blood and urine 
samples; and completion of the patient-reported outcome (PRO) EuroQol-5 Dimension-5 Level 
Questionnaire (EQ-5D-5L) survey. After completion of these assessments, subjects are 
randomized using Interactive Response Technology (IRT) to 1 of 4 treatment arms receiving 
volixibat 5 mg, 10 mg, or 20 mg, or PBO. The initial supply of study drug is dispensed to ensure 
adequate daily dosing until the next scheduled study visit.
7.1.3
Treatment and Assessment Period (Visits 3 through 9/EOS) 
During the 48 weeks of double-blind treatment, 7 clinic visits are scheduled to occur as follows:

Visit 3 - Week 2, Day 14 (+/- 3 days)

Visit 4 - Week 4, Day 28 (+/- 3 days)

Visit 5 - Week 8, Day 56 (+/- 5 days)

Visit 6 - Week 12, Day 84 (+/- 5 days)

Visit 7 - Week 24, Day 168 (+/- 7 days) – Interim Analysis

Visit 8 - Week 36, Day 252 (+/- 7 days)

Visit 9 - Week 48, Day 336 (+/- 7 days) – End of Study
Subjects are reminded not to eat and not to take their study drug on the day of scheduled study 
visits prior to completion of assessments. They should bring their study drug with them to the 
visit. All assessments should be completed at least 30 minutes prior to administration of the IP.
IP should be taken 30 minutes prior to the first meal of the day containing approximately 10-20 
grams of fat. 
The Schedule of Assessments provided in Table 1 details the procedures to be completed at each 
visit. All Treatment visits (3 through 9) will include weight and waist/hip measurements, 
assessment of vital signs, and blood sampling for completion of biochemistry, hematology, 
serum glucose, lipid panel, HbA1c, and serum liver-related blood tests. At all visits, adverse 
events, and concomitant medications will be collected for all subjects, and female subjects of 
childbearing potential will have a urine pregnancy test. Subjects will return containers of unused 
study drug for assessment of accountability and compliance which will be documented in the 
IRT. New supplies of study drug will be dispensed at Visits 3 through 8. 
Additional assessments will also occur less frequently during the Treatment Period for 
coagulation panel, vitamin D, insulin, thyroid testing, urinalysis, ECG, physical examinations, 
and completion of the EQ-5D-5L. 


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An MRI will be repeated at Visit 7 for the 24-week IA and at Visit 9 (Week 48) for the subjects 
in the IA set only. A final liver biopsy will be performed at Visit 9 (Week 48) for all subjects 
unless a subject discontinues prior to Week 44, in which case the EOS liver biopsy is not 
required.
7.1.4
Follow-up (Visit 10)
The follow-up period for this protocol is 4 weeks after the last dose of study drug with a final 
Follow-up visit scheduled for Week 52. Procedures to be completed at this final visit include 
physical examination, weight, waist/hip measurements, vital signs, samples for biochemistry and 
hematology, serum glucose, lipid panel, HbA1c, serum liver-related blood tests, insulin, thyroid 
testing, and urine pregnancy test (for women of childbearing potential). Adverse events and 
concomitant medications will be recorded. All AEs and SAEs that are not resolved at the time of 
this contact will be followed to closure (see Section 8.1).
7.1.5
Additional Care of Subjects after the Study
No after care is planned for this study.
7.2
Study Evaluations and Procedures
All assessments and procedures are to be performed by the Investigator or a qualified designee 
who has been trained in the protocol. Assessments are to be performed according to the 
schedules shown in Table 1. If a subject terminates the study early, the CRC will make 
reasonable effort to perform the EOS and safety follow-up assessments and procedures for the 
subject’s safety and well-being.
7.2.1
Demographic and Other Baseline Characteristics
Demographic details will be obtained at screening and recorded on the eCRF. Data collected will 
include age, gender, ethnicity, height, and weight.
7.2.2
Efficacy
7.2.2.1
Liver Biopsy
Liver biopsies will provide histologic data for confirmation of the diagnosis of NASH, 
assessment and grading of NASH activity, and scoring of steatosis, lobular inflammation, 
ballooning, as well as fibrosis and additional features (see Appendix 2 and Laboratory Manual 
for additional information). 
7.2.2.2
MRI
The presence of ≥ 5% steatosis on screening MRI from a centrally read radiologist will be 
performed either during the Screening period or within 6 months prior to the first visit. Steatosis 
is assessed by MRI hepatic fat fraction. The Week 24 and Week 48 MRIs will be conducted for 
subjects in the IA set only.


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7.2.3
Safety
7.2.3.1
Medical History and Medications 
Medical history including important medical events and concomitant medication and illnesses 
will be obtained at Screening and will be recorded on the eCRF. Any existing medical condition 
present prior to the time of randomization should be reported as medical history
7.2.3.2
Physical Examination 
A complete physical examination will be performed with a thorough review of body systems at 
Screening, Baseline prior to randomization, and at study visits specified in Table 1.  Physical 
examinations will include a review of the subject’s general appearance, as well as evaluation of 
the body systems including:

Eyes, ears, nose, throat

Lymph nodes

Cardiovascular

Skin

Abdomen

Neurological

Spine and extremities
Abnormalities identified at the Screening visit (Visit 1) will be documented in the subject’s 
source documents and on the medical history eCRF. Changes after the Screening visit (Visit 1) 
will be captured as AEs on the AE eCRF page, if deemed clinically significant by the 
investigator.
Height will be measured at the Screening visit only while weight and waist and hip 
circumference will be recorded at all study visits. BMI will be calculated programmatically.   
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”).  
Adverse events are collected from the time informed consent is signed.  (Please refer to Section 
8, Adverse and Serious Adverse Events Assessment.)
7.2.3.4
Vital Signs
Vital signs include oral or tympanic temperature, sitting blood pressure, pulse, and respiratory 
rate. Blood pressure should be determined by cuff (using the same method, the same arm, and in 


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the same position throughout the study). Any deviations from Baseline (Visit 2) vital signs which 
are deemed clinically significant in the opinion of the investigator are to be recorded as an AE.
7.2.3.5
Clinical Laboratory Evaluations 
All clinical laboratory assays will be performed according to the central laboratory’s normal 
procedures.  Reference ranges supplied by the central laboratory will be used to assess the 
clinical laboratory data for clinical significance and out-of-range pathological changes.  The 
investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Clinically 
significant findings should be evaluated for recording as adverse events on the eCRF. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry
Albumin (ALB)
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT; SGPT)
Aspartate aminotransferase (AST; SGOT)
Blood urea nitrogen (BUN)
C4
Calcium (Ca)
Bicarbonate (CO2)
Chloride (Cl)
Creatinine
Creatine kinase
Gamma glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
Magnesium (Mg)
Phosphate (P)
Potassium (K)
Sodium (Na)
Total and direct bilirubin
Total cholesterol
Protein
Triiodothyronine (T3)
Thyroid-stimulating hormone 
(TSH)
Triglycerides
Uric acid


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Hematology
Hemoglobin 
Hematocrit
Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin 
concentration (MCHC)
Platelets
Red blood cell (RBC) 
White blood cell (WBC) count with 
differential
Prothrombin time (PTT)
Activated partial thromboplastin time 
(aPTT)
International normalized ratio (INR)
Urinalysis
Appearance (clarity and color)
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Microscopic examination of sediment
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Oxalate
7.2.3.6
Additional Laboratory Assessments
Laboratory samples will be collected and assessed for:

HIV testing and assessment of Hepatitis B/C including HBcAb, HBsAg, HBVDNA, and 
HCVAb, and HCVRNA will occur at the Screening visit only

Lipid panel including fasting total cholesterol, HDL-C, LDL-C, and triglycerides at each 
scheduled study visit (Visits 1 through 10)

HbA1c will be tested at every scheduled visit (Visits 1 through 10)

Full coagulation panel will be done at Screening and Baseline, but only INR and PT are 
required at remaining time points at Visits 4, 7, and 9

Insulin will be tested at Screening, Baseline, at Visit 4 and Visits 6 through 10

HOMA2-IR and HOMA2-%B: will be calculated programmatically from serum glucose 
tested at Screening, Baseline, Visits 7, 9, and 10


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
Vitamin D will be tested at Screening, Baseline, and Visits 4, 7, and 9

Thyroid testing including TSH and T3 will be tested at Screening, Baseline, and Visits 4, 
6, 7, 9, and 10

C4 samples will be collected at Baseline and Visits 6, 7, 9, and 10
7.2.3.7
Pregnancy Test 
A urine pregnancy test is performed on all females of child-bearing potential at the Screening 
visit (Visit 1), Baseline visit (Visit 2), at each Treatment visit (Visits 3 through 9) and at the 
Final visit (Visit 10), or if pregnancy is suspected, or on withdrawal of the subject from the 
study. A positive urine pregnancy test must be followed with a serum pregnancy test performed 
by the central laboratory. Additional testing can be performed at the investigator’s discretion. 
Also, refer to Section 8.1.7.
7.2.3.8
Drug and Alcohol Testing 
A urine screen for drugs of abuse and blood test for alcohol will be performed at Screening and 
Baseline as described in Table 1. Additional drug and alcohol screens may be performed at the 
investigator’s discretion.
Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiate metabolite, and phencyclidine. 
Results of drug and alcohol screens will be reviewed and verified by the study monitor, but will 
not be collected in the eCRF database.
Any positive result for drugs of abuse at the Screening or Baseline visits may exclude the subject 
from further participation in the study. A positive test for drugs of abuse or alcohol done at the 
investigator’s discretion discovered at any time during the study will be grounds for study 
discontinuation.
7.2.3.9
Electrocardiogram 
An ECG (12-lead) will be performed at the times specified in Table 1 in accordance with the 
clinical site’s standard practice(s) and equipment supplied by the CRC.  Recordings of ECGs 
will be read locally at the clinical site by the investigator or designee. The ECG will include 
assessments of heart rate and PR, RR, QRS, and QT intervals. Identification of any clinically 
significant findings and/or abnormalities will be recorded on the eCRF. 
7.2.3.10
Health-related Quality of Life Assessments
The EuroQol (EuroQol. 2016. Available at: http://www.euroqol.org. [Accessed 17 February 
2016]) EQ-5D-5L (“EQ-5D”) is a widely used standardized questionnaire that assesses generic 
HRQoL and is also recommended for health-economic evaluations.  The EQ-5D includes two 
components: a descriptive profile and a visual analogue scale (VAS).  The descriptive profile 
includes five dimensions (ie, pain/discomfort, mobility, usual activities, self-care and 


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anxiety/depression), each with five levels (ie, no problems, slight problems, moderate problems, 
severe problems, extreme problems). An EQ-5D index can also be derived from the data which 
summarizes health status using a single value (ie, health-state utility).  The psychometric 
properties of the EQ-5D-5L have been established and well documented (see Appendix 3).
7.2.3.11
Volume of Blood to be Drawn from Each Subject
During this study, it is expected that approximately 124 mL of blood will be drawn from all 
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate.  The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 124 mL. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments may be combined.  


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4.  This includes events occurring during the screening phase of the 
study, regardless of whether or not the IP is administered.  Where possible, a diagnosis rather 
than a list of symptoms should be recorded.  If a diagnosis has not been made, then each 
symptom should be listed individually.  All AEs should be captured on the appropriate AE pages 
in the eCRF and in source documents.  In addition to untoward AEs, unexpected benefits outside 
the IP indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study.  Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained.  When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity.  An event that changes in severity should be captured as a new 
event.  Worsening of pre-treatment events, after initiation of the IP, must be recorded as new 
AEs (for example, if a subject experiences mild intermittent dyspepsia prior to dosing of the IP, 
but the dyspepsia becomes severe and more frequent after first dose of the IP has been 
administered, a new AE of severe dyspepsia (with the appropriate date of onset) is recorded on 
the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of daily 
living.
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.


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Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Appendix 4 provides criteria to assess the severity of liver-related adverse events.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to the IP for each AE.  The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the IP.  If there is no valid reason for 
suggesting a relationship, then the AE should be classified as “not related”.  Otherwise, if there is 
any valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect 
relationship between the IP and the occurrence of the AE, then the AE should be considered 
“related”.  The causality assessment must be documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the IP is 
compelling and/or follows a known or suspected response pattern to that product, and 
the event cannot be explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the IP and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF.  Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown.
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 


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data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the IP, a shift of a parameter is 
observed from a normal value to an abnormal value, or a further worsening of an already 
abnormal value.  When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range, either while continuing treatment or after 
the end of treatment with the IP, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Criteria for Discontinuation of Treatment
Appendix 5 provides guidelines for discontinuation of treatment based on elevated ALT, AST, 
TB, and associated signs and symptoms.  
8.1.7
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.
Any report of pregnancy for any female study participant (or the female partner of a male 
participant) must be reported within 24 hours to the Shire Global Pharmacovigilance and Risk 
Management Department using the Shire Investigational and Marketed Products Pregnancy 
Report Form.  A copy of the Shire Investigational and Marketed Products Pregnancy Report 
Form (and any applicable follow-up reports) must also be sent to the CRO medical monitor and 
the Shire clinical physician using the details specified in the emergency contact information 
section of the protocol. The pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days post 
partum. 


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Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form.  Note:  An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and Non-
serious AEs Required by the Protocol Form as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form.  The test date of the first positive serum/urine -HCG test or 
ultrasound result will determine the pregnancy onset date.
8.1.8
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2.  Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of the IP when used for a non-medical 
purpose (eg, to alter one’s state of consciousness or get high) in a manner that may be 
detrimental to the individual and/or society

Misuse – Intentional use of the IP other than as directed or indicated at any dose (Note: 
this includes a situation where the IP is not used as directed at the dose prescribed by the 
protocol)

Overdose – Intentional or unintentional intake of a dose of an IP exceeding a pre-
specified total daily dose of the product.  

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an IP.  For studies, medication errors are reportable to the sponsor only as defined 
below.
Cases of subjects missing doses of the IP are not considered reportable as medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired IP should be considered as a reportable medication 
error.


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8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the Volixibat Potassium (SHP626) 
Investigator’s Brochure which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire GCDL within 24 hours of 
the first awareness of the event.  Note: The 24-hour reporting requirement for SAEs does not 
apply to reports of abuse, misuse, overdose, or medication errors (see Section 8.1.8) unless they 
result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note:  Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the Shire GCDL using the details specified in the emergency contact 
information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to the IP or not) that at any dose:

Results in death

Is life-threatening.  Note: The term ‘life-threatening’ in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization.  Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs.  For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect


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
Is an important medical event.  Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions 
that do not result in inpatient hospitalization; or the development of drug dependency or 
drug abuse.  
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4, and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the Shire GCDL 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the IP and discovered by the investigator at any 
interval after the study has completed must be reported to the Shire Global Pharmacovigilance 
and Risk Management Department within 24 hours of the first awareness of the event.
8.2.4
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic.  In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.5
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date.  
For all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another IP action was previously taken (eg, drug interrupted, reduced, withdrawn), the action 
taken with the IP should be recorded as “dose not changed” or “not applicable” (if the subject 
never received the IP). The IP action of “withdrawn” should not be selected solely as a result of 
the subject’s death. 
8.2.6
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The CRO is responsible for notifying the relevant regulatory authorities as appropriate: USA 
central IRBs/EU central ECs of related, unexpected SAEs.


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In addition the CRO is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the SHP626-201 program.  
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.


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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan.  
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification are 
to be communicated to the site for resolution.  Only authorized personnel will make corrections 
to the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, IP serum concentrations, 
antibiotics to investigation product, treatment allocation, and IP preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available.  If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.  
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, IP exposure, and prior and concomitant medications.  The SAP will also include 
a description of how missing, unused and spurious data will be addressed.


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The SAP will be finalized prior to unblinding to preserve the integrity of the statistical analysis 
and study conclusions.  
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513). 
9.5
Planned Interim Analysis 
Study enrollment will be paused after 92 subjects have been randomized in order for an IA to be 
conducted by an independent DMC after at least 80 subjects have received 24 weeks of 
treatment.  The IA will evaluate the safety, tolerability and efficacy of 3 doses of volixibat each 
compared to PBO. The Interim Analysis Set (IAS; see Section 9.7) will be used for the analyses 
conducted at the IA. The IA will be used to drop one or more doses of volixibat, or to terminate 
the trial.
Decisions about whether or not to continue randomizing to a particular dose following the 
24 week IA should be made in accord with Figure 2 and its associated decision rules.  In the 
figure, a net positive benefit risk assessment implies that the drug is more effective than any 
negative safety concerns.  Effectively, randomization should be discontinued to any dose 
determined to be intolerable or to have a net negative benefit risk.  Hepatic fat fraction as 
measured by MRI is abbreviated HFF in the figure.  The liver enzyme alanine aminotransferase 
is abbreviated ALT.


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Figure 2:
Process Flow for Volixibat Dose Decisions at 24 Week IA
Decision Rules:
If randomization is discontinued to at least one dose, then randomize equally to the remaining 
volixibat dose(s) and PBO.  That is, if two doses are determined to be tolerable and to have a net 
positive benefit risk assessment, then randomization to those two doses (and PBO) should 
continue.  Further, if only one dose is determined to be tolerable and to have a net positive 
benefit risk assessment, then randomization to only that dose (and PBO) should continue.
Otherwise, the choice of doses to which randomization should continue should be made 
according to the following general principles and specific rules which are embodied in Appendix 
6.


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Subjects recruited into the study prior to the IA will continue with the same dosing regimen for 
the duration of the planned study participation. That is, subjects receiving a dose to which 
randomization is stopped at the IA will continue to receive that same dose throughout the course 
of the study, and complete all required assessments. Subjects recruited in the study after 
completion of the IA will be randomized evenly to the remaining dose groups or PBO group by 
IRT.  Subjects will be randomized to at most two volixibat doses as well as to PBO.  Thus, 
depending on the results from the IA, the study may be terminated, or one or more doses of 
volixibat will be discontinued.  If the study is not terminated, subjects will receive a total of 48 
weeks of IP.
9.5.1
Tolerability
Tolerability will be assessed by the number of discontinuations due to any one TEAE.  The most 
common causes of discontinuation seen in healthy human trials were gastrointestinal events, 
most notably, diarrhea, loose stools, increased evacuations, and abdominal pain.  Thus, 
calculations used to determine dropping one or more doses of volixibat in this study were based 
upon the rate of evacuations seen in the Phase 1 trial SHP626-101, as this TEAE was felt to be 
most objectively measured.  The average rate of evacuations was ~ 1.27 per subject per day for 
PBO.  The lowest rate of evacuations on volixibat occurred on 10 mg, and was ~ 1.64 per subject 
per day.  If this frequency of evacuations translates to average numbers of discontinuations, a 
difference of 6 or more discontinuations on volixibat when compared to PBO would occur by 
chance with less than 1% probability.  Consequently, if 6 or more additional subjects treated with 
a specific dose of volixibat discontinue due to any particular TEAE when compared to PBO 
(absolute difference) then randomization to that dose will be stopped.  A particular volixibat dose 
will be considered tolerable if fewer than 6 additional subjects discontinue due to any TEAE 
when compared to PBO.  If none of the doses are tolerated, the study will be terminated.   
9.5.2
Efficacy
Efficacy at the IA will be based on reduction of steatosis (as measured change from Baseline in 
HFF on MRI). If a volixibat dose does not achieve efficacy as measured by HFF reduction on 
MRI, percent change from Baseline in ALT at Week 24 will then be evaluated. 
The sample size of 80 subjects provides 80% power to test for a net difference in HFF (volixibat 
dose minus PBO) of 5% at the two-sided 10% significance level.  The net difference of 5% was 
based on the colesevelam clinical trial (Davidson et al. 2010).   The statistical method used to 
test reduction in HFF will be an ANCOVA model which includes change from Baseline as the 
dependent variable, and treatment and baseline HFF as independent variables.  Treatment will be 
a class variable and baseline HFF will be continuous.  Each volixibat dose will be separately 
compared to PBO to assess whether its net reduction is significantly different from zero at the 
10% significance level. A Holm multiplicity adjustment will be applied.  If the dose is 
significantly different from PBO, then that dose will be considered effective at the interim 
assessment.
If a volixibat dose does not achieve efficacy as measured by HFF reduction on MRI, percent 
change from Baseline in ALT at 24 weeks will be evaluated. If the difference is at least 20% 
when compared to PBO, then that dose will be considered effective at the interim assessment. In 


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addition, if multiple doses exhibit a difference of a least 20% when compared to PBO then the 
statistical method used to test reduction in ALT will be an ANCOVA model which includes 
change from Baseline as the dependent variable, and treatment and baseline ALT as independent 
variables. Treatment will be a class variable and baseline ALT will be continuous.  Each 
volixibat dose will be separately compared to PBO to assess whether its net reduction is 
significantly different from zero at the 10% significance level. A Holm multiplicity adjustment 
will be applied.  If the dose is significantly different from PBO, then that dose will be considered 
effective at the interim assessment.
Data Monitoring Committee
An independent DMC will be established to assess safety, tolerability and efficacy during the 
study, as well as to ensure the validity and scientific merit of the trial.  In addition, the DMC will 
evaluate efficacy of different doses of volixibat at the 24 week IA (using the process flow and 
decision rules specified previously).  Based on their evaluation, the DMC will make 
recommendations concerning study discontinuation due to intolerability or futility, or the 
continuation of one or more dose groups to the 48 week liver biopsy.  The DMC will monitor 
ongoing data generated by the study at regular intervals for the duration of the study. Their role 
is to protect the interests of the subjects in the study and of those still to be entered, by review of 
accumulating data generated in the study. 
The roles, responsibilities and rules governing operation of the DMC will be discussed in full in 
a DMC charter.  The DMC charter will define the primary responsibilities of the DMC; guide its 
activities, its relationship with other study components, its membership, and the purpose and 
timings of its meetings.  It will provide the procedures for ensuring confidentiality, formal 
communication, and outline of the content of reports that will be provided by the DMC.  Data 
provided to the DMC will not be considered ‘clean’ until the database is locked.  
Appropriate summary statistics and data listings will be provided to the DMC by an independent 
statistician supported by an independent statistical reporting group not otherwise assigned to the 
study.  
The recommendations made by the DMC to alter the conduct of the study will be forwarded to 
Shire for final decision.  Shire will forward such decisions to regulatory authorities, as 
appropriate.
9.6
Sample Size Calculation and Power Considerations 
These are the primary hypotheses that are being tested in this study:

Null: The proportion of subjects at Week 48 with a reduction of at least 2 points without 
worsening of fibrosis from Baseline NAS does not differ between any of the volixbat 
doses and PBO.


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
Alternative: The proportion of subjects at Week 48 with a reduction of at least 2 points 
without worsening of fibrosis from Baseline NAS does differ between at least one 
volixbat dose and PBO.
Response rates of 21% (PBO) and 45% (active) were reported in the FLINT trial 
(Neuschwander-Tetri et al. 2015) using the same primary end-point of reduction of NAS by at 
least two points (without worsening of fibrosis).   Based on those response rates, 67 subjects per 
group completing the trial are needed for 80% power with a 10% type I error for a study 
comparing two volixibat doses to PBO.  Holm multiplicity adjustment was included in the 
sample size estimate.
Approximately 334 subjects will be screened to enroll 266 subjects to achieve 201 completers. 
After enrollment of at least 80 subjects (20/treatment arm – 3 active and 1 PBO) a 24-week IA 
will eliminate at least one dose group based on the criteria provided to the DMC; enrollment will 
continue to include approximately 67 subjects in each of the remaining arms. The sample size 
target for this study is 67 completers in each of the treatment groups (201 total if 3 arms 
continue).  Including an additional 20 subjects to account for one dose dropped at the IA, 221 
subjects are needed.   Therefore, approximately 266 (accounts for 20% of 221 dropping out) 
subjects will be randomized if three arms (2 SHP626 and 1 PBO) continue.  Fewer subjects are 
needed if more than one SHP626 dose is dropped.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Safety Analysis Set will consist of all subjects who take at least 1 dose of randomized IP, 
and have at least 1 post-Baseline safety assessment (eg, coming back for any visit, reporting of 
an AE or reporting the absence of AEs).
The Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have a 
valid scored liver biopsy.
The IAS will consist of all subjects in the Safety Set who have a valid post-baseline hepatic fat 
fraction assessed by MRI and a valid post-baseline ALT at 24 weeks. 
9.8
Efficacy Analyses
All efficacy analyses will be based on the FAS and all statistical tests will be 2-sided hypothesis 
tests performed at the 10% level of significance. Also, all confidence intervals will be 2-sided 
confidence intervals, unless otherwise stated.
9.8.1
Primary Efficacy Endpoint
The primary endpoint is the binary response indicating (yes/no) whether a subject responded at 
Week 48 with a reduction, of at least 2 points without worsening of fibrosis, from baseline NAS. 


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The FAS will be used to assess the primary efficacy endpoint. The proportion of subjects at 
Week 48 with a reduction of at least 2 points without worsening of fibrosis from baseline NAS 
will be analyzed. The difference between a volixibat dose and PBO will be tested with a 
stratified Cochran-Mantel-Haenzel test. The test will be stratified by presence or absence of 
T2DM at baseline and baseline NAS separated into two groups (NAS={4, 5} or NAS={6,7,8}). 
Holm multiplicity adjustment will be applied prior to determining statistical significance at the 
0.1 level.
Sensitivity analyses may also be conducted in addition to the primary analysis.  If the proportion
of subjects missing the Week 48 liver biopsy reading does not exceed 10%, then no sensitivity 
analyses will be conducted for the primary efficacy endpoint. Otherwise, analyses which explore 
the impact of the missing data on the primary efficacy endpoint will be conducted. These 
sensitivity analyses may compare imputations of the missing values which favor the PBO and/or 
imputations which favor the active.  Further, if the pattern of missing values does not appear 
uniformly distributed among the treatment arms, imputation method(s) based on informative 
missingness may also be performed.  The sensitivity analyses will be detailed in the Statistical 
Analysis Plan.
9.8.2
Secondary Efficacy Endpoints

Change from Baseline to Week 48 in safety and tolerability of volixibat as measured by 
the number of subjects discontinuing treatment due to any one treatment-emergent 
adverse event (TEAE).

Change from Baseline to Week 48 on liver histology as measured by the individual NAS 
components (ballooning, inflammation, steatosis).

Change from Baseline to Week 48 on hepatic steatosis as measured by MRI-HFF for 
subjects included in the IA.

Change from Baseline to Week 48 on liver histology as measured by fibrosis stage.
(NASH CRN) 

Resolution of NASH (defined as an overall histologic interpretation of no fatty liver 
disease or simple steatosis without steatohepatitis or isolated steatosis without 
steatohepatitis) without worsening of fibrosis as assessed by liver histology at Week 48.

Change from Baseline to Week 48 on serum liver-related biochemistry as measured by:

alanine aminotransferase (ALT)

aspartate aminotransferase (AST)

alkaline phosphatase (ALP)

gamma glutamyl transferase (GGT)

total bilirubin (TB)


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
Change from Baseline to Week 48 on metabolic indicators as measured by:

fasting serum glucose levels

insulin levels

HbA1c

Change from Baseline to Week 48 on serum lipids measured by:

fasting total cholesterol

HDL-C

LDL-C

triglycerides
Descriptive statistics for all secondary endpoints will be presented for each time point at which 
the variable is measured (see Table 1: Schedule of Assessments).
9.8.3
Exploratory Efficacy Endpoints

Change from Baseline to Week 48 on liver histology as measured by the SAF scoring 
components: Steatosis (S), Activity (A), and Fibrosis (F)

Change from Baseline to Week 48 on anthropomorphic measures: 

body weight

BMI 

waist circumference 

waist-hip ratio 

Change from Baseline to Week 48 in subjects with T2DM on homeostasis measured by: 

Homeostasis model assessment 2-IR (HOMA2-IR) 

HOMA2-beta cell function (HOMA2-%B) 

Change from Baseline to Week 48 on the EQ-5D index, a patient-reported-measure of 
HRQL and health status.

Change from Baseline to Week 48 on the EQ-5D VAS score.


