Conditions: Pruritus
Keywords: Cholestasis GLISTEN GSK2330672 Itch Primary biliary cholangitis Pruritus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 238
Healthy volunteers: no

Brief summary:
This is a 2-part study in PBC participants with cholestatic pruritus and will evaluate the efficacy, safety and impact on health-related quality of life of linerixibat compared with placebo.

Detailed description:

Arms:
arm 1: Participants were randomized to receive linerixibat 40 mg tablet orally twice a day (BID) in Part A (up to Week 24). arm 2: Participants were randomized to receive Placebo orally twice a day (BID) in Part A (up to Week 24). arm 3: Participants who were randomized to receive Placebo (up to Week 24) orally twice a day (BID) in Part A, continued to receive Placebo (from Week 24 to Week 32) orally twice a day (BID) in Part B. arm 4: Participants who were randomized to receive Placebo (up to Week 24) orally twice a day (BID) in Part A, switched to receive linerixibat 40 mg tablet orally twice a day (BID) (from Week 24 to Week 32) in Part B. arm 5: Participants who were randomized to receive linerixibat 40 mg tablet orally BID (up to Week 24) in Part A, switched to receive Placebo (from Week 24 to Week 32) orally twice a day (BID) in Part B. arm 6: Participants who were randomized to receive linerixibat 40 mg tablet orally twice a day (BID) (up to Week 24) in Part A, continued to receive linerixibat 40 mg twice a day (BID) (from Week 24 to Week 32) in Part B.

Interventions: intervention 1: Linerixibat intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive linerixibat. intervention 2: Participants will receive placebo.

Protocol document:
Prot_000.pdf: 
TMF-16740250 
 CONFIDENTIAL 
212620 
GlaxoSmithKline group of companies 
 
Protocol amendment 04 
 
1 
TITLE PAGE 
Protocol Title:  
A two-part, randomized, placebo controlled, double blind, multicenter, Phase 3 study to 
evaluate the efficacy and safety of linerixibat for the treatment of cholestatic pruritus in 
participants with primary biliary cholangitis (PBC).  
Protocol Number: 212620/Amendment 04 
Compound Number 
or Name: 
GSK2330672 (linerixibat) 
Brief Title:  
Global Linerixibat Itch STudy of Efficacy and Safety iN PBC (GLISTEN) 
Study Phase: Phase 3 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Sponsor Signatory 
Alexander Cobitz, MD, PhD  
Senior Clinical Development Director 
Development-Clinical Sciences-Hepatology GI 
Regulatory Agency Identifying Number(s):  
IND: 130391 
EudraCT: 2021-000007-21 
Approval Date: 20 Nov 2023 
 
Copyright 2023 the GSK group of companies. All rights reserved. Unauthorized copying 
or use of this information is prohibited. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
2 
INVESTIGATOR PROTOCOL AMENDMENT AGREEMENT PAGE 
PROTOCOL NUMBER: 212620 
AMENDMENT NUMBER: 04 
PROTOCOL TITLE: A two-part, randomized, placebo controlled, double blind, 
multicenter, Phase 3 study to evaluate the efficacy and safety of linerixibat for the 
treatment of cholestatic pruritus in participants with primary biliary cholangitis (PBC) 
• 
I confirm agreement to conduct the study in compliance with the protocol. 
• 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
• 
I agree to ensure that all associates, colleagues, and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in place 
to ensure that site staff receives the appropriate information throughout the study. 
 
 
 
Investigator Name:   
______________________________ 
Investigator Address:  
 
______________________________ 
 
______________________________ 
 
 
 
 
 
Investigator Signature 
 
Date 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 04 
20 Nov 2023 
TMF-16740250 
Amendment 03 ISR-1 
24-MAR-2022 
TMF-14529451 
Amendment 03 
02-SEP-2021 
TMF-13946603 
Amendment 02 
12-JUL-2021 
TMF-13852487 
Amendment 01 
01-MAR-2021 
TMF-11835634 
Original Protocol 
27-JAN-2021 
TMF-2096421 
 
Amendment [04]: 20 Nov 2023 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.  
Overall Rationale for the Amendment:  
Change in analysis strategy to perform primary analysis after the end of Part A including 
available Part B data and final analysis after the end of Part B, addition of allowed early 
access to certain data to enable kinetic-pharmacodynamic (K-PD) modelling, and 
introduction of blinding strategy to support these changes. Removal of exclusion criteria 
no longer needed, other changes to fulfill the EU CTR requirements, and clarifications in 
line with updated sponsor protocol template also included. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
4 
Section # and Name Description of Change 
Brief Rationale 
Meaningful Content Changes and Notable Clarifications 
Synopsis, Section 
1.1, and throughout 
Protocol 
• The terminology of 
Mean Worst Daily Itch 
(MWDI) Score was 
changed to Weekly Itch 
Score (WIS). 
• The terminology of 
Mean Daily Sleep Score 
was changed to Weekly 
Sleep Score. 
Adoption of more intuitive 
terminology for the concept – 
the calculation remains the 
same. 
Section 2.3.1, Risk 
Assessment; 
Section 5.2, 
Exclusion Criteria 
• Updated rationale for 
the potential increased 
risk of colon cancer in 
association with 
increased fecal excretion 
of bile acids’ and 
removed mitigation 
excluding participants 
from the study with 
current/ previous 
diagnosis of colorectal 
cancer. 
• Exclusion criteria for 
current/previous 
diagnosis of colorectal 
cancer was removed. 
(Any current 
malignancies remains as 
an exclusion criterion.) 
Current review of the totality of 
data on the potential risk of 
'colorectal cancer' is not 
consistent with this theoretical 
association with patients 
receiving linerixibat. Hence, to 
prevent unnecessary exclusion 
of participants with history of 
colorectal cancer, this exclusion 
has been removed.   


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
5 
Section # and Name Description of Change 
Brief Rationale 
Meaningful Content Changes and Notable Clarifications 
Section 5.2, 
Exclusion Criteria 
Removed Exclusion #1 
regarding participants with 
recent positive COVID-19 
test results, symptoms 
suggestive of active 
COVID-19 infection. 
To prevent unnecessary screen 
failure of participants 
considering the changes in 
COVID pandemic and 
management. 
Section 5.2, 
Exclusion Criteria  
Exclusion criteria revised to 
clarify that the presence of 
viral hepatitis B (HBsAg 
positive) or C (anti-HCV 
positive and RNA detected) 
infection is exclusionary. 
Clarification of exclusion 
criteria specificities. 
Section 5.2, 
Exclusion Criteria 
Exclusion criteria for skin 
disorders was updated to 
clarify that a current 
diagnosis of primary skin 
disorders with itch as a 
characteristic feature is 
exclusionary. 
Clarification of exclusion 
criterion. 
Section 5.4, Screen 
Failures 
• Added additional 
rescreening and details 
of the rescreenings.  
• Added text for 
participants who have a 
COVID-19 diagnosis 
during the Screening 
period.  
• Clarified participant 
numbering and 
documentation in the 
eCRF for screening/ 
rescreening events. 
Change in text to permit 
additional rescreenings. 
Section 6.4, Blinding Added text to indicate 
possible access to data for 
population K-PD modelling 
before study unblinding and 
blinding strategy around 
new analysis plan. 
To facilitate activities for the 
new analysis strategy to perform 
primary analysis after the end of 
Part A. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
6 
Section # and Name Description of Change 
Brief Rationale 
Meaningful Content Changes and Notable Clarifications 
Section 7.1.4, QTc 
Stopping Criteria 
Clarified stopping criteria 
for QTc is based on increase 
in values. 
Clarification text. 
Section 8.4, Adverse 
Events (AEs), 
Serious Adverse 
Events (SAEs) and 
Other Safety 
Reporting 
Added all events meeting 
permanent stopping criteria, 
except for pregnancy, will 
be recorded as a (S)AE. 
Clarification of approach 
already in place in line with new 
sponsor protocol template. 
Section 8.4.1, Time 
Period and 
Frequency for 
Collecting AE and 
SAE Information 
• Clarified AE/SAE 
reporting period.  
• Clarified the 
documentation required 
for participants meeting 
increased monitoring or 
stopping criteria at 
Week 32 requiring 
additional follow-up 
after being enrolled in 
the follow-on Study 
212358 (LLSAT) and 
when AEs/ SAEs should 
be entered in the 
GLISTEN eCRF or the 
LLSAT eCRF.  
In line with clarified definition 
of Last Visit in Section 4.4, End 
of Study Definition. 
Further clarification and 
guidance text. 
Section 8.5, 
Pharmacokinetics 
Added text that PK sample 
collection and/or analysis 
may be terminated when 
sufficient data has been 
collected, and any 
remaining samples may be 
discarded if not required. 
To allow an earlier analysis as 
appropriate. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
7 
Section # and Name Description of Change 
Brief Rationale 
Meaningful Content Changes and Notable Clarifications 
Section 8.7, 
Biomarkers 
Added text that Biomarker 
sample collection and/or 
analysis may be terminated 
when sufficient data has 
been collected, and any 
remaining samples may be 
discarded if not required. 
To allow an earlier analysis as 
appropriate. 
Section 9.4, 
Statistical Analyses 
Added details for the new 
statistical analysis strategy 
involving a primary analysis 
after all participants have 
completed the Part A 
intervention period and a 
final analysis after all 
participants have completed 
the Part B intervention 
period, and the follow-up 
period. 
Change in analysis strategy.  
Section 10.3.5, 
Reporting of SAE to 
GSK 
Updated contact for SAE 
reporting by phone from 
SAE coordinator to GSK 
Medical Monitor. 
In line with updated process of 
SAE reporting if done by phone. 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
8 
Section # and Name Description of Change 
Brief Rationale 
Other Changes: Clarifications; EU CTR Requirements; Sponsor Protocol Template 
requirements; formatting or typographical corrections 
Synopsis, Section 
1.1 and Section 4.1, 
Overall Design 
Separated details of Part A 
and Part B intervention 
treatment periods. 
Change in analysis strategy to 
clarify that primary analysis will 
be completed after the end of 
Part A. 
Section 1.3, 
Schedule of 
Assessments (SoA) 
• Added a row and note 
for visit windows to 
indicate applicable 
visits. 
• Added a row and note 
for the medication diary.  
• Added notes that the 
medication diary, 
exploratory biomarker 
collection, and PK 
collection are not 
required if study 
treatment is 
discontinued 
permanently. 
Clarification. 
Section 1.3, 
Schedule of 
Assessments (SoA) 
Added note that genetic 
samples will not be 
collected in China or Israel. 
Incorporation of country specific 
requirements. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
9 
Section # and Name Description of Change 
Brief Rationale 
Other Changes: Clarifications; EU CTR Requirements; Sponsor Protocol Template 
requirements; formatting or typographical corrections 
Section 3, Objectives 
and Endpoints/ 
Estimands 
• In exploratory 
endpoints, added the 
Quality of Life and 
Patient-Reported 
Outcomes (PROs) 
endpoints for Part B on 
MSS, MFS, ESS, 
BDI-II, PGI-S, and 
PGI-C.  
• Clarified that 
exploratory biomarker 
endpoints and the effect 
of bile acid binding 
resins on linerixibat 
pharmacodynamics will 
be assessed in Part B. 
• In exploratory markers 
of liver fibrosis 
endpoints, clarified that 
ELF will be assessed in 
Part B. 
Clarification of previously 
omitted Part B endpoints. 
Section 4.1, Overall 
Design 
Section 4.2.2, 
Rationale for 
Stratification 
Amended text describing 
concomitant medications for 
cholestatic pruritus 
medications to include 
fibrates and selective 
serotonin reuptake inhibitors 
(SSRIs). 
Clarification. 
Section 4.2.4, 
Rationale for 
Concomitant 
Medications 
Added fibrates to the list. 
Updated the linerixibat 
interaction with OCA 
description based on data 
from Study 213688. 
Clarification and modification in 
line with updated information. 
Section 4.4, End of 
Study Definition 
Clarified the last visit for 
participants. 
Clarification. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
10 
Section # and Name Description of Change 
Brief Rationale 
Other Changes: Clarifications; EU CTR Requirements; Sponsor Protocol Template 
requirements; formatting or typographical corrections 
Section 5.1, 
Inclusion Criteria 
• Added note in Inclusion 
#4 to highlight that 
careful planning may be 
needed to confirm 
negative pregnancy test 
in time if serum test is 
required. 
• Removed reference to 
Pregnancy Testing 
details that is duplicated 
and with incorrect 
Section number. 
Clarification of logistical 
approach for serum pregnancy 
as needed. 
Section 5.2, 
Exclusion Criteria 
In exclusion criteria for 
abnormal liver chemistry, 
updated note to clarify that 
Sample 1 and Sample 2 
must be collected at least 
4 weeks apart. 
Clarification of exclusion 
criteria requirements. 
Section 5.2, 
Exclusion Criteria 
In exclusion criteria for 
initiation, discontinuation, 
or change in dose, fibrates 
replaced bezafibrate and 
fenofibrate. 
Clarification of broader 
concomitant medication 
terminology. 
Section 5.3.2, 
Caffeine, Alcohol, 
and Tobacco 
Clarified number of 
alcoholic drinks for women 
and men. 
Clarification from previous 
inconsistency. 
Section 6, Study 
Interventions and 
Concomitant 
Therapy 
• Referred the reader to 
the List of Definitions 
for study intervention.  
• Added authorization 
status of the IMP, 
linerixibat. 
In line with the updated sponsor 
protocol template. Added to 
comply with EU CTR 
requirements. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
11 
Section # and Name Description of Change 
Brief Rationale 
Other Changes: Clarifications; EU CTR Requirements; Sponsor Protocol Template 
requirements; formatting or typographical corrections 
Section 6.2, 
Preparation/ 
Handling/ Storage/ 
Accountability 
• Added timing for start of 
study intervention.  
• Clarified allowable 
shipment of study 
intervention to and from 
the participant. 
• Added reference to 
Section 10.8.4 for home 
healthcare permissions.  
Clarification.  
Section 6.3, 
Assignment to Study 
Intervention 
Heading changed from 
Measures to Minimize Bias: 
Randomization and 
Blinding to Assignment to 
Study Intervention. 
In line with the updated sponsor 
protocol template. 
Section 6.3.1, 
Unblinding 
Procedures 
Heading was removed and 
details of blinded and 
unblinded data were moved 
to Section 6.4, Blinding. 
In line with the updated sponsor 
protocol template. 
Section 6.5, Study 
Intervention 
Compliance 
Clarified study intervention 
administration should be 
documented daily in the 
eDiary and clarified the 
assessment of compliance.  
Clarification.  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
12 
Section # and Name Description of Change 
Brief Rationale 
Other Changes: Clarifications; EU CTR Requirements; Sponsor Protocol Template 
requirements; formatting or typographical corrections 
Section 6.9.1, 
Permitted 
Medications 
Under concomitant 
medications that must be 
stable prior to screening and 
throughout the screening 
and treatment periods, 
pregabalin was added and 
fibrates replaced bezafibrate 
and fenofibrate. 
Clarification of previous 
inconsistency 
Section 7, 
Discontinuation of 
Study Intervention 
and Participant 
Discontinuation/ 
Withdrawal 
Added: No replacement is 
planned for participant 
discontinuing/withdrawing 
from the study. 
Clarification to comply with EU 
CTR requirements. 
Section 7.1, 
Discontinuation of 
Study Intervention 
• Clarified the study 
assessments to be 
completed if participants 
withdraw from study 
treatment but remain on 
study.  
• Clarified the timing of 
Discontinuation Visit 
and follow-up phone 
call Visit requirements 
in certain circumstances. 
Clarification of study 
assessment requirements. 
Section 7.1.1.2, 
Stopping Criteria 
Clarified that study 
intervention restart may be 
considered after liver safety 
follow-up if there is a clear 
underlying non-Drug 
Induced Liver Injury [DILI] 
event cause. 
Clarification of previous 
inconsistency with 7.1.9, Restart 
of Study Intervention. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
13 
Section # and Name Description of Change 
Brief Rationale 
Other Changes: Clarifications; EU CTR Requirements; Sponsor Protocol Template 
requirements; formatting or typographical corrections 
Section 7.2, 
Participant 
Discontinuation/ 
Withdrawal from the 
Study 
• Clarified participants 
may withdraw from the 
study for any reason or 
without providing a 
reason.  
• Clarified data and 
samples to be included 
in the study analysis if 
participant withdraws 
from the study.  
Clarification of text in line with 
revised sponsor protocol 
template. 
Section 8, Study 
Assessments and 
Procedures 
Referred to Section 10.8 for 
further details on home 
healthcare availabilities. 
Clarification of approach. 
Section 8.1, 
Administrative 
Procedures 
Added this heading and new 
text to describe 
demographic data collected 
and rationale. 
Clarification in line with revised 
sponsor protocol template. 
Section 8.3.1, 
Physical 
Examination 
Clarified that visits 
performed at locations other 
than a trial site include those 
by a home healthcare 
provider in the description 
of allowed physical exams 
and referred to Section 10.8 
for home healthcare 
activities. 
Clarification.  
Section 8.3.4, 
Clinical Safety 
Laboratory 
Assessments 
Added reference to List of 
Clinical Laboratories. 
Clarified when local 
laboratory results must be 
recorded in eCRF.  
Clarification of local laboratory 
results recording and text in line 
with new sponsor protocol 
template 
Section 8.3.5, 
Pregnancy Testing 
Clarified requirements for 
pregnancy testing in females 
of childbearing potential. 
Clarification.  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
14 
Section # and Name Description of Change 
Brief Rationale 
Other Changes: Clarifications; EU CTR Requirements; Sponsor Protocol Template 
requirements; formatting or typographical corrections 
Section 8.3.6, Study 
Safety Monitoring 
Added heading and text to 
describe how participant 
safety will be monitored. 
Clarification of approach 
already in place in line with new 
sponsor protocol template. 
Section 8.4.7, 
Adverse Events of 
Special Interest 
Clarified that details of 
AESIs will be recorded on 
the AESI eCRF and on the 
AE/SAE eCRF. 
Clarification of approach 
already in place. 
Section 8.4.8, 
Participant Card 
Added heading and text that 
describes the participant 
card. 
Clarification of approach 
already in place in line with 
updated sponsor protocol 
template. 
Section 9.4.5, Other 
Analyses 
Added additional details on 
blinded PRO data analysis 
to support the establishment 
of a clinically meaningful 
within-patient change 
threshold or range of 
thresholds.  
Clarification of approach in line 
with FDA guidance. 
Section 10.1.3, 
Informed Consent 
Process 
• Clarified consent 
process for collecting 
information on the baby 
in case of unexpected 
pregnancy.  
• Clarified that 
investigator will explain 
the objectives of the 
exploratory research. 
Clarification of expectations in 
line with updated sponsor 
protocol template. 
Section 10.1.4, 
Recruitment Strategy 
Added this heading and text 
on the recruitment strategy 
for the study. 
Added details describing current 
strategy to support EU CTR 
requirements and in line with the 
updated sponsor protocol 
template. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
15 
Section # and Name Description of Change 
Brief Rationale 
Other Changes: Clarifications; EU CTR Requirements; Sponsor Protocol Template 
requirements; formatting or typographical corrections 
Section 10.1.5, Data 
Protection 
• Added text that GSK 
will ensure protection of 
personal data of the 
investigator and site 
staff and added that data 
protection is specified in 
the contract between 
sponsor and study sites.  
• Added text to indicate 
the information 
technology provides 
participant personal 
protection. 
Clarification in line with 
updated sponsor protocol 
template. 
Section 10.1.6.1, 
Safety Review Team 
• Added heading and text 
on the Safety Review 
Team (SRT) and who 
comprises the SRT.  
• Added text that SRT 
contribute to the 
continual assessment of 
incoming new efficacy 
and safety information. 
Clarification in line with 
updated sponsor protocol 
template. 
Section 10.1.7, 
Dissemination of 
Clinical Study Data 
• Added details regarding 
how/where key design 
elements of this protocol 
and results will be 
posted.  
• Added details regarding 
study results information 
to be available for the 
investigator. 
Clarification in line with 
updated sponsor protocol 
template.  
Section 10.1.9, 
Source Documents 
Clarified the sponsor or 
designee will perform 
ongoing source data 
verification monitoring.  
Clarification in line with 
updated sponsor protocol 
template. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
16 
Section # and Name Description of Change 
Brief Rationale 
Other Changes: Clarifications; EU CTR Requirements; Sponsor Protocol Template 
requirements; formatting or typographical corrections 
Section 10.1.10, 
Study and Site Start 
and Closure 
Clarified that site 
termination could occur if 
the total number of 
participants are included 
earlier than expected. 
Clarification. 
Section 10.1.11, 
Publication Policy 
Clarified results of this 
study may be published in 
peer reviewed scientific 
literature. 
Clarification in line with 
updated sponsor protocol 
template. 
Section 10.2, 
Clinical Laboratory 
Test 
Clarified investigators must 
document their review of 
each laboratory safety 
report.  
Clarification in line with 
updated sponsor protocol 
template. 
Section 10.3.2, 
Definition of SAE 
Added in SAE definition 
table: Abnormal pregnancy 
outcomes (e.g., spontaneous 
abortion, fetal death, 
stillbirth, congenital 
anomalies, ectopic 
pregnancy). 
More prominent placement of 
information in line with updated 
sponsor protocol template. 
Section 10.3.4, 
Recording and 
Follow-up of AE and 
SAE 
Clarified the follow-up 
process/procedures for 
pregnancies. 
Clarification of process already 
in place and in line with updated 
sponsor protocol template. 
Section 10.5, 
Genetics 
• Clarified genetic 
samples may be 
analyzed as part of a 
multi-study assessment 
of genetic factors and 
may be reported in the 
CSR or in a separate 
study summary.  
• Clarified details of 
sponsor storage and 
retainment of DNA 
samples. 
Clarification in line with 
updated sponsor protocol 
template. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
17 
Section # and Name Description of Change 
Brief Rationale 
Other Changes: Clarifications; EU CTR Requirements; Sponsor Protocol Template 
requirements; formatting or typographical corrections 
10.7.1.3, China 
Schedule of 
Activities 
Clarifications made to SoA 
for consistency with 
Section 1.3. 
Consistency with Section 1.3, 
SoA. 
Section 10.7.2, Israel Added the Israel heading 
and content. 
Consolidation of Israel-specific 
protocol version. 
Section 10.7.3, 
France 
Added the France heading 
and content. 
Consolidation of country 
specific annex within protocol 
amendment. 
Section 10.8, Home 
Healthcare/ Remote 
Activities 
The heading was changed 
from COVID-19 to Home 
Healthcare/Remote 
Activities and the section 
clarified and restructured to 
remove specific references 
to COVID-19. Including: 
• Clarified the inclusion 
of a fully remote 
metasite, if allowed by 
country regulation/ 
ethics. 
• Clarified that the 
process for laboratory 
sample shipments must 
be agreed upon with 
GSK, if performed by 
the clinical site. 
Clarification that remote 
activities and home healthcare is 
not limited to COVID-19 
scenarios and can be used 
broadly across the study where 
permitted. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
18 
Section # and Name Description of Change 
Brief Rationale 
Other Changes: Clarifications; EU CTR Requirements; Sponsor Protocol Template 
requirements; formatting or typographical corrections 
Section 10.8.4, 
Study Intervention(s) 
• Clarified allowable 
shipment of study 
intervention to and from 
the participant.   
• Clarified the process for 
collection of used and/or 
unused IMP. 
• Clarified compliance 
with study intervention 
administration can be 
performed by trained 
home healthcare 
professionals. 
Clarification. 
Section 10.8.5, Data 
Management/ 
Monitoring 
Corrected the eDC platform 
to Veeva CDMS. 
Correction. 
Section 10.10, 
Abbreviations, 
Definition of Terms, 
and Trademarks 
Added the Definition of 
Terms header and table. 
Updated the list of 
abbreviations to align with 
protocol changes. 
Clarification in line with 
updated sponsor protocol 
template. 
Section 10.11, 
Protocol 
Amendment history 
Added the overview and 
summary of changes table 
from the Israel amendment 
(Amendment 03 ISR-1). 
Consolidation of full protocol 
amendment history. 
Section 11, 
References 
The original McKibben 
reference was corrected to 
Key 2020. 
Correction of error in previous 
amendment. 
Synopsis, Section 
1.1 and throughout 
Protocol 
General editorial and 
formatting changes made 
throughout the synopsis and 
protocol to improve clarity. 
Clarification. 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
19 
TABLE OF CONTENTS 
PAGE 
INVESTIGATOR PROTOCOL AMENDMENT AGREEMENT PAGE ............................... 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
TABLE OF CONTENTS ................................................................................................ 19 
LIST OF TABLES .......................................................................................................... 23 
LIST OF FIGURES ........................................................................................................ 24 
1. 
PROTOCOL SUMMARY ........................................................................................ 25 
1.1. 
Synopsis ..................................................................................................... 25 
1.2. 
Schema ...................................................................................................... 32 
1.3. 
Schedule of Assessments (SoA) ................................................................. 33 
2. 
INTRODUCTION .................................................................................................... 39 
2.1. 
Study Rationale .......................................................................................... 39 
2.2. 
Background ................................................................................................ 39 
2.2.1. 
Overview of Disease .................................................................... 39 
2.2.2. 
Background information on the product ....................................... 40 
2.2.3. 
Clinical Studies ............................................................................ 40 
2.3. 
Benefit/Risk Assessment ............................................................................ 44 
2.3.1. 
Risk Assessment ......................................................................... 45 
2.3.2. 
Benefit Assessment ..................................................................... 49 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 49 
3. 
OBJECTIVES AND ENDPOINTS/ESTIMANDS ..................................................... 49 
3.1. 
Primary Estimand ....................................................................................... 52 
3.2. 
Summary Measures .................................................................................... 53 
3.3. 
Supplementary Estimand ............................................................................ 54 
4. 
STUDY DESIGN .................................................................................................... 54 
4.1. 
Overall Design ............................................................................................ 54 
4.2. 
Scientific Rationale for Study Design .......................................................... 56 
4.2.1. 
Rationale for Study Blinding and Placebo Control ........................ 56 
4.2.2. 
Rationale for Stratification Factors ............................................... 56 
4.2.3. 
Rationale for Part B ..................................................................... 57 
4.2.4. 
Rationale for Concomitant Medications ........................................ 57 
4.2.5. 
Rationale for Use of Itch Numerical Rating Scale as the 
Primary Endpoint ......................................................................... 58 
4.2.6. 
Rationale for Questionnaires........................................................ 58 
4.2.7. 
Patient Input into Study Design .................................................... 59 
4.3. 
Justification for Dose .................................................................................. 59 
4.4. 
End of Study Definition ............................................................................... 60 
5. 
STUDY POPULATION ........................................................................................... 60 
5.1. 
Inclusion Criteria ......................................................................................... 60 
5.2. 
Exclusion Criteria ........................................................................................ 62 
5.3. 
Lifestyle Considerations .............................................................................. 64 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
20 
5.3.1. 
Meals and Dietary Restrictions .................................................... 64 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 64 
5.3.3. 
Activity ......................................................................................... 64 
5.4. 
Screen Failures........................................................................................... 65 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 65 
6.1. 
Study Intervention(s) Administered ............................................................. 65 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 66 
6.3. 
Assignment to Study Intervention ............................................................... 67 
6.4. 
Blinding ....................................................................................................... 67 
6.5. 
Study Intervention Compliance ................................................................... 68 
6.6. 
Dose Modification ....................................................................................... 68 
6.7. 
Continued Access to Study Intervention after the End of the Study ............ 68 
6.8. 
Treatment of Overdose ............................................................................... 69 
6.9. 
Concomitant Therapy.................................................................................. 69 
6.9.1. 
Permitted Medications ................................................................. 69 
6.9.2. 
Prohibited Medications ................................................................. 71 
6.9.3. 
Rescue Medication ...................................................................... 71 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 71 
7.1. 
Discontinuation of Study Intervention .......................................................... 71 
7.1.1. 
Liver Chemistry Monitoring/Discontinuation Criteria ..................... 72 
7.1.2. 
Hepatic Encephalopathy .............................................................. 75 
7.1.3. 
Diarrhea Management Criteria and Stopping Criteria ................... 75 
7.1.4. 
QTc Stopping Criteria .................................................................. 76 
7.1.5. 
Renal Stopping Criteria ................................................................ 77 
7.1.6. 
Diagnosis of Colon Cancer .......................................................... 77 
7.1.7. 
Pregnancy ................................................................................... 77 
7.1.8. 
Temporary Discontinuation due to AEs ........................................ 77 
7.1.9. 
Restart of Study Intervention........................................................ 77 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 78 
7.3. 
Lost to Follow Up ........................................................................................ 79 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 80 
8.1. 
Administrative Procedures .......................................................................... 80 
8.1.1. 
Collection of demographic data .................................................... 80 
8.2. 
Efficacy Assessments ................................................................................. 81 
8.2.1. 
Patient Reported Outcomes (PROs) ............................................ 81 
8.3. 
Safety Assessments ................................................................................... 83 
8.3.1. 
Physical Examinations ................................................................. 83 
8.3.2. 
Vital Signs .................................................................................... 83 
8.3.3. 
Electrocardiograms (ECGs) ......................................................... 84 
8.3.4. 
Clinical Safety Laboratory Assessments ...................................... 84 
8.3.5. 
Pregnancy Testing ....................................................................... 85 
8.3.6. 
Study Safety Monitoring ............................................................... 85 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 86 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 86 
8.4.2. 
Method of Detecting AEs and SAEs ............................................. 87 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 87 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
21 
8.4.4. 
Regulatory Reporting Requirements for SAEs ............................. 87 
8.4.5. 
Pregnancy ................................................................................... 87 
8.4.6. 
Cardiovascular and Death Events ................................................ 88 
8.4.7. 
Adverse Events of Special Interest .............................................. 88 
8.4.8. 
Participation Card ........................................................................ 88 
8.5. 
Pharmacokinetics ....................................................................................... 89 
8.6. 
Genetics ..................................................................................................... 89 
8.7. 
Biomarkers ................................................................................................. 90 
8.7.1. 
Biomarkers of Disease Progression ............................................. 90 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 91 
9.1. 
Statistical Hypotheses................................................................................. 91 
9.1.1. 
Primary endpoint .......................................................................... 91 
9.1.2. 
Secondary endpoints ................................................................... 91 
9.2. 
Sample Size Determination ........................................................................ 92 
9.2.1. 
Sample size assumptions ............................................................ 92 
9.3. 
Analysis Sets .............................................................................................. 94 
9.4. 
Statistical Analyses ..................................................................................... 94 
9.4.1. 
General Considerations ............................................................... 95 
9.4.2. 
Primary and Secondary Endpoint(s) ............................................ 95 
9.4.3. 
Safety Endpoint(s) ..................................................................... 100 
9.4.4. 
Exploratory Endpoint(s) ............................................................. 101 
9.4.5. 
Other Analyses .......................................................................... 101 
9.5. 
Interim Analysis ........................................................................................ 101 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................. 102 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations .......................................................................................... 102 
10.1.1. 
Regulatory and Ethical Considerations ...................................... 102 
10.1.2. 
Financial Disclosure ................................................................... 102 
10.1.3. 
Informed Consent Process ........................................................ 103 
10.1.4. 
Recruitment Strategy ................................................................. 104 
10.1.5. 
Data Protection .......................................................................... 104 
10.1.6. 
Committee Structure .................................................................. 105 
10.1.7. 
Dissemination of Clinical Study Data ......................................... 105 
10.1.8. 
Data Quality Assurance ............................................................. 106 
10.1.9. 
Source Documents .................................................................... 106 
10.1.10. Study and Site Start and Closure ............................................... 107 
10.1.11. Publication Policy ....................................................................... 108 
10.2. 
Appendix 2: Clinical Laboratory Tests ....................................................... 109 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 111 
10.3.1. 
Definition of AE .......................................................................... 111 
10.3.2. 
Definition of SAE ........................................................................ 112 
10.3.3. 
Definition of Cardiovascular Events ........................................... 113 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................. 114 
10.3.5. 
Reporting of SAE to GSK ........................................................... 116 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..................................... 117 
10.4.1. 
Definitions: ................................................................................. 117 
10.4.2. 
Contraception Guidance: ........................................................... 118 
10.5. 
Appendix 5: Genetics ................................................................................ 120 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
22 
10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................ 121 
10.7. 
Appendix 7: Country-Specific Requirements ............................................. 123 
10.7.1. 
China ......................................................................................... 123 
10.7.2. 
Israel .......................................................................................... 131 
10.7.3. 
France ....................................................................................... 132 
10.8. 
Appendix 8: Home Healthcare/Remote Activities ...................................... 134 
10.8.1. 
Overall Rationale for this Appendix ............................................ 134 
10.8.2. 
Home Healthcare Provisioning ................................................... 134 
10.8.3. 
Protocol Defined Procedures/Visits ............................................ 135 
10.8.4. 
Study Intervention(s) .................................................................. 136 
10.8.5. 
Data Management/Monitoring .................................................... 137 
10.9. 
Appendix 9: Activities of Daily Living (ADLs) ............................................. 138 
10.10. Appendix 10: Abbreviations, Definitions of Terms, and Trademarks ......... 139 
10.11. Appendix 11: Protocol Amendment History ............................................... 150 
11. REFERENCES ..................................................................................................... 161 
 