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
Change from Baseline to Week 48 in the proportion of subjects reporting having 
problems (no problems, slight problems, moderate problems, severe problems, extreme 
problems) with pain/discomfort, mobility, usual-activities, self-care, anxiety/depression 
in the EQ-5D questionnaire
Descriptive statistics for all exploratory endpoints will be presented for each time point at which 
the variable is measured (see Table 1: Schedule of Assessments).
9.9
Safety Analyses
The Safety Set will be used to assess the safety endpoints. 
The number of discontinuations due to any 1 TEAE will be summarized for each treatment 
group. 
The number of events, incidence, and percentage of TEAEs will be presented for each treatment 
group by system organ class, and by the preferred term using the agreed upon version of the 
Medical Dictionary for Regulatory Activities. 
Treatment-emergent AEs will be further summarized by severity.
Adverse events related to the IP, AEs leading to withdrawal, SAEs, and deaths will also be 
summarized. 
Vital signs, ECG findings, and clinical laboratory tests will be summarized for each treatment 
group. Potentially clinically important findings will be summarized. Graphical presentation may 
be used when deemed necessary
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  The 
number of events, incidence, and percentage of TEAEs will be calculated overall, by SOC, by 
preferred term, and by treatment group. Treatment-emergent adverse events will be further 
summarized by severity and relationship to the IP. Adverse events related to the IP, AEs leading 
to withdrawal, SAEs, and deaths will be similarly summarized/listed.
Vital signs, ECG findings, and clinical laboratory tests will be summarized for each treatment 
group. Potentially clinically important findings will be summarized. Graphical presentation may 
be used when deemed necessary.
9.10 Other Analyses
Serum samples to be stored.
9.10.1
Health-related Quality of Life Analyses

Change from Baseline to Week 48 on the EQ-5D index (Appendix 3). The EQ-5D index 
will be derived using published UK-based preference weights. Univariate descriptive 


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statistics and multivariate regression analyses adjusting for selected baseline covariates 
will be undertaken.

Change from Baseline to Week 48 on the EQ-5D VAS score. Univariate descriptive 
statistics and multivariate regression analyses adjusting for selected baseline covariates 
will be undertaken.

Change from Baseline to Week 48 in the proportion of subjects reporting having 
problems (none, slight, moderate, severe, extreme) with pain/discomfort, mobility, usual-
activities, self-care, anxiety/depression in the EQ-5D questionnaire.  Proportions and 
95% confidence intervals will also be generated for the baseline and Week 48 values as 
well as for change from baseline.
9.10.2
Stool Assessment
Stool hardness and number of evacuations will be assessed throughout the study. Stool hardness 
will be assessed for the softest evacuation within 24 hours of each clinic visit using the Bristol 
Stool Chart, a medical aid designed to classify the form of human feces into 7 categories where 
Type 1 is the hardest and Type 7 is the softest. Appendix 7 provides a sample of the Bristol Stool 
Chart.  Number of evacuations within the past 24 hours prior to the clinic visit will be recorded 
at specified times as per Table 1. 


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10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study.  The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of the IP 
for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 


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Community guideline on GCP.  This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason.  
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.do
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification.  Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies.  Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document.  The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria.  Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.


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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation.  The 
investigator will also return all the IP, containers, and other study materials to the sponsor.  Upon 
study completion, the investigator will provide the sponsor, IRB/EC, and regulatory agency with 
final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
eCRFs are supplied by the sponsor and should be handled in accordance with instructions from 
the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. eCRFs must be completed by 
the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
All data sent to the sponsor must be endorsed by the investigator.
The CRA/study monitor will verify the contents against the source data per the monitoring plan.  
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents.  The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 


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appointment books, original laboratory reports, images, etc.).  Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other 
USA national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor.  The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in the IP; any significant equity 
interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments.  All consent 
documentation must be in accordance with applicable regulations and GCP.  Each subject or the 
subject’s legally-authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally-authorized representative, as applicable. This document may 
require translation into the local language.  Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form which was 
reviewed by the IRB/EC and which received their favorable opinion/approval.  A copy of the 
IRB/EC’s written favorable opinion/approval of these documents must be provided to the 


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sponsor, prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to study start that another party (ie, sponsor 
or coordinating principal investigator) is responsible for this action.  Additionally, if the IRB/EC 
requires modification of the sample subject information and consent document provided by the 
sponsor, the documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
IP supplies will not be released until the Sponsor or its designee has received written IRB/EC 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions.  The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All USA-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996.  A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the Sponsor or its designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study.  These records and data may, 
in addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market volixibat; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 


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approval for the study to proceed.  The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded.  They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted.  The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative.  Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire.  The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.  The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study.  To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications.  To the extent that the principal investigator has such sole, 
joint or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 


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submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results.  If such a multicenter publication is not submitted to 
a journal for publication by the sponsor within an 18-month period after conclusion, 
abandonment, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section.  The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards.  Participation as an investigator does not confer any rights to 
authorship of publications.


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11. REFERENCES 
Adibi, A., Janghorbani, M., Shayganfar, S. & Amini, M. 2007. First-degree relatives of patients 
with type 2 diabetes mellitus and risk of non-alcoholic Fatty liver disease. Rev Diabet Stud, 4,
236-41.
Angulo, P. 2002. Nonalcoholic fatty liver disease. N Engl J Med, 346, 1221-31.
Assy, N., Kaita, K., Mymin, D., Levy, C., Rosser, B. & Minuk, G. 2000. Fatty infiltration of 
liver in hyperlipidemic patients. Dig Dis Sci, 45, 1929-34.
Bedossa, P. 2012. Lesions in nanolcoholic fatty liver disease. Rev Prat, 62, 1419.
Davidson, M. H., Donovan, J. M., Misir, S. & Jones, M. R. 2010. A 50-week extension study on 
the safety and efficacy of colesevelam in adults with primary hypercholesterolemia. Am J 
Cardiovasc Drugs, 10, 305-14.
Day, C. P. & James, O. F. 1998. Steatohepatitis: a tale of two "hits"? Gastroenterology, 114,
842-5.
Donati, G., Stagni, B., Piscaglia, F., Venturoli, N., Morselli-Labate, A. M., Rasciti, L. & 
Bolondi, L. 2004. Increased prevalence of fatty liver in arterial hypertensive patients with normal 
liver enzymes: role of insulin resistance. Gut, 53, 1020-3.
Halilbasic, E., Claudel, T. & Trauner, M. 2013. Bile acid transporters and regulatory nuclear 
receptors in the liver and beyond. J Hepatol, 58, 155-68.
Hamaguchi, M., Kojima, T., Takeda, N., Nakagawa, T., Taniguchi, H., Fujii, K., Omatsu, T., 
Nakajima, T., Sarui, H., Shimazaki, M., Kato, T., Okuda, J. & Ida, K. 2005. The metabolic 
syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med, 143, 722-8.
Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., 
Ferrell, L. D., Liu, Y. C., Torbenson, M. S., Unalp-Arida, A., Yeh, M., Mccullough, A. J. & 
Sanyal, A. J. 2005. Design and validation of a histological scoring system for nonalcoholic fatty 
liver disease. Hepatology, 41, 1313-21.
Loomba, R., Abraham, M., Unalp, A., Wilson, L., Lavine, J., Doo, E., Bass, N. M. & 
Nonalcoholic Steatohepatitis Clinical Research, N. 2012. Association between diabetes, family 
history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology, 56, 943-51.
Loomba, R., Sirlin, C. B., Ang, B., Bettencourt, R., Jain, R., Salotti, J., Soaft, L., Hooker, J., 
Kono, Y., Bhatt, A., Hernandez, L., Nguyen, P., Noureddin, M., Haufe, W., Hooker, C., Yin, M., 
Ehman, R., Lin, G. Y., Valasek, M. A., Brenner, D. A. & Richards, L. 2015. Ezetimibe for the 
treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and 


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magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology, 61, 1239-
50.
Marchesini, G., Marzocchi, R., Agostini, F. & Bugianesi, E. 2005. Nonalcoholic fatty liver 
disease and the metabolic syndrome. Curr Opin Lipidol, 16, 421-7.
Mathus-Vliegen, L., Toouli, J., Fried, M., Khan, A. G., Garisch, J., Hunt, R., Fedail, S., Stimac, 
D., Lemair, T., Krabshuis, J., Kaufmann, P., Roberts, E. & Riccardi, G. 2012. World 
Gastroenterology Organisation global guidelines on obesity. J Clin Gastroenterol, 46, 555-61.
Miethke, A. G., Zhang, W., Simmons, J., Taylor, A. E., Shi, T., Shanmukhappa, S. K., Karns, R., 
White, S., Jegga, A. G., Lages, C. S., Nkinin, S., Keller, B. T. & Setchell, K. D. 2016. 
Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile 
composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout 
mice. Hepatology, 63, 512-23.
Musso, G., Gambino, R. & Cassader, M. 2013. Cholesterol metabolism and the pathogenesis of 
non-alcoholic steatohepatitis. Prog Lipid Res, 52, 175-91.
N.C.E.P. 2002. Third Report of the National Cholesterol Education Program (NCEP) Expert 
Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult 
Treatment Panel III) final report. Circulation, 106, 3143-421.
Neuschwander-Tetri, B. A. 2005. Nonalcoholic steatohepatitis and the metabolic syndrome. Am 
J Med Sci, 330, 326-35.
Neuschwander-Tetri, B. A., Loomba, R., Sanyal, A. J., Lavine, J. E., Van Natta, M. L., 
Abdelmalek, M. F., Chalasani, N., Dasarathy, S., Diehl, A. M., Hameed, B., Kowdley, K. V., 
Mccullough, A., Terrault, N., Clark, J. M., Tonascia, J., Brunt, E. M., Kleiner, D. E. & Doo, E. 
2015. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic 
steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet, 385, 956-
65.
Pagano, G., Pacini, G., Musso, G., Gambino, R., Mecca, F., Depetris, N., Cassader, M., David, 
E., Cavallo-Perin, P. & Rizzetto, M. 2002. Nonalcoholic steatohepatitis, insulin resistance, and 
metabolic syndrome: further evidence for an etiologic association. Hepatology, 35, 367-72.
Permutt, Z., Le, T. A., Peterson, M. R., Seki, E., Brenner, D. A., Sirlin, C. & Loomba, R. 2012. 
Correlation between liver histology and novel magnetic resonance imaging in adult patients with 
non-alcoholic fatty liver disease - MRI accurately quantifies hepatic steatosis in NAFLD. 
Aliment Pharmacol Ther, 36, 22-9.
Qayyum, A., Goh, J. S., Kakar, S., Yeh, B. M., Merriman, R. B. & Coakley, F. V. 2005. 
Accuracy of liver fat quantification at MR imaging: comparison of out-of-phase gradient-echo 
and fat-saturated fast spin-echo techniques--initial experience. Radiology, 237, 507-11.


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Rao, A., Kosters, A., Mells, J., Keller, B., Yin, H., Banton, S., Li, S., Jones, D. P., Wu, H., 
Dawson, P. & Karpen, S. 2015. Administration of an ileal apical sodium-dependent bile acid 
transporter inhibitor protects against non-alcoholic fatty liver disease in high fat diet-fed mice. 
Hepatology, 62, 217A.
Raptis, D. A., Fischer, M. A., Graf, R., Nanz, D., Weber, A., Moritz, W., Tian, Y., Oberkofler, 
C. E. & Clavien, P. A. 2012. MRI: the new reference standard in quantifying hepatic steatosis? 
Gut, 61, 117-27.
Reeder, S. B., Cruite, I., Hamilton, G. & Sirlin, C. B. 2011. Quantitative Assessment of Liver Fat 
with Magnetic Resonance Imaging and Spectroscopy. J Magn Reson Imaging, 34, 1011-1014.
Reeder, S. B., Hu, H. H. & Sirlin, C. B. 2012. Proton density fat-fraction: a standardized MR-
based biomarker of tissue fat concentration. J Magn Reson Imaging, 36, 1011-4.
Roldan-Valadez, E., Favila, R., Martinez-Lopez, M., Uribe, M., Rios, C. & Mendez-Sanchez, N. 
2010. In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty liver 
disease: Correlation with biochemical method and morphometry. J Hepatol, 53, 732-7.
Sanyal, A. J., Campbell-Sargent, C., Mirshahi, F., Rizzo, W. B., Contos, M. J., Sterling, R. K., 
Luketic, V. A., Shiffman, M. L. & Clore, J. N. 2001. Nonalcoholic steatohepatitis: association of 
insulin resistance and mitochondrial abnormalities. Gastroenterology, 120, 1183-92.
Schwenzer, N. F., Springer, F., Schraml, C., Stefan, N., Machann, J. & Schick, F. 2009. Non-
invasive assessment and quantification of liver steatosis by ultrasound, computed tomography 
and magnetic resonance. J Hepatol, 51, 433-45.
Souza, M. R., Diniz Mde, F., Medeiros-Filho, J. E. & Araujo, M. S. 2012. Metabolic syndrome 
and risk factors for non-alcoholic fatty liver disease. Arq Gastroenterol, 49, 89-96.
Springer, F., Ballweg, V., Schweizer, R., Schick, F., Ranke, M. B., Binder, G. & Ehehalt, S. 
2015. Changes in whole-body fat distribution, intrahepatic lipids, and insulin resistance of obese 
adolescents during a low-level lifestyle intervention. Eur J Pediatr, 174, 1603-12.
Szczepaniak, L. S., Nurenberg, P., Leonard, D., Browning, J. D., Reingold, J. S., Grundy, S., 
Hobbs, H. H. & Dobbins, R. L. 2005. Magnetic resonance spectroscopy to measure hepatic 
triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol 
Endocrinol Metab, 288, E462-8.
Torres, D. M. & Harrison, S. A. 2008. Diagnosis and therapy of nonalcoholic steatohepatitis. 
Gastroenterology, 134, 1682-98.
Torres, D. M., Williams, C. D. & Harrison, S. A. 2012. Features, diagnosis, and treatment of 
nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol, 10, 837-58.


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Urdzik, J., Bjerner, T., Wanders, A., Weis, J., Duraj, F., Haglund, U. & Noren, A. 2012. The 
value of pre-operative magnetic resonance spectroscopy in the assessment of steatohepatitis in 
patients with colorectal liver metastasis. J Hepatol, 56, 640-6.
Vernon, G., Baranova, A. & Younossi, Z. M. 2011. Systematic review: the epidemiology and 
natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. 
Aliment Pharmacol Ther, 34, 274-85.
Williams, C. D., Stengel, J., Asike, M. I., Torres, D. M., Shaw, J., Contreras, M., Landt, C. L. & 
Harrison, S. A. 2011. Prevalence of nonalcoholic fatty liver disease and nonalcoholic 
steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a 
prospective study. Gastroenterology, 140, 124-31.
World Gastroenterology Organisation 2012. World Gastroenterology Organisation Global 
Guidelines: Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis.


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12. APPENDICES


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APPENDIX 1
PROTOCOL HISTORY 
Document
Date
Global/Country/Site Specific
Original Protocol
24 February 2016
Global
Amendment 1
8 April 2016
Global


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APPENDIX 2
FATTY LIVER DISEASE HISTOLOGY SCORING
Diagnosis: NASH, Suspicious/Borderline NASH (type a or b), NAFLD, Not NAFLD
NAS SCORING
Steatosis
0       <5%
1        5-33%
2        34-66%
3        67-100%
Lobular Inflammation
0        no foci
1        < 2 foci per 200x field
2        2-4 foci per 200x field
3        > 4 foci per 200 x field
Ballooning
0       None
1       Rare or diagnostically borderline
2       Many or Prominent ballooned hepatocytes
            SAF SCORING
Steatosis
0         <5%
1        5-33%
2        34-66%
3        67-100%
Ballooning
0        normal hepatocytes with  cuboidal shape and pink cytoplasm
1       clusters of hepatocytes with rounded shape and pale cytoplasm usually  reticulated      
2       grade 1 plus enlarged hepatocytes, 2 x bigger than normal cells. 
Lobular Inflammation
0       none
1       < 2 foci per 200x field
2       >2 foci per 200x field
Steatosis 1,2,3 + Ballooning 1,2 + Lobular Inflammation  1,2 = NASH
Steatosis 1,2,3 +Ballooning 0 + Lobular Inflammation 0,1,2 = NAFLD
Steatosis 1,2,3 + Ballooning 1,2 + Lobular 0 = NAFLD
Steatosis 0 = no NAFLD
FIBROSIS SCORE
None
0
Mild zone 3 perisinusoidal (requires trichrome)
1a
Moderate Zone 3 perisinusoidal (visible on H&E)
1b
Portal/periportal only
1c
Portal, periportal and perisinusoidal
2
Bridging
3
Cirrhosis
4
References: Kleiner et al. 2005; Bedossa 2012


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ADDITIONAL SCORING FEATURES
Expanded Balloon Score
0: None
1: Few Non classic
2: Few Classic
3. Many Classic
4: Severe Classic
Portal Inflammation
0: None
1: Minimal
2: Mild
3: More than Mild
Megamitochondria
0: None
1: Present
Acidophil Bodies
0: None or rare
1: Present
For stage 2 or greater fibrosis
Portal Predominant
Central Predominant
No predominance
Steatosis Zone
Zone 1 predominant
Zone 3 predominant
Azonal
Panacinar
Glycogenosis
None
Focal
Diffuse


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APPENDIX 3
EQ-5D-5L HEALTH QUESTIONNAIRE
UK SAMPLE ONLY, NOT FOR OFFICIAL USE


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Under each heading, piease tick the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems in walking about 
I have sJight problems in walking about 
I have moderate problems in walking about 
I have severe problems in walking about 
I am unable to walk about 
SELF-CARE 
I have no problems washing or dressing mys.elf 
I have slight problems washing or dressing myself 
I have moderate probtems washing or dressing mysetf 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, housework, famHy or 
leisure activities) 
I have no problems doing my usual activities 
I have sJtght problems doing my usual activities 
I have moderate problems doing my usual activities 
I have severe probtems doing my usuaJ activities 
I am unable to do my usual activities 
PAIN I DISCOMFORT 
I have no pain or discomfort 
I have sHght pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
ANXIETY I DEPRESSION 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderatety anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
2 
to< (Engish) (> 2C09 Eun>Qol Grocf> E~N 
Gallade"""* dille Eun>Qol Grocf> 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 


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• 
We would like to know how good or bad your health is TODAY. 
• 
This sea~ is numbered from 0 to 100. 
• 
100 means the best heatth you can imagine. 
o means the worst he ann you can Imagine. 
• 
Mar1t an X on the scale to indicate how your heafth is TODAY. 
• 
Now, please write the number you marked on the scate in the box 
below. 
YOUR HEALTH TODAY = D 
3 
t.M ~) <~ 2()(}9 EIIOQol <iroq:) EQ-50""' is a trademark offhe 6xoQol Gn:q) 
1he best ~alth 
you can imagine 
100 
95 
go 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
The worst health 
you c..m imagine 
15 
10 
5 
0 


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APPENDIX 4
CRITERIA TO ASSESS SEVERITY OF LIVER-
RELATED ADVERSE EVENTS
Parameter
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
ALT
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
AST
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
Alkaline 
Phosphatase
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
GGT
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
Bilirubin
Normal
>1.0-1.5
>1.5-2.5
>2.5-5
>5
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = 
gamma glutamyl transferase. 
NOTE: Values expressed as multiples of the upper limit of the normal range (ULN).


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APPENDIX 5
STOPPING RULES FOR LIVER-RELATED BLOOD 
TESTS 

ALT or AST >6xULN (confirmed with repeat within 24hrs)

ALT or AST >5xULN for more than 2 weeks 

ALT or AST >3xULN and (TBL >2xULN or INR >1.5) 

ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
If ALT or AST elevations do not fall within the above parameters, but are > 4 ×ULN 
subject should remain on study drug with close observation which includes: 
1. Immediately contacting the CRO medical monitor. 
2. Repeating liver enzyme and serum bilirubin tests two or three times weekly. 
Frequency of retesting can decrease to once a week or less if abnormalities stabilize or 
the trial drug has been discontinued and the subject is asymptomatic. 
3. Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
4. Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets. 
5. Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease., or other disease at the 
discretion of the investigator
6. Obtaining a history of exposure to environmental chemical agents. 
7. Obtaining additional tests to evaluate liver function, as appropriate (eg, INR, direct 
bilirubin). 


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APPENDIX 6
GENERAL PRINCIPLES AND SPECIFIC RULES FOR 
DOSE DISCONTINUATION AT 24 WEEK INTERIM 
ANALYSIS – GUIDANCE FOR DATA MONITORING 
COMMITTEE ONLY
General Principles
A net positive benefit risk assessment on HFF takes precedence over effectiveness on ALT.  
Covers the situations when 2 doses show net positive benefit risk on HFF and 1 dose shows 
positive or net positive benefit risk on ALT.
Choose the dose(s) that have the largest difference in dose from amongst those exhibiting a net 
positive benefit risk.
As a minimally absorbed drug, volixibat at higher doses is less likely than absorbed drugs to 
exhibit additional TEAEs in large longer duration trials that were not seen in smaller shorter 
trials.
Specific Rules
If 3 doses are determined to be tolerable and to have a net positive benefit risk assessment on 
HFF, then Scheffe’s statistical multiple comparisons test should be applied to the three HFF 
values.  The test will result in one of eighteen possibilities.  The 18 possible cases are detailed 
below in Table 1.  For example, if the multiple comparisons test indicates that the low dose (L) 
is less effective on HFF than the medium and high doses (M and H) then the medium and high 
doses should be selected for continued randomization from among the three doses.  This case is 
depicted as case 1 in the table.  If doses are indistinguishable on HFF then use Scheffe’s test 
on ALT (case 2).
Table 1  
Possible Results from Applying a Multiple Comparison Test to Three Doses 
based on Change from Baseline in Hepatic Fat Fraction 
Case
Results
Action
1
L <  M   H
M, H
2
L    M   H
If can’t decide using ALT, then L,H
3
L >  M  H
L, If can’t decide using ALT, then L,H
4
L   M  > H
L, M
5
L  >  M >  H
L, M
6
L  < M <  H
M, H


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Table 1  
Possible Results from Applying a Multiple Comparison Test to Three Doses 
based on Change from Baseline in Hepatic Fat Fraction 
Case
Results
Action
7
L   M <  H
H, If can’t decide using ALT, then L,H
8
M <  L    H
L, H
9
M >  L    H
M, If can’t decide using ALT, then H
10
M L  >  H
L, M
11
M >  L   > H
L, M
12
M <  L  <  H
L, H
13
M L  <  H
H, If can’t decide using ALT, then M
14
L  <  H   M
M, H
15
L >  H  M
L, If can’t decide using ALT, then H
16
L  H  > M
L, H
17
L >  H >  M
L, H
18
L <  H <  M
M, H
L = low dose (5 mg), M = medium dose (10 mg), H = high dose (20 mg)
If 3 doses are determined to be tolerable and to have a net positive benefit risk assessment on 
only ALT, then Scheffe’s statistical multiple comparison test should be applied to the three 
ALT values.  The test will result in one of eighteen possibilities.  The 18 possible cases are 
detailed below in Table 2.  For example, if the multiple comparison test indicates that the low 
dose (L), medium dose (M) and high dose (H) are indistinguishably effective on ALT, then the 
low and high dose should be selected.  This case is depicted as case 2 in the table.  


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Table 2 
Possible Results from Applying a Multiple Comparison Test to Three Doses 
based on Change from Baseline in ALT
Case
Results
Action
1
L <  M   H
M, H
2
L    M   H
L,H
3
L >  M  H
L and H
4
L   M  > H
L, M
5
L  >  M >  H
L, M
6
L  < M <  H
M, H
7
L   M <  H
H, L
8
M <  L    H
L, H
9
M >  L    H
M, H
10
M L  >  H
L, M
11
M >  L   > H
L, M
12
M <  L  <  H
L, H
13
M L  <  H
H, L
14
L  <  H   M
M, H
15
L >  H  M
L, H
16
L  H  > M
L, H
17
L >  H >  M
L, H
18
L <  H <  M
M, H
L = low dose (5 mg), M = medium dose (10 mg), H = high dose (20 mg)
If three doses are tolerable and effective and only one of them is tolerable and exhibits 
effectiveness on HFF, then randomization to that dose should continue.  One of the remaining 
doses which are tolerable and effective only on ALT should be chosen based on a Scheffe’s 
multiple comparisons test for ALT.  If neither of the remaining two separates from the other 
with respect to ALT, then randomization should continue to the highest dose of the remaining 
two active doses (and PBO).


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APPENDIX 7
BRISTOL STOOL CHART


PROTOCOL: SHP626-201
TITLE:
A Phase 2 Double-Blind, Randomized, Placebo-controlled, Dose-finding 
Study to Evaluate the Safety, Tolerability and Efficacy of Volixibat 
Potassium, an Apical Sodium-Dependent Bile Acid Transporter 
Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
DRUG:
Volixibat potassium  (SHP626)
IND:
123,847
EUDRACT NO.:
2016-000203-82
SPONSOR: 
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
Philip Newsome MD
Director of Centre for Liver Research 
University of Birmingham
Edgbaston, Birmingham B15 2TT UK
NATIONAL/
COORDINATING
INVESTIGATOR/UK
Guruprasad P Aithal MBBS, MD, FRCP, PhD
Head of the Division, Nottingham Digestive Diseases Centre
Director, NIHR Nottingham Digestive Diseases Biomedical Research 
Unit 
Nottingham University Hospitals and University of Nottingham
Queen's Medical Centre
Nottingham NG7 2UH
PROTOCOL 
HISTORY:
Original Protocol:  24 February 2016
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations.  This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.


Shire 
CONFIDE>J"TIAL 
Protocol SHP626-20 l 
PROTOCOL SIGNATURE PAGE 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP626-20 I. 
Page2 
24 February 2016 
Title: A Phase 2 Double-Blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate the 
Safety, Tolerability and Efficacy ofVolixjbat Potassium, an Apical Sodium-Dependent Bile Acid 
Transporter Inhibitor (ASBTi) in Adults with Nonalcoholic Steatobepatitis (NASH) 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct tbis study according to tbis protocol and to comply with its requirements, 
subject to etbical and safety considerations and guidelines, and to conduct the sn1dy in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study 1 will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: ----------------------
Date: 


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24 February 2016
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to the Shire Global Pharmacovigilance and Risk Management 
Department.  Applicable fax numbers and e-mail address can be found on the form (sent under 
separate cover). A copy of this form must also be sent to the contract research organization 
(CRO) by fax or e-mail using the details below.
For protocol- or safety-related issues during normal business hours 8:30 a.m. to 4:30 p.m.
(EST), the investigator must contact the CRO Medical Monitor:
CRO Medical Monitor: Anthony Japour, MD
telephone number: +1 215 616 6439
fax number: +1 215 616 3096
mobile number: +1 267 429 6601
e-mail address: Anthony.Japour@iconplc.com
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the CRO On-call Mobile Phone:
On-call mobile number: +1 215 353 2206


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product (IP) quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products).  For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
PQC@shire.com
European Union and Rest of World
PQCROW@shire.com
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA) 
1-888-300-6414 or 1-800-828-2088


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE ............................................................................................2
EMERGENCY CONTACT INFORMATION...........................................................................3
PRODUCT QUALITY COMPLAINTS.....................................................................................4
TABLE OF CONTENTS............................................................................................................5
LIST OF TABLES....................................................................................................................10
LIST OF FIGURES ..................................................................................................................11
LIST OF APPENDICES...........................................................................................................12
ABBREVIATIONS ..................................................................................................................13
STUDY SYNOPSIS .................................................................................................................16
1.
BACKGROUND INFORMATION.............................................................................26
1.1
Indication and Current Treatment Options...................................................................26
1.2
Product Background and Clinical Information.............................................................26
1.3
Benefits and Risks ........................................................................................................29
2.
STUDY OBJECTIVES AND PURPOSE ....................................................................31
2.1
Rationale for the Study.................................................................................................31
2.2
Study Objectives...........................................................................................................31
2.2.1
Primary Objective ..................................................................................................31
2.2.2
Secondary Objectives.............................................................................................31
2.2.3
Exploratory Objectives ..........................................................................................31
3.
STUDY DESIGN .........................................................................................................33
3.1
Study Design and Flow Chart.......................................................................................33
3.2
Duration and Study Completion Definition..................................................................34
3.3
Sites and Regions..........................................................................................................34


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4.
STUDY POPULATION...............................................................................................35
4.1
Inclusion Criteria ..........................................................................................................35
4.2
Exclusion Criteria.........................................................................................................35
4.3
Restrictions ...................................................................................................................37
4.4
Reproductive Potential .................................................................................................38
4.4.1
Female Contraception ............................................................................................38
4.4.2
Male Contraception................................................................................................38
4.5
Discontinuation of Subjects..........................................................................................39
4.5.1
Subject Withdrawal Criteria...................................................................................39
4.5.2
Reasons for Discontinuation..................................................................................40
4.5.3
Subjects Lost to Follow-up Prior to Last Scheduled Visit.....................................40
4.5.4
Safety-related Stopping Rules................................................................................41
5.
PRIOR AND CONCOMITANT TREATMENT.........................................................42
5.1
Prior Treatment.............................................................................................................42
5.2
Concomitant Treatment ................................................................................................42
5.2.1
Permitted Treatment...............................................................................................42
5.2.2
Prohibited Treatment..............................................................................................42
6.
INVESTIGATIONAL PRODUCT ..............................................................................44
6.1
Identity of Investigational Product ...............................................................................44
6.1.1
Blinding the Treatment Assignment ......................................................................44
6.2
Administration of Investigational Product(s) ...............................................................44
6.2.1
Interactive Response Technology for Investigational Product Management ........44
6.2.2
Allocation of Subjects to Treatment ......................................................................45
6.2.3
Dosing....................................................................................................................45
6.2.4
Unblinding the Treatment Assignment..................................................................45
6.3
Labeling, Packaging, Storage, and Handling ...............................................................46
6.3.1
Labeling .................................................................................................................46
6.3.2
Packaging...............................................................................................................46
6.3.3
Storage ...................................................................................................................47
6.4
Drug Accountability .....................................................................................................47
6.5
Subject Compliance......................................................................................................48


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7.
STUDY PROCEDURES..............................................................................................49
7.1
Study Schedule .............................................................................................................49
7.1.1
Screening (Visit 1) .................................................................................................49
7.1.2
Baseline (Visit 2) ...................................................................................................50
7.1.3
Treatment and Assessment Period (Visits 3 through 9/EOS)................................50
7.1.4
Follow-up (Visit 10)...............................................................................................51
7.1.5
Additional Care of Subjects after the Study...........................................................51
7.2
Study Evaluations and Procedures ...............................................................................51
7.2.1
Demographic and Other Baseline Characteristics .................................................51
7.2.2
Efficacy..................................................................................................................52
7.2.2.1
Liver Biopsy ................................................................................................52
7.2.2.2
MRI..............................................................................................................52
7.2.3
Safety .....................................................................................................................52
7.2.3.1
Medical History and Medications................................................................52
7.2.3.2
Physical Examination ..................................................................................52
7.2.3.3
Adverse Event Collection............................................................................53
7.2.3.4
Vital Signs ...................................................................................................53
7.2.3.5
Clinical Laboratory Evaluations..................................................................53
7.2.3.6
Additional Laboratory Assessments............................................................55
7.2.3.7
Pregnancy Test ............................................................................................55
7.2.3.8
Drug and Alcohol Testing ...........................................................................55
7.2.3.9
Electrocardiogram .......................................................................................56
7.2.3.10 Health-related Quality of Life Assessments................................................56
7.2.3.11 Volume of Blood to be Drawn from Each Subject......................................56
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT..........................57
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events.57
8.1.1
Severity Categorization..........................................................................................57
8.1.2
Relationship Categorization...................................................................................58
8.1.3
Outcome Categorization ........................................................................................58
8.1.4
Symptoms of the Disease Under Study..................................................................59
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................59
8.1.6
Criteria for Discontinuation of Treatment .............................................................59
8.1.7
Pregnancy...............................................................................................................59


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8.1.8
Abuse, Misuse, Overdose, and Medication Error ..................................................60
8.2
Serious Adverse Event Procedures...............................................................................61
8.2.1
Reference Safety Information................................................................................61
8.2.2
Reporting Procedures.............................................................................................61
8.2.3
Serious Adverse Event Definition..........................................................................61
8.2.4
Serious Adverse Event Onset and Resolution Dates .............................................62
8.2.5
Fatal Outcome........................................................................................................63
8.2.6
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................63
9.
DATA MANAGEMENT AND STATISTICAL METHODS.....................................64
9.1
Data Collection.............................................................................................................64
9.2
Clinical Data Management ...........................................................................................64
9.3
Data Handling Considerations......................................................................................64
9.4
Statistical Analysis Process ..........................................................................................64
9.5
Planned Interim Analysis..............................................................................................65
9.5.1
Tolerability.............................................................................................................67
9.5.2
Efficacy..................................................................................................................67
9.6
Sample Size Calculation and Power Considerations....................................................68
9.7
Study Population...........................................................................................................69
9.8
Efficacy Analyses.........................................................................................................69
9.8.1
Primary Efficacy Endpoint.....................................................................................69
9.8.2
Secondary Efficacy Endpoints...............................................................................70
9.8.3
Exploratory Efficacy Endpoints.............................................................................71
9.9
Safety Analyses ............................................................................................................72
9.10
Other Analyses .............................................................................................................72
9.10.1 Health-related Quality of Life Analyses ................................................................73
9.10.2 Stool Assessment ...................................................................................................73
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES.................................74
10.1
Sponsor’s Responsibilities............................................................................................74
10.1.1 Good Clinical Practice Compliance.......................................................................74
10.1.2 Indemnity/Liability and Insurance.........................................................................74


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10.1.3 Public Posting of Study Information......................................................................75
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees...............................................75
10.1.5 Study Suspension, Termination, and Completion..................................................75
10.2
Investigator’s Responsibilities......................................................................................75
10.2.1 Good Clinical Practice Compliance.......................................................................75
10.2.2 Protocol Adherence and Investigator Agreement ..................................................76
10.2.3 Documentation and Retention of Records .............................................................76
10.2.3.1 Electronic Case Report Forms.....................................................................76
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents..77
10.2.3.3 Audit/Inspection ..........................................................................................78
10.2.3.4 Financial Disclosure ....................................................................................78
10.3
Ethical Considerations..................................................................................................78
10.3.1 Informed Consent...................................................................................................78
10.3.2 Institutional Review Board or Ethics Committee ..................................................79
10.4
Privacy and Confidentiality..........................................................................................79
10.5
Study Results / Publication Policy................................................................................80
11.
REFERENCES .............................................................................................................82
12.
APPENDICES..............................................................................................................86


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LIST OF TABLES
Table 1:
Schedule of Assessments .......................................................................................22


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LIST OF FIGURES
Figure 1:
Study Design Flow Chart.......................................................................................34
Figure 2:
Process Flow for Volixibat Dose Decisions at 24 Week IA..................................66


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LIST OF APPENDICES
APPENDIX 1
Protocol History...........................................................................................87
APPENDIX 2
Fatty Liver Disease Histology Scoring........................................................88
APPENDIX 3
EQ-5D-5L Health Questionnaire UK Sample Only, Not for Official Use..90
APPENDIX 4
Criteria to Assess Severity of Liver-Related Adverse Events.....................93
APPENDIX 5
Stopping Rules for Liver-related Blood Tests.............................................94
APPENDIX 6
General Principles and Specific Rules for Dose Discontinuation at 24 
Week Interim Analysis – Guidance for Data Monitoring Committee Only.................95
APPENDIX 7
Bristol Stool Chart.......................................................................................98


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ABBREVIATIONS
AE
adverse event
ALP 
alkaline phosphatase
ALT 
alanine aminotransferase
aPPT
activated partial thromboplastin time
ASBT
apical sodium-dependent bile acid transporter
ASBTi 
ASBT inhibitor
AST 
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BA 
bile acid
BMI
body mass index
C4
7-alpha-hydroxy-4-cholesten-3-one
CRA
clinical research associate
CRC 
clinical research center
CRO
contract research organization
DMC 
data monitoring committee
eCRF
electronic case report form
EQ-5D-5L 
EuroQol-5 Dimension-5 Level Questionnaire
ECG
electrocardiogram
EOS
end of study
EU
European Union
FAS
full analysis set
FBA 
fecal bile acid
FDA
Food and Drug Administration
FXR 
farnesoid X receptor
GCP
Good Clinical Practice
GGT 
gamma glutamyl transferase
GLP1 RA
glucagon-like peptide-1 receptors agonists
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HBVDNA
hepatitis B virus deoxyribonucleic acid
HCV
hepatitis C virus


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HCVAb
hepatitis C virus antibody
HCVRNA
hepatitis C virus ribonucleic acid
HDL-C
high-density lipoprotein-cholesterol
HFD
high fat diet
HFF
hepatic fat fraction
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HOMA2-%B 
homeostatic model assessment in β-cell function
HOMA2-IR 
homeostatic model assessment insulin resistance
HRQoL 
health-related quality of life
IA 
interim analysis
IAS
interim analysis set
ICH
International Conference on Harmonisation
IND 
investigational new drug
INR
international normalized ratio
IP
investigational product
IR
insulin resistance
IRB
Institutional Review Board
IRT
interactive response technology
LDL-C 
low-density lipoprotein-cholesterol
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MedDRA
Medical Dictionary for Regulatory Activities
MR
magnetic resonance
MRI 
magnetic resonance imaging
MRS
magnetic resonance spectroscopy
MOA
mechanism of action
NAFLD 
nonalcoholic fatty liver disease
NAS 
NAFLD Activity Score
NASH 
nonalcoholic steatohepatitis
NASH CRN
NASH Clinical Research Network
NOAEL 
no observed adverse effect level
PBC
primary biliary cirrhosis
PBO
placebo
PDFF
proton density fat-fraction


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PO
by mouth
POC
proof of concept
PRO 
patient-reported outcome
PSC
primary sclerosing cholangitis
PTT
prothrombin time
PVRM
Pharmacovigilance and Risk Management
QD 
once daily
RBC
red blood cell 
SAE 
serious adverse event
SAF
steatosis, activity, and fibrosis score
SAP 
statistical analysis plan
T2DM
type 2 diabetes mellitus
T3
triiodothyronine
TA
therapeutic area
TB
total bilirubin
TEAE
treatment-emergent adverse event
TGR5 G 
transmembrane G protein-coupled receptor
TPN
total parenteral nutrition
TSH
thyroid-stimulating hormone
TZD
thiazolidinediones
ULN
upper limit of normal
USA
United States of America
VAS
visual analogue scale


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STUDY SYNOPSIS
Protocol number: SHP626-201
Drug: Volixibat potassium (SHP626)
Title of the study: A Phase 2 Double-Blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate 
the Safety, Tolerability and Efficacy of Volixibat Potassium, an Apical Sodium-Dependent Bile Acid 
Transporter Inhibitor (ASBTi) in Adults with Nonalcoholic Steatohepatitis (NASH) 
Number of subjects (total and for each treatment arm): Approximately 334 subjects will be screened to 
enroll 266 subjects to achieve 201 completers. After enrollment of at least 80 subjects (20/treatment arm – 3 
active and 1 placebo [PBO]) a 24-week interim analysis (IA) will eliminate at least one dose group based on the 
criteria provided to the Data Monitoring Committee; enrollment will continue to include approximately 67 
subjects in each of the remaining arms. The sample size target for this study is 67 completers in each of the 
treatment groups (201 total if 3 arms continue).  Including an additional 20 subjects to account for one dose 
dropped at the IA, 221 subjects are needed.   Therefore, approximately 266 (accounts for 20% of 221 dropping 
out) subjects will be randomized if three arms (2 SHP626 and 1 PBO) continue.  Fewer subjects are needed if 
more than one SHP626 dose is dropped.
Investigator(s): Multicenter study
Site(s) and Region(s): 
Anticipated regions -US, Canada, and EU 
Estimated number of sites planned – 60 to 80
Study period (planned):
July 2016 to July 2019
Clinical phase:
2
Objectives:
Primary:  To evaluate the effect of volixibat compared to PBO on liver histology 
Secondary:  
•
To evaluate the safety and tolerability of volixibat compared to PBO
•
To evaluate the effect of volixibat compared to PBO on hepatic steatosis  (measured by MRI)
•
To evaluate the effect of volixibat compared to PBO on liver histology (measured by individual 
nonalcoholic fatty liver disease (NAFLD) activity score (NAS) components and fibrosis stage)
•
To evaluate the effect of volixibat compared to PBO on liver histology (measured by NASH resolution 
without worsening fibrosis)
•
To evaluate the effect of volixibat compared to PBO on serum liver-related biochemistry 
•
To evaluate the effect of volixibat compared to PBO on metabolic indicators (glucose, insulin, 
hemoglobin A1c [HbA1c]) 
•
To evaluate the effect of volixibat compared to PBO on serum lipids (cholesterol, HDL-C, LDL-C, 
triglycerides) 
Rationale: Currently, there is no approved medication for the treatment of NASH. Volixibat is under 
development for the treatment of NASH based on its mechanism of action (MOA) and is supported by 
nonclinical and Phase 1 data.  This is a Phase 2, 48-week, dose-finding study to examine the efficacy, 
tolerability, and safety of volixibat in adults with NASH.
Investigational product, dose, and mode of administration:

Volixibat 5, 10, and 20 mg and matched PBO capsules by mouth (PO) once daily (QD). Investigational 


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product (IP) should be given 30 minutes prior to the first meal of the day containing fat

Identical PBO will be used as comparator 

Subjects should take the IP at the same time each day and should not take more than one dose in a day if 
they miss a dose
Methodology:
This study will be a Phase 2, 48-week, multicenter, double-blind, randomized, PBO-controlled, parallel group, 
proof of concept, dose-finding study, with one IA after 24 weeks of treatment.  There will be 3 active arms of 
volixibat (5, 10 and 20 mg) and a PBO arm.  Subjects will be randomized to receive one of three doses of 
volixibat (5, 10, or 20 mg once daily (QD) or PBO in a 1:1:1:1 ratio.  Depending on the results of the IA, the 
study may be terminated or the randomization to one or more doses will be stopped.  The follow-up period will 
be 4 weeks after last dose. Subjects will be expected to visit the study center at least 10 times. 


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Inclusion and exclusion criteria:
Inclusion Criteria:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions.
2.
Ability to voluntarily provide written, signed, and dated (personally or via a legally-authorized 
representative, as applicable) informed consent to participate in the study.
3.
Age 18-80 years inclusive.  This inclusion criterion will only be assessed at the first Screening visit.
4.
Male, or non-pregnant, non-lactating female who is sexually active and who agrees to comply with any 
applicable contraceptive requirements of the protocol or females of non-childbearing potential.
Males and females of child-bearing potential who are sexually active, or are not currently sexually 
active during the period of the study, but become sexually active during the study and 30 days 
following the last dose of the IP, must agree to use acceptable contraception.
5.
Presence of ≥ 5% steatosis on screening MRI from a centrally read radiologist performed either during 
the Screening period or within 6 months prior to the first visit.
6.
Histologic confirmation of NASH without cirrhosis from a centrally read liver biopsy performed either 
during the Screening period or within 6 months prior to the first visit with a NAS of ≥ 4 with a score of 
at least 1 in each component (steatosis, lobular inflammation, and hepatocyte ballooning).
Exclusion Criteria:
1.
Presence of or history of cirrhosis or evidence of decompensated liver disease (ie, ascites, variceal 
bleeding, etc.) or hepatocellular carcinoma.
2.
History or presence of other concomitant liver disease as assessed by the investigator or determined by 
laboratory findings including, but not limited to: active hepatitis B virus (HBV) infection (hepatitis B 
surface antigen (HBsAg) positive and/or HBVDNA positive; subjects who are hepatitis B core 
antibody (HBcAb) positive may be eligible as long as HBsAg is negative and HBVDNA is 
nondetectable), active hepatitis C virus (HCV) infection (prior exposure to HCV (defined as HCVAb 
positive without a current or prior history of a detectable HCVRNA) will be eligible, alcoholic liver 
disease, proven autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis 
(PSC), hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, bile duct obstruction, liver 
primary or metastatic cancer.
3.
Current or recurrent disease that could affect the action, absorption, disposition, or laboratory 
assessment of the IP (including bile salt metabolism in the intestine) eg, uncontrolled inflammatory 
bowel disease, uncontrolled celiac disease, gastric bypass procedures (gastric lap band is acceptable), 
ileal or ileocecal resection, uncontrolled irritable bowel syndrome with predominant diarrhea, or 
history of chronic diarrhea or loose stools of any etiology.
4.
Weight change ≥ 5% after qualifying liver biopsy performed.
5.
Contraindications to MRI (ie, claustrophobia, coronary stents, coronary implantable devices, girth, 
etc.).
6.
Current or relevant history of physical or psychiatric illness, any medical disorder that may require 
treatment or make the subject unlikely to complete the study, or any condition that presents undue risk 
from the IP or procedures.
7.
Vitamin E, thiazolidinediones (TZD), and glucagon-like peptide-1 receptors agonists (GLP1 RA) 
unless subject on a stable dose for 6 months prior to qualifying liver biopsy and not initiated after 
qualifying liver biopsy and will continue the same dosing regimen throughout study participation. 
8.
Uncontrolled diabetes defined as HbA1c of ≥ 9.0% within 60 days prior to enrollment. 
9.
Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) that 
could affect the action, absorption, or disposition of the IP, or clinical or laboratory assessment.  


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(Current use is defined as use within 14 days of Screening).  
10. Use of drugs, herbs or supplements historically associated with causing or worsening NAFLD/NASH 
for less than 6 months prior to qualifying liver biopsy, or initiated any time after qualifying liver biopsy 
performed, including the use of total parenteral nutrition (TPN). 
11. Serum AST > 5 times upper limit of normal (ULN) at Screening.
12. Serum ALT > 5 times ULN at Screening.
13. Elevated serum creatinine ≥ 2.0 mg/dL.
14. International normalized ratio (INR) >1.3.
15. Total bilirubin (TB) ≥ 2.0 x ULN at Screening (Except for documented Gilbert’s syndrome with 
bilirubin levels 20 µmol/L to 90 µmol/L (1.2 to 5.3 mg/dL) and with a ratio of 
unconjugated/conjugated bilirubin that is commensurately higher).
16. Platelet count < 130 × 109L
17. Medical history of impaired hemostasis or use of anticoagulant medication (baby aspirin (ASA) will be 
allowed).
18. Uncontrolled thyroid disease.
19. Type 1 diabetes mellitus.
20. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or any of the 
stated ingredients.
21. Known history of alcohol or other substance abuse within the last year.  Weekly alcohol intake greater 
than 21 units for males and 14 units for females on average or inability to reliably quantify alcohol 
consumption based on investigator’s judgment.
22. Within 6 months of MRI and liver biopsy:

Have used any IP

Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study
23. Inability to safely obtain a liver biopsy.
24. The anticipated need for a surgical procedure during the study that could interfere with the treatment. 
25. Known positivity for human immunodeficiency virus (HIV) infection.
26. Cancer within 5 years of Screening, except for basal or squamous cell carcinoma of the skin or in situ 
cervical carcinoma that has been treated with no evidence of recurrence.
27. History of noncompliance with medical regimens, unreliability, mental instability or incompetence that 
could compromise the validity of informed consent or lead to noncompliance with the study protocol.
28. Any other conditions or abnormalities which, in the opinion of the investigator, may compromise the 
safety of the subject, or interfere with the subject participating.
29. Subject has failed Screening or was previously enrolled in this study or is currently enrolled in this 
study at any study site (unless the subject is transferring to another qualified study site with prior 
Sponsor approval).
30. Subjects who are employees at the investigational site.
Maximum duration of subject involvement in the study:

Planned duration of screening period:  42 days 


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
Planned duration of enrollment period: 364 days

Planned duration of treatment period: 336 days 

Planned duration of follow-up: 28 days 
Endpoints and statistical analysis:
Safety Analysis Set will consist of all subjects who take at least 1 dose of randomized IP, and have at least 1 
post-Baseline safety assessment (eg, coming back for any visit, reporting of an adverse event (AE) or reporting 
the absence of AEs).
Full Analysis Set (FAS) will consist of all subjects in the Safety Set who have a valid scored liver biopsy.
Interim Analysis Set (IAS) will consist of all subjects in the Safety Set who have a valid post-baseline hepatic 
fat fraction (HFF) assessed by MRI and a valid post-baseline ALT at Week 24. 
Screened Set will consist of all subjects who have signed an informed consent.
Endpoints:

Primary: Binary response indicating (yes/no) whether a subject responded at Week 48 with a reduction 
of at least 2 points without worsening of fibrosis from Baseline NAS.

Secondary: 

Change from Baseline to Week 48 in safety and tolerability of volixibat as measured by the 
number of subjects discontinuing treatment due to any one treatment-emergent adverse event 
(TEAE). 

Change from Baseline to Week 48 on liver histology as measured by the individual NAS 
components (ballooning, inflammation, steatosis).  

Change from Baseline to Week 48 on hepatic steatosis as measured by MRI-HFF

Change from Baseline to Week 48 on liver histology as measured by fibrosis stage. (NASH 
Clinical Research Network (CRN) system and Ishak)

Resolution of NASH (defined as an overall histologic interpretation of no fatty liver disease or 
simple steatosis without steatohepatitis or isolated steatosis without steatohepatitis) without 
worsening of fibrosis as assessed by liver histology at week 48.

Change from Baseline to Week 48 on serum liver-related biochemistry as measured by:
o
alanine aminotransferase (ALT)
o
aspartate aminotransferase (AST)
o
alkaline phosphatase (ALP)
o
gamma glutamyl transferase (GGT)
o
total bilirubin (TB)

Change from Baseline to Week 48 on metabolic indicators as measured by
o
fasting serum glucose levels
o
insulin levels
o
HbA1c 

Change from Baseline to Week 48  on serum lipids measured by 
o
fasting total cholesterol
o
HDL-C
o
LDL-C
o
triglycerides 
Primary hypothesis: The proportion of subjects at Week 48 with a reduction of at least 2 points without 
worsening of fibrosis from Baseline NAS differs between at least one volixibat dose and PBO.
The FAS will be used to assess the primary efficacy endpoint. The difference between a volixibat dose and PBO
will be tested with a stratified Cochran-Mantel-Haenzel test. The test will be stratified by presence or absence of 
Type 2 diabetes mellitus (T2DM) at Baseline, NAS, and fibrosis. Holm multiplicity adjustment will be applied 
prior to determining statistical significance at the 0.1 level. Histology will be read by one central 
hepatohistopathologist who will use the NASH CRN standard scoring system – NAS. The SAF Steatosis (S), 


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Activity (A), and Fibrosis (F) scoring system will be determined for exploratory purposes.
The Safety Set will be used to assess the safety endpoints including AEs (including changes from Baseline in 
physical examination findings), vital signs, ECGs, and clinical laboratory tests (chemistry, hematology, 
coagulation and urinalysis).
AEs will be coded using the agreed upon version of the Medical Dictionary for Regulatory Activities 
(MedDRA). TEAEs are defined as AEs that started or worsened on or after the date of the dose of IP, and no 
later than the study completion visit (or follow-up visit for subjects who terminate the study early). The number 
of events, incidence, and percentage of TEAEs will be presented by system organ class and preferred term. 
TEAEs will be further summarized by severity and the relationship to the IP. AEs related to the IP, AEs leading 
to withdrawal, SAEs, and death will be listed. The number of discontinuations due to any 1 TEAE will be 
summarized for each treatment group.
Vital signs, ECG findings, and clinical laboratory tests will be listed for each subject and summarized for each 
treatment arm, including a flag for any potentially clinically important findings. Graphical presentation may be 
used when deemed necessary.
For safety parameters, baseline is defined as the last assessment prior to the dose of the IP.
Planned Interim Analysis:
An IA will be conducted by an independent data monitoring committee (DMC) after at least 80 subjects have 
received 24 weeks of treatment. The IA will evaluate the safety, tolerability and efficacy of 3 doses of volixibat
each compared to PBO, on reduction of steatosis as measured by HFF by MRI and ALT. 
Tolerability will be assessed by the number of discontinuations due to any one TEAE, presumably 
gastrointestinal events, most notably, diarrhea, loose stools, increased evacuations, and abdominal pain. Efficacy 
at the IA will be based on reduction of steatosis or ALT. Steatosis is assessed by MRI-HFF. Depending on the 
results from the IA, one or more doses of volixibat may be discontinued or the study may be terminated.  If the 
study is not terminated, subjects will receive a total of 48 weeks of the IP.


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Table 1:
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9
EOS
10
In-Clinic
Week
-6 to 0
0
2
4
8
12
24
36
48
52
Study Day
-42 to -1
0
14
28
56
84
168
252
336
364
Informed consent
X
Inclusion/exclusion criteria
X
X (review)
Demography, medical & medication 
history 
X
Physical examination
X
X
X
X
X
Heightc, weightd, waist circumference 
and waist:hip ratio
X
X
X
X
X
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
X
X
X
PRO (EQ-5D-5L)
X
X
X
Liver biopsyf
X
X
MRIg
X
Xh
Xh
ECG (12-lead) i
X
X
X
X
Biochemistry and Hematologyj
X
X
X
X
X
X
X
X
X
X
Serum Glucosej,k
X
X
X
X
X
X
X
X
X
X
Urinalysisl
X
X
X
Urine Drug and Serum Alcohol Tests
X
X
Urine Pregnancy Testm
X
X
X
X
X
X
X
X
X
X
Lipid Panelj,n
X
X
X
X
X
X
X
X
X
X
Coagulation Panelj,o
X
X
X
X
X
Vitamin Dj
X
X
X
X
X


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Table 1:
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9
EOS
10
In-Clinic
Week
-6 to 0
0
2
4
8
12
24
36
48
52
Study Day
-42 to -1
0
14
28
56
84
168
252
336
364
HbA1cj
X
X
X
X
X
X
X
X
X
X
Serum Liver-Related Blood Testsj,p
X
X
X
X
X
X
X
X
X
X
Insulinj
X
X
X
X
X
X
X
X
HIV, Hepatitis B/Cj,q
X
Thyroid testingj,r
X
X
X
X
X
X
X
C4 Sampling
X
X
X
X
X
IRT Accessed
X
X
X
X
X
X
X
X
X
X
Randomization
X
IP Dispenseds
X
X
X
X
X
X
X
IP Returned/Accountability & 
Compliance Assessed 
X
X
X
X
X
X
X
Stool Assessmentt
X
X
X
X
X
X
Adverse Eventsu
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; EOS = end of study; HOMA = Homeostasis Model Assessment; IA = interim analysis; IP = investigational product; IRT = Interactive 
Response Technology; MRI = magnetic resonance imaging; PRO = patient-reported outcome.
a Visit Windows (calculated from Visit 2): Bi-weekly (Visits 3-4): +/- 3 days; Monthly (Visits 5-6): +/-5 days; Tri-monthly (Visits 7-9/DC): +/- 7 days.   
b Subjects will be reminded not to eat prior to their scheduled visit.  Additionally, during the double-blind treatment period, they should not take their study drug 
prior to the visit. They should bring their study drug with them to the visit to take 30 minutes prior to their first meal of the day containing fat.
c Height to be measured at Screening only.
d BMI to be calculated programmatically by the Sponsor or designee for the following visits: Screening (Visit 1), Baseline (Visit 2), Visits 7 and 9/DC.   


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Table 1:
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9
EOS
10
In-Clinic
Week
-6 to 0
0
2
4
8
12
24
36
48
52
Study Day
-42 to -1
0
14
28
56
84
168
252
336
364
e Vital signs to include oral or tympanic temperature, sitting blood pressure, pulse, and respiratory rate.
f Biopsy performed within 6 months of Screening can be used. All biopsies will be centrally read by a hepatic histopathologist.
g MRI from a centrally read radiologist performed either during the Screening period or within 6 months prior to the first visit. 
h MRI at Visit 7 (Week 24) and at Visit 9 (Week 48) for the Interim Analysis Set only.
i Three ECGs will be recorded with approximately 10 minutes between each ECG for the Baseline evaluation.
j All blood tests are fasting blood tests.
k HOMA2-IR and HOMA2-%B: will be calculated programmatically by the Sponsor or designee for the following visits: Screening (Visit 1), Baseline (Visit 2), 
Visits 7, 9/DC, and 10.   
l Urinalysis to include oxalate testing.
m For all females of child-bearing potential (FOCP).  Positive on-site urine dipstick results must have serum reflex testing performed by central lab.
Additional testing can be performed at the investigator’s discretion.
n Lipid Panel includes fasting total cholesterol, HDL-C, LDL-C, and triglycerides.
o Full coagulation panel will be done at Screening and Baseline, but only INR and PT are required at remaining time points. 
p Serum Liver-Related Blood Tests include ALT, AST, ALP, GGT, and total bilirubin.
q Hepatitis B/C testing includes HBcAb, HBsAg, HBVDNA and HCVAb, HCVRNA, respectively.
r Thyroid testing includes thyroid stimulating hormone (TSH) and triiodothyronine (T3).
s Investigational product may be dispensed at an unscheduled visit outside of this schedule as needed to replace lost or damaged product.
t Subjects will be queried about the number of stool evacuations during the 24- hour period before the clinical research center (CRC) visit and asked to describe 
the consistency of the softest stool during that 24- hour period using the Bristol Stool Chart.
u Adverse events will be collected beginning from the signing of informed consent.  All AEs must be followed to closure (the subject’s health has returned to 
his/her Baseline status or all variables have returned to normal), regardless of whether the subject is still participating in the study. Closure indicates that an 
outcome is reached, stabilization achieved (the investigator does not expect any further improvement or worsening of the event), or the event is otherwise 


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Table 1:
Schedule of Assessments
Period
Screening
Baseline
Double-blind Treatment
Follow-up
Visita, b
1
2
3
4
5
6
7
IA
8
9
EOS
10
In-Clinic
Week
-6 to 0
0
2
4
8
12
24
36
48
52
Study Day
-42 to -1
0
14
28
56
84
168
252
336
364
explained. When appropriate, medical tests and examinations are performed so that resolution of event(s) can be documented.