 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
23 
LIST OF TABLES 
Table 1 
Scenarios for Participant Discontinuation ............................................... 72 
Table 2 
CTCAE 5 Severity Scale for Diarrhea ..................................................... 76 
Table 3 
Study Intervention Actions for Severe Diarrhea (CTCAE 5 
criteria) ................................................................................................... 76 
Table 4 
Expected Change from Baseline in Weekly Itch Score (WIS) ................. 93 
Table 5 
Protocol Required Safety Laboratory Tests .......................................... 109 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
24 
LIST OF FIGURES 
Figure 1 
Difference from Placebo in change from baseline in Monthly Itch 
Score over the entire 12-week treatment period (Intend To Treat 
[ITT] population) ..................................................................................... 42 
Figure 2 
Mean difference from placebo in percentage itch responder days 
during 12 weeks’ treatment (ITT population) .......................................... 43 
Figure 3 
Expected Change from Baseline in MWDI* ............................................ 93 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
25 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A two-part, randomized, placebo controlled, double blind, multicenter, 
Phase 3 study to evaluate the efficacy and safety of linerixibat for the treatment of 
cholestatic pruritus in participants with primary biliary cholangitis (PBC).  
Brief Title: Global Linerixibat Itch STudy of Efficacy and Safety iN PBC (GLISTEN) 
Rationale:  
Cholestatic pruritus burdens up to three quarters of patients with PBC during the course 
of their disease. This itch due to this rare and chronic liver disease, represents a serious 
condition that continues to lack effective treatments. 
Linerixibat, an ileal bile acid transporter inhibitor administered as an oral tablet, is 
minimally absorbed from gastrointestinal tract. Linerixibat is anticipated to reduce 
pruritus and associated symptoms in patients with PBC by increasing the excretion of bile 
acids and reducing bile acid concentrations in systemic circulation. Twice daily 
linerixibat has demonstrated significant improvement in cholestatic pruritus in PBC 
patients in previous Phase 2a and Phase 2b studies.  
Moreover, the Phase 2b dose ranging study (201000 – NCT02966834 –referred to as the 
GLIMMER study) demonstrated linerixibat 40 mg twice daily (BID) as the minimally 
effective dose providing improvement in cholestatic pruritus over 12 weeks of treatment 
with a low rate of discontinuation due to gastrointestinal (GI) intolerability.  
This Phase 3 study will further investigate the efficacy and safety of 24 weeks of 40 mg 
BID oral linerixibat for the treatment of pruritus in PBC patients with moderate to severe 
cholestatic pruritus (Part A), as well as assess the return of itch over 8-weeks after 
withdrawal of 40 mg BID oral linerixibat compared to placebo (Part B). Participants 
enrolled in the study may be treatment naïve, have been previously treated, or may take 
stable background itch therapy at the discretion of the physician in the best interest of the 
patient. Definitions of cholestatic pruritus treatments can be found in the main protocol 
text. 
Participants will record itch scores twice daily using an electronic Diary (eDiary). A 0-10 
Numerical Rating Scale (NRS), which has been validated in the PBC population, will be 
used to assess itch with a response option of 0 representing no itching and 10 the worst 
imaginable itching. Every morning the participant will record the worst itch experienced 
the night before and every evening, the participant will record the worst itch experienced 
that day. 
The itch scores for any day, week, and month will then be determined as follows: 
• 
Worst Daily Itch Score: the worst of the two scores recorded daily will be 
considered the score for that day 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
26 
• 
Weekly Itch Score (WIS) (formerly referred to as Mean Worst Daily Itch 
[MWDI] Score): the average of the Worst Daily Itch scores in one week 
• 
Monthly Itch Score: the worst Weekly Itch Score for that month (i.e., worst 
week score of the 4 weeks) 
Cholestatic pruritus has a negative impact on health-related quality of life (QoL) for PBC 
patients. The Primary Biliary Cholangitis-40 Questionnaire (PBC-40) is a disease-
specific health-related QoL instrument consisting of 6 domains: social, emotional, 
symptoms, fatigue, itch (including an item on sleep disturbance from itching) and 
cognitive. Results from the GLIMMER study demonstrated significant improvement 
from baseline in the social and emotional domains of PBC-40 for participants receiving 
40mg BID linerixibat. Therefore, this study will further evaluate the effect of linerixibat 
on PBC-40 domains. Since sleep is only a single item in PBC-40 and sleep disturbance is 
a major complaint of PBC patients, participant’s sleep will also be evaluated using the 
daily eDiary. Participants will record a sleep interference score each morning using a 
0-10 NRS, where 0 represents no sleep interference and 10 represents complete sleep 
interference. For each week, the average of the Daily Sleep Scores will be used to 
calculate the Weekly Sleep Score (formerly referred to as the Mean Daily Sleep Score). 
The Monthly Sleep Score is the worst Weekly Sleep Score for that month (i.e., worst 
week score of the 4 weeks). 
Objectives: 
Objectives* 
Endpoints 
Primary 
To investigate the effect of treatment 
with oral linerixibat compared with 
placebo on itch in PBC patients with 
cholestatic pruritus over 24 weeks 
(Part A) 
• 
Change from Baseline in Monthly Itch 
Scores over 24 weeks using a 0-10 NRS 
Secondary 
To evaluate the early effects of oral 
linerixibat compared to placebo on itch 
in PBC patients with cholestatic 
pruritus (Part A) 
• 
Change from baseline in Weekly Itch 
Score at Week 2 
To characterize the effects of treatment 
with oral linerixibat compared with 
placebo on health related QoL (Part A) 
• 
Change from Baseline in Monthly Sleep 
Score as measured by 0-10 NRS over 
24 weeks 
• 
Change from Baseline in PBC-40 
domain scores at Week 24 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
27 
Objectives* 
Endpoints 
Secondary (continued) 
To evaluate the effects of 24 weeks of 
treatment with oral linerixibat 
compared to placebo on itch response 
rates in PBC patients with cholestatic 
pruritus (Part A) 
• 
Responder defined as achieving a 
≥2-point reduction from Baseline in the 
Monthly Itch Score at Week 24.  
• 
Responder defined as achieving a 
≥3-point reduction from Baseline in the 
Monthly Itch Score at Week 24.  
• 
Responder defined as achieving a 
≥4-point reduction from Baseline in the 
Monthly Itch Score at Week 24.  
To investigate the treatment effect of 
oral linerixibat compared with placebo 
on Patient’s Global Impression of 
Severity (PGI-S) and Patient’s Global 
Impression of Change (PGI-C) 
throughout the treatment period 
(Part A) 
• 
Change from baseline in PGI-S over 
24 weeks 
• 
PGI-C over 24 weeks 
To evaluate the effects of treatment 
with linerixibat on markers of PBC 
disease activity and progression 
(Part A) 
• 
Change from baseline in alkaline 
phosphatase (ALP) at Week 24 
• 
Change from baseline in bilirubin at 
Week 24 
Safety 
To evaluate the safety of oral 
linerixibat compared with placebo 
(Part A and Part B) 
Clinical assessments including, but not 
limited to:  
• 
Adverse Events (AEs) and Serious 
Adverse Events (SAEs) 
• 
Vital signs 
• 
12-lead Electrocardiogram (ECG) 
• 
Clinical laboratory evaluation (including 
liver chemistry panel and fasting lipids) 
Exploratory 
To investigate the improvement, 
maintenance, or return of itch (Part B)  
• 
Change from Baseline (Part A) in 
Weekly Itch Score at 8 weeks 
• 
Change from Baseline (Part B) in 
Monthly Itch Score over 8 weeks 
(maintenance) 
*Linerixibat refers to linerixibat with stable background itch therapy if applicable. Placebo refers to placebo 
with stable background itch therapy if applicable. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
28 
Estimands: 
Unless otherwise specified, all primary and secondary study objectives will be assessed 
using estimands defined with the following common elements in terms of population, 
treatment comparison and approach for managing intercurrent events. 
Population 
• 
PBC patients with cholestatic pruritus 
Treatment 
• 
Linerixibat + background itch therapy if applicable 
• 
Placebo + background itch therapy if applicable 
Intercurrent 
events 
• 
Permanent treatment discontinuation, disruptions in treatment or 
treatment delays unrelated to the COVID-19 pandemic: 
addressed with treatment policy strategy, i.e., regardless of the 
intercurrent event occurring.  
• 
Permanent treatment discontinuation, disruptions in treatment, or 
treatment delays related to the COVID-19 pandemic: addressed 
with hypothetical strategy, i.e., the outcomes impacted by the 
COVID-19 related intercurrent events will be discarded 
• 
Change in background itch therapy or use of rescue medication: 
addressed with treatment policy strategy, i.e., regardless of the 
intercurrent event occurring 
 
Summary Measures for the study objectives are as follows: 
Endpoint 
Summary Measure 
Primary objective 
Change from Baseline in Monthly Itch 
Scores over 24 weeks using a 0-10 NRS 
Difference in means averaged over 
24 weeks between treatment groups 
Secondary objectives 
Change from baseline in Weekly Itch 
Score at Week 2 
Difference in means between treatment 
groups 
Change from Baseline in Monthly Sleep 
Score as measured by 0-10 NRS over 
24 weeks 
Difference in means averaged over 
24 weeks between treatment groups 
Responder defined as achieving a 
≥2-point reduction from Baseline in the 
Monthly Itch Score at Week 24 
Difference in proportions between 
treatment groups 
Responder defined as achieving a 
≥3-point reduction from Baseline in the 
Monthly Itch Score at Week 24 
Difference in proportions between 
treatment groups 
Responder defined as achieving a 
≥4-point reduction from Baseline in the 
Monthly Itch Score at Week 24 
Difference in proportions between 
treatment groups 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
29 
Endpoint 
Summary Measure 
Secondary objectives (continued) 
Change from Baseline in PBC-40 domain 
scores at Week 24 
Difference in means between treatment 
groups 
Change from baseline in PGI-S over 
24 weeks 
Difference in means averaged over 
24 weeks between treatment groups 
PGI-C over 24 weeks 
Difference in means averaged over 
24 weeks between treatment groups 
Change from baseline in ALP at Week 24 Difference in means between treatment 
groups 
Change from baseline in bilirubin at 
Week 24 
Difference in means between treatment 
groups 
Supplementary Estimand for the Primary Objective 
A supplementary estimand for the primary objective will be defined to assess the 
hypothetical treatment effect of linerixibat compared to placebo in the absence of 
intercurrent events including treatment discontinuation, disruptions in treatment or 
treatment delays, changes in itch therapy or use of rescue. In this case all Daily Itch Score 
data impacted by the intercurrent events will be discarded. 
Overall Design: 
This study is a Phase 3, multicenter, 2-part (Part A and Part B), randomized, 
double-blind, placebo-controlled study in PBC patients with moderate to severe pruritus. 
Part A will evaluate the efficacy, safety and impact on health-related quality of life of 
linerixibat compared with placebo over 24 weeks, while Part B will assess the return of 
itch over 8 weeks after withdrawal of linerixibat. In both Part A and Part B, participants 
may be treatment naïve, have had prior itch therapy and/or may take stable background 
itch therapy at the discretion of the physician in the best interest of the patient or rescue 
medication where applicable.   
This study consists of four Periods (Screening, Intervention (Part A and Part B) and 
Follow-up): 
Screening Period: Participants will attend two screening visits to assess eligibility as 
described below: 
• 
Screening 1 (Visit 1): Assessments to be performed as described in the schedule 
of assessments (SoA). Itch severity will be assessed retrospectively based on 
participant recall and then prospectively for eligibility purposes using a twice 
daily eDiary throughout the screening period. 
• 
Screening 2 (Visit 2): Additional liver biochemistry assessments to be 
performed at least 4 weeks after screening visit 1 to ensure stability of liver 
disease for participant safety and eligibility purposes. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
30 
Intervention (Treatment) Period Part A (Day 1 through Week 24): Eligible participants 
will be randomized in a 1:1:1:1 ratio to receive linerixibat 40 mg BID in Part A and Part 
B, linerixibat 40 mg BID in Part A and placebo in Part B, placebo in Part A and Part B, 
or placebo in Part A and linerixibat 40 mg BID in Part B.  
The primary analysis will be performed when all randomized participants have completed 
the Part A intervention period (up to Week 24/Visit 9), as described in Section 9.4. The 
blinding strategy is described in Section 6.4. 
Randomization will be stratified by:  
• 
Severity of pruritus based on Monthly Itch Score for the 28 days preceding 
randomization: 
o Moderate: ≥ 4 and < 7  
o Severe: ≥ 7 
• 
Concomitant cholestatic pruritus treatment regimen (definitions of cholestatic 
pruritus treatments can be found in the main protocol text):  
o Bile acid binding resin-containing regimen 
o Regimen that does not contain bile acid binding resins  
o No cholestatic pruritus treatment.  
The region (US or rest of the world) and site categorized by whether the visits will be 
conducted fully remotely will serve as an administrative stratification factor. The primary 
analysis will not adjust for this administrative stratification factor. Further details will be 
provided in the SAP. 
Intervention (Treatment) Period Part B (Week 24 through Week 32): Participants who 
had initially been taking linerixibat in Part A will either continue on linerixibat or switch 
to placebo at Week 24 for Part B. Participants who had been taking placebo in Part A will 
either continue on placebo or switch to linerixibat at Week 24 for Part B. 
Follow-up Period or Follow-on Study:  
Participants who complete treatment in Part A and Part B will be offered the opportunity 
to take part in a separate long-term follow-on study, where linerixibat will be provided in 
an open-label manner. This open-label, long-term study will assess safety and tolerability 
(and efficacy in participants transferring from this study). Participants who do not enter 
the follow-on study or are discontinued from study treatment but remain in the study will 
have a follow up phone call approximately 7-14 days after the last dose of study drug. 
Where applicable country and local regulations allow, some or all of the participant visits 
may be conducted remotely or via a virtual trial platform. Home healthcare services may 
also be utilized to support these activities where local regulations and infrastructure 
allow. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
31 
Number of Participants: 
This study plans to randomize approximately 230 participants with PBC and moderate to 
severe cholestatic pruritus. 
Participants receiving concomitant bile acid binding resins may comprise up to 15% of 
the overall Phase 3 study population. 
Based on GLIMMER (201000) study, it is expected that at least 20% of participants in 
the study will be receiving concomitant itch therapy and/or have had prior itch therapy; 
patients entering the study have moderate to severe itch and as such these patients have 
not adequately responded to or are intolerant to available standard of care. 
Intervention Groups and Duration: 
The total duration of the study including screening, treatment and follow up phone-call (if 
performed) is not expected to exceed 42 weeks. Visit frequency will be approximately 
every 4 weeks during treatment. 
• 
Screening: Up to 56-day screening window. 
• 
Part A: 24 weeks treatment with either linerixibat 40 mg BID or placebo 
• 
Part B: 8 weeks treatment with either linerixibat 40 mg BID or placebo 
• 
Follow-up: 2 weeks (for those not enrolling in the follow-on study) 
Data Monitoring / Other Committee: Yes 
An Independent Data Monitoring Committee (IDMC) will perform a futility analysis of 
efficacy at the planned interim analysis for the study and evaluate the safety of 
participants. 
 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
32 
1.2. 
Schema 
 