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1.
BACKGROUND INFORMATION
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease 
worldwide (Vernon et al. 2011), and is estimated to occur in 30-40% of adults in the United 
States and up to 30% of European adults.  These numbers approach 95% in those with morbid 
obesity (Mathus-Vliegen et al. 2012).  NAFLD ranges from simple steatosis, which is typically 
nonprogressive, to nonalcoholic steatohepatitis (NASH), which has a 20% likelihood of 
progression to advanced disease including fibrosis, cirrhosis and its complications including liver 
failure and the need for a liver transplant (Angulo 2002).  Hepatocellular carcinoma is also a 
complication of NASH that may occur with or without the presence of cirrhosis (Torres et al. 
2012).  NAFLD is typically associated with type 2 diabetes mellitus (T2DM) (Adibi et al. 2007;
Loomba et al. 2012), central or visceral obesity (Souza et al. 2012), dyslipidemia (Assy et al. 
2000; N.C.E.P. 2002), and hypertension (Donati et al. 2004).  Together these conditions
comprise the metabolic syndrome, and NASH is considered to be the hepatic component of this 
syndrome (Hamaguchi et al. 2005, Neuschwander-Tetri 2005, Marchesini et al. 2005). Notably, 
NAFLD is a clinical condition occurring in individuals who do not drink excessive alcohol (>20 
grams/day), yet have hepatic histology which is indistinguishable from that seen with alcoholic 
excess.  The pathophysiology of NASH is likely multifactorial and may include combinations of 
metabolic, genetic, environmental, and gut microbial factors.       
Most individuals with NASH are asymptomatic or have nonspecific symptoms such as fatigue. 
They typically first come to medical attention incidentally following routine blood testing or on 
imaging studies performed routinely or during the evaluation of an unrelated condition. While 
ultrasound and magnetic resonance imaging (MRI) can detect the presence of steatosis (Reeder 
et al. 2011), a liver biopsy is required to diagnose NASH and the extent of liver fibrosis. 
1.1
Indication and Current Treatment Options 
There are currently no drugs approved for the treatment of NASH and it is estimated that there 
are between 6-16 million people in the United States with NASH, of which 600,000 have severe 
disease (Williams et al. 2011 and Torres and Harrison 2008), with similar percentages reported 
throughout most areas of the world (World Gastroenterology Organisation 2012). Treatment of 
associated metabolic comorbidities, weight reduction, and incorporation of an exercise routine 
remain the cornerstone of management.  However, lifestyle changes are seldom successful. Thus, 
NASH represents a disease with an unmet medical need that is growing at an epidemic rate, and 
that if untreated, carries a risk of significant morbidity and mortality.
1.2
Product Background and Clinical Information
Volixibat potassium (SHP626; formerly LUM002), hereafter referred to as volixibat, is a highly 
selective inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that is being 
evaluated for the treatment of NASH.  


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Bile acids (BA) promote bile flow, activation of digestive enzymes, and micellization of fats and 
fat-soluble vitamins, thereby permitting their intestinal absorption.  BAs serve as signaling 
molecules acting via receptors, such as farnesoid X receptor (FXR) and transmembrane G 
protein-coupled receptor (TGR5 G), in the intestine, liver and other tissues which play an 
important role in regulating insulin homeostasis and stimulating the release of fibroblast growth 
factors in the liver (Halilbasic et al. 2013).  Lipid peroxidation and oxidant stress have been 
proposed as one link between the accumulation of fat and subsequent injury (Day and James 
1998).  All of these metabolic actions have important effects to prevent the ongoing liver damage 
in NASH. 
High fat diet (HFD) fed mice treated with an ASBT inhibitor (ASBTi) (SC-435 a surrogate 
SHP626) normalized hepatic triglycerides and serum cholesterol, significantly improved insulin 
resistance (IR), and decreased NAS, predominantly steatosis.  In addition the BA pool reflected 
increases in BA that were agonists to FXR and decreases in levels that were antagonist to the 
FXR (Rao et al. 2015). Miethke and colleagues (2016) found that pharmacological inhibition of 
the ileal, ASBT (SC-435 the surrogate molecule of volixibat), blocked progression of sclerosing 
cholangitis in mdr2–/– mice. Beneficial effects in liver histology in these mice included a 
reduction in the severity of hepatic fibrosis, a decrease which correlated with a reduction of 
hepatic profibrogenic gene expression. While very encouraging, whether or not the findings in 
this mouse sclerosing cholangitis model can translate to histologic improvements in patients with 
NASH is unknown.
Volixibat, as a potent inhibitor of ASBT, increases BA excretion and facilitates signaling in the 
intestine that regulates serum and hepatic BA concentrations, glucose metabolism, serum 
cholesterol and fatty acid metabolism in the liver.  The combined events resulting from inhibiting 
BA reuptake are hypothesized to have a positive metabolic, anti-inflammatory, anti-steatotic, and 
potentially antifibrotic effect that will lead to a therapeutic benefit for patients with NASH. 
One of the factors contributing to the pathogenesis of NASH is abnormal cholesterol metabolism 
and the accumulation of free cholesterol in the liver. The free cholesterol is directly toxic to 
hepatocytes, which leads to inflammation and fibrosis (Musso et al. 2013). One treatment 
approach is to remove the cholesterol from the liver to decrease and possibly reverse the damage 
to the hepatocytes. This is one of the mechanisms by which SHP626 will treat NASH.
Due to the mechanism of action (MOA), volixibat is under development for the treatment of 
NASH and may also be able to improve the metabolic syndrome that is associated with NASH. 
Volixibat inhibits ASBT therefore BAs are excreted in the feces and this loss forces the liver to 
synthesize new BA which utilizes cholesterol in the liver and serum. Volixibat also has the 
potential to reduce IR, which is considered to be the most common underlying risk factor for the 
development of NASH (Pagano et al. 2002; Sanyal et al. 2001). 
Volixibat was initially being evaluated for its use as an intervention for dyslipidemia.  As a result 
of initial observations in animals that serum low-density lipoprotein cholesterol (LDL-C) and 
total liver cholesterol content could be decreased after administration of volixibat, additional 
work was undertaken to support the safety and tolerability of the drug in healthy volunteers. 


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Clinical and non-clinical studies have demonstrated very low systemic exposure across species. 
Oral administration of volixibat at doses up to 300 mg once daily and 50 mg administered daily 
for 14 days to healthy male subjects was generally safe.  A Phase 1 study revealed that volixibat
is tolerated at the 10 mg dose for 28 days and that there were trends towards increasing high-
density lipoprotein cholesterol (HDL-C), decreasing LDL-C, and decreasing fasting glucose in 
patients with T2DM (LUM002-101 trial). 
A healthy volunteer study investigating 12 days of varying levels of repeat doses of volixibat has 
provided key pharmacodynamic information for dose selection as measured by the effect of 
volixibat on excreted fecal bile acid (FBA) levels (SHP626-101).  In addition, the study 
investigated safety and tolerability over the dose range that was considered for this Phase 2 
study.
Data from Phase 1 studies support the position that volixibat is basically a non-absorbed drug 
that works locally in the GI tract and results in virtually no systemic exposure. Thus 
pharmacokinetic sampling will not be done in this study.
The current proof of concept (POC) Phase 2 trial will evaluate the safety, tolerability, and 
efficacy of three doses of volixibat (5, 10, and 20 mg) in adult subjects with NASH. Due to the 
MOA of volixibat, efficacy will be assessed at an interim analysis (IA) by a change of steatosis 
from Baseline to Week 24 compared to placebo (PBO).  While the gold standard for 
quantification of steatosis has historically been an invasive liver biopsy, quantitative magnetic 
resonance (MR) imaging–based biomarkers for liver fat have evolved rapidly over the last 
decade, and are increasingly being incorporated into NASH clinical trials.  Both MR 
spectroscopy (S) and MR imaging (I) proton density fat-fraction (PDFF) provide non-invasive 
means of quantifying intrahepatic lipid content (Reeder et al. 2012).  Both techniques have been 
shown to be accurate, reproducible with a low degree of variability in interpretation, cost-
effective and reliable biomarkers of quantitative hepatic fat (Roldan-Valadez et al. 2010) (Urdzik 
et al. 2012; Raptis et al. 2012).  Importantly, studies demonstrate a close correlation with 
steatosis grade histologically (Qayyum et al. 2005; Schwenzer et al. 2009).  
In a study of 51 adult subjects with NAFLD, PDFF correlated well with the grade of histologic 
steatosis, as the mean fat-fraction values of 8.9%, 16.3%, and 25.0% corresponded to histologic 
steatosis grades 1, 2, and 3, respectively (P < .0001) (Permutt et al. 2012).  Thus, MRI will be 
utilized to evaluate the degree of steatosis change from Baseline in this study during the IA. The 
Mozart trial was a randomized, double-blind, PBO-controlled trial of 50 patients with NASH 
who were randomized to 24 weeks of either ezetimibe or PBO, evaluating the reduction of liver 
fat by MRI-PDFF as well as by histology. Results revealed that compared to histologic non-
responders, histologic responders, defined as a two-point reduction in NAFLD activity score 
(NAS) without worsening fibrosis, had a statistically significant reduction in net MRI-PDFF of -
4.1% ± 4.9 vs. +0.6% ± 4.1 (P < 0.036) with a mean percent change of -29.3% ± 33.0 vs. +2.0% 
± 24.0 (P < 0.004), respectively (Loomba et al. 2015).  Thus, in the current trial during the IA, an 
active dose will be considered to be efficacious if a ≥ 5% steatosis reduction compared to PBO is 
seen after 24 weeks of therapy. 


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Intrahepatic lipid content of less than 1% is considered to be within the normal range (Springer et 
al. 2015), however, from a study of 2349 people in a general population undergoing MRS, it was 
concluded that a PDFF value of 5.56% represented the upper limit of the normal range, as 
determined from the 95th percentile of PDFF in 345 individuals who were not at increased risk 
for hepatic steatosis (Szczepaniak et al. 2005).  Thus, in the current trial, similar to other NASH 
trials utilizing MR for evaluation, an MRI ≥5% steatosis will be used as an inclusion criterion 
(Loomba et al. 2015).  
1.3
Benefits and Risks
By virtue of volixibat’s ability to inhibit ASBT bile acid reabsorption, there is an increase in BA
excretion and signaling in the intestine that results in improvements in glucose metabolism and 
changes in cholesterol and fatty acid synthesis in the liver. Recently, HFD fed mice treated with 
an ASBTi (SC435 a surrogate of SHP626) normalized hepatic triglycerides and serum 
cholesterol, significantly improved IR, and decreased NAS (predominantly steatosis). In 
addition, these HFD-fed mice did not gain weight when treated with SC435, in spite of 
consuming increased calories. Finally, the BA pool in these mice changed to predominantly FXR
agonist (Rao et al. 2015).
These metabolic actions and preclinical results may prove to be clinically relevant to subjects 
with NASH.
NASH has recently received considerable attention as awareness of the problem of liver damage 
and prevalence of the disorder has increased, paralleling the obesity epidemic.  Consequences of 
liver damage are detrimental and can lead to liver failure, hepatocellular carcinoma, and the need 
for liver transplantation. There is no currently approved medical therapy for NASH. The large 
unmet medical need and the increased medical resource burden have led to the search for 
potential therapies to treat NASH.
Nonclinical testing established that the no observed adverse effect level (NOAEL) for volixibat 
in rats and dogs following 13 weeks of once-daily administration were 1000 and 500 mg/kg/day, 
respectively. Similarly, testing confirmed that the NOAEL for volixibat in a 6-month study in 
rats and a 9-month study in dogs were 1000 and 500 mg/kg/day, respectively. In both cases, 
these were the highest doses tested. Genotoxicity testing has yielded negative findings. 
Volixibat is minimally absorbed. The pharmacokinetic profiles performed in clinical studies 
completed to date repeatedly suggest negligible systemic exposure. Furthermore, there has been 
no observation of clinically relevant changes in fat absorption parameters such as those related to 
fat-soluble vitamins.
The most frequent TEAEs in the Phase 1 studies were GI and were considered mechanism-based 
due to elevated BA concentrations in the colon. The percentage of subjects reporting at least 1 
TEAE in the GI disorders SOC generally increased with an increasing volixibat dose level (Part 


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1 Study TDU10632 and Study LUM002-101). Most TEAEs were mild in intensity, and none 
were assessed as severe.
In the multiple dose studies, the most commonly reported TEAEs in subjects (both healthy and 
with T2DM) who received volixibat for the longest duration of 28 days in Study LUM002-101 
included diarrhea and abdominal pain. The most commonly reported TEAEs in subjects 
receiving 50 mg volixibat for 14 days (part 3 Study TDR10633) were diarrhea and GI pain.
Overall, there were 2 SAEs (ALT increased and retinal detachment), both of which led to the 
discontinuation of volixibat. In part 3 of the initial Phase 1 study (TDU10633), 1 subject dosed 
with 50 mg volixibat  for 13 days was withdrawn from the study due to a mild TEAE (which 
became a SAE due to prolonged hospitalization) of ALT increased that was considered related to 
volixibat . The subject’s ALT level returned to normal after discontinuation of volixibat. A 
second subject dosed with 10 mg volixibat for 12 days in Study LUM002-101 reported a 
moderate SAE of ablation of the retina with a bleed in the vitreous body of the right eye that was 
considered not related to volixibat.
Overall, 3 subjects, all dosed with 5 mg volixibat in Study LUM002-101, discontinued volixibat 
due to non-serious TEAEs: 1 due to a related TEAE of mild hemorrhagic diarrhea, 1 due to an 
unrelated TEAE of moderate Epstein-Barr virus infection, and 1 due to mild related TEAEs of 
diarrhea and anal erosion.
Overall, the observed AEs attributable to volixibat have been self-limited as would be expected 
given the local MOA of ASBT inhibition in the terminal ileum. Generally, among subjects who 
experienced GI TEAEs, the events have been mild and diminished over the course of treatment.
Volixibat is a novel drug candidate, demonstrating limited systemic exposure across species with 
the potential to affect important metabolic pathways associated with NASH. The overall safety, 
tolerability, and preliminary activity of volixibat in available clinical trials suggest that further 
investigation is warranted and that there is a positive benefit to risk profile.
Always refer to the latest version of the Volixibat Potassium (SHP626) Investigator’s Brochure 
for the overall risk/benefit assessment and the most accurate and current information regarding 
the drug metabolism, pharmacokinetics, efficacy, and safety of volixibat. 


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Currently there is no approved medication for the treatment of NASH. Volixibat is under 
development for the treatment of NASH based on its MOA and is supported by nonclinical and 
Phase 1 data.  This is a Phase 2, 48-week, dose-finding study to examine the efficacy, 
tolerability, and safety of volixibat in adults with NASH.
2.2
Study Objectives
2.2.1
Primary Objective
To evaluate the effect of volixibat compared to PBO on liver histology 
2.2.2
Secondary Objectives

To evaluate the safety and tolerability of volixibat compared to PBO

To evaluate the effect of volixibat compared to PBO on hepatic steatosis  (measured by 
MRI)

To evaluate the effect of volixibat compared to PBO on liver histology (measured by 
individual NAS components and fibrosis stage)

To evaluate the effect of volixibat compared to PBO on liver histology (measured by 
NASH resolution without worsening fibrosis)

To evaluate the effect of volixibat compared to PBO on serum liver-related biochemistry 

To evaluate the effect of volixibat compared to PBO on metabolic indicators (glucose, 
insulin, hemoglobin A1c [HbA1c]) 

To evaluate the effect of volixibat compared to PBO on serum lipids (cholesterol, HDL-
C, LDL-C, triglycerides) 
2.2.3
Exploratory Objectives

To explore the effect of volixibat compared to PBO on liver histology (measured by 
individual SAF scoring components: Steatosis (S), Activity (A), and Fibrosis (F)) 


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
To explore the effect of volixibat compared to PBO on anthropometric measures (body 
weight, body mass index (BMI), waist circumference and waist-hip ratio) 

To explore the effect of volixibat compared to PBO on homeostasis model assessment 2-
IR (HOMA2-IR) and HOMA2-beta cell function (HOMA2-%B) in subjects with T2DM 

To explore the effect of volixibat compared to PBO on BA synthesis (7-alpha-hydroxy-4-
cholesten-3-one [C4])

To explore the effect of volixibat on patient-reported health-related quality of life
(HRQoL) and overall health status.


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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This study will be a Phase 2, 48-week, multicenter, double-blind, randomized, PBO-controlled, 
parallel group, proof of concept, dose-finding study, with one IA after 24 weeks of treatment.  
There will be 3 active arms of volixibat (5, 10 and 20 mg) and a PBO arm. Subjects will be 
randomized to receive one of three doses of volixibat (5, 10, or 20 mg once daily (QD) or PBO
in a 1:1:1:1 ratio such that a target of 266 subjects is achieved (221x1.2 is approximately 266).  
The 221 subjects include 201 subjects for the three arms analyzed at 48 weeks plus an additional 
20 subjects to account for one dose dropped at the IA). Attempt will be made to perform the IA 
before any subject has had their 48-week post-treatment liver biopsy, although this will be 
dependent upon the rate of enrollment and dropout.
There will be up to 3 periods (Screening, Treatment and Follow-up) and an IA. The duration of 
the Treatment period will be 48 weeks, with an IA at Week 24.  Depending on the results of the 
IA, the study may be terminated or the randomization to one or more doses will be stopped.  The 
follow-up period will be 4 weeks after last dose.  Subjects will be expected to visit the study 
center at least 10 times.
The IA will be conducted by an independent data monitoring committee (DMC) after at least 
80 subjects have received 24 weeks of treatment. Study enrollment will be paused after 
92 subjects have been randomized. The IA will evaluate the safety, tolerability and efficacy of 3 
doses of volixibat each compared to PBO, on reduction of steatosis as measured by high fat 
fraction (HFF) by MRI and ALT. 
Once decisions as to dose elimination are made, study enrollment will be reopened and 
additional sites may be added. Subjects recruited into the study prior to the IA will continue with 
the same dosing regimen for the duration of the planned study participation. Subjects recruited 
into the study after completion of the IA will be randomized evenly to the remaining dose groups 
or PBO group by IRT. Thus, depending on the results from the IA, the study may be terminated, 
or one or more doses of volixibat will be discontinued. If the study is not terminated, subjects 
will receive a total of 48 weeks of investigational product (IP).
The study will be conducted over 3 periods: Screening (6 weeks), Treatment (48 weeks), and 
Follow-up (4 weeks), with an IA at 24 weeks as outlined in Figure 1.  


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Figure 1:
Study Design Flow Chart
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 364 days.  The 
last visit is an in-clinic safety follow-up visit. The study will be completed in approximately 3 
years.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment.  Please note that this includes the follow-up visit.  The 
Study Completion Date is used to ascertain timing for study results posting and reporting.
3.3
Sites and Regions
This study will be conducted at approximately 60 to 80 clinical sites in the USA, Canada, and 
EU.


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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.
2. Ability to voluntarily provide written, signed, and dated (personally or via a legally 
authorized representative, as applicable) informed consent to participate in the study.
3. Age 18-80 years inclusive. This inclusion criterion will only be assessed at the first 
Screening visit.
4. Males and females of child-bearing potential who are sexually active, or are not currently 
sexually active during the study, but become sexually active during the period of the study 
and 30 days following the last dose of the IP, must agree to use acceptable contraception.
Males and females of child-bearing potential who are not currently sexually active must 
agree to use acceptable contraception, if they become sexually active during the period of the 
study and 30 days following the last dose of the IP.
5. Presence of ≥ 5% steatosis on screening MRI from a centrally read radiologist performed 
either during the Screening period or within 6 months prior to the first visit.
6. Histologic confirmation of NASH without cirrhosis from a centrally read liver biopsy 
performed either during the Screening period or within 6 months prior to the first  visit with a 
NAS of ≥ 4 with a score of at least 1 in each component (steatosis, lobular inflammation, and 
hepatocyte ballooning).
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Presence of or history of cirrhosis or evidence of decompensated liver disease (ie, ascites, 
variceal bleeding, etc.) or hepatocellular carcinoma.
2. History or presence of other concomitant liver disease as assessed by the investigator or 
determined by laboratory findings including, but not limited to: active hepatitis B virus 
(HBV) infection (hepatitis B surface antigen (HBsAg) positive and/or HBVDNA positive; 
subjects who are hepatitis B core antibody (HBcAb) positive may be eligible as long as 
HBsAg is negative and HBVDNA is nondetectable), active hepatitis C virus (HCV) infection 
(prior exposure to HCV (defined as HCVAb positive without a current or prior history of a 
detectable HCVRNA) may be eligible alcoholic liver disease, proven autoimmune hepatitis, 


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primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, 
Wilson’s disease, alpha-1 antitrypsin deficiency, bile duct obstruction, liver primary or 
metastatic cancer.
3. Current or recurrent disease that could affect the action, absorption, disposition, or laboratory 
assessment of the investigational product (IP) (including bile salt metabolism in the intestine) 
eg, uncontrolled inflammatory bowel disease, uncontrolled celiac disease, gastric bypass 
procedures (gastric lap band is acceptable), ileal or ileocecal resection, uncontrolled irritable 
bowel syndrome with predominant diarrhea, or history of chronic diarrhea or loose stools of 
any etiology.
4. Weight change ≥ 5% after qualifying liver biopsy performed.
5. Contraindications to MRI (eg, claustrophobia, coronary stents, coronary implantable devices, 
girth, etc.).
6. Current or relevant history of physical or psychiatric illness, any medical disorder that may 
require treatment or make the subject unlikely to complete the study, or any condition that 
presents undue risk from the IP or procedures.
7. Vitamin E, thioglitazones, and glucagon-like peptide-1 receptors agonists (GLP1 RA) unless 
subject on a stable dose for 6 months prior to qualifying liver biopsy and not initiated after 
qualifying liver biopsy and will continue the same dosing regimen throughout study 
participation. 
8. Uncontrolled diabetes defined as HbA1c of ≥ 9.0% within 60 days prior to enrollment. 
9. Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations) that could affect the action, absorption, or disposition of the IP, or clinical or 
laboratory assessment.  (Current use is defined as use within 14 days of Screening).  Patients 
currently taking insulin will not be excluded; however, they must be on a stable dose for at 
least 30 days prior to Screening.
10. Use of drugs, herbs or supplements historically associated with causing or worsening 
NAFLD/NASH for less than 6 months prior to liver biopsy, or initiated any time after liver 
biopsy performed, including the use of total parenteral nutrition (TPN). 
11. Serum AST > 5 times upper limit of normal (ULN) at Screening.
12. Serum ALT > 5 times ULN at Screening.
13. Elevated serum creatinine ≥ 2.0 mg/dL.
14. International normalized ratio (INR) >1.3
15. TB ≥ 2.0 x ULN at Screening (Except for documented Gilbert’s syndrome with bilirubin 
levels 20 µmol/L to 90 µmol/L (1.2 to 5.3 mg/dL) and with a ratio of 
unconjugated/conjugated bilirubin that is commensurately higher).
16. Platelet count < 130 × 109/L
17. Medical history of impaired hemostasis or use of anticoagulant medication (baby aspirin 
(ASA) will be allowed).
18. Uncontrolled thyroid disease.


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19. Type 1 diabetes mellitus.
20. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or 
any of the stated ingredients.
21. Known history of alcohol or other substance abuse within the last year. Weekly alcohol 
intake greater than 21 units for males and 14 units for females on average or inability to 
reliably quantify alcohol consumption based on investigator’s judgment.
22. Within 6 months of MRI and liver biopsy:

Have used any IP

Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study
23. Inability to safely obtain a liver biopsy.
24. The anticipated need for a surgical procedure during the study that could interfere with the 
treatment. 
25. Known positivity for human immunodeficiency virus (HIV) infection.
26. Cancer within 5 years of Screening, except for basal or squamous cell carcinoma of the skin 
or in situ cervical carcinoma that has been treated with no evidence of recurrence.
27. History of noncompliance with medical regimens, unreliability, mental instability or 
incompetence that could compromise the validity of informed consent or lead to 
noncompliance with the study protocol.
28. Any other conditions or abnormalities which, in the opinion of the investigator, may 
compromise the safety of the subject, or interfere with the subject participating.
29. Subject has failed Screening or was previously enrolled in this study or is currently enrolled 
in this study at any study site (unless the subject is transferring to another qualified study site 
with prior Sponsor approval).
30. Subjects who are employees at the investigational site.
4.3
Restrictions 
Subjects must adhere to the following restrictions for the duration of the study:

Subjects must remain compliant with inclusion/exclusion criteria.

Subjects should not become pregnant, father a child, or nurse/breastfeed a baby. 

Subjects should be encouraged to adhere to the same exercise routine and a healthy diet
throughout the study.


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4.4
Reproductive Potential
4.4.1
Female Contraception
Sexually active females of child-bearing potential should be using an acceptable form of 
contraception. Females of child-bearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 30 days following the last dose of the IP.  If 
hormonal contraceptives are used they should be administered according to the package insert. 
Females of child-bearing potential who are not currently sexually active must agree to use 
acceptable contraception, as defined below, if they become sexually active during the period of 
the study and 30 days following the last dose of the IP. 
Female subjects should be either:

Post-menopausal (12 consecutive months of spontaneous amenorrhea and age 51 years)

Surgically sterile (having undergone one of the following surgical acts:  hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of child-bearing potential with a negative urine and/or serum -human chorionic 
gonadotropin (-HCG) pregnancy test each study visit.  Females of child-bearing 
potential must agree to abstain from sexual activity that could result in pregnancy or 
agree to use acceptable methods of contraception.
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the Screening visit (Visit 1), plus condoms.  Note:  if subject 
becomes sexually active during the study, they should use one of the other acceptable 
methods noted above in addition to the hormonal contraceptive until it has been stabilized 
for 30 days.
4.4.2
Male Contraception
Contraception is required for all sexually-active male subjects and their partners. All male 
subjects (including those who are sterile) agree not to donate sperm, and to use 1 of the following 
approved methods of contraception from the Baseline visit on Day 0 until 30 days following 
study discharge:


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
Male condom with spermicide

Sterile sexual partner

Intrauterine device with spermicide (use by female sexual partner)

Female condom with spermicide (use by female sexual partner)

Contraceptive sponge with spermicide (use by female sexual partner)

Intravaginal system (eg, NUVARING. with spermicide, a diaphragm with spermicide,
a cervical cap with spermicide) (use by female sexual partner)

Oral, implantable, transdermal, or injectable hormonal contraceptive (use by female 
sexual partner).
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety).  The investigator is 
encouraged to discuss withdrawal of a subject from the IP with the medical monitor when 
possible.
If the IP is discontinued, regardless of the reason, the evaluations listed for both Visit 9/end of 
study (EOS) and Visit 10/Follow-up, are to be performed as completely as possible; however, the 
EOS liver biopsy will not be required for patients discontinuing prior to Week 44. 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
source documents.  The reason for termination, date of stopping the IP, and the total amount of 
the IP taken must be recorded in the electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
A subject will be withdrawn from the study if they have missed > 3 consecutive days of study 
drug dosing for any reason.
4.5.1
Subject Withdrawal Criteria
Medically important events that in the opinion of the investigator, medical monitor or sponsor 
would compromise the subject’s ability to safely continue in the study may result in withdrawal
of the subject from the study. 