 
 
 
linerixibat 40 mg BID
6 to 8 weeks
8 weeks
24 weeks
Screening
Period
Intervention Period
Part B
2 weeks
*The follow-up period will only apply to participants who do not enrol into a follow-on study
Part A
Follow Up
Period*
placebo
Placebo
linerixibat 40 mg BID
R
Day 1
Week 24
linerixibat 40 mg BID
Placebo
R = Randomization


TMF-16740250 
CONFIDENTIAL 
212620
 
 
Protocol Amendment 04 
 
33 
1.3. 
Schedule of Assessments (SoA) 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
Part A 
Part B 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial site 
to perform study assessments (Please 
see Section 10.8). 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit window 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to 
-6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Recheck clinical status before 
randomization. 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Including height and weight. 
Brief physical 
examination  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Please see Section 8.3.1; physical 
exams may be performed as symptom 
directed exams or by other means if 
assessment performed at locations 
other than the clinical site. 


TMF-16740250 
CONFIDENTIAL 
212620
 
 
Protocol Amendment 04 
 
34 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
Part A 
Part B 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial site 
to perform study assessments (Please 
see Section 10.8). 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit window 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to 
-6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Medical history 
and prior/current 
conditions  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Including substance usage (drugs, 
alcohol, tobacco and caffeine), family 
history of premature cardiovascular 
(CV) disease and PBC specific 
Medical History and past-PBC-related 
procedures. 
Any change in medical history since 
screening should be reviewed at Day 1, 
and a baseline stool frequency should 
be recorded as described in 
Section 7.1.3.  
Background Itch 
Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
The investigator will ask participants to 
rate their overall itch severity for the 2 
months preceding the screening visit as 
described in Section 8.2.1.1. 
Urine Pregnancy 
test (Women of 
Childbearing 
Potential 
[WOCBP] only) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Refer to Section 8.3.5, serum 
pregnancy may be required locally in 
some locations. 


TMF-16740250 
CONFIDENTIAL 
212620
 
 
Protocol Amendment 04 
 
35 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
Part A 
Part B 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial site 
to perform study assessments (Please 
see Section 10.8). 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit window 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to 
-6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Human 
Immunodeficiency 
Virus (HIV), 
Hepatitis B and C 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Laboratory tests  
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Refer to Section 10.2, Clinical 
laboratory tests at Visit 2 refer to liver 
biochemistry parameters only. 
Fecal Occult 
Blood Test 
(FOBT) 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Please see Section 8.3.4.2.  
Exploratory 
Biomarkers 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Please see Section 8.7.  
Sample on Day 1 should be taken prior 
to any study intervention 
administration. 
Assessment is not required if study 
treatment is permanently discontinued. 
Enhanced Liver 
Fibrosis (ELF) 
Test 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
ELF may not be performed in China 
due to operational limitations. 


TMF-16740250 
CONFIDENTIAL 
212620
 
 
Protocol Amendment 04 
 
36 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
Part A 
Part B 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial site 
to perform study assessments (Please 
see Section 10.8). 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit window 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to 
-6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Fibroscan 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
To be performed only where site 
availability permits; please see 
Section 8.7.1.2.  
Pharmacokinetics 
(PK) 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
PK samples are required at a total of 3 
timepoints, 1 sample is required prior 
to first study intervention 
administration at Visit 3 and 2 further 
samples will be required at any 2 
additional visits between weeks 8 and 
24. 
Assessment is not required if study 
treatment is permanently discontinued. 
12-lead ECG 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
Vital signs 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic sample 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Please see Section 8.6. Sample is 
optional and to be taken predose if 
possible. 
Genetic samples will not be collected 
in China or Israel.   


TMF-16740250 
CONFIDENTIAL 
212620
 
 
Protocol Amendment 04 
 
37 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
Part A 
Part B 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial site 
to perform study assessments (Please 
see Section 10.8). 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit window 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to 
-6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Study intervention 
dispensing 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Study intervention 
administration 
 
 
 
======================================→ 
 
 
Day 1 is the day on which the first 
study intervention administration takes 
place and may differ from the 
randomization date. 
Medication diary 
 
 
 
======================================→  
 
Study medication diary to be 
completed daily throughout the study. 
The medication diary is not required if 
study treatment is permanently 
discontinued. 
Study intervention 
return/compliance 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Event 
(AE) review 
 
 
 
=====================================→ 
X 
X 
AEs will be collected from the start of 
study intervention.  
Serious Adverse 
Event (SAE) 
review 
=======================================================→ 
X 
X 
 
Concomitant 
medication review 
=======================================================→ 
X 
X 
Including PBC-specific Medications 
(past and present). 


TMF-16740250 
CONFIDENTIAL 
212620
 
 
Protocol Amendment 04 
 
38 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
Part A 
Part B 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial site 
to perform study assessments (Please 
see Section 10.8). 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit window 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to 
-6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Symptom 
Questionnaire 
=======================================================→ 
X 
 
Symptom Questionnaire includes the 
itch, sleep and fatigue NRS. Please see 
Section 8.2.1.1. 
Gastrointestinal 
Symptom Rating 
Scale 
 
 
================================================→ X 
 
Questionnaire on GI symptoms to be 
completed weekly in eDiary with a 
seven day recall as described in 
Section 8.2.1.3.  
PGI-C 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient Global Impression of Change 
Questionnaire 
PGI-S 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient Global Impression of Severity 
PBC-40  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PBC-40 Health Related Quality of Life 
Scale 
BDI-II 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
Beck Depression Inventory II 
ESS 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
Epworth Sleepiness Scale 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
 
39 
2. 
INTRODUCTION 
2.1. 
Study Rationale 
Cholestatic pruritus burdens up to three quarters of PBC patients through the course of 
their disease [Hegade, 2014; Hegade, 2019]. This itch due to the rare, chronic liver 
disease is a serious condition that causes significant impairment of day-to-day 
functioning, including sleep disturbance, fatigue, depression, and suicidality [Jin, 2016; 
Hegade, 2016; Younossi, 2000; Hönig, 2018]. 
Limitations of efficacy and tolerability of current treatments mean that patients are left 
with restricted choices. Thus, there is a continued urgent unmet medical need for new 
treatments for cholestatic pruritus in PBC that provide symptomatic relief and reduce the 
impact of pruritus on quality of life. 
Linerixibat, an ileal bile acid transporter inhibitor administered as a twice daily (BID) 
oral tablet, has shown significant improvement in cholestatic pruritus in PBC patients in 
Phase 2 studies (BAT117213 and the previously mentioned GLIMMER study). 
Moreover, the GLIMMER study demonstrated linerixibat 40 mg BID as the minimally 
effective dose providing improvement on cholestatic pruritus over 12 weeks of treatment 
with a low rate of discontinuation due to gastrointestinal (GI) intolerability. 
Primary Biliary Cholangitis-40 Questionnaire (PBC-40) is a disease-specific health-
related quality of life (QoL) instrument consisting of 6 domains: social, emotional, 
symptoms, fatigue, itch (including an item on sleep disturbance from itch domain) and 
cognitive. Results from the GLIMMER study demonstrated clinically and statistically 
significant improvement from baseline in the social and emotional domains of PBC-40 
for participants receiving 40 mg BID linerixibat. Since sleep is only a single item in 
PBC-40 and sleep disturbance is a major complaint of PBC patients with cholestatic 
pruritus, participant’s sleep was also evaluated daily in the eDiary using an NRS scale 
and concordant improvements in itch and sleep were observed in GLIMMER. The 
Epworth Sleepiness Scale (ESS) has also been included to further assess the impact of 
itch relief on sleep and daytime somnolence. 
This Phase 3 study will further investigate the efficacy and safety of 24 weeks of 40 mg 
BID oral linerixibat with stable background itch therapy, if applicable, for the treatment 
of pruritus in PBC patients with moderate to severe cholestatic pruritus (Part A), as well 
as assess the return of itch over 8-weeks after withdrawal of 40 mg BID oral linerixibat 
compared to placebo (Part B). Participants enrolled in the study can take stable 
background itch therapy (if applicable) at the discretion of the physician in the best 
interest of the patient. 
2.2. 
Background 
2.2.1. 
Overview of Disease 
Primary biliary cholangitis is a rare, chronic autoimmune disease characterized by 
granulomatous inflammatory destruction of intrahepatic bile ducts leading to intrahepatic 
cholestasis, retention of bile acids and other toxic metabolites, and eventual cirrhosis and 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
 