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4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the eCRF.  If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the eCRF.  
Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol violation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Death

Screen failure 

Noncompliance with study 

Physician decision

Pregnancy

Progressive disease

Study terminated by sponsor

Other - If “Other” is selected, the investigator must specify on the eCRF 
4.5.3
Subjects Lost to Follow-up Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact clinic visit.  At least 1 of these documented 
attempts must include a written communication sent to the subject’s last known address via 
courier or mail (with an acknowledgement of receipt request) asking that they return to the site 
for final safety evaluations and return any unused IP.


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4.5.4
Safety-related Stopping Rules
Refer to Appendix 4 and Appendix 5 for criteria to assess severity of liver-related AEs and 
stopping rules for liver-related blood tests, respectively.
An urgent safety review will be conducted within 7 days by the sponsor if one or more of the
following criteria are met:

Death that is considered related to the study drug

Two SAEs of similar type (defined as same or similar Medical Dictionary for Regulatory 
Activities (MedDRA) higher level group code), and considered related to the study drug
The urgent review will be performed by a sponsor safety review group, which will include the
study Pharmacovigilance and Risk Management (PVRM) physician and the PVRM therapeutic 
area (TA) Head. The PVRM TA Head, not the PVRM physician involved in the study, may be 
unblinded as part of this urgent safety review, if required. Following the sponsor’s review of 
safety data, one of the following actions will be taken with respect to study status:

Continue study with protocol unchanged

Continue study with modifications to the protocol

Terminate study
Subject safety will be monitored on a continuous basis during this study until the last subject
completes his or her last scheduled study visit/assessment.


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5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to signing informed consent at the Screening visit (Visit 1) and through the 
final study contact (including protocol-defined follow-up period) must be recorded on the 
appropriate eCRF page.
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
and behavioral treatment, non-pharmacological treatment, such as psychotherapy, as 
appropriate), received within 30 days of the date of first dose of the IP. Prior treatment 
information must be recorded on the appropriate eCRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of the IP
and the end of the follow-up period, inclusive.  Concomitant treatment information must be 
recorded on the appropriate eCRF page.
5.2.1
Permitted Treatment
Medications and supplements including vitamin E, thiazolidinediones (TZDs) and GLP1 RAs 
that have been used to treat NAFLD/NASH are allowed during the course of the study if the 
subject has been on a stable dosing regimen (ie, same dose and frequency in the previous 6 
months prior to the qualifying liver biopsy and not initiated after qualifying liver biopsy) and 
will continue this dosing regimen throughout study participation. The investigator must contact 
the CRO medical monitor then the sponsor medical monitor to discuss any changes to 
concomitant medications that may impact the study.
5.2.2
Prohibited Treatment
The following list of prohibited drugs cannot have been taken for more than 2 weeks within the 
year prior to randomization and are excluded while on study.

Systemic Glucocorticoids

Tamoxifen

Amiodarone

Valproate

Nucleoside Analogues

Tetracycline

Estrogens at doses greater than 


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
Methotrexate

Alcohol (see Section 4.2)

Griseofulvin

Total parenteral nutrition
used for hormone replacement

Anabolic steroids

Bile acid sequestrants such as 
cholestyramine or colestipol

Any other known hepatotoxins
Treatments not listed above are considered allowable, unless considered a potential hepatotoxin. 
Antidiarrheals will be allowed at the discretion of the investigator, with the exception of BA
sequestrants.


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is volixibat potassium (formerly LUM002, formerly SHP626, hereafter referred 
to as volixibat) which will be provided in 5, 10 and 20 mg capsule form.  Additional information 
is provided in the current Volixibat Potassium (SHP626) Investigator’s Brochure.
The reference/comparator product is an identical PBO which will be provided in capsule form.  
6.1.1
Blinding the Treatment Assignment
The IP will be supplied as double-blind blister packs. The actual double-blind treatment given to 
individual subjects is determined by a randomization schedule which will be automatically 
assigned by the interactive response technology (IRT). Placebo capsules, which exactly match 
the IP, will be used in the blister packs to provide the same number and size capsules for each of 
the doses within the treatment groups.
6.2
Administration of Investigational Product(s)
All IP and supplies will be provided by Shire or its designee. At each visit, subjects will be 
supplied with enough IP to last until the subsequent visit. Lost or damaged IP will be replaced as 
needed. Volixibat will be supplied to the clinical research center (CRC) as powder in capsule.
Volixibat will be supplied in identical capsules in strengths of 5, 10, and 20 mg (with matched 
PBO). All doses of volixibat or matching PBO will be administered orally as a capsule in a 
double-blinded fashion.  The first dose of IP for each subject will be administered in the clinic. 
The dose will be administered with 240 mL of water and should be given 30 minutes prior to the 
first meal of the day containing fat. All assessments should be completed at least 30 minutes
prior to administration of the IP.
6.2.1
Interactive Response Technology for Investigational Product Management
IRT will be used for the following investigational tasks:

Randomization

Supply management

Inventory management and supply ordering

Expiration tracking


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
Returns

Emergency unblinding
6.2.2
Allocation of Subjects to Treatment 
This is a double-blind, PBO-controlled study. The actual treatment given to individual subjects is 
determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to the IP allocated to the 
subject, once eligibility has been determined.  
Individual subject treatment is automatically assigned by the IRT.
Once a randomization number/unique identifier has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study.  If a randomization number/unique 
identifier is allocated incorrectly, the clinical research associate (CRA)/study monitor must be 
notified as soon as the error is discovered. 
IP packaging identification numbers, separate from randomization numbers/unique identifiers, 
may also be assigned to subjects for specific treatment assignment as dictated by the study.  In 
these cases, the same IP packing identification number may not be assigned to more than 1 
subject.
Subjects will be equally allocated to all volixibat doses and PBO whether their randomization 
precedes or follows the 24 week IA. The randomization will be stratified by treatment arm,
baseline T2DM and NAS ≥ 6 or NAS = {4, 5}.
6.2.3
Dosing
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the IP is required for further treatment of the subject. The investigator 
should contact the CRO medical monitor and the sponsor medical monitor at the same time and 
as soon as possible after the investigator has been unblinded.  
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code and the reason for breaking the code are recorded on the IRT and the source 


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documents.  Upon breaking the blind, the subject is withdrawn from the study, but should be 
followed up for safety purposes. Any code-breaks that occur must be reported to the CRO
medical monitor.  Code-break information is held by the pharmacist/designated person at the site 
and by the CRO medical monitor for the study or designee.
For blinded studies, there will be a provision for unblinding to ensure adequate treatment of the 
subject in the case of an emergency.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the IP container. 
All IP is labeled with a minimum of the protocol number, medication identification number, 
dosage form (including product name and quantity in pack), directions for use, storage 
conditions, expiry date (if applicable), batch number and/or packaging reference, the statements 
‘For clinical trial use only’, and/or ‘CAUTION: New Drug - Limited by Federal (or USA) Law 
to Investigational Use’, ‘Keep out of reach of children’, and the sponsor's name and address. Any 
additional labeling requirements for participating countries will also be included on the label.
Additional labels may, on a case-by-case basis, be applied to the IP in order to satisfy local or 
institutional requirements, but must not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
The sponsor or designee will provide the IP for this study. The IP is packaged in the following 
labeled containers:

Volixibat 5 mg capsules

Volixibat 10 mg capsules

Volixibat 20 mg capsules


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
Volixibat PBO capsules
6.3.3
Storage
The investigator has overall responsibility for ensuring that the IP is stored in a secure, limited-
access location.  Limited responsibility may be delegated to the pharmacy or member of the 
study team, but this delegation must be documented.  
IPs are distributed by the pharmacy or nominated member of the study team. The 
pharmacist/nominated team member will enter the unique subject identifier on the IP labels as 
they are distributed. 
All IP must be stored at the clinic at 20 - 25oC (68 - 77oF); excursions are allowed between 15 -
30oC (59 - 86oF).
IPs must be stored in accordance with labeled storage conditions.  Temperature monitoring is 
required at the storage location to ensure that the IP is maintained within an established 
temperature range. The investigator is responsible for ensuring that the temperature is monitored 
throughout the duration of the study and that records are maintained; the temperature should be 
monitored continuously by using either an in-house system, a mechanical recording device such 
as a calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.  Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording.  The sponsor must be notified immediately upon discovery of any excursion below 
15oC (59oF) or above 30oC (86oF); these excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the IP and will 
provide supportive documentation as necessary.  Under no circumstances should the product be 
dispensed to subjects until the impact has been determined and the product is deemed appropriate 
for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the IP
that could affect the integrity of the product(s), eg, fumigation of a storage room or a change in 
storage location.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the IP to carry out this protocol for the 
agreed number of subjects.  The investigator or designee will acknowledge receipt of the IP, 
documenting shipment content and condition.  Accurate records of all IP dispensed, used, 
returned, and/or destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing the IP.  Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 


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trained in the protocol and who works under the direct supervision of the investigator.  This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the IP only to subjects included in this study 
following the procedures set out in the study protocol.  Each subject will be given only the IP
carrying his/her treatment assignment. All dispensed IP will be documented on the eCRFs and/or 
other IP record. The investigator is responsible for assuring the retrieval of all study supplies 
from subjects.
No IP stock or returned inventory from a Shire-sponsored study may be removed from the site 
where originally shipped without prior knowledge and consent by the sponsor.  If such transfer is 
authorized by the sponsor, all applicable local, state, and national laws must be adhered to for the 
transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
With the written agreement of the sponsor, at the end of the study all unused stock, subject 
returned IP, and empty/used IP packaging may be destroyed at the site or a local facility.  In this 
case, destruction records identifying what was destroyed, when and how, must be obtained with 
copies provided to the sponsor.  Destruction of IP must be in accordance with local, state, and 
national laws.
Alternately, at the end of the study, or as instructed by the sponsor, all unused stock, 
subject-returned IP, and empty/used IP packaging are to be sent to a nominated contractor on 
behalf of the sponsor.  IP being returned to the sponsor’s designated contractors must be counted 
and verified by clinical site personnel and the sponsor (or designated CRO).  For unused supplies 
where the original supplied tamper-evident feature is verified as intact, the tamper-evident 
feature must not be broken and the labeled amount is to be documented in lieu of counting.  
Shipment return forms, when used, must be signed prior to shipment from the site.  Validated 
electronic return systems (ie, IRT) do not require a shipment form.  Returned IP must be packed 
in a tamper-evident manner to ensure product integrity.  Contact the sponsor for authorization to 
return any IP prior to shipment.  Shipment of all returned IP must comply with local, state, and 
national laws.
6.5
Subject Compliance
Subjects must be instructed to bring their unused IP and empty/used IP packaging to every visit. 
Drug accountability must be assessed at the container/packaging level for unused IP that is 
contained within the original tamper-evident sealed container (eg, blister pack) or at the 
individual count level for opened containers/packaging. The pharmacist/nominated person will 
record details on the drug accountability form.


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7.
STUDY PROCEDURES
7.1
Study Schedule
This study will consist of a Screening period of up to 42 days, a 48-week Treatment period, and a 
Follow-up visit 4 weeks after treatment ends. A detailed display of all study procedures is 
provided in Table 1: Schedule of Assessments. 
Patients will be assessed according to the following schedule:

Screening – Visit 1 (Weeks -6 to 0 [Day -42 to Day -1])

Baseline – Visit 2  (Week 0 [Day 0])

Treatment and Assessments – Visits 3 through 9 (Week 1 through Week 48)

Follow-up – Visit 10 (Week 52, 4 weeks after completion of dosing)
7.1.1
Screening (Visit 1) 
Screening procedures must be completed within 42 days prior to randomization for the first dose 
of the IP. At the Screening visit, considered Visit 1 (Week -6 to 0, Day -42 to -1), all screening 
assessments and procedures are to be performed by the principal investigator or a qualified 
designee. See Table 1 for a complete list of screening procedures to be performed.
Written, signed, and dated informed consent from the subject prior to the performance of any 
study-related procedures must be obtained by the principal investigator or a designee. A copy of 
the signed informed consent form must be given to the subject for their records.
The following Screening procedures should be assessed at the beginning of the visit window, 
preferably between Day -42 and Day -35: inclusion/exclusion criteria, collection of subject
information (demographics, medical and medication history AEs, and concomitant medications), 
a physical examination including vital signs, height, weight, and waist/hip measurements; 
collection of blood and urine samples for screening and safety assessments, and performance of 
an electrocardiogram (ECG). MRI and liver biopsy (if one has not been completed in the 
previous 6 months) should be performed with sufficient time to ensure results are received prior 
to the Baseline visit. 
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered the 
IP. Subjects cannot be rescreened once they have been designated as a screen failure. 


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7.1.2
Baseline (Visit 2)
Following the Screening visit, subjects will return to the clinic within 28 days for Visit 2, 
(considered Week 0, Day 0), for Baseline assessments including review of the 
inclusion/exclusion criteria, adverse events, and concomitant medications; physical examination
with vital signs, weight, and waist/hip measurements; ECG; collection of blood and urine 
samples; and completion of the patient-reported outcome (PRO) EuroQol-5 Dimension-5 Level 
Questionnaire (EQ-5D-5L) survey. After completion of these assessments, subjects are 
randomized using Interactive Response Technology (IRT) to 1 of 4 treatment arms receiving 
volixibat 5 mg, 10 mg, or 20 mg, or PBO. The initial supply of study drug is dispensed to ensure 
adequate daily dosing until the next scheduled study visit.
7.1.3
Treatment and Assessment Period (Visits 3 through 9/EOS) 
During the 48 weeks of double-blind treatment, 7 clinic visits are scheduled to occur as follows:

Visit 3 - Week 2, Day 14 (+/- 3 days)

Visit 4 - Week 4, Day 28 (+/- 3 days)

Visit 5 - Week 8, Day 56 (+/- 5 days)

Visit 6 - Week 12, Day 84 (+/- 5 days)

Visit 7 - Week 24, Day 168 (+/- 7 days) – Interim Analysis

Visit 8 - Week 36, Day 252 (+/- 7 days)

Visit 9 - Week 48, Day 336 (+/- 7 days) – End of Study
Subjects are reminded not to eat and not to take their study drug on the day of scheduled study 
visits prior to completion of assessments. They should bring their study drug with them to the 
visit. All assessments should be completed at least 30 minutes prior to administration of the IP.
IP should be taken 30 minutes prior to the first meal of the day containing fat.
The Schedule of Assessments provided in Table 1 details the procedures to be completed at each 
visit. All Treatment visits (3 through 9) will include weight and waist/hip measurements, 
assessment of vital signs, and blood sampling for completion of biochemistry, hematology, 
serum glucose, lipid panel, HbA1c, and serum liver-related blood tests. At all visits, adverse 
events, and concomitant medications will be collected for all subjects, and female subjects of 
childbearing potential will have a urine pregnancy test. Subjects will return containers of unused 
study drug for assessment of accountability and compliance which will be documented in the 
IRT. New supplies of study drug will be dispensed at Visits 3 through 8. 


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Additional assessments will also occur less frequently during the Treatment Period for
coagulation panel, vitamin D, insulin, thyroid testing, urinalysis, ECG, physical examinations, 
and completion of the EQ-5D-5L. 
An MRI will be repeated at Visit 7 for the 24-week IA and at Visit 9 (Week 48) for the subjects 
in the IA set only. A final liver biopsy will be performed at Visit 9 (Week 48) for all subjects 
unless a subject discontinues prior to Week 44, in which case the EOS liver biopsy is not 
required.
7.1.4
Follow-up (Visit 10)
The follow-up period for this protocol is 4 weeks after the last dose of study drug with a final 
Follow-up visit scheduled for Week 52. Procedures to be completed at this final visit include 
physical examination, weight, waist/hip measurements, vital signs, samples for biochemistry and 
hematology, serum glucose, lipid panel, HbA1c, serum liver-related blood tests, insulin, thyroid 
testing, and urine pregnancy test (for women of childbearing potential). Adverse events and 
concomitant medications will be recorded. All AEs and SAEs that are not resolved at the time of 
this contact will be followed to closure (see Section 8.1).
7.1.5
Additional Care of Subjects after the Study
No after care is planned for this study.
7.2
Study Evaluations and Procedures
All assessments and procedures are to be performed by the Investigator or a qualified designee 
who has been trained in the protocol. Assessments are to be performed according to the 
schedules shown in Table 1. If a subject terminates the study early, the CRC will make 
reasonable effort to perform the EOS and safety follow-up assessments and procedures for the 
subject’s safety and well-being.
7.2.1
Demographic and Other Baseline Characteristics
Demographic details will be obtained at screening and recorded on the eCRF. Data collected will 
include age, gender, ethnicity, height, and weight.


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7.2.2
Efficacy
7.2.2.1
Liver Biopsy
Liver biopsies will provide histologic data for confirmation of the diagnosis of NASH, 
assessment and grading of NASH activity, and scoring of steatosis, lobular inflammation, 
ballooning, as well as fibrosis and additional features (see Appendix 2 and Laboratory Manual 
for additional information). 
7.2.2.2
MRI
The presence of ≥5% steatosis on screening MRI from a centrally read radiologist will be 
performed either during the Screening period or within 6 months prior to the first visit. Steatosis 
is assessed by MRI hepatic fat fraction. The 48-week MRI will be conducted for subjects in the 
IA set only.
7.2.3
Safety
7.2.3.1
Medical History and Medications 
Medical history including important medical events and concomitant medication and illnesses 
will be obtained at Screening and will be recorded on the eCRF. Any existing medical condition 
present prior to the time of randomization should be reported as medical history
7.2.3.2
Physical Examination 
A physical complete examination will be performed with a thorough review of body systems at 
Screening, Baseline prior to randomization, and at study visits specified in Table 1.  Physical 
examinations will include a review of the subject’s general appearance, as well as evaluation of 
the body systems including:

Eyes, ears, nose, throat

Lymph nodes

Cardiovascular

Skin

Abdomen

Neurological


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
Spine and extremities
Abnormalities identified at the Screening visit (Visit 1) will be documented in the subject’s 
source documents and on the medical history eCRF. Changes after the Screening visit (Visit 1) 
will be captured as AEs on the AE eCRF page, if deemed clinically significant by the 
investigator.
Height will be measured at the Screening visit only while weight and waist and hip 
circumference will be recorded at all study visits. BMI will be calculated programmatically.   
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”).  
Adverse events are collected from the time informed consent is signed.  (Please refer to Section 
8, Adverse and Serious Adverse Events Assessment.)
7.2.3.4
Vital Signs
Vital signs include oral or tympanic temperature, sitting blood pressure, pulse, and respiratory 
rate. Blood pressure should be determined by cuff (using the same method, the same arm, and in 
the same position throughout the study). Any deviations from Baseline (Visit 2) vital signs which 
are deemed clinically significant in the opinion of the investigator are to be recorded as an AE.
7.2.3.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the central laboratory’s normal 
procedures.  Reference ranges supplied by the central laboratory will be used to assess the 
clinical laboratory data for clinical significance and out-of-range pathological changes.  The 
investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Clinically 
significant findings should be evaluated for recording as adverse events on the eCRF. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry
Albumin (ALB)
Alkaline phosphatase (ALP)
Lactate dehydrogenase (LDH)
Magnesium (Mg)


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Alanine aminotransferase (ALT; SGPT)
Aspartate aminotransferase (AST; SGOT)
Blood urea nitrogen (BUN)
C4
Calcium (Ca)
Bicarbonate (CO2)
Chloride (Cl)
Creatinine
Creatine kinase
Gamma glutamyl transferase (GGT)
Glucose
Phosphate (P)
Potassium (K)
Sodium (Na)
Total and direct bilirubin
Total cholesterol
Protein
Triiodothyronine (T3)
Thyroid-stimulating hormone 
(TSH)
Triglycerides
Uric acid
Hematology
Hemoglobin 
Hematocrit
Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin 
concentration (MCHC)
Platelets
Red blood cell (RBC) 
White blood cell (WBC) count with 
differential
Prothrombin time (PTT)
Activated partial thromboplastin time 
(aPTT)
International normalized ratio (INR)
Urinalysis
Appearance (clarity and color)
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Microscopic examination of sediment
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Oxalate


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7.2.3.6
Additional Laboratory Assessments
Laboratory samples will be collected and assessed for:

HIV testing and assessment of Hepatitis B/C including HBcAb, HBsAg, HBVDNA, and 
HCVAb, and HCVRNA will occur at the Screening visit only

Lipid panel including fasting total cholesterol, HDL-C, LDL-C, and triglycerides at each 
scheduled study visit (Visits 1 through 10)

HbA1c will be tested at every scheduled visit (Visits 1 through 10)

Serum liver-related blood tests including ALT, AST, ALP, GGT, and TB will be 
analyzed at every visit (Visits 1 through 10)

Full coagulation panel will be done at Screening and Baseline, but only INR and PT are 
required at remaining time points at Visits 4, 7, and 9

Insulin will be tested at Screening, Baseline, at Visit 4 and Visits 6 through 10

Vitamin D will be tested at Screening, Baseline, and Visits 4, 7, and 9

Thyroid testing including TSH and T3 will be tested at Screening, Baseline, and Visits 4, 
6, 7, 9, and 10

C4 samples will be collected at Baseline and Visits 6, 7, 9, and 10
7.2.3.7
Pregnancy Test 
A urine pregnancy test is performed on all females of child-bearing potential at the Screening 
visit (Visit 1), Baseline visit (Visit 2), at each Treatment visit (Visits 3 through 9) and at the 
Final visit (Visit 10), or if pregnancy is suspected, or on withdrawal of the subject from the 
study. A positive urine pregnancy test must be followed with a serum pregnancy test performed 
by the central laboratory. Additional testing can be performed at the investigator’s discretion. 
Also, refer to Section 8.1.7.
7.2.3.8
Drug and Alcohol Testing
A urine screen for drugs of abuse and blood test for alcohol will be performed at Screening and 
Baseline as described in Table 1. Additional drug and alcohol screens may be performed at the 
investigator’s discretion.
Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiate metabolite, and phencyclidine. 


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Results of drug and alcohol screens will be reviewed and verified by the study monitor, but will 
not be collected in the eCRF database.
Any positive result for drugs of abuse at the Screening or Baseline visits will exclude the subject 
from further participation in the study. A positive test for drugs of abuse or alcohol done at the 
investigator’s discretion discovered at any time during the study will be grounds for study 
discontinuation.
7.2.3.9
Electrocardiogram 
An ECG (12-lead) will be performed at the times specified in Table 1 in accordance with the 
clinical site’s standard practice(s) and equipment supplied by the CRC. The Baseline visit ECG 
will be completed in triplicate with a 10 minute interval between each reading. The remaining 
ECGs may consist of a single reading. Recordings of ECGs will be read locally at the clinical 
site by a qualified cardiologist. The ECG will include assessment of heart rate, sinus rhythm, 
atrial or ventricular hypertrophy, and assessment of PR, RR, QRS, and QT intervals. 
Identification of any clinically significant findings and/or conduction abnormalities will be 
recorded on the eCRF.
7.2.3.10 Health-related Quality of Life Assessments
The EuroQoL (Euroql. 2016. Available at: http://www.euroqol.org. [Accessed 17 February 16]) 
EQ-5D-5L (“EQ-5D”) is a widely used standardized questionnaire that assesses generic HRQoL
and is also recommended for health-economic evaluations.  The EQ-5D includes two 
components: a descriptive profile and a visual analogue scale (VAS).  The descriptive profile 
includes five dimensions (ie, pain/discomfort, mobility, usual activities, self-care and 
anxiety/depression), each with five levels (ie, no problems, slight problems, moderate problems, 
severe problems, extreme problems). An EQ-5D index can also be derived from the data which 
summarizes health status using a single value (ie, health-state utility).  The psychometric 
properties of the EQ-5D-5L have been established and well documented (see Appendix 3).
7.2.3.11 Volume of Blood to be Drawn from Each Subject
During this study, it is expected that approximately 124 mL of blood will be drawn from all 
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate.  The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 124 mL. When more than 1 blood assessment is to be done at the time
point/period, if they require the same type of tube, the assessments may be combined.  


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4.  This includes events occurring during the screening phase of the 
study, regardless of whether or not the IP is administered.  Where possible, a diagnosis rather 
than a list of symptoms should be recorded.  If a diagnosis has not been made, then each 
symptom should be listed individually.  All AEs should be captured on the appropriate AE pages 
in the eCRF and in source documents.  In addition to untoward AEs, unexpected benefits outside 
the IP indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study.  Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained.  When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity.  An event that changes in severity should be captured as a new 
event.  Worsening of pre-treatment events, after initiation of the IP, must be recorded as new 
AEs (for example, if a subject experiences mild intermittent dyspepsia prior to dosing of the IP, 
but the dyspepsia becomes severe and more frequent after first dose of the IP has been 
administered, a new AE of severe dyspepsia (with the appropriate date of onset) is recorded on 
the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of daily 
living.


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Moderate: A type of AE that is usually alleviated with specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Appendix 4 provides criteria to assess the severity of liver-related adverse events.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to the IP for each AE.  The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the IP.  If there is no valid reason for 
suggesting a relationship, then the AE should be classified as “not related”.  Otherwise, if there is 
any valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect 
relationship between the IP and the occurrence of the AE, then the AE should be considered 
“related”.  The causality assessment must be documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the IP is 
compelling and/or follows a known or suspected response pattern to that product, and 
the event cannot be explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the IP and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF.  Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 


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
Recovering/Resolving

Unknown.
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the IP, a shift of a parameter is 
observed from a normal value to an abnormal value, or a further worsening of an already 
abnormal value.  When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range, either while continuing treatment or after 
the end of treatment with the IP, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Criteria for Discontinuation of Treatment
Appendix 5 provides guidelines for discontinuation of treatment based on elevated ALT, AST, 
TB, and associated signs and symptoms.  
8.1.7
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.


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Any report of pregnancy for any female study participant (or the female partner of a male 
participant) must be reported within 24 hours to the Shire Global Pharmacovigilance and Risk 
Management Department using the Shire Investigational and Marketed Products Pregnancy 
Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy Report 
Form (and any applicable follow-up reports) must also be sent to the CRO/Shire Medical 
Monitor using the details specified in the emergency contact information section of the protocol.
The pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days post
partum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form.  Note:  An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and Non-
serious AEs Required by the Protocol Form as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form.  The test date of the first positive serum/urine -HCG test or 
ultrasound result will determine the pregnancy onset date.
8.1.8
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2.  Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of the IP when used for a non-medical 
purpose (eg, to alter one’s state of consciousness or get high) in a manner that may be 
detrimental to the individual and/or society

Misuse – Intentional use of the IP other than as directed or indicated at any dose (Note: 
this includes a situation where the IP is not used as directed at the dose prescribed by the 
protocol)

Overdose – Intentional or unintentional intake of a dose of an IP exceeding a pre-
specified total daily dose of the product.  


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
Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an IP.  For studies, medication errors are reportable to the sponsor only as defined 
below.
Cases of subjects missing doses of the IP are not considered reportable as medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired IP should be considered as a reportable medication 
error.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the Volixibat Potassium (SHP626)
Investigator’s Brochure which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO/Shire Medical Monitor
within 24 hours of the first awareness of the event.  Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see Section
8.1.8) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note:  Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the CRO/Shire Medical Monitor using the details specified in the emergency 
contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to the IP or not) that at any dose:


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
Results in death

Is life-threatening.  Note: The term ‘life-threatening’ in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization.  Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs.  For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event.  Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions 
that do not result in inpatient hospitalization; or the development of drug dependency or 
drug abuse.  
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4, and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the CRO/Shire 
Medical Monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the IP and discovered by the investigator at any 
interval after the study has completed must be reported to the Shire Global Pharmacovigilance 
and Risk Management Department within 24 hours of the first awareness of the event.
8.2.4
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic.  In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.


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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.5
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date.  
For all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another IP action was previously taken (eg, drug interrupted, reduced, withdrawn), the action 
taken with the IP should be recorded as “dose not changed” or “not applicable” (if the subject 
never received the IP). The IP action of “withdrawn” should not be selected solely as a result of 
the subject’s death. 
8.2.6
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The CRO is responsible for notifying the relevant regulatory authorities as appropriate: USA
central IRBs/EU central ECs of related, unexpected SAEs.
In addition the CRO is responsible for notifying active sites of all related, unexpected SAEs
occurring during all interventional studies across the SHP626-201 program.  
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.