40 
liver failure. A combination of genetic risk factors and environmental exposures has been 
proposed for the etiology of PBC [Lindor, 2019].  
The major symptoms of PBC affecting QoL are cholestatic pruritus (itch) and fatigue 
[Lindor, 2019, Zakharia, 2018; Younossi, 2000]. While the origin of cholestatic pruritus 
in PBC is still unknown, it has long been suspected that some component of bile that 
accumulates in serum contributes to pruritus. Patients with clinically significant pruritus 
fare worse than those with mild or no itch on all the QoL domains (fatigue, social, 
emotional, cognitive, and other symptoms) of the PBC-40, a disease specific health-
related quality of life instrument [Carey, 2020]. 
Overall, pruritus has been reported to affect almost three quarters of PBC patients at 
some time during their disease, but the prevalence of pruritus at any given point in time is 
around 50% [Hegade, 2014; Hegade, 2019]. Recent observational studies report the 
prevalence of approximately 30% when restricted to moderate to severe pruritus [Hegade, 
2014; Tanaka, 2016; Yagi, 2017; Carey, 2018; Hönig, 2018]. Intractable pruritus may be 
an indication for liver transplantation [Lindor, 2019].  
In clinical practice, response rates <50% are common for most of the guideline-
recommended therapies for cholestatic pruritus [Levy, 2011]. Bile acid sequestrants are 
recommended as first-line therapy in treatment guidelines for cholestatic pruritus in PBC, 
despite a limited evidence base and tolerability is often an issue [Lindor, 2019; EASL, 
2017; Komori, 2014; Chengwei, 2015]. Only one therapy, cholestyramine, is approved in 
the United States [Questran USPI] and China for pruritus associated with partial biliary 
obstruction and in Europe [Questran SmPC] for pruritus associated with partial biliary 
obstruction and partial biliary cirrhosis. Reduction of serum bile acids through ileal bile 
acid transporter (IBAT) inhibition is showing promise in treating pruritus in PBC and 
other cholestatic conditions [Karpen, 2020]. 
2.2.2. 
Background information on the product 
Linerixibat (also referred to as GSK2330672) is a soluble and selective inhibitor of the 
human ileal bile acid transporter (IBAT) [Wu, 2013], also known as apical sodium-
dependent bile acid transporter (ASBT), that is minimally absorbed from the GI tract. 
Linerixibat is being developed as a novel, oral treatment for cholestatic pruritus 
associated with PBC. 
Inhibition of the IBAT by linerixibat decreases pruritic serum bile acids through fecal 
elimination [Hegade, 2017]. Linerixibat has demonstrated reduction in itch and potential 
for improvement in sleep and health-related quality of life (QoL) in cholestatic pruritus in 
PBC patients in both Phase 2a (BAT117213) and GLIMMER studies as described in the 
below sections and in the Investigator’s Brochure (IB).  
2.2.3. 
Clinical Studies 
The effect of linerixibat on cholestatic pruritus in PBC was evaluated in the BAT117213 
study and the GLIMMER dose-range finding study.  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
 
41 
BAT117213 was a randomized, double-blind, placebo-controlled 2-period cross-over trial 
in which linerixibat was administered as 45 mg BID for the first 3 days and increased to 
90 mg BID on Day 4 of the randomized active treatment period. This study enrolled 
participants with severe pruritus and newly diagnosed or untreated pruritus who qualified 
based on disease status and clinical symptoms. Linerixibat treatment for 14 days resulted 
in significant reductions from baseline in itch intensity scores as measured by numerical 
rating scale (NRS), PBC-40 itch domain and 5-D itch scale (p<0.0001 for all) in both 
treatment sequences after linerixibat treatment [Hegade, 2017]. Compared to the 
double-blind placebo treatment, linerixibat reduced itch intensity significantly more in all 
three scales; between treatment differences were: –23% (95% CI, –1 to –45, p=0·0374) 
for NRS, –14% (95% CI, –1 to –26, p=0·0335) for PBC-40 itch domain, and –20% (95% 
CI, –7 to –34, p=0·0045) for 5-D itch. This was accompanied by a significant reduction 
in serum total bile acid concentrations of more than 50%, which was reversed within 
2 weeks of stopping linerixibat. In contrast, there was a 12% increase in serum total bile 
acid concentrations after placebo dosing. In this study, linerixibat also demonstrated 
statistically significant improvements in the fatigue domain of PBC-40 and sleep 
interference following 14 days of treatment [Hegade, 2017]. In general, linerixibat was 
well tolerated without SAEs. An equal number of AEs were reported during placebo and 
study intervention treatment periods. There was a 33% incidence of diarrhea reported as 
an adverse event while on linerixibat vs. 5% on placebo. The individual episodes tended 
to be mild in severity and short lived in the majority of cases. No subjects discontinued 
dosing or had their dose decreased secondary to diarrhea. 
The GLIMMER study was a randomized, double-blind parallel-group, dose-finding study 
further evaluating linerixibat for the treatment of pruritus in patients with PBC. This 
study assessed the efficacy, safety, and tolerability, and assessed dose and dosing 
regimen (once vs. twice daily). Participants must have had proven PBC, rated their itch 
severity as being ≥ 4 on a 0 to 10-point NRS for the majority of time during the 8 weeks 
prior to the screening visit, and on stable doses of ursodeoxycholic acid (UDCA) (or 
enrolled 8 weeks after their last dose of UDCA if not taking UDCA due to intolerance). 
Eligible patients were randomized based on an NRS itch score of ≥ 3. Additionally, they 
could continue to receive therapies including anti-histamines, rifampicin, naltrexone, 
naloxone, nalfurafine or sertraline for the treatment of cholestatic pruritus in PBC 
provided the medications were maintained at stable doses with no plan to discontinue 
them during the study. Concomitant use of cholestyramine, colesevelam, colestimide or 
colestipol was not permitted until after completion of the treatment period. 
Participants were randomized to treatment with placebo or one of the five linerixibat 
doses of 20 mg, 90 mg, 180 mg once daily (QD), 40 or 90 mg BID for up to 12 weeks. 
Itch was measured morning and evening using an NRS anchored with 0 (no itching) and 
10 (worst imaginable itching).  
Following the Screening period, there were four study periods: a 4-week single-blind 
Run-in Period where all participants received placebo; a 12-week Main Study Period 
where participants received double-blind treatment with placebo or linerixibat, a 4-week 
Final Period where all participants received placebo, and a 2-week follow-up period. The 
147 eligible participants were randomized based on Mean Worst Daily Itch Score (now 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
 
42 
referred to as the Weekly Itch Score in Study 212620 [GLISTEN]) of ≥3 (averaged over 
the 7 days prior to randomization).  
Mean pruritus intensity scores were reduced (itch improved) at the end of the Main Study 
Period for all treatment groups including the placebo arm (please refer to IB Section 
5.4.4). Due to the potential for itch to fluctuate over time, the change from Baseline in 
Monthly Itch Score (worst week of the month) over the entire treatment period was used 
to evaluate the duration and stability of treatment effect. A mixed-effect repeated 
measure (MMRM) analysis of this endpoint thus utilized data across the whole 12-week 
Main Study period (as opposed to an analysis using a single timepoint) and resulted in a 
statistically significant difference from placebo for 40 mg BID (p=0.0105), 90 mg BID 
(p=0.0370) and 180 mg QD (p=0.0424) doses (Figure 1).  
Figure 1 
Difference from Placebo in change from baseline in Monthly Itch 
Score over the entire 12-week treatment period (Intend To Treat [ITT] 
population) 
 
Note: Error bars show 95% Confidence Interval (CI). 
Furthermore, a rapid reduction of itch was observed for the 40 mg BID and 90 mg BID 
dosing groups compared to placebo as early as Weeks 1 and 2 (data on file). Based on 
this observation, a secondary endpoint assessing change in Weekly Itch Score at Week 2 
will be evaluated in the current study.  
In addition, within person change using the responder definition (defined as ≥2-point 
improvement in mean worst daily itch score [now referred to as Weekly Itch Score in the 
current 212620 (GLISTEN) study] from baseline) provides interpretation for the primary 
endpoint in terms of clinical meaningfulness of the result. Percentage of itch responder 
days also favored BID dosing, with a mean increase of 20% for 40 mg BID and 27% for 
90 mg BID groups relative to placebo (Figure 2).  
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
 
43 
Figure 2 
Mean difference from placebo in percentage itch responder days 
during 12 weeks’ treatment (ITT population) 
 
Note: Error bars show Standard Error (SE). 
Of note, among the total study population approximately 29% (42/147) had prior history 
of treatment with bile acid binding resins and 29% (42/147) of participants were 
receiving concomitant itch therapy during the study. Neither prior treatment with bile 
acid binding resins nor concomitant treatment with pruritus therapy during the study were 
significant after accounting for treatment groups in an analysis of covariates. 
Impact on health-related QoL was also evident following treatment with linerixibat. 
Improvement on sleep interference was highly correlated to improvement on itch score 
across all treatment groups (R=0.84, data on file).  
All arms including placebo showed significant improvement from baseline in the itch 
domain of PBC-40 but only the 40 mg BID dose demonstrated significant improvements 
from baseline in the PBC-40 social and emotional domains.  
The most frequently reported drug-related AEs across all treatment groups were diarrhea 
and abdominal pain, with diarrhea demonstrating an increase of incidence with increasing 
dose (placebo 8%, 20 mg QD 31%, 90 mg QD 48%, 180 mg QD 59%, 40 mg BID 39%, 
90 mg BID 64%). Diarrhea and abdominal pain were also the AEs most frequently 
leading to study drug discontinuation across all treatment groups (10 participants and 
5 participants, respectively). The discontinuation incidence due to diarrhea was lower in 
the 40 mg BID group (4%) compared to the 90 mg BID (14%) and 180 mg QD (19%) 
treatment groups. Diarrhea was mostly mild to moderate in severity, there were no SAEs 
related to diarrhea and no case of dehydration during the treatment period were observed.  
There were 3 SAEs which were all considered not related to study treatment (lumbar 
spinal stenosis 90 mg QD; lower respiratory tract infection 20 mg QD; constipation 
180 mg QD).   
No notable change from Baseline or difference from placebo was observed for Enhanced 
Liver Fibrosis (ELF) tests, liver function tests (LFTs), bone biochemistry or liposoluble 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol Amendment 04 
 