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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan.  
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification are 
to be communicated to the site for resolution.  Only authorized personnel will make corrections 
to the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, IP serum concentrations, 
antibiotics to investigation product, treatment allocation, and IP preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available.  If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.  
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 


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summarizing other study information such as subject disposition, demographics and baseline 
characteristics, IP exposure, and prior and concomitant medications.  The SAP will also include 
a description of how missing, unused and spurious data will be addressed.
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical analysis 
and study conclusions.  
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513). 
9.5
Planned Interim Analysis
Study enrollment will be paused after 92 subjects have been randomized in order for an IA to be 
conducted by an independent DMC after at least 80 subjects have received 24 weeks of 
treatment.  The IA will evaluate the safety, tolerability and efficacy of 3 doses of volixibat each 
compared to PBO. The Interim Analysis Set (IAS; see Section 9.7) will be used for the analyses 
conducted at the IA. The IA will be used to drop one or more doses of volixibat, or to terminate 
the trial.
Decisions about whether or not to continue randomizing to a particular dose following the 
24 week IA should be made in accord with Figure 2 and its associated decision rules.  In the 
figure, a net positive benefit risk assessment implies that the drug is more effective than any 
negative safety concerns.  Effectively, randomization should be discontinued to any dose 
determined to be intolerable or to have a net negative benefit risk.  Hepatic fat fraction as 
measured by MRI is abbreviated HFF in the figure.  The liver enzyme alanine aminotransferase 
is abbreviated ALT.


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Figure 2:
Process Flow for Volixibat Dose Decisions at 24 Week IA
Decision Rules:
If randomization is discontinued to at least one dose, then randomize equally to the remaining 
volixibat dose(s) and PBO.  That is, if two doses are determined to be tolerable and to have a net 
positive benefit risk assessment, then randomization to those two doses (and PBO) should 
continue.  Further, if only one dose is determined to be tolerable and to have a net positive 
benefit risk assessment, then randomization to only that dose (and PBO) should continue.
Otherwise, the choice of doses to which randomization should continue should be made 
according to the following general principles and specific rules which are embodied in Appendix 
6.


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Subjects recruited into the study prior to the IA will continue with the same dosing regimen for 
the duration of the planned study participation. That is, subjects receiving a dose to which 
randomization is stopped at the IA will continue to receive that same dose throughout the course 
of the study, and complete all required assessments. Subjects recruited in the study after 
completion of the IA will be randomized evenly to the remaining dose groups or PBO group by 
IRT.  Subjects will be randomized to at most two volixibat doses as well as to PBO.  Thus, 
depending on the results from the IA, the study may be terminated, or one or more doses of 
volixibat will be discontinued.  If the study is not terminated, subjects will receive a total of 48 
weeks of IP.
9.5.1
Tolerability
Tolerability will be assessed by the number of discontinuations due to any one TEAE.  The most 
common causes of discontinuation seen in healthy human trials were gastrointestinal events, 
most notably, diarrhea, loose stools, increased evacuations, and abdominal pain.  Thus, 
calculations used to determine dropping one or more doses of volixibat in this study were based 
upon the rate of evacuations seen in the Phase 1 trial SHP626-101, as this TEAE was felt to be 
most objectively measured.  The average rate of evacuations was ~ 1.27 per subject per day for 
PBO.  The lowest rate of evacuations on volixibat occurred on 10 mg, and was ~ 1.64 per subject 
per day.  If this frequency of evacuations translates to average numbers of discontinuations, a 
difference of 6 or more discontinuations on volixibat when compared to PBO would occur by 
chance with less than 1% probability.  Consequently, if 6 or more additional subjects treated with 
a specific dose of volixibat discontinue due to any particular TEAE when compared to PBO
(absolute difference) then randomization to that dose will be stopped.  A particular volixibat dose 
will be considered tolerable if fewer than 6 additional subjects discontinue due to any TEAE 
when compared to PBO.  If none of the doses are tolerated, the study will be terminated.   
9.5.2
Efficacy
Efficacy at the IA will be based on reduction of steatosis (as measured change from Baseline in 
HFF on MRI). If a volixibat dose does not achieve efficacy as measured by HFF reduction on 
MRI, change from Baseline in ALT at Week 24 will then be evaluated.  
The sample size of 80 subjects provides 80% power to test for a net difference in HFF (volixibat
dose minus PBO) of 5% at the two-sided 10% significance level.  The net difference of 5% was 
based on the colesevelam clinical trial (Davidson et al. 2010).   The statistical method used to 
test reduction in HFF will be an ANCOVA model which includes change from Baseline as the 
dependent variable, and treatment and baseline HFF as independent variables.  Treatment will be 
a class variable and baseline HFF will be continuous.  Each volixibat dose will be separately 
compared to PBO to assess whether its net reduction is significantly different from zero at the 
10% significance level. A Holm multiplicity adjustment will be applied.  If the dose is 
significantly different from PBO, then that dose will be considered effective at the interim 
assessment.


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If a volixibat dose does not achieve efficacy as measured by HFF reduction on MRI, percent 
change from Baseline in ALT at 24 weeks will be evaluated. If the difference is at least 20% 
when compared to PBO, then that dose will be considered effective at the interim assessment. In 
addition, if multiple doses exhibit a difference of a least 20% when compared to PBO then the 
statistical method used to test reduction in ALT will be an ANCOVA model which includes 
change from Baseline as the dependent variable, and treatment and baseline ALT as independent 
variables. Treatment will be a class variable and baseline ALT will be continuous.  Each 
volixibat dose will be separately compared to PBO to assess whether its net reduction is 
significantly different from zero at the 10% significance level. A Holm multiplicity adjustment 
will be applied.  If the dose is significantly different from PBO, then that dose will be considered 
effective at the interim assessment.
Data Monitoring Committee
An independent DMC will be established to assess safety, tolerability and efficacy during the 
study, as well as to ensure the validity and scientific merit of the trial.  In addition, the DMC will 
evaluate efficacy of different doses of volixibat at the 24 week IA (using the process flow and 
decision rules specified previously).  Based on their evaluation, the DMC will make 
recommendations concerning study discontinuation due to intolerability or futility, or the 
continuation of one or more dose groups to the 48 week liver biopsy.  The DMC will monitor 
ongoing data generated by the study at regular intervals for the duration of the study. Their role 
is to protect the interests of the subjects in the study and of those still to be entered, by review of 
accumulating data generated in the study. 
The roles, responsibilities and rules governing operation of the DMC will be discussed in full in 
a DMC charter.  The DMC charter will define the primary responsibilities of the DMC; guide its 
activities, its relationship with other study components, its membership, and the purpose and 
timings of its meetings.  It will provide the procedures for ensuring confidentiality, formal 
communication, and outline of the content of reports that will be provided by the DMC.  Data 
provided to the DMC will not be considered ‘clean’ until the database is locked.  
Appropriate summary statistics and data listings will be provided to the DMC by an independent 
statistician supported by an independent statistical reporting group not otherwise assigned to the 
study.  
The recommendations made by the DMC to alter the conduct of the study will be forwarded to 
Shire for final decision.  Shire will forward such decisions to regulatory authorities, as 
appropriate.
9.6
Sample Size Calculation and Power Considerations
Primary hypothesis: The proportion of subjects at Week 48 with a reduction of at least 2 points 
without worsening of fibrosis from Baseline NAS differs between at least one volixibat dose and 
PBO.


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Response rates of 21% (PBO) and 45% (active) were reported in the FLINT trial 
(Neuschwander-Tetri et al. 2015) using the same primary end-point of reduction of NAS by at 
least two points (without worsening of fibrosis).   Based on those response rates, 67 subjects per 
group completing the trial are needed for 80% power with a 10% type I error for a study 
comparing two volixibat doses to PBO.  Holm multiplicity adjustment was included in the 
sample size estimate.
Approximately 334 subjects will be screened to enroll 266 subjects to achieve 201 completers. 
After enrollment of at least 80 subjects (20/treatment arm – 3 active and 1 PBO) a 24-week IA
will eliminate at least one dose group based on the criteria provided to the DMC; enrollment will 
continue to include approximately 67 subjects in each of the remaining arms. The sample size 
target for this study is 67 completers in each of the treatment groups (201 total if 3 arms 
continue).  Including an additional 20 subjects to account for one dose dropped at the IA, 221 
subjects are needed.   Therefore, approximately 266 (accounts for 20% of 221 dropping out) 
subjects will be randomized if three arms (2 SHP626 and 1 PBO) continue.  Fewer subjects are 
needed if more than one SHP626 dose is dropped.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Safety Analysis Set will consist of all subjects who take at least 1 dose of randomized IP, 
and have at least 1 post-Baseline safety assessment (eg, coming back for any visit, reporting of 
an AE or reporting the absence of AEs).
The Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have a 
valid scored liver biopsy.
The IAS will consist of all subjects in the Safety Set who have a valid post-baseline hepatic fat 
fraction assessed by MRI and a valid post-baseline ALT at 24 weeks. 
9.8
Efficacy Analyses
All efficacy analyses will be based on the FAS and all statistical tests will be 2-sided hypothesis 
tests performed at the 10% level of significance. Also, all confidence intervals will be 2-sided 
confidence intervals, unless otherwise stated.
9.8.1
Primary Efficacy Endpoint
The primary endpoint is the binary response indicating (yes/no) whether a subject responded at 
Week 48 with a reduction, of at least 2 points without worsening of fibrosis, from baseline NAS. 


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The FAS will be used to assess the primary efficacy endpoint. The proportion of subjects at 
Week 48 with a reduction of at least 2 points without worsening of fibrosis from baseline NAS 
will be analyzed. The difference between a volixibat dose and PBO will be tested with a 
stratified Cochran-Mantel-Haenzel test. The test will be stratified by presence or absence of 
T2DM at baseline and baseline NAS separated into two groups (NAS={4, 5} or NAS={6,7,8}). 
Holm multiplicity adjustment will be applied prior to determining statistical significance at the 
0.1 level.
Sensitivity analyses may also be conducted in addition to the primary analysis.  If the proportion 
of subjects missing the Week 48 liver biopsy reading does not exceed 10%, then no sensitivity 
analyses will be conducted for the primary efficacy endpoint. Otherwise, analyses which explore 
the impact of the missing data on the primary efficacy endpoint will be conducted. These 
sensitivity analyses may compare imputations of the missing values which favor the PBO and/or 
imputations which favor the active.  Further, if the pattern of missing values does not appear 
uniformly distributed among the treatment arms, imputation method(s) based on informative 
missingness may also be performed.  The sensitivity analyses will be detailed in the Statistical 
Analysis Plan.
9.8.2
Secondary Efficacy Endpoints

Change from Baseline to Week 48 in safety and tolerability of volixibat as measured by 
the number of subjects discontinuing treatment due to any one treatment-emergent 
adverse event (TEAE).

Change from Baseline to Week 48 on liver histology as measured by the individual NAS 
components (ballooning, inflammation, steatosis).

Change from Baseline to Week 48 on hepatic steatosis as measured by MRI-HFF for 
subjects included in the IA.

Change from Baseline to Week 48 on liver histology as measured by fibrosis stage.
(NASH CRN system and Ishak)

Resolution of NASH (defined as an overall histologic interpretation of no fatty liver 
disease or simple steatosis without steatohepatitis or isolated steatosis without 
steatohepatitis) without worsening of fibrosis as assessed by liver histology at Week 48.

Change from Baseline to Week 48 on serum liver-related biochemistry as measured by:
o
alanine aminotransferase (ALT)
o
aspartate aminotransferase (AST)
o
alkaline phosphatase (ALP)
o
gamma glutamyl transferase (GGT)


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o
total bilirubin (TB)

Change from Baseline to Week 48 on metabolic indicators as measured by:
o
fasting serum glucose levels
o
insulin levels
o
HbA1c

Change from Baseline to Week 48 on serum lipids measured by:
o
fasting total cholesterol
o
HDL-C
o
LDL-C
o
triglycerides
Descriptive statistics for all secondary endpoints will be presented for each time point at which 
the variable is measured (see Table 1: Schedule of Assessments).
9.8.3
Exploratory Efficacy Endpoints

Change from Baseline to Week 48 on liver histology as measured by the SAF scoring 
components: Steatosis (S), Activity (A), and Fibrosis (F)

Change from Baseline to Week 48 on anthropomorphic measures: 
o
body weight
o
BMI 
o
waist circumference 
o
waist-hip ratio 

Change from Baseline to Week 48 in subjects with T2DM on homeostasis measured by: 
o
Homeostasis model assessment 2-IR (HOMA2-IR) 
o
HOMA2-beta cell function (HOMA2-%B) 

Change from Baseline to Week 48 on the EQ-5D index, a patient-reported-measure of 
HRQL and health status.


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
Change from Baseline to Week 48 on the EQ-5D VAS score.

Change from Baseline to Week 48 in the proportion of subjects reporting having 
problems (no problems, slight problems, moderate problems, severe problems, extreme
problems) with pain/discomfort, mobility, usual-activities, self-care, anxiety/depression 
in the EQ-5D questionnaire
Descriptive statistics for all exploratory endpoints will be presented for each time point at which 
the variable is measured (see Table 1: Schedule of Assessments).
9.9
Safety Analyses
The Safety Set will be used to assess the safety endpoints. 
The number of discontinuations due to any 1 TEAE will be summarized for each treatment 
group. 
The number of events, incidence, and percentage of TEAEs will be presented for each treatment 
group by system organ class, and by the preferred term using the agreed upon version of the 
Medical Dictionary for Regulatory Activities. 
Treatment-emergent AEs will be further summarized by severity.
Adverse events related to the IP, AEs leading to withdrawal, SAEs, and deaths will also be 
summarized. 
Vital signs, ECG findings, and clinical laboratory tests will be summarized for each treatment 
group. Potentially clinically important findings will be summarized. Graphical presentation may 
be used when deemed necessary
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  The 
number of events, incidence, and percentage of TEAEs will be calculated overall, by SOC, by 
preferred term, and by treatment group. Treatment-emergent adverse events will be further 
summarized by severity and relationship to the IP. Adverse events related to the IP, AEs leading 
to withdrawal, SAEs, and deaths will be similarly summarized/listed.
Vital signs, ECG findings, and clinical laboratory tests will be summarized for each treatment 
group. Potentially clinically important findings will be summarized. Graphical presentation may 
be used when deemed necessary.
9.10 Other Analyses
Serum samples to be stored.


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9.10.1
Health-related Quality of Life Analyses

Change from Baseline to Week 48 on the EQ-5D index (Appendix 3). The EQ-5D index 
will be derived using published UK-based preference weights. Univariate descriptive 
statistics and multivariate regression analyses adjusting for selected baseline covariates 
will be undertaken.

Change from Baseline to Week 48 on the EQ-5D VAS score. Univariate descriptive 
statistics and multivariate regression analyses adjusting for selected baseline covariates 
will be undertaken.

Change from Baseline to Week 48 in the proportion of subjects reporting having 
problems (none, slight, moderate, severe, extreme) with pain/discomfort, mobility, usual-
activities, self-care, anxiety/depression in the EQ-5D questionnaire.  Proportions and 
95% confidence intervals will also be generated for the baseline and Week 48 values as 
well as for change from baseline.
9.10.2
Stool Assessment
Stool hardness and number of evacuations will be assessed throughout the study. Stool hardness 
will be assessed for the softest evacuation within 24 hours of each clinic visit using the Bristol 
Stool Chart, a medical aid designed to classify the form of human feces into 7 categories where 
Type 1 is the hardest and Type 7 is the softest. Appendix 7 provides a sample of the Bristol Stool 
Chart. Number of evacuations within the past 24 hours prior to the clinic visit will be recorded 
at specified times as per Table 1. 


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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study.  The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of the IP
for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied to the CRO as necessary.


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10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites.  
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP.  This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason.  
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.do
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 


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qualification.  Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies.  Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document.  The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria.  Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation.  The 
investigator will also return all the IP, containers, and other study materials to the sponsor.  Upon 
study completion, the investigator will provide the sponsor, IRB/EC, and regulatory agency with 
final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Electronic Case Report Forms
eCRFs are supplied by the sponsor and should be handled in accordance with instructions from 
the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. eCRFs must be completed by 
the investigator or designee as stated in the site delegation log.


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All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
All data sent to the sponsor must be endorsed by the investigator.
The CRA/study monitor will verify the contents against the source data per the monitoring plan.  
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
Incorrect entries must be crossed with a single line as to not obscure the original entry.  
Corrections must be made adjacent to the item to be altered, initialed, and dated by an authorized 
investigator or designee as stated in the site delegation log.  Overwriting of this information or 
use of liquid correcting fluid is not allowed.
All data sent to the sponsor must be endorsed by the investigator.
Once the CRA/study monitor has verified the contents of the completed eCRF pages against the 
source data, the duplicate pages are retrieved and forwarded to the study sponsor (or designee) 
for data entry. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents.  The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, images, etc.).  Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.


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Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other 
USA national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor.  The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in the IP; any significant equity 
interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments.  All consent 
documentation must be in accordance with applicable regulations and GCP.  Each subject or the 
subject’s legally-authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally-authorized representative, as applicable. This document may 
require translation into the local language.  Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form which was 
reviewed by the IRB/EC and which received their favorable opinion/approval.  A copy of the 
IRB/EC’s written favorable opinion/approval of these documents must be provided to the 
sponsor, prior to the start of the study unless it is agreed to and documented (abiding by 


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regulatory guidelines and national provisions) prior to study start that another party (ie, sponsor 
or coordinating principal investigator) is responsible for this action.  Additionally, if the IRB/EC 
requires modification of the sample subject information and consent document provided by the 
sponsor, the documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
IP supplies will not be released until the Sponsor or its designee has received written IRB/EC 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions.  The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All USA-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996.  A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the Sponsor or its designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study.  These records and data may, 
in addition, be reviewed by others including the following: independent auditors who validate the 


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data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market volixibat; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed.  The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded.  They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted.  The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative.  Additionally, Shire adheres to external guidelines (eg,
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire.  The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.  The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study.  To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications.  To the extent that the principal investigator has such sole, 
joint or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 


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include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results.  If such a multicenter publication is not submitted to 
a journal for publication by the sponsor within an 18-month period after conclusion, 
abandonment, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section.  The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards.  Participation as an investigator does not confer any rights to 
authorship of publications.


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11.
REFERENCES
Adibi, A., Janghorbani, M., Shayganfar, S. & Amini, M. 2007. First-degree relatives of patients 
with type 2 diabetes mellitus and risk of non-alcoholic Fatty liver disease. Rev Diabet Stud, 4,
236-41.
Angulo, P. 2002. Nonalcoholic fatty liver disease. N Engl J Med, 346, 1221-31.
Assy, N., Kaita, K., Mymin, D., Levy, C., Rosser, B. & Minuk, G. 2000. Fatty infiltration of 
liver in hyperlipidemic patients. Dig Dis Sci, 45, 1929-34.
Bedossa, P. 2012. Lesions in nanolcoholic fatty liver disease. Rev Prat, 62, 1419.
Davidson, M. H., Donovan, J. M., Misir, S. & Jones, M. R. 2010. A 50-week extension study on 
the safety and efficacy of colesevelam in adults with primary hypercholesterolemia. Am J 
Cardiovasc Drugs, 10, 305-14.
Day, C. P. & James, O. F. 1998. Steatohepatitis: a tale of two "hits"? Gastroenterology, 114,
842-5.
Donati, G., Stagni, B., Piscaglia, F., Venturoli, N., Morselli-Labate, A. M., Rasciti, L. & 
Bolondi, L. 2004. Increased prevalence of fatty liver in arterial hypertensive patients with normal 
liver enzymes: role of insulin resistance. Gut, 53, 1020-3.
Halilbasic, E., Claudel, T. & Trauner, M. 2013. Bile acid transporters and regulatory nuclear 
receptors in the liver and beyond. J Hepatol, 58, 155-68.
Hamaguchi, M., Kojima, T., Takeda, N., Nakagawa, T., Taniguchi, H., Fujii, K., Omatsu, T., 
Nakajima, T., Sarui, H., Shimazaki, M., Kato, T., Okuda, J. & Ida, K. 2005. The metabolic 
syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med, 143, 722-8.
Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., 
Ferrell, L. D., Liu, Y. C., Torbenson, M. S., Unalp-Arida, A., Yeh, M., Mccullough, A. J. & 
Sanyal, A. J. 2005. Design and validation of a histological scoring system for nonalcoholic fatty 
liver disease. Hepatology, 41, 1313-21.
Loomba, R., Abraham, M., Unalp, A., Wilson, L., Lavine, J., Doo, E., Bass, N. M. & 
Nonalcoholic Steatohepatitis Clinical Research, N. 2012. Association between diabetes, family 
history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology, 56, 943-51.
Loomba, R., Sirlin, C. B., Ang, B., Bettencourt, R., Jain, R., Salotti, J., Soaft, L., Hooker, J., 
Kono, Y., Bhatt, A., Hernandez, L., Nguyen, P., Noureddin, M., Haufe, W., Hooker, C., Yin, M., 
Ehman, R., Lin, G. Y., Valasek, M. A., Brenner, D. A. & Richards, L. 2015. Ezetimibe for the 
treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and 


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magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology, 61, 1239-
50.
Marchesini, G., Marzocchi, R., Agostini, F. & Bugianesi, E. 2005. Nonalcoholic fatty liver 
disease and the metabolic syndrome. Curr Opin Lipidol, 16, 421-7.
Mathus-Vliegen, L., Toouli, J., Fried, M., Khan, A. G., Garisch, J., Hunt, R., Fedail, S., Stimac, 
D., Lemair, T., Krabshuis, J., Kaufmann, P., Roberts, E. & Riccardi, G. 2012. World 
Gastroenterology Organisation global guidelines on obesity. J Clin Gastroenterol, 46, 555-61.
Miethke, A. G., Zhang, W., Simmons, J., Taylor, A. E., Shi, T., Shanmukhappa, S. K., Karns, R., 
White, S., Jegga, A. G., Lages, C. S., Nkinin, S., Keller, B. T. & Setchell, K. D. 2016. 
Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile 
composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout 
mice. Hepatology, 63, 512-23.
Musso, G., Gambino, R. & Cassader, M. 2013. Cholesterol metabolism and the pathogenesis of 
non-alcoholic steatohepatitis. Prog Lipid Res, 52, 175-91.
N.C.E.P. 2002. Third Report of the National Cholesterol Education Program (NCEP) Expert 
Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult 
Treatment Panel III) final report. Circulation, 106, 3143-421.
Neuschwander-Tetri, B. A. 2005. Nonalcoholic steatohepatitis and the metabolic syndrome. Am 
J Med Sci, 330, 326-35.
Neuschwander-Tetri, B. A., Loomba, R., Sanyal, A. J., Lavine, J. E., Van Natta, M. L., 
Abdelmalek, M. F., Chalasani, N., Dasarathy, S., Diehl, A. M., Hameed, B., Kowdley, K. V., 
Mccullough, A., Terrault, N., Clark, J. M., Tonascia, J., Brunt, E. M., Kleiner, D. E. & Doo, E. 
2015. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic 
steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet, 385, 956-
65.
Pagano, G., Pacini, G., Musso, G., Gambino, R., Mecca, F., Depetris, N., Cassader, M., David, 
E., Cavallo-Perin, P. & Rizzetto, M. 2002. Nonalcoholic steatohepatitis, insulin resistance, and 
metabolic syndrome: further evidence for an etiologic association. Hepatology, 35, 367-72.
Permutt, Z., Le, T. A., Peterson, M. R., Seki, E., Brenner, D. A., Sirlin, C. & Loomba, R. 2012. 
Correlation between liver histology and novel magnetic resonance imaging in adult patients with 
non-alcoholic fatty liver disease - MRI accurately quantifies hepatic steatosis in NAFLD. 
Aliment Pharmacol Ther, 36, 22-9.
Qayyum, A., Goh, J. S., Kakar, S., Yeh, B. M., Merriman, R. B. & Coakley, F. V. 2005. 
Accuracy of liver fat quantification at MR imaging: comparison of out-of-phase gradient-echo 
and fat-saturated fast spin-echo techniques--initial experience. Radiology, 237, 507-11.


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Rao, A., Kosters, A., Mells, J., Keller, B., Yin, H., Banton, S., Li, S., Jones, D. P., Wu, H., 
Dawson, P. & Karpen, S. 2015. Administration of an ileal apical sodium-dependent bile acid 
transporter inhibitor protects against non-alcoholic fatty liver disease in high fat diet-fed mice. 
Hepatology, 62, 217A.
Raptis, D. A., Fischer, M. A., Graf, R., Nanz, D., Weber, A., Moritz, W., Tian, Y., Oberkofler, 
C. E. & Clavien, P. A. 2012. MRI: the new reference standard in quantifying hepatic steatosis? 
Gut, 61, 117-27.
Reeder, S. B., Cruite, I., Hamilton, G. & Sirlin, C. B. 2011. Quantitative Assessment of Liver Fat 
with Magnetic Resonance Imaging and Spectroscopy. J Magn Reson Imaging, 34, 1011-1014.
Reeder, S. B., Hu, H. H. & Sirlin, C. B. 2012. Proton density fat-fraction: a standardized MR-
based biomarker of tissue fat concentration. J Magn Reson Imaging, 36, 1011-4.
Roldan-Valadez, E., Favila, R., Martinez-Lopez, M., Uribe, M., Rios, C. & Mendez-Sanchez, N. 
2010. In vivo 3T spectroscopic quantification of liver fat content in nonalcoholic fatty liver 
disease: Correlation with biochemical method and morphometry. J Hepatol, 53, 732-7.
Sanyal, A. J., Campbell-Sargent, C., Mirshahi, F., Rizzo, W. B., Contos, M. J., Sterling, R. K., 
Luketic, V. A., Shiffman, M. L. & Clore, J. N. 2001. Nonalcoholic steatohepatitis: association of 
insulin resistance and mitochondrial abnormalities. Gastroenterology, 120, 1183-92.
Schwenzer, N. F., Springer, F., Schraml, C., Stefan, N., Machann, J. & Schick, F. 2009. Non-
invasive assessment and quantification of liver steatosis by ultrasound, computed tomography 
and magnetic resonance. J Hepatol, 51, 433-45.
Souza, M. R., Diniz Mde, F., Medeiros-Filho, J. E. & Araujo, M. S. 2012. Metabolic syndrome 
and risk factors for non-alcoholic fatty liver disease. Arq Gastroenterol, 49, 89-96.
Springer, F., Ballweg, V., Schweizer, R., Schick, F., Ranke, M. B., Binder, G. & Ehehalt, S. 
2015. Changes in whole-body fat distribution, intrahepatic lipids, and insulin resistance of obese 
adolescents during a low-level lifestyle intervention. Eur J Pediatr, 174, 1603-12.
Szczepaniak, L. S., Nurenberg, P., Leonard, D., Browning, J. D., Reingold, J. S., Grundy, S., 
Hobbs, H. H. & Dobbins, R. L. 2005. Magnetic resonance spectroscopy to measure hepatic 
triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol 
Endocrinol Metab, 288, E462-8.
Torres, D. M. & Harrison, S. A. 2008. Diagnosis and therapy of nonalcoholic steatohepatitis. 
Gastroenterology, 134, 1682-98.
Torres, D. M., Williams, C. D. & Harrison, S. A. 2012. Features, diagnosis, and treatment of 
nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol, 10, 837-58.


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Urdzik, J., Bjerner, T., Wanders, A., Weis, J., Duraj, F., Haglund, U. & Noren, A. 2012. The 
value of pre-operative magnetic resonance spectroscopy in the assessment of steatohepatitis in 
patients with colorectal liver metastasis. J Hepatol, 56, 640-6.
Vernon, G., Baranova, A. & Younossi, Z. M. 2011. Systematic review: the epidemiology and 
natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. 
Aliment Pharmacol Ther, 34, 274-85.
Williams, C. D., Stengel, J., Asike, M. I., Torres, D. M., Shaw, J., Contreras, M., Landt, C. L. & 
Harrison, S. A. 2011. Prevalence of nonalcoholic fatty liver disease and nonalcoholic 
steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a 
prospective study. Gastroenterology, 140, 124-31.
World Gastroenterology Organisation 2012. World Gastroenterology Organisation Global 
Guidelines: Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis.