44 
vitamins across the treatment arms. There were no clinically significant patterns of 
abnormal vital sign measurements, ECG changes, or clinical laboratory findings 
observed.  
Overall, the 40 mg BID dose demonstrated significant improvement in pruritus over 
12 weeks of treatment, as well as significant change from baseline in the social and 
emotional domains of PBC-40. Gastrointestinal tolerability data also favored 40 mg BID 
dosing over higher doses.  
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of linerixibat may be found in the IB. 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
45 
2.3.1. 
Risk Assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product [GSK2330672/linerixibat] 
• Gastrointestinal 
effects including 
diarrhea, abdominal 
pain and abdominal 
discomfort. 
• Animal studies including altered bowel motions (see 
the IB, Section 4.5). 
• AEs in humans including diarrhea and loose stools (see 
the IB, Section 5.3).  
• Diarrhea adverse events were seen in studies with PBC 
participants and cholestatic pruritus (BAT117213 and 
GLIMMER) as described in Section 2.2.3 and the IB, 
Section 5.3.3.2. 
• Abdominal pain events were reported in healthy 
participants and in studies with PBC participants with 
cholestatic pruritus (BAT117213 and GLIMMER) as 
described in Section 2.2.3 and the IB, Section 5.3.3.2. 
• Exclusion of participants with current 
clinically significant diarrhea in the 
Investigator’s medical opinion (see 
Section 5.2).  
• Monitoring/stopping criteria for participants 
experiencing diarrhea have been provided 
as found in Section 7.1.3.  
• Study aids providing guidance to 
investigators for management of diarrhea 
will be provided in the Study Reference 
Manual (SRM). 
• Potential gallstones 
due to interruption of 
enterohepatic 
recirculation of bile 
acids. 
• A single SAE of acute cholecystitis (imaging 
confirmed cholelithiasis) was reported in GSK study 
200185 in a Type 2 diabetes (T25D) participant (see 
the IB, Section 5.3.3.1). 
• A phenome-wide association study (PheWAS) 
conducted by GSK under the United Kingdom 
Biobank Ethics and Governance Framework, using 
data from a large cohort (379,337 participants from the 
• Exclusion of participants with current 
symptomatic cholelithiasis or inflammatory 
gallbladder disease (cholecystitis) (see 
Section 5.2). 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
46 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
UK Biobank) suggested an association between 
genetically determined impairment of the 
enterohepatic recirculation of bile acids with an 
increased risk of gallbladder disease and 
cholecystectomy, but not with colorectal cancer 
[Campbell, 2018]. An additional pheWAS performed 
in up to 2.5 million European ancestry (EUR) 
23andMe cohort participants identified significant 
associations among 82,913 participants with a history 
of gallstones for two IBAT Lack of Function (LOF) 
variants with experimentally validated effects on 
SLC10A2 function [McLaughlin, 2020]. 
• Hypertriglyceridemia 
due to interruption of 
enterohepatic 
recirculation of bile 
acids. 
• Slight increases in triglycerides were seen in T2D 
participants in study 201351 (see the IB, Section 5.3). 
• Lipid profiles will be monitored throughout 
the study as at the timepoints listed in 
Section 1.3. 
• Increase in alanine 
aminotransferase 
(ALT). 
• Transient elevations in alanine aminotransferase 
(ALT) of up to 3x upper limit of normal (ULN) have 
been observed in 4 healthy participants (see the IB, 
Section 5.3). 
• Liver increased monitoring criteria (increase ALT >2 x 
baseline and ALT> 3 x ULN) were reached in 7 PBC 
participants in the GLIMMER study (see the IB, 
Section 5.3). 
• Stopping/monitoring rules for liver 
chemistry have been implemented as 
described in Section 7.1.1.  
• Liver enzymes will be monitored throughout 
the study at the timepoints listed in 
Section 1.3. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
47 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
• In the GLIMMER study, one participant in the 
linerixibat 90 mg BID group met the liver stopping 
criteria for ALT levels (reported as an AE of abnormal 
liver test) 60 days after receiving linerixibat. This 
event resolved after a duration of 98 days. The 
investigator noted that the AE of abnormal liver test 
could have been related to study medication and study 
medication was permanently discontinued. The 
participant had also experienced a non-serious AE of 
tooth abscess approximately 6 weeks prior, which 
resulted in tooth extraction and associated dental 
infection and was treated with amoxicillin and 
metronidazole antibiotics. Based on the information, 
there is a possibility that the concomitant antibiotics 
and painkillers may have contributed to the abnormal 
LFTs (see the IB, Section 5.4.3).  
• Increased risk of 
colon cancer in 
association with 
increased fecal 
excretion of bile 
acids  
• Although a theoretical association between increased 
colonic bile acids and colorectal cancer has been 
postulated there is no direct evidence of causation 
between bile acids and the development of colon 
cancer [Acosta, 2014].  
• Two large pheWAS studies in 379,337 and up to 2.5 
million European ancestry participants respectively, 
did not suggest an association between genetically 
determined impairment of the enterohepatic 
recirculation of bile acids (loss of function IBAT 
variants, SLC10A2) with an increased risk of 
• FOBTs will be collected at the timepoints 
shown in the SoA (see Section 1.3) as 
described in Section 8.3.4.2.  
• Stopping criteria for participants diagnosed 
with colon cancer at any point have been 
provided as found in Section 7.1.6. 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
48 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
colorectal cancer [Campbell, 2018, McLaughlin, 
2020]. These findings were also supported by a 
genome -wide association study (GWAS) in 58,131 
European ancestry cases [Huyghe, 2019]. The genetic 
findings were consistent with published long-term 
follow-up of participants with ileal bypass surgery, 
which did not support an effect of enterohepatic 
circulation on colon cancer risk [Buchwald, 1990].   
• No reports of colon cancer (or similar events) have 
been reported in the linerixibat clinical program (see 
IB, Section 6.3.2.2). 
• Currently, the data suggests that there is no increase in 
risk of colorectal cancer in patients receiving 
linerixibat for cholestatic pruritus in patients with PBC 
(see IB, Section 6.3.2.2). 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
49 
2.3.2. 
Benefit Assessment 
There may be a number of potential benefits of participating in this study including: 
• Potential improvement in symptoms of pruritus associated with PBC during 
intervention. 
• Medical evaluations/assessments associated with study procedures that assess 
participant’s PBC (e.g., physical examinations, laboratory assessments). 
• Contribution to the process of developing new therapies for the treatment of pruritus 
associated with PBC. 
• Potential opportunity to participate in a long-term study of linerixibat as defined in 
Section 6.7. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with linerixibat are justified by the 
anticipated benefits that may be afforded to participants with PBC. 
3. 
OBJECTIVES AND ENDPOINTS/ESTIMANDS 
Itch will be recorded by participants twice daily using an eDiary as described in 
Section 8.2.1.1. A 0-10 NRS will be used, where 0 represents no itching and 10 the worst 
imaginable itching. Every morning the participant will record the worst itch experienced 
the night before and every evening, the participant will record the worst itch experienced 
that day. The itch scores for any day, week, and month will then be determined as 
follows: 
• 
Worst Daily Itch Score: the worst of the two scores recorded daily will be 
considered the score for that day 
• 
Weekly Itch Score (WIS) (formerly referred to as Mean Worst Daily Itch Score 
[MWDI]): the average of the Worst Daily Itch Scores in one week 
• 
Monthly Itch Score: the worst Weekly Itch Score for that month (i.e., worst 
week score of the 4 weeks) 
Cholestatic pruritus has a negative impact on health-related QoL for PBC patients. The 
PBC-40 is a disease-specific QoL instrument consisting of 6 domains: social, emotional, 
symptoms, fatigue, itch (including an item on sleep disturbance from itch domain) and 
cognitive. Results from the GLIMMER study demonstrated significant improvement 
from baseline in the social and emotional domains of PBC-40 for participants receiving 
40 mg BID linerixibat. Therefore, this study will further evaluate the effect of linerixibat 
on PBC-40 domains. Since sleep is only a single item in PBC-40 and sleep disturbance is 
a major complaint of PBC patients, participant’s sleep will also be evaluated using the 
daily eDiary. Participants will record a sleep interference score each morning using a 
0-10 NRS, where 0 represents no sleep interference and 10 represents complete sleep 
interference. For each week, the average of the Daily Sleep Score will be used to 
calculate the Weekly Sleep Score (formerly referred to as Mean Daily Sleep Score). The 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
50 
Monthly Sleep Score is the worst Weekly Sleep Score for that month (i.e., worst week 
score of the 4 weeks). 
Objectives* 
Endpoints 
Primary 
To investigate the effect of treatment 
with oral linerixibat compared with 
placebo on itch in PBC patients with 
cholestatic pruritus over 24 weeks 
(Part A) 
• 
Change from Baseline in Monthly Itch 
Scores over 24 weeks using a 0-10 
numerical rating scale (NRS) 
Secondary 
To evaluate the early effects of oral 
linerixibat compared to placebo on 
itch in PBC patients with cholestatic 
pruritus (Part A) 
• 
Change from baseline in Weekly Itch 
Score at Week 2 
To characterize the effects of 
treatment with oral linerixibat 
compared with placebo on health 
related QoL (Part A) 
• 
Change from Baseline in Monthly Sleep 
Score as measured by 0-10 NRS over 
24 weeks 
• 
Change from Baseline in PBC-40 domain 
scores at Week 24 
To evaluate the effects of 24 weeks 
of treatment with oral linerixibat 
compared to placebo on itch 
response rates in PBC patients with 
cholestatic pruritus (Part A) 
• 
Responder defined as achieving a ≥2-point 
reduction from Baseline in the Monthly 
Itch score at Week 24.  
• 
Responder defined as achieving a ≥3-point 
reduction from Baseline in the Monthly 
Itch score at Week 24.  
• 
Responder defined as achieving a ≥4-point 
reduction from Baseline in the Monthly 
Itch score at Week 24.  
To investigate the treatment effect of 
oral linerixibat compared with 
placebo on Patient’s Global 
Impression of Severity (PGI-S) and 
Patient’s Global Impression of 
Change (PGI-C) throughout the 
treatment period (Part A) 
• 
Change from baseline in Patient's Global 
Impression of Severity (PGI-S) over 
24 weeks 
• 
PGI-C over 24 weeks 
To evaluate the effects of treatment 
with linerixibat on markers of PBC 
disease activity and progression 
(Part A) 
• 
Change from baseline in ALP at Week 24 
• 
Change from baseline in bilirubin at 
Week 24 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
51 
Objectives* 
Endpoints 
Safety 
• 
To evaluate the safety of oral 
linerixibat compared with 
placebo (Part A and Part B) 
Clinical assessments including, but not limited 
to:  
• 
Adverse Events (AEs) and Serious 
Adverse Events (SAEs) 
• 
Vital signs 
• 
12-lead Electrocardiogram (ECG) 
• 
Clinical laboratory evaluation (including 
liver chemistry panel and fasting lipids) 
• 
Exploratory 
• 
To evaluate the gastrointestinal 
(GI) tolerability of oral 
linerixibat compared with 
placebo on gastrointestinal 
symptoms (Part A and Part B) 
• Change from Baseline in Gastrointestinal 
Symptom Rating Scale (GSRS) over time 
• 
To evaluate the effects of oral 
linerixibat compared to placebo 
on the percentage of itch 
response days (Part A) 
• 
Percentage of days participant achieves a 
≥2 point reduction from Baseline in the 
Worst Daily Itch score over 24 weeks. 
• 
Percentage of days participant achieves a 
≥3 point reduction from Baseline in the 
Worst Daily Itch score over 24 weeks. 
• 
Percentage of days participant achieves a 
≥4 point reduction from Baseline in the 
Worst Daily Itch score over 24 weeks. 
• 
To investigate the improvement, 
maintenance, or return of itch 
(Part B)  
• 
Change from Baseline (Part A) in Weekly 
Itch Score at 8 weeks 
• 
Change from Baseline (Part B) in Monthly 
Itch Score over 8 weeks (maintenance) 
• 
To investigate the improvement, 
maintenance, or decline of 
health-related quality of life 
(QoL) and other patient-reported 
outcomes (Part B) 
• Change from Baseline in  
o PBC-40 domain scores at 8 weeks 
o Monthly Sleep Score at 8 weeks 
o Monthly Fatigue Score at 8 weeks 
o Epworth Sleepiness Scale at 8 weeks 
o BDI-II at 8 weeks 
o PGI-S at 8 weeks 
• PGI-C at 8 weeks 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
52 
Objectives* 
Endpoints 
• 
Exploratory (continued) 
• 
To evaluate the effects of oral 
linerixibat compared with 
placebo on exploratory 
biomarkers (Part A and Part B) 
• 
Change from Baseline in concentrations of 
exploratory biomarkers including: 
o Serum C4 
o Total serum bile acids 
o Autotaxin  
o Fibroblast Growth Factor-19 (FGF-19)  
• 
Explore the effect of bile acid 
binding resins on linerixibat 
Pharmacodynamics (PD) (Part A 
and Part B) 
• 
Linerixibat serum biomarkers including: 
o Serum C4 
o Total serum bile acids  
o Autotaxin  
o FGF-19 
• 
To characterize the PK in PBC 
participants (Part A) 
• Determination of PK parameters by 
population PK analysis. 
• 
To evaluate the effect of 
linerixibat compared to placebo 
on non-invasive markers of liver 
fibrosis (where available) 
(Part A and Part B, if applicable) 
• 
Change from Baseline (Part A) in 
Enhanced Liver Fibrosis (ELF) at Week 24 
• 
Change from Baseline (Part B) in ELF at 
Week 8 
• 
Change from Baseline in Transient 
Elastography (Fibroscan) at Week 24 
• 
To further characterize the 
effects of oral linerixibat 
compared with placebo on 
symptoms and health-related 
quality of life (Part A) 
• 
Change from Baseline in Epworth 
Sleepiness Scale (ESS) over 24 weeks 
• 
Change from Baseline in Beck Depression 
Inventory-II (BDI-II) at 24 weeks 
• 
Change from Baseline in Monthly Fatigue 
Score as measured by 0 – 10 NRS over 24 
weeks. 
*Linerixibat refers to linerixibat with stable background itch therapy if applicable. Placebo refers to 
placebo with stable background itch therapy if applicable. 
3.1. 
Primary Estimand 
Unless otherwise specified, all primary and secondary study objectives will be assessed 
using estimands defined with the following common elements in terms of population, 
treatment comparison and approach for managing intercurrent events. 
Population 
• 
PBC patients with cholestatic pruritus 
Treatment 
• 
Linerixibat + background itch therapy if applicable 
• 
Placebo + background itch therapy if applicable 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
53 
Intercurrent 
events 
• 
Permanent treatment discontinuation, disruptions in treatment 
or treatment delays unrelated to the COVID-19 pandemic: 
addressed with treatment policy strategy, i.e., regardless of the 
intercurrent event occurring.  
• 
Permanent treatment discontinuation, disruptions in treatment 
or treatment delays related to the COVID-19 pandemic: 
addressed with hypothetical strategy, i.e., the outcomes 
impacted by the COVID-19 related intercurrent events will be 
discarded 
• 
Change in background itch therapy or use of rescue medication: 
addressed with treatment policy strategy, i.e., regardless of the 
intercurrent event occurring 
3.2. 
Summary Measures  
Endpoint 
Summary Measure 
Primary objective 
Change from Baseline in Monthly Itch 
Scores over 24 weeks using a 0-10 NRS 
Difference in means averaged over 
24 weeks between treatment groups 
Secondary objectives 
Change from baseline in Weekly Itch 
Score at Week 2 
Difference in means between treatment 
groups 
Change from Baseline in Monthly Sleep 
Score as measured by 0-10 NRS over 
24 weeks 
Difference in means averaged over 
24 weeks between treatment groups 
Responder defined as achieving a 
≥2-point reduction from Baseline in the 
Monthly Itch score at Week 24 
Difference in proportions between 
treatment groups 
Responder defined as achieving a 
≥3-point reduction from Baseline in the 
Monthly Itch score at Week 24 
Difference in proportions between 
treatment groups 
 
Responder defined as achieving a 
≥4-point reduction from Baseline in the 
Monthly Itch score at Week 24 
Difference in proportions between 
treatment groups 
 
Change from Baseline in PBC-40 domain 
scores at Week 24 
Difference in means between treatment 
groups 
Change from baseline in PGI-S over 
24 weeks 
Difference in means averaged over 
24 weeks between treatment groups 
PGI-C over 24 weeks 
 
Difference in means averaged over 
24 weeks between treatment groups 
Change from baseline in ALP at Week 24 
Difference in means between treatment 
groups 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
54 
Endpoint 
Summary Measure 
Change from baseline in bilirubin at 
Week 24 
Difference in means between treatment 
groups 
 
Summary measures for Part B are not included as these objectives are exploratory. For 
further details, please see Section 9.4.  
3.3. 
Supplementary Estimand  
A supplementary estimand for the primary objective will be defined to assess the 
hypothetical treatment effect of linerixibat compared to placebo in the absence of 
intercurrent events including treatment discontinuation, disruptions in treatment or 
treatment delays, changes in itch therapy or use of rescue. In this case all Daily Itch Score 
data impacted by the intercurrent events will be discarded (see Section 9.4 for further 
details). 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This study is a Phase 3, multicenter, 2-part (Part A and Part B), randomized, 
double-blind, placebo-controlled study in PBC patients with moderate to severe pruritus. 
Part A will evaluate the efficacy, safety, and impact on health-related quality of life of 
linerixibat with background itch therapy, if applicable, compared with placebo with 
background itch therapy, if applicable, over 24 weeks, while Part B will assess the return 
of itch over 8 weeks after withdrawal of linerixibat. Participants may be treatment naïve, 
have had prior itch therapy and/or may take stable background itch therapy at the 
discretion of the physician in the best interest of the patient or rescue medication where 
applicable.   
This study will consist of four periods:  
• 
Screening Period (up to 56 days) 
At Screening Visit 1 (Visit 1), screening assessments will be performed as described in 
the Schedule of Assessments (SoA) (Section 1.3). This will include a baseline itch 
evaluation in which the participant will be asked to rate their overall itch severity in the 
2 months preceding screening as described in Section 8.2.1.1. Participants will then enter 
the screening period during which participants must complete a symptom questionnaire 
in an electronic Diary (eDiary) for eligibility purposes which include itch and sleep NRS 
scores as defined in Section 8.2.1.1.  
Participants must also attend a second screening visit (Visit 2) to take place at least 
4 weeks after Visit 1, for further assessment of liver biochemistry. This is to ensure 
stability of liver disease and for participant safety and eligibility purposes as described in 
Section 8.3.4.1. 
• 
Intervention Period: Part A (Day 1 through Week 24) 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
55 
Eligible participants will be randomized in a 1:1:1:1 ratio to receive linerixibat 40 mg 
BID in Part A and Part B, linerixibat 40 mg BID in Part A and placebo in Part B, placebo 
in Part A and Part B, or placebo in Part A and linerixibat 40 mg BID in Part B.  
Randomization will be stratified by:  
• 
Severity of pruritus based on Monthly Itch Score for the 28 days preceding 
randomization: 
o Moderate: ≥ 4 and < 7  
o Severe: ≥ 7 
• 
Concomitant cholestatic pruritus treatment regimen (definitions of cholestatic 
pruritus treatments can be found in the main protocol text):  
o Bile acid binding resin-containing regimen 
o Regimen that does not contain bile acid binding resins  
o No cholestatic pruritus treatment.  
Bile acid binding resins include cholestyramine, colesevelam, colestimide and 
colestipol. Other cholestatic pruritus medications include antihistamines, 
fibrates, rifampicin, naltrexone, naloxone, nalfurafine, pregabalin, gabapentin or  
selective serotonin reuptake inhibitors (SSRIs). Please see further information 
on concomitant medications in Section 6.9. 
The region (US or rest of the world) and site categorized by whether the visits will be 
conducted fully remotely will serve as an administrative stratification factor. The primary 
analysis will not adjust for this administrative stratification factor. Further details will be 
provided in the SAP. 
The primary analysis will be performed when all randomized participants have completed 
the Part A intervention period (up to Week 24/Visit 9), as described in Section 9.4. The 
blinding strategy is described in Section 6.4. Part A is completed when the Week 24 Visit 
(Visit 9) is completed.  
• 
Intervention Period: Part B (Week 24 through Week 32) 
Participants who had initially been taking linerixibat in Part A will either continue on 
linerixibat or switch to placebo at Week 24 for Part B. Participants who had been taking 
placebo in Part A will either continue on placebo or switch to linerixibat at Week 24 for 
Part B. 
Part B is completed at the completion of Week 32 Visit (Visit 11). 
• Follow up (approximately 2 weeks) 
Participants who complete treatment in Part A and Part B will be offered the opportunity 
to take part in a separate long-term follow-on study as described in Section 6.7. 
Participants who do not enter the follow-on study or are discontinued from study 
treatment but remain in the study will complete a follow-up telephone call approximately 
7-14 days after the last dose of linerixibat. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
56 
The total expected duration of study participation for each participant is approximately 
40-42 weeks. 
Where applicable country and local regulations allow, some or all of the participant visits 
may be conducted remotely or via a virtual trial platform. Home healthcare services also 
may be utilized to support these activities where local regulations and infrastructure 
allow. 
Approximately 230 total participants with PBC and moderate to severe cholestatic 
pruritus are expected to be randomized into this study. Participants receiving concomitant 
bile acid binding resins may comprise up to approximately 15% of the overall total study 
population.  
Based on GLIMMER (201000) study, it is expected that at least 20% of participants in 
the study will be receiving concomitant itch therapy and/or have had prior itch therapy; 
patients entering the study have moderate to severe itch and as such these patients have 
not adequately responded to or are intolerant to available standard of care. 
An Independent Data Monitoring Committee (IDMC) will be utilized to evaluate futility 
for the interim analysis planned for the study (please see Section 9.5). Further detail on 
the IDMC will be provided in a separate charter. 
4.2. 
Scientific Rationale for Study Design 
4.2.1. 
Rationale for Study Blinding and Placebo Control 
This is a Phase 3, placebo-controlled study with a 24-week double-blind Part A, followed 
by an 8-week double-blind Part B. Previous studies of IBAT inhibitors in PBC patients 
have demonstrated that patient-reported itch may show some improvement on placebo 
treatment [Hegade, 2017; Mayo, 2019]. A placebo arm is employed in the study to help 
determine the true clinical effect of linerixibat relative to background cholestatic pruritus 
treatment. 
4.2.2. 
Rationale for Stratification Factors 
In order to balance the baseline itch score, treatment assignment for Randomization at 
Day 1 will be stratified according to the Monthly Itch Score during the 28 days before 
Day 1, using the categories: Moderate: Monthly Itch score ≥ 4 and < 7; Severe: Monthly 
Itch Score≥ 7. 
Concomitant use of stable treatments for cholestatic pruritus will be allowed (see 
Section 6.9.1), consistent with published guidelines by American Association for the 
Study of Liver Diseases (AASLD) [Lindor, 2019], European Association for the Study of 
the Liver [EASL, 2017], Ministry of Health, Labor and Welfare of Japan [Komori, 2014] 
and guidelines in China [Chengwei, 2015]. In order to balance the use of treatments for 
cholestatic pruritus, randomization will also be stratified by concomitant cholestatic 
pruritus treatment regimen (bile acid binding resin-containing regimen, regimen that does 
not contain bile acid binding resins, and no cholestatic pruritus treatment). Bile acid 
binding resins include cholestyramine, colesevelam, colestimide and colestipol.  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
57 
Other cholestatic pruritus medications include antihistamines, fibrates, rifampicin, 
naltrexone, naloxone, nalfurafine, pregabalin, gabapentin or SSRIs. Participants receiving 
concomitant bile acid binding resins may comprise up to 15% of the overall Phase 3 
study population. 
4.2.3. 
Rationale for Part B 
The Intervention Period will start with Part A (Day 1 through Week 24) followed by Part 
B (Week 24 through Week 32). Eligible participants will be randomized in a 1:1:1:1 ratio 
to receive linerixibat 40 mg BID in Part A and Part B, linerixibat 40 mg BID in Part A 
and placebo in Part B, placebo in Part A and Part B, or placebo in Part A and linerixibat 
40 mg BID in Part B. Therefore, participants who received placebo in Part A will either 
continue on placebo or switch to linerixibat at Week 24 for Part B. Participants who had 
received linerixibat in Part A will either continue on linerixibat or switch to placebo at 
Week 24 for Part B. 
Based on results of the GLIMMER data, it is expected that participants switched from 
linerixibat in Part A to placebo in Part B will have some return of their itch. The current 
8-week randomized-withdrawal in Part B allows evaluation of what occurs once 
linerixibat is removed compared to those who are maintained