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12.
APPENDICES


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APPENDIX 1
PROTOCOL HISTORY 
Document
Date
Global/Country/Site Specific
Original Protocol
24 February 2016
Global


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APPENDIX 2
FATTY LIVER DISEASE HISTOLOGY SCORING
Diagnosis: NASH, Suspicious/Borderline NASH (type a or b), NAFLD, Not NAFLD
NAS SCORING
Steatosis
0       <5%
1        5-33%
2        34-66%
3        67-100%
Lobular Inflammation
0        no foci
1        < 2 foci per 200x field
2        2-4 foci per 200x field
3        > 4 foci per 200 x field
Ballooning
0       None
1       Rare or diagnostically borderline
2       Many or Prominent ballooned hepatocytes
            SAF SCORING
Steatosis
0         <5%
1        5-33%
2        34-66%
3        67-100%
Ballooning
0        normal hepatocytes with  cuboidal shape and pink cytoplasm
1       clusters of hepatocytes with rounded shape and pale cytoplasm usually  reticulated      
2       grade 1 plus enlarged hepatocytes, 2 x bigger than normal cells. 
Lobular Inflammation
0       none
1       < 2 foci per 200x field
2       >2 foci per 200x field
Steatosis 1,2,3 + Ballooning 1,2 + Lobular Inflammation  1,2 = NASH
Steatosis 1,2,3 +Ballooning 0 + Lobular Inflammation 0,1,2 = NAFLD
Steatosis 1,2,3 + Ballooning 1,2 + Lobular 0 = NAFLD
Steatosis 0 = no NAFLD
FIBROSIS SCORE
None
0
Mild zone 3 perisinusoidal (requires trichrome)
1a
Moderate Zone 3 perisinusoidal (visible on H&E)
1b
Portal/periportal only
1c
Portal, periportal and perisinusoidal
2
Bridging
3
Cirrhosis
4
References: Kleiner et al. 2005; Bedossa 2012


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ADDITIONAL SCORING FEATURES
Expanded Balloon Score
0: None
1: Few Non classic
2: Few Classic
3. Many Classic
4: Severe Classic
Portal Inflammation
0: None
1: Minimal
2: Mild
3: More than Mild
Megamitochondria
0: None
1: Present
Acidophil Bodies
0: None or rare
1: Present
For stage 2 or greater fibrosis
Portal Predominant
Central Predominant
No predominance
Steatosis Zone
Zone 1 predominant
Zone 3 predominant
Azonal
Panacinar
Glycogenosis
None
Focal
Diffuse


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APPENDIX 3
EQ-5D-5L HEALTH QUESTIONNAIRE
UK SAMPLE ONLY, NOT FOR OFFICIAL USE


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Under each heading, piease tick the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems in walking about 
I have sJight problems in walking about 
I have moderate probJems in walking about 
I have severe prob~ms in walking about 
I am unable to walk about 
SELF-CARE 
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate probtems washing or dressing mysetf 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, housework, famHy or 
leisure activities) 
I have no problems doing my usual activities 
I have sJtght problems doing my usual activities 
I have moderate problems doing my usual activities 
I have severe probtems doing my usuaJ activities 
I am unable to do my usual activities 
PAIN I DISCOMFORT 
I have no pain or discomfort 
I have sHght pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
ANXIETY I DEPRESSION 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderatety anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
2 
(.t( (&jish) 0 2009 EuroQol Grocf> E~N 
;. a llade n>arlc of file EuroQol Grocf> 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 


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• 
We would like to know how good or bad your health is TODAY. 
• 
This scale is numbered from 0 to 100. 
• 
100 means the best health you can imagine. 
0 means the worst heafth you can imagine. 
• 
Mar1t an X on the scale to indicate how your heafth is TODAY. 
• 
Now, please write the number you marked on the scate in the box 
below. 
YOUR HEALTH TODAY = D 
3 
t.M (Entjish)C~ 2.()()fl EIIOQol <iroq:) EQ.SDno i:sa trademark clfhe EJXOQol Gn:ql 
1he best ~alth 
you can imagine 
100 
95 
go 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
The worst health 
you can imagine 
15 
10 
5 
0 


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APPENDIX 4
CRITERIA TO ASSESS SEVERITY OF LIVER-
RELATED ADVERSE EVENTS
Parameter
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
ALT
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
AST
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
Alkaline 
Phosphatase
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
GGT
<1.25
1.25-2.5
>2.5-5.0
>5.0-10
>10
Bilirubin
Normal
>1.0-1.5
>1.5-2.5
>2.5-5
>5
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = 
gamma glutamyl transferase. 
NOTE: Values expressed as multiples of the upper limit of the normal range (ULN).


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APPENDIX 5
STOPPING RULES FOR LIVER-RELATED BLOOD 
TESTS

ALT or AST >6xULN (confirmed with repeat within 24hrs)

ALT or AST >5xULN for more than 2 weeks 

ALT or AST >3xULN and (TBL >2xULN or INR >1.5) 

ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
If ALT or AST elevations do not fall within the above parameters, but are > 4 ×ULN 
subject should remain on study drug with close observation which includes: 
1. Immediately contacting the Shire medical monitor. 
2. Repeating liver enzyme and serum bilirubin tests two or three times weekly. 
Frequency of retesting can decrease to once a week or less if abnormalities stabilize or 
the trial drug has been discontinued and the subject is asymptomatic. 
3. Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
4. Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets. 
5. Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease., or other disease at the 
discretion of the investigator
6. Obtaining a history of exposure to environmental chemical agents. 
7. Obtaining additional tests to evaluate liver function, as appropriate (eg, INR, direct 
bilirubin). 


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APPENDIX 6
GENERAL PRINCIPLES AND SPECIFIC RULES FOR 
DOSE DISCONTINUATION AT 24 WEEK INTERIM 
ANALYSIS – GUIDANCE FOR DATA MONITORING 
COMMITTEE ONLY
General Principles
A net positive benefit risk assessment on HFF takes precedence over effectiveness on ALT.  
Covers the situations when 2 doses show net positive benefit risk on HFF and 1 dose shows 
positive or net positive benefit risk on ALT.
Choose the dose(s) that have the largest difference in dose from amongst those exhibiting a net 
positive benefit risk.
As a minimally absorbed drug, volixibat at higher doses is less likely than absorbed drugs to 
exhibit additional TEAEs in large longer duration trials that were not seen in smaller shorter 
trials.
Specific Rules
If 3 doses are determined to be tolerable and to have a net positive benefit risk assessment on 
HFF, then Scheffe’s statistical multiple comparisons test should be applied to the three HFF 
values.  The test will result in one of eighteen possibilities.  The 18 possible cases are detailed 
below in Table 1.  For example, if the multiple comparisons test indicates that the low dose (L) 
is less effective on HFF than the medium and high doses (M and H) then the medium and high 
doses should be selected for continued randomization from among the three doses.  This case is 
depicted as case 1 in the table.  If doses are indistinguishable on HFF then use Scheffe’s test 
on ALT (case 2).
Table 1  
Possible Results from Applying a Multiple Comparison Test to Three Doses
based on Change from Baseline in Hepatic Fat Fraction 
Case
Results
Action
1
L <  M   H
M, H
2
L    M   H
If can’t decide using ALT, then L,H
3
L >  M  H
L, If can’t decide using ALT, then L,H
4
L   M  > H
L, M
5
L  >  M >  H
L, M
6
L  < M <  H
M, H


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Table 1  
Possible Results from Applying a Multiple Comparison Test to Three Doses
based on Change from Baseline in Hepatic Fat Fraction 
Case
Results
Action
7
L   M <  H
H, If can’t decide using ALT, then L,H
8
M <  L    H
L, H
9
M >  L    H
M, If can’t decide using ALT, then H
10
M L  >  H
L, M
11
M >  L   > H
L, M
12
M <  L  <  H
L, H
13
M L  <  H
H, If can’t decide using ALT, then M
14
L  <  H   M
M, H
15
L >  H  M
L, If can’t decide using ALT, then H
16
L  H  > M
L, H
17
L >  H >  M
L, H
18
L <  H <  M
M, H
L = low dose (5 mg), M = medium dose (10 mg), H = high dose (20 mg)
If 3 doses are determined to be tolerable and to have a net positive benefit risk assessment on 
only ALT, then Scheffe’s statistical multiple comparison test should be applied to the three 
ALT values.  The test will result in one of eighteen possibilities.  The 18 possible cases are 
detailed below in Table 2.  For example, if the multiple comparison test indicates that the low 
dose (L), medium dose (M) and high dose (H) are indistinguishably effective on ALT, then the 
low and high dose should be selected.  This case is depicted as case 2 in the table.  


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Table 2 
Possible Results from Applying a Multiple Comparison Test to Three Doses 
based on Change from Baseline in ALT
Case
Results
Action
1
L <  M   H
M, H
2
L    M   H
L,H
3
L >  M  H
L and H
4
L   M  > H
L, M
5
L  >  M >  H
L, M
6
L  < M <  H
M, H
7
L   M <  H
H, L
8
M <  L    H
L, H
9
M >  L    H
M, H
10
M L  >  H
L, M
11
M >  L   > H
L, M
12
M <  L  <  H
L, H
13
M L  <  H
H, L
14
L  <  H   M
M, H
15
L >  H  M
L, H
16
L  H  > M
L, H
17
L >  H >  M
L, H
18
L <  H <  M
M, H
L = low dose (5 mg), M = medium dose (10 mg), H = high dose (20 mg)
If three doses are tolerable and effective and only one of them is tolerable and exhibits 
effectiveness on HFF, then randomization to that dose should continue.  One of the remaining 
doses which are tolerable and effective only on ALT should be chosen based on a Scheffe’s 
multiple comparisons test for ALT.  If neither of the remaining two separates from the other 
with respect to ALT, then randomization should continue to the highest dose of the remaining 
two active doses (and PBO).


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APPENDIX 7
BRISTOL STOOL CHART

SAP_000.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
SHP626-201 
Protocol Title: 
A Phase 2 Double-Blind, Randomized, Placebo-
controlled, Dose-finding Study to Evaluate the Safety, 
Tolerability and Efficacy of Volixibat Potassium, an 
Apical Sodium-Dependent Bile Acid Transporter 
Inhibitor (ASBTi) in Adults with Nonalcoholic 
Steatohepatitis (NASH) 
Drug: 
Volixibat potassium (SHP626) 
Sponsor:  
Shire Development Inc.  
Shire Human Genetic Therapies, Inc. 
300 Shire Way 
Lexington, MA 02421 USA  
 
Version No. and Date 
Version 2.0, Date 26 July 2018 
 
 
Version No: 
Document History 
Description of Update 
Author(s) 
Effective Date 
Version 0.1  
Draft version 
Ramesh 
Vishwakarma  
 
18Apr2017 
Version 0.2  
Updates for client comments  
David Raj      
 
18Aug2017 
Version 0.3 
 
Updates for client comments (Final 
Cycle 
Review) 
and 
Protocol 
Amendment 4 
David Raj      
 
20Oct2017 


Version 1.0 
Updates for client comments and ToC 
updates, up-version for signoff 
David Raj      
 
21Nov2017 
Version 2.0 
Updates for Final Analyses for 
abbreviated Clinical Study Report 
Yi Chen 
26Jul2018 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 3 
LIST OF TABLES ...................................................................................................................... 5 
ABBREVIATIONS .................................................................................................................... 6 
1. 
INTRODUCTION .......................................................................................................... 7 
2. 
STUDY DESIGN ........................................................................................................... 8 
3. 
STUDY OBJECTIVES .................................................................................................. 9 
4. 
SUBJECT POPULATION SETS ................................................................................. 10 
4.1 
All Screened Set ........................................................................................................... 10 
4.2 
Randomized Set ............................................................................................................ 10 
4.3 
Safety Analysis Set ....................................................................................................... 10 
4.4 
Full Analysis Set .......................................................................................................... 10 
4.5 
Interim Analysis Set ..................................................................................................... 10 
4.6 
Pharmacodynamic (PD) Analysis Set .......................................................................... 10 
5. 
SUBJECT DISPOSITION ........................................................................................... 11 
6. 
PROTOCOL DEVIATIONS ........................................................................................ 12 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 13 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ............................. 15 
8.1 
Exposure to Investigational product ............................................................................. 15 
8.2 
Measurement of Treatment Compliance ...................................................................... 15 
9. 
PRIOR AND CONCOMITANT MEDICATION AND THERAPIES ....................... 17 
10. 
SAFETY ANALYSES ................................................................................................. 18 
10.1 
Adverse Events ............................................................................................................. 18 
10.2 
Clinical Laboratory Variables ...................................................................................... 20 
10.3 
Vital Signs .................................................................................................................... 27 
10.4 
Electrocardiogram (ECG) ............................................................................................. 27 
10.5 
Other Safety Variables ................................................................................................. 28 
10.5.1 Bristol Stool Chart ........................................................................................................ 28 


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11. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES ................................................................................................................. 30 
11.1    Pharmacokinetics Population and Pharmacodynamics Population ............................... 30 
11.2    Pharmacokinetic Methods ............................................................................................. 30 
11.3    Statistical Analysis of Pharmacokinetic Data ................................................................ 30 
11.4    Pharmacodynamic Methods........................................................................................... 30 
11.5    Statistical Analysis of Pharmacodynamic Data ............................................................. 30 
12. 
OTHER ANALYSES ................................................................................................... 30 
12.1 
HEALTH-RELATED QUALITY OF LIFE ANALYSES .......................................... 30 
13. 
COMPUTER METHODS ............................................................................................ 30 
14. 
DATA HANDLING CONVENTIONS ....................................................................... 31 
14.1 
General Data Reporting Conventions ........................................................................... 31 
14.2 
Derived Efficacy Endpoints ......................................................................................... 31 
14.3 
Association of Early Termination Assessments to Scheduled Visits ........................... 32 
14.4 
Repeated or Unscheduled Assessments of Safety Parameters ..................................... 32 
14.5 
Missing Date of Investigational Product ...................................................................... 33 
14.6 
Missing Date Information for Prior or Concomitant Medications ............................... 33 
14.6.1 Incomplete Start Date ............................................................................................ 33 
14.6.2 Incomplete Stop Date ............................................................................................ 34 
14.7 
Missing Date Information for Adverse Events ............................................................. 36 
14.7.1 Incomplete Start Date ............................................................................................ 36 
14.7.2 Incomplete Stop Date ............................................................................................ 36 
14.8 
Missing Severity Assessment for Adverse Events ....................................................... 36 
14.9 
Missing Relationship to Investigation Product for Adverse Events ............................. 36 
14.10 Character Values of Clinical Laboratory Variables ..................................................... 37 
15. 
APPENDIX .................................................................................................................. 38 
16. 
REFERENCES ............................................................................................................. 39 
17. 
TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS .................... 40 
17.1 
Tables ........................................................................................................................... 40 
17.2 
Listings ......................................................................................................................... 42 


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LIST OF TABLES 
Table 1: Clinical Laboratory Evaluations ............................................................................ 20 
Table 2: Criteria for Potentially Clinically Important Laboratory Tests ......................... 23 
Table 3: Criteria for Potentially Clinically Significant Vital Signs ................................... 27 
Table 4: Criteria for Potentially Clinically Important ECG values .................................. 28 


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 ABBREVIATIONS 
 
AE 
Adverse event 
ALP  
Alkaline phosphatase 
ALT  
Alanine aminotransferase 
BMI 
Body mass index 
DMC 
Data monitoring committee 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
FoTA 
Final on Treatment Assessment 
HbA1c 
Hemoglobin A1c 
HFF 
Hepatic fat fraction 
IA  
Interim analysis 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAS  
NAFLD activity score 
NAFLD  
Nonalcoholic Fatty Liver Disease 
NASH  
Nonalcoholic steatohepatitis 
NASH CRN 
NASH Clinical Research Network 
OC 
Observed cases 
PBO 
Placebo 
PCI 
potentially clinically important 
PD 
Pharmacodynamic 
QTcB 
QT Interval Corrected for Heart Rate using Bazett’s Formula 
QTcF 
QT Interval Corrected for Heart Rate using Fridericia’s Formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System organ class 
TEAE  
Treatment-emergent adverse event 
TFLs  
Tables, Figures, and Listings 
T2DM 
Type 2 Diabetes Mellitus 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) is based on the approved final study Protocol SHP626-201 
Amendment 4 dated 25 Aug 2017. The plan provides a technical and detailed elaboration of 
the statistical analyses of safety, tolerability, and efficacy of volixibat in adults with 
nonalcoholic steatohepatitis (NASH). The specifications for tables, figures, and listings 
(TFLs) will be included in a separate document.  
On Jun. 6th, 2018, the Data Monitoring Committee (DMC) for the SHP626-201 study 
recommended that the study be terminated after determining that no dose of volixibat was 
effective based on the predefined interim analysis criteria set for week-24 MRI PDFF and 
ALT. On Jun. 7th, 2018, the Shire Unblinded DMC Recommendation Review Team 
(Unblinded DMC RRT) reviewed the IA data and concurred with the DMC recommendation 
of SHP626-201 study termination. 
As a result of the termination of the SHP626-201 study, an abbreviated clinical study report 
(CSR) will be written based on the results of the statistical analyses planned within this SAP. 
This SAP will not be used for any other analyses. 


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2. 
STUDY DESIGN  
Refer to study Protocol SHP626-201 Amendment 4 dated 25 Aug 2017 for details on study 
design. 
 
 


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3. 
STUDY OBJECTIVES 
Refer to study Protocol SHP626-201 Amendment 4 dated 25 Aug 2017 for details on study 
objectives. 
 
 


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4. 
SUBJECT POPULATION SETS 
4.1 
All Screened Set  
The Screened Set will consist of all subjects who have signed an informed consent. 
4.2 
Randomized Set  
The Randomized Set will consist of all subjects in the Screened Set who have been 
randomized into the study. 
4.3 
Safety Analysis Set  
The Safety Analysis Set will consist of all subjects who take at least 1 dose of randomized IP, 
and have at least 1 post-baseline safety assessment (e.g., coming back for any visit, reporting 
of an AE or reporting the absence of AEs). 
4.4 
Full Analysis Set  
The Full Analysis Set (FAS) will consist of all subjects in the safety analysis set who have at 
least 1 post-baseline efficacy assessment (e.g., MRI, liver biopsy, serum liver-related 
biochemistry measurement). 
4.5 
Interim Analysis Set  
The Interim Analysis Set (IAS) will consist of all subjects in the safety analysis set who have 
both baseline and scheduled Week 24 efficacy assessment (MRI and ALT biochemistry 
measurement) at the data cut time of the IA. 
4.6 
Pharmacodynamic (PD) Analysis Set  
The PD Set will consist of all subjects who receive the IP and for whom at least 1 post first 
dose PD blood sample is collected. 
 
 


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5. 
SUBJECT DISPOSITION 
The number of subjects included in each subject set (i.e., Screened, Safety, Randomized, 
FAS, Interim, and Pharmacodynamic) will be summarized by treatment group. 
A listing of all screen failures (i.e., subjects who were screened but not randomized) will be 
presented along with reasons for screen fail and details of any AEs.   
 The number and percentage of subjects who completed and prematurely discontinued during 
the study will be presented for each treatment group and overall for safety analysis set 
subjects. Reasons for premature discontinuation from the study as recorded on the termination 
page of the eCRF will be summarized (number and percentage) by treatment group for the 
safety analysis set. All subjects who prematurely discontinued from the study will be listed by 
discontinuation reason for the randomized set.  
The number of subjects enrolled, randomized and completed will be tabulated by site and 
country.  In addition, the duration of enrollment, in days, will be summarized for each site, 
country, and overall.  Duration of enrollment will be calculated as (last date of contact for any 
subject at that site - the first date of informed consent for any subject at that site + 1). 
A listing for subject disposition and study analysis sets will be produced for all randomized 
analysis set. 
 
 
 
 
 
 


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6. 
PROTOCOL DEVIATIONS 
A full list of protocol deviations will be compiled and reviewed by the clinical team to 
identify key versus non-key deviations before final database lock. For deviations at study 
entry, patients will be assessed against the inclusion and exclusion criteria of the protocol. For 
on-study deviations, compliance with the protocol will be examined using blinded review of 
the database with regard to prohibited therapies, timing and availability of planned 
assessments. All protocol deviation data will be listed.  
 


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7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for the Safety Analysis Set. Baseline will be determined using the 
last observation collected before the first dose of investigational product. 
The following demographic and baseline characteristics will be summarized in the tables: age, 
gender, ethnicity, race, weight, height, BMI, BMI category (<18.5, 18.5 - 25, 25 - 30 and 
>=30), waist circumference, hip circumference, waist to hip ratio, smoking history, baseline 
T2DM, NAS ={6, 7, 8} or NAS = {4, 5}, NAS (4, 5, 6, 7, 8), NAS, individual NAS 
components (steatosis, lobular inflammation, ballooning), SAF score, individual SAF 
components (steatosis, ballooning, lobular inflammation), fibrosis score, magnetic resonance 
imaging (MRI) hepatic proton density fat fraction (PDFF),  expanded balloon score, portal 
inflammation, megamitochondria, acidophil bodies, fibrosis location if ≥ stage 2, steatosis 
zone, glycogenosis. Continuous variables will be summarized by descriptive statistics 
including number of subjects, mean, standard deviation (SD), median, minimum, and 
maximum. Categorical variables will be summarized by the number of subjects in each 
category and the percentage of subjects out of the total in the corresponding analysis set. 
Age will be calculated as the difference between date of birth and date of informed consent, 
rounded down to the last whole year. In the cases where there is a partial date of birth, if only 
day of the month is missing then the day will be imputed as 15, if both the day and month are 
missing then the day will be imputed as 1 and the month will be imputed as 7 (July). 
Height and weight will be collected and used to calculate BMI using the following formula: 
BMI =
Weight [Kg]
[Height (m) ∗Height(m)] 
BMI should be rounded to 1 decimal place for reporting purposes. 


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Waist to hip ratio is calculated as waist measurement divided by hip measurement (waist 
(cm) / hip (cm)). Waist to hip ratio should be rounded to 2 decimal places for reporting 
purposes. 
A listing will be created to show all the demographic and baseline characteristics for each 
Safety Analysis Set subject.  
Medical history will also be listed for the Safety Analysis Set.  
Smoking history will be listed for the Safety Analysis Set. 
 
 


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8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
Exposure to Investigational product  
Exposure to double-blind investigational product for the Safety Analysis Set will be 
summarized with descriptive statistics (n, mean, SD, minimum, median, and maximum) and 
presented by treatment group. Exposure and compliance to investigational product will be 
listed for the Safety Analysis Set. The following will be calculated for the investigational 
product: 
• Treatment duration, which is calculated as the number of days from the date of first 
dose of double-blind investigational product taken to the date of the last dose of 
double-blind investigational product taken, inclusively. Investigators are allowed to 
interrupt the study treatment to allow adverse events to resolve, if necessary.  Any 
drug interruption will be subtracted off the treatment duration above to get the final 
treatment duration. Treatment duration will be presented as the number of weeks in 
the summary tables. 
• Total dose, which is calculated as (total dispensed – total returned) * xxmg. 
• The average daily dose will be calculated as total dose from above / duration of study 
drug exposure in days. 
8.2 
Measurement of Treatment Compliance 
Investigational product dosing compliance for a specified period is defined as the total 
number of capsules actually taken by a subject during that period divided by the number of 
capsules expected to be taken during the same period multiplied by 100.  The total number of 
capsules actually taken is calculated by the total number of capsules dispensed minus the 
number of capsules returned.  If a blister pack is not returned, the number of capsules returned 
for that blister pack will be imputed to zero.  The number of capsules expected to be taken is 
calculated as the number of days that subject was in the particular period multiplied by the 
number of capsules to be taken per day during that period.  The investigational treatment 
compliance over the entire study will be therefore calculated using the formula: 100 × [(total 


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number of capsules dispensed) – (total number of capsules returned)]/ (total number of 
capsules planned to be taken per day × duration of study drug exposure in days). The 
investigational treatment compliance will be categorized as < 80, 80-120, and > 120% and the 
number and percentage of patients in the Safety Analysis Set will be presented by treatment 
group. 


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9. 
PRIOR AND CONCOMITANT MEDICATION AND THERAPIES  
Version WHODRUG Jun_2016_DDE (Enhanced) of the World Health Organization (WHO) 
drug dictionary will be used to classify prior and concomitant medications and therapies by 
therapeutic class.  
Prior medication/therapy is defined as any medication/therapy received within 30 days of the 
date of first dose of investigational product.  Concomitant medication/therapy is defined as all 
treatment taken between the dates of the first dose of the IP and the end of the follow-up 
period, inclusive. Any medication with a start date after the end of follow-up period will not 
be considered a concomitant medication.  
All prior, concomitant medications and therapies will be listed. 
 
. 
 
 
 


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10. 
SAFETY ANALYSES 
The safety analysis will be performed by treatment using the safety analysis set. Safety 
variables include AEs, clinical laboratory variables, vital signs, and ECG variables. For each 
safety variable, the last value collected before the first dose of double-blind investigational 
product will be used as baseline for all analyses of that safety variable. A Final on-Treatment 
Assessment (FoTA) will be defined as the last valid assessment obtained after Baseline and 
whilst on investigational product and will be summarized in addition to all scheduled visits. 
No inferential statistical analyses of safety endpoints will be performed.  
10.1 
Adverse Events  
Adverse events will be coded using Version 19.0 of the Medical Dictionary for Regulatory 
Activities (MedDRA).  
An AE (classified by preferred term) that occurs during the Double-blind Evaluation Phase or 
Follow-up Phase will be considered a TEAE if it has a start date on or after the first dose of 
double-blind investigational product and no later than the follow-up visit, or it has a start date 
before the date of the first dose of double-blind investigational product, but increases in 
severity on or after the date of the first dose of double-blind investigational product and no 
later than the follow-up visit. If more than 1 AE with the same preferred term is reported 
before the date of the first dose of double-blind investigational product, then the AE with the 
greatest severity will be used as the benchmark for comparison to the AEs occurring during 
the Double-blind Evaluation Phase or Follow-up Phase under the preferred term.  
An overall summary of the number of subjects with TEAEs will be presented by treatment, 
including the number and percentage of subjects and absolute count of events for:  
• Any TEAE,  
• Any serious TEAE,  
• Any TEAE related to investigational product in the opinion of the investigator,  
• Any serious TEAE related to investigational product in the opinion of the investigator,  


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• Any TEAE leading to withdrawal of investigational product,  
• Any severe TEAE,  
• Any related severe TEAE 
• Any TEAE leading to death 
The number and percentage of subjects reporting TEAEs in each treatment group will be 
tabulated in the following ways:  
• By System Organ Class (SOC) and preferred term;  
• By Preferred term  
• By SOC, preferred term, and maximum severity,  
• Serious TEAEs by SOC and preferred term,  
• TEAEs related to investigational product in the opinion of the investigator by SOC 
and preferred term  
• TEAEs leading to withdrawal of investigational product (IP) by SOC and preferred 
term  
If more than 1 AE occurs with the same preferred term for the same subject, then the subject 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarization by severity and by relationship to investigational product. 
The overall frequency will be considered for sorting purposes for the tables with SOC and PT. 
In addition, for treatment emergent Diarrhea AEs the following will be summarized by 
treatment group: relative onset day, counts and percentages of events per subject, events 
treated with medication, outcome, drug withdrawn, duration of individual events (in days), 
duration of individual events treated with medication (in days), duration of individual events 
not treated with medication (in days), severity of diarrhea AEs, and worst severity of diarrhea 
AEs. 


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The incidence and prevalence of treatment emergent Diarrhea AEs will be summarized and 
plotted by study week for each treatment group. In addition a figure of all Diarrhea AEs over 
time will be presented displaying the severity of AEs, duration of AEs, and medication given. 
All information about AEs collected on the eCRF will be listed alongside the treatment, 
preferred term, and SOC. For Serious AEs, deaths, AEs related to the investigational product, 
and TEAEs leading to study discontinuation, a separate listing will also be provided. 
10.2 
Clinical Laboratory Variables 
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline at 
each post-baseline visit and at the FoTA visit for quantitative variables will be presented by 
treatment group for the clinical laboratory parameters in Table 1. A summary of liver enzyme 
elevations at each post-baseline visit, the FoTa visit, and overall post-baseline will be 
presented by treatment group for AST, ALT, and total bilirubin. The clinical laboratory test 
results will be listed for all subjects. The Evaluation of Drug Induced Serious Hepatotoxicity 
(eDISH) graph will also be provided for total bilirubin vs. ALT. Each point in the figure 
should represent a unique subject’s peak serum ALT and peak serum total bilirubin (TB) 
values. Peak serum ALT is shown along the x-axis and peak TB is shown along the y-axis as 
x-fold upper limits of normal (ULN) on a log scale. The individual subject time course of 
ALT, AST, ALP, GGT and Total Bilirubin for Subjects with a Post-baseline ALT > 3xULN 
or Total Bilirubin > 2xULN will also be presented graphically (Figure 4.6.9.1). Subjects with 
Liver Enzyme Elevations: AST, ALT, ALP, GGT and Bilirubin will also be listed. 
Table 1: Clinical Laboratory Evaluations 
Biochemistry  
Albumin (ALB) 
 
Alkaline phosphatase (ALP) 
Lactate dehydrogenase (LDH) 
Alanine aminotransferase (ALT; 
SGPT) 
Protein 
Aspartate aminotransferase 
(AST; SGOT) 
Magnesium (Mg) 
Blood urea nitrogen (BUN) 
Potassium (K) 
C4 
Uric acid 


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Calcium (Ca) 
Sodium (Na) 
 Chloride (Cl) 
Bicarbonate (CO2) 
Creatinine 
Gamma glutamyl transferase (GGT) 
Creatine kinase 
Glucose 
Phosphate (P) 
Total and direct bilirubin 
Coagulation 
Activated partial thromboplastin 
time 
International normalized ratio 
Prothrombin time 
 
Lipid Panel 
Total Cholesterol  
HDL Cholesterol  
LDL Cholesterol  
Triglycerides 
Endocrinology 
Triodothyronine (T3) 
Thyroid-stimulating hormone (TSH) 
Hematology 
Hemoglobin  
Red blood cell (RBC)  
Hematocrit 
White blood cell (WBC) count with 
differential 
Mean corpuscular hemoglobin 
(MCH) 
Mean corpuscular volume (MCV) 
Platelets  
Prothrombin time (PT) 
Activated partial thromboplastin 
time (aPTT) 
International normalized ratio (INR) 
Urinalysis 
Appearance (clarity and color) 
Microscopic examination of sediment 
 
Bilirubin 
 
Nitrite 
 
Blood 
 
pH 
 
Glucose 
 
Protein 
 
Ketones 
 
Specific gravity 
 
Leukocyte esterase 
Oxalate 
Urobilinogen 
 
Other Lab Tests Vitamin A 
Vitamin D 


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Vitamin E 
HbA1c 
HOMA-IR 
HOMA-%B 
 
Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 2. A supportive listing of subjects with post-baseline 
PCI values will be provided including the subject number, site, baseline, and post-baseline 
values. 
 


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Table 2: Criteria for Potentially Clinically Important Laboratory Tests  
Test Name  
PCI Criteria 
Chemistry Panel 
Albumin 
 <3g/dl 
Alkaline phosphatase (ALP) 
 >5 x ULN  
Transaminase, SGOT, AST 
 >5 x ULN 
Transaminase, SGPT, ALT 
 >5 x ULN 
ALT or AST in combination with other events (1) ALT or AST >3xULN and (Total 
Bilirubin >2xULN or INR >1.5) at same 
visit 
or 
(2) ALT or AST >3xULN with the 
appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%) at 
same visit 
Blood Urea nitrogen (BUN) 
 >2.5 x ULN* (or alternatively H 
>30mg/dl**) 
Calcium 
 <8mg/dl or >11.5mg/dl 
Bicarbonate 
 <20 mEq/L  or >30  mEq/L   
Chloride 
 <90mEq/L or >110mEq/L 
Creatinine, serum 
 >1.5 x ULN (or alternatively H >2mg/dl**) 
Creatine Kinase 
 >1.5 x ULN 
Gamma Glutamyl Transpeptidase (GGT) 
 >5 x ULN 
Glucose, serum  
 <55mg/dl or >160mg/dl 


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Lactate dehydrogenase (LDH) 
 >3 x ULN* 
Magnesium 
<1.233mEq/L or >1.997mEq/L 
Phosphorus, inorganic 
 <2.5mg/dl or >7.0mg/dl**  
Potassium, serum/plasma 
 <3mEq/L (grade 3) or >5.5mEq/L 
Sodium 
 <130mEq/L (grade 3) or >150mEq/L 
Bilirubin, total 
 >2.0 x ULN 
Direct bilirubin 
 >2.0 x ULN 
Total protein, plasma or serum 
 <5g/dl* or >9g/dl* 
Uric acid, serum / Urate 
 >8mg/dl 
Endocrinology  Panel 
Free T3/ Triodothyronine 
 < 1.4 pg/mL or > 7.5 pg/mL 
Thyroid Stimulating Hormone (TSH) / 
Thyrotropin 
 <0.35 mIU/L or >6 mIU/L 
Lipid  Panel 
Total Cholesterol 
 <100mg/dL or ≥300mg/dl 
HDL Cholesterol 
 ≤40mg/dL 
LDL Cholesterol 
 <50mg/dL or ≥150mg/dl 
Triglycerides 
 >400mg/dL 
Other Chemistry Tests 
Hemoglobin A1c 
 >0.09 Fraction of 1 
Vitamin D, 25 Hydroxy 
 <12ng/mL 


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Retinol; Vitamin A 
  
<1.0 x LLN 
AlphaTocopherol 
 <1.0 x LLN 
 
Coagulation 
Activated partial thromboplastin time 
 >1.3 x ULN 
International normalized ratio 
 >1.3 
Prothrombin time 
 >1.3 x ULN 
Hematology 
Hemoglobin (HgB.) 
 <10g/dl 
Hematocrit  
 <0.30 Fraction of 1 or >0.50 Fraction of 1 
Mean Corpuscular Hemoglobin (MCH)~ 
 <27pg or >32pg 
Mean Corpuscular Volume (MCV)~ 
 <70fL or >110 fL 
Platelet count 
 <75 x 109/L or >500 x 109/L  
Red Blood Cells (RBC) / Erythrocytes 
 male:  
<2.5 x1012/L 
 female: 
 <2.0 x1012/L 
White Blood Cell Count (WBC) / Leukocytes  <3 x 109/L or >16 x 109/L 
Neutrophils (absolute)  
 <1.3x109/L 
Neutrophils/Leukocytes 
 <0.15 Fraction of 1 
Eosinophils/Leukocytes 
 <0.10 Fraction of 1 


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Basophils/Leukocytes 
 <0.15 Fraction of 1 
Lymphocytes/Leukocytes 
 >0.80 Fraction of 1 
Monocytes/Leukocytes 
 <0.40 Fraction of 1 
Urinalysis 
Clarity 
Any result other than clear 
Color 
Any results other than yellow 
Bilirubin 
Positive Value (excluding trace) 
Blood / Occult Blood 
Positive Value (excluding trace) 
Glucose 
Positive Value (excluding trace) 
Ketones 
Positive Value (excluding trace) 
Leukocyte esterase 
Positive Value (excluding trace) 
Nitrite 
Positive Value (excluding trace) 
pH 
<4.5 or >8 
Protein 
Positive Value (excluding trace) 
Specific gravity 
<1.005 or >1.025 
Urobilinogen 
>1 EU/dL 
Microscopic Examination 
Red Blood Cells/Erythrocytes 
≥ 5 /HPF 
White Blood Cells/Leukocytes 
≥ 5 /HPF 
Bacteria 
Any character value that is not “None” or 
“Rare” (or their equivalent) 
Calcium oxalate crystals 
Any present/positive (or equivalent) 


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*The NCI has not specified a value, Shire physicians have agreed on lab values 
provided.  
 
** Values taken from the Reviewer Guidance, Conducting a Clinical Safety Review of a New Product Application and 
Preparing a Report on the Review, Table 7.1.7.3.2.1 pp 70-72. US DHHS FDA CDER, February 2005.  
 
LLN: Lower limit of normal value provided by the laboratory  
ULN: Upper limit of normal value provided by the laboratory   
10.3 
Vital Signs 
Descriptive statistics for vital signs (temperature, sitting blood pressure (systolic blood 
pressure, diastolic blood pressure), pulse, respiratory rate, weight, waist circumference and 
waist:hip ratio ) and their changes from baseline at each post-baseline visit and at the FoTA 
will be presented by treatment group. Vital signs data will be listed. 
Vital sign values will be considered PCI if they meet the criteria listed in Table 3. A listing of 
subjects with post-baseline PCI values will be provided including the subject number, 
baseline, and post-baseline PCI values. 
Table 3: Criteria for Potentially Clinically Significant Vital Signs 
 
Vital Sign Parameter 
 
Flag 
PCI Criteria 
Observed Value 
Change from Baseline 
Systolic blood pressure 
(mmHg) 
High 
≥160 
- 
Low 
<90 
- 
Diastolic blood pressure 
(mmHg) 
High 
≥100 
- 
Low 
<60 
- 
Respiratory Rate  
(breaths per minute) 
High 
>25 
- 
Low 
<12 
- 
Pulse rate 
(beats per minute) 
High 
≥110 
- 
Low 
≤50 
- 
Weight (kg) 
High 
- 
Increase of ≥5% 
Low 
- 
Decrease of ≥5% 
Temperature (deg. C) 
High 
>39 
- 
Low 
<35 
- 
 
10.4 
Electrocardiogram (ECG) 
Descriptive statistics for ECG variables (heart rate, PR, RR, QRS, QTc and QT intervals) and 
their changes from baseline at each assessment time point will be presented by treatment 


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group. QTc interval will be calculated using both Bazett (QTcB=QT/(RR)1/2) and Fridericia 
(QTcF=QT/(RR)1/3) corrections; and if RR is not available, it will be replaced with 60/hr in 
the correction formula.   A listing for 12-lead ECG results and interpretation by central reader. 
Electrocardiogram variable values will be considered PCI if they meet or exceed the values 
listed in Table 4. A listing of all subjects with post-baseline PCI value will be provided 
including the subject number, baseline, and post-baseline PCI values.  
Table 4: Criteria for Potentially Clinically Important ECG values  
ECG Parameter 
Unit 
PCI Criteria 
ECG Parameter 
ECG Result 
- 
- 
Abnormal and  
clinically significant 
from investigator 
Heart Rate 
beats/minute 
≤50 
≥110 
PR Interval 
msec 
- 
≥220 
QT Interval 
msec 
- 
≥480 
QTc Interval 
msec 
- 
≥460 and <480 
≥480 and <500 
≥500 
QT/QTc increase 
from baseline 
Msec 
- 
≥30 and <60 
≥60 
QRS Interval 
Msec 
- 
≥120 
 
10.5 
Other Safety Variables 
10.5.1 
Bristol Stool Chart 
The Bristol Stool Chart (BSC) is a medical aid designed to classify the form of human feces 
into seven categories, where 1 is the hardest and 7 is the softest. Types 3 and 4 would be 
normal and types at either end of the scale would be severe. Stools will be assessed by the 
bowel movement consistency of the softess stool within the last 24 hours prior to the clinic 
visit. BSC responses on the rating scale of stool hardness (Type 1 to Type 7) will be listed by 
time point and treatment group. Summaries of stool hardness by time point and treatment 
group will be provided. 


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Stool frequency will be assessed by the number of bowel movements within the last 24 hours 
prior to the clinic visit. Summary statistics (number of observations, mean, SD, median, 
maximum, and minimum) will also be presented by treatment group for frequency of bowel 
movements by day. The stool frequency would be PCI if it is ≥6 BM/day. 


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11. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES  
11.1    Pharmacokinetics Population and Pharmacodynamics Population 
Pharmacokinetic data was not collected in this study.  For pharmacodynamics population, see 
section 4.6. 
11.2    Pharmacokinetic Methods 
N/A 
11.3    Statistical Analysis of Pharmacokinetic Data 
N/A 
11.4    Pharmacodynamic Methods 
BA synthesis will be assessed via alpha-hydroxy-4-cholesten-3-one [C4] concentrations. 
11.5    Statistical Analysis of Pharmacodynamic Data 
C4 concentration data will be listed. 
 
12. 
OTHER ANALYSES 
12.1 
Health-related Quality of Life Analyses 
All Health-related Quality of Life data will be listed for the full analysis set.  
 
13. 
COMPUTER METHODS  
Data analyses will be performed by ICON. Statistical analyses will be performed using 
Version 9.3 (or newer) of SAS on a suitably qualified environment. 


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14. 
DATA HANDLING CONVENTIONS 
14.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, SD, minimum, maximum. The minimum and maximum values will be presented to 
the same number of decimal places as the raw data. The mean and median will be presented to 
one more decimal place than the raw data. The SD will be presented to two more decimal 
places than the raw data.  
Categorical data and count variables will be summarized using n and percentages based on the 
number of non-missing values. Percentages will be presented to one decimal place. The 
number of missing values will be presented as a separate category with no percentage, but 
only if 1 or more patients are missing data for the summary. Otherwise, all categories will be 
presented (even if no patients are counted in the category). Counts of zero in any category will 
be presented without a percentage. 
14.2 
Derived Efficacy Endpoints  
NAS, MRI-PDFF, HOMA-IR, and SAF will be derived in the dataset according to the rules in 
Appendix 2 of the protocol.  If any of the individual components are missing, then the 
corresponding NAS, SAF, MRI and HOMA –IR will be set to missing.  
MRI hepatic PDFF will be derived based on images from multi-echo (ME) and double double 
echo (DDE) sequences.   
The 
MRI 
hepatic 
PDFF 
endpoint 
will 
be 
derived 
in 
four 
ways: 
1) The first analyzable ME result will be used at a visit. If the ME is not analyzable the DDE 
will be used at a visit.  ME results are selected preferentially. If neither ME nor DDE is 
analyzable, a repeat will be requested and if repeat is requested then the result to use is based 
on the ME preferentially then the DDE on this repeated imaging.  It is possible for the 
baseline to come from ME and week 24 to come from DDE and vice versa.  This will be the 
primary definition of the MRI hepatic PDFF endpoint as suggested by the expert radiologist. 


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2) Use MRI hepatic PDFF only based on ME images. Only those subjects with both an 
analyzable ME at baseline and at week 24 will be included in change from baseline analyses. 
3) Use MRI hepatic PDFF only based on DDE images. Only those subjects with both an 
analyzable DDE at baseline and at week 24 and week 24 will be included in change from 
baseline analyses. 4) If ME is available at both baseline and week 24 then the MRI hepatic 
PDFF endpoint should be based on ME images. Otherwise, if DDE is available at both 
baseline and week 24 then the MRI hepatic PDFF endpoint should be based on DDE images.   
14.3 
Association of Early Termination Assessments to Scheduled Visits 
For purposes of reporting early termination assessments during the study, each early 
termination visit will be mapped to a visit according to the visits window in Appendix 1.  This 
rule applies to both efficacy variables (e.g., ALT) and safety variables (e.g., vital signs) that 
are analyzed and/or summarized by visit. 
14.4 
Repeated or Unscheduled Assessments of Safety Parameters  
Unscheduled visits will be mapped to a visit according to the visits window in Appendix 1. 
If a subject has repeated assessments before the start of investigational product, then the 
results from the final assessment made prior to the start of investigational product will be used 
as baseline.  
If a subject has repeated assessments after the start of investigational product within a visit 
window, only the scheduled visit will be used for efficacy analyses. For safety analyses, the 
results from scheduled visit will be used first, if no scheduled visit, the record from the visit 
closest to target date will be used. If there are multiple records with the same distance to the 
target date, the latest record will be used. 
If the final on-treatment safety assessments are repeated or unscheduled, the last post-baseline 
assessment will be used as the final on-treatment assessment for generating descriptive 
statistics. 


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However, all post-baseline assessments will be used for PCI value determination and all 
assessments will be presented in the data listings. 
14.5 
Missing Date of Investigational Product  
When the date of the last dose of investigational product is missing for a subject in the Safety 
Analysis Set, all efforts should be made to obtain the date from the investigator.  If it is still 
missing after all efforts, then the last visit date when investigational product was returned will 
be used in the calculation of treatment duration.   
14.6 
Missing Date Information for Prior or Concomitant Medications  
For prior or concomitant medications, including rescue medications, incomplete (i.e., partially 
missing) start date and/or stop date will be imputed. When the start date and the stop date are 
both incomplete for a subject, impute the start date first.  
14.6.1 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing day and month  
 
• If the year of the incomplete start date is the same as the year of the date of the first 
dose of investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields  
• If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields  
• If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields.  
Missing month only  
 
• The day will be treated as missing and both month and day will be replaced.  


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• If the year of the incomplete start date is the same as the year of the date of the first 
dose of investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields  
• If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields  
• If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields.  
Missing day only 
  
• If the month and year of the incomplete start date are the same as the month and year 
of the date of the first dose of investigational product, then the day of the date of the 
first dose of investigational product will be assigned to the missing day  
• If either the year is before the year of the date of the first dose of investigational 
product or if both years are the same but the month is before the month of the date of 
the first dose of investigational product, then the last day of the month will be assigned 
to the missing day  
• If either the year is after the year of the date of the first dose of investigational product 
or if both years are the same but the month is after the month of the date of the first 
dose of investigational product, then the first day of the month will be assigned to the 
missing day.  
14.6.2 
Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields. If the date of the 
last dose of investigational product is missing, then replace it with the last visit date. If the 
imputed stop date is before the start date (imputed or non-imputed start date), then the 
imputed stop date will be equal to the start date.  
Missing day and month 
 


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• If the year of the incomplete stop date is the same as the year as of the date of the last 
dose of investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields 
• If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields  
• If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields.  
Missing month only 
 
• The day will be treated as missing and both month and day will be replaced.  
• If the year of the incomplete stop date is the same as the year as of the date of the last 
dose of investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields  
• If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields  
• If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields.  
Missing day only 
 
• If the month and year of the incomplete stop date are the same as the month and year 
of the date of the last dose of investigational product, then the day of the date of the 
last dose of investigational product will be assigned to the missing day  
• If either the year is before the year of the date of the last dose of investigational 
product or if both years are the same but the month is before the month of the date of 
the last dose of investigational product, then the last day of the month will be assigned 
to the missing day  
• If either the year is after the year of the last dose of investigational product or if both 
years are the same but the month is after the month of the date of the last dose of 


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investigational product, then the first day of the month will be assigned to the missing 
day.  
14.7 
Missing Date Information for Adverse Events  
For AEs, the default is to only impute incomplete (i.e., partially missing) start dates.  
Incomplete stop dates may also be imputed when calculation of the duration of an AE is 
required per the protocol.  If imputation of an incomplete stop date is required, and both the 
start date and the stop date are incomplete for a subject, impute the start date first. 
14.7.1 
Incomplete Start Date  
Follow same rules as in Section 14.6.1. 
14.7.2 
Incomplete Stop Date  
Follow the same rules as in 14.6.2.  
14.8 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned. If the severity is missing for an AE 
starting on or after the date of the first dose of investigational product, then a severity of 
“Severe” will be assigned. The imputed values for severity assessment will be used for 
incidence summaries, while the actual values will be used in data listings. 
14.9 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting on or after the date 
of the first dose of investigational product, a causality of “Related” will be assigned. The 
imputed values for relationship to double-blind investigational product will be used for 
incidence summaries, while the actual values will be presented in data listings. 


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14.10 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis 
due to, for example, that a character string is reported for a numerical variable.  The 
appropriately determined coded value will be used in the statistical analysis.  However, the 
actual values as reported in the database will be presented in data listings. 
 
 


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15. 
APPENDIX 
Appendix 1: Classification of Visits Window 
Timing of assessment  (days relative to 
Treatment a) 
Visit 
Visit Name to 
display for Analysis 
<=-1 Day 
Screening 
Visit 1 (Screening ) 
Visit 2 (Week 0 [Day 1])  
Baseline 
Visit 2 (Baseline) 
Week 2, Day 14 (2-22 Days) 
Visit 3 
Visit 3 (Week 2) 
Week 4, Day 28 (23-43 Days)   
Visit 4 
Visit 4 (Week 4) 
Week 8, Day 56 (44-71 Days)   
Visit 5 
Visit 5 (Week 8) 
Week 12, Day 84 (72-127 Days)   
Visit 6 
Visit 6 (Week 12) 
Week 24, Day 168 (128-211 Days)   
Visit 7 
Visit 7 (Week 24) 
Week 36, Day 252 (212-295 Days)   
Visit 8 
Visit 8 (Week 36) 
Week 48, Day 336 (296 Days-End of Study)  
Visit 9- End of 
Treatment 
Visit 9 (Week 48) 
Week 52, 4 weeks after completion of dosing 
(>End of Study) 
Visit 10-Follow-up 
Visit 10 (Week 52) 
* For early termination patients, MRI and liver biopsy visits happened after early termination 
date will be mapped to same visit as the early termination visit, even though the visit date is 
later than End of Study date. 


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16. 
REFERENCES 
1. SAS Institute, Inc. Common Risk Difference, Base SAS(R) 9.4 Procedures Guide: 
Statistical Procedures, Third Edition. 2014; http://support.sas.com/documentation 
/cdl/en/procstat/67528/HTML/default/viewer.htm#procstat_freq_details63.htm. Accessed 
November 21, 2017. 
2. Neuschwander-Tetri, B. A., Loomba, R., Sanyal, A. J., Lavine, J. E., Van Natta, M. L., 
Abdelmalek, M. F., Chalasani, N., Dasarathy, S., Diehl, A. M., Hameed, B., Kowdley, K. 
V., Mccullough, A., Terrault, N., Clark, J. M., Tonascia, J., Brunt, E. M., Kleiner, D. E. & 
Doo, E. 2015. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-
alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. 
Lancet, 385, 956-65. 
 


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17. 
TABLE OF CONTENTS FOR FIGURES, TABLES, AND 
LISTINGS 
17.1 
Tables 
Table 
Title (Population) 
 
STUDY SUBJECTS 
Table 1.1.1 
Disposition by Treatment Group (All Screened Subjects) 
Table 1.1.2 
Summary of Enrollment (All Screened Subjects) 
Table 1.2.1 
Demographic and Baseline Characteristics by Treatment Group 
(Safety Analysis set) 
  
SAFETY 
Table 2.1.1 
Investigational Product Exposure by Treatment Group (Safety 
Analysis set) 
Table 2.2.1 
Overall Treatment-emergent Adverse Events (TEAEs) by 
Treatment Group (Safety Analysis set) 
Table 2.2.2 
Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group (Safety Analysis set) 
Table 2.2.3 
Treatment-emergent Adverse Events by Preferred Term and 
Treatment Group (Safety Analysis set) 
Table 2.3.1 
Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group (Safety 
Analysis set) 
Table 2.3.2 
Treatment-emergent Adverse Events considered Related to 
Investigational Product by System Organ Class, Preferred Term 
and Treatment Group (Safety Analysis set) 
Table 2.4.1 
Serious Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, and Treatment Group (Safety Analysis set) 
Table 2.4.2 
Treatment-Emergent Adverse Events Leading to Drug Withdrawn 
by System Organ Class, Preferred Term, and Treatment Group 
(Safety Analysis set) 
Table 2.5.1 
Summary of Onset and Duration of All Treatment-emergent 
Diarrhoea Adverse Events by Treatment Group (Safety Analysis 
Set) 
Table 2.6.1 
Quantitative Clinical Laboratory Results by Treatment Group: 
Biochemistry (Safety Analysis set) 
Table 2.6.2 
Quantitative Clinical Laboratory Results by Treatment Group: 
Coagulation (Safety Analysis set) 
Table 2.6.3 
Quantitative Clinical Laboratory Results by Treatment Group: 
Hematology (Safety Analysis set) 
Table 2.6.4 
Quantitative Clinical Laboratory Results by Treatment Group: 
Lipid Panel (Safety Analysis set) 


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Table 2.6.5 
Quantitative Clinical Laboratory Results by Treatment Group: 
Endocrinology (Safety Analysis set) 
Table 2.6.6 
Quantitative Clinical Laboratory Results by Treatment Group: 
HbA1c (Safety Analysis set) 
Table 2.6.7 
Quantitative Clinical Laboratory Results by Treatment Group: 
Vitamins (Safety Analysis set) 
Table 2.6.8 
Quantitative Clinical Laboratory Results by Treatment Group: 
Urinalysis (Safety Analysis set) 
Table 2.6.9 
Summary of Liver Enzyme Elevations: AST, ALT, Bilirubin 
(Safety Analysis set) 
Table 2.7.1 
Actual Values and Change from Baseline in Vital Signs by 
Treatment Group  (Safety Analysis set)  
Table 2.8.1 
Summary of Stool Hardness of the Softest Stool in the Last 24 
Hours Prior to Visit by Treatment Group (Safety Analysis set)  
Table 2.8.2 
Summary of Bowel Movements in the Last 24 hours Prior to Visit 
by Treatment  Group (Safety Analysis set) 
 
 
 


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17.2 
Listings 
Listing 16.1.7 
Randomization Assignments (All Randomized Set) 
Listing 1.1 
Subjects with Screen Failures (All Screened Set) 
Listing 1.2 
Subject Disposition (Randomized Set) 
Listing 1.3 
Subjects Who Terminated from the Study (All Randomized Subjects) 
 
 
Listing 2.1  
Listing of Protocol Deviations (All Randomized Subjects) 
Listing 4.1  
Subject Demographic and Baseline Characteristics (Safety Analysis 
Set) 
Listing 4.2  
Medical History (Safety Analysis Set) 
Listing 4.3 
Smoking History (Safety Analysis Set) 
Listing 4.4 
Prior and Concomitant Medications (Safety Analysis Set) 
Listing 4.5 
Prior and Concomitant Therapies (Safety Analysis Set) 
Listing 5.1 
Investigational Product Accountability (Safety Analysis Set) 
Listing 5.2 
Bile Acids (BA) Sampling C4 Concentrations (Pharmacodynamic 
Analysis Set) 
Listing 6.1.1 
Liver Biopsy – Part 1 (Full Analysis Set) 
Listing 6.1.2 
Liver Biopsy – Part 2 (Full Analysis Set) 
Listing 6.1.3 
Liver Biopsy – Part 3 (Full Analysis Set) 
Listing 6.2 
Magnetic Resonance Imaging (MRI) Hepatic Proton Density Fat 
Fraction (PDFF) (Full Analysis Set) 
Listing 6.3 
EQ-5D-5L and EQ-5D VAS Score (Full Analysis Set) 
Listing 7.1  
Adverse Events (Safety Analysis Set) 
Listing 7.2  
Serious Treatment-emergent Adverse Events (Safety Analysis Set) 
Listing 7.3  
Treatment-emergent Adverse Events Considered Related to 
Investigational Product (Safety Analysis Set) 
Listing 7.4  
Treatment-emergent Adverse Events Leading to Withdrawal of 
Investigational Product (Safety Analysis Set) 
Listing 7.5  
Treatment-emergent Adverse Events Leading to Death (Safety 
Analysis Set) 
Listing 7.6 
Diarrhoea Treatment-emergent Adverse Events (Safety Analysis Set) 
Listing 8.1.1 
Clinical Laboratory Sample Collection and Results for Preganancy 
Listing 8.1.2 
Clinical Laboratory Test Results 
Listing 8.1.3 
Subjects with Potentially Clinically Important Laboratory Test Results 
(Safety Analysis Set) 
Listing 8.1.4 
Subjects with Liver Enzyme Elevations: AST, ALT, Bilirubin (Safety 
Analysis Set) 
Listing 8.2.1.1 
Vital Signs – Part 1 (Safety Analysis Set) 
Listing 8.2.1.2 
Vital Signs – Part 2 (Safety Analysis Set) 
Listing 8.2.2 
Subjects with Potentially Clinically Important Vital Signs (Safety 


Shire  
CONFIDENTIAL  
26Jul2018 
SHP626-201 
SAP V2.0 
Page 43 of 43 
 
 
Analysis Set) 
Listing 8.3.1 
12-lead ECG results and Interpretation by Central Reader (Safety 
Analysis Set) 
Listing 8.3.2 
Subjects with Potentially Clinically Important ECG results (Safety 
Analysis Set) 
Listing 8.4 
Stool Hardness and Stool Frequency (Safety Analysis Set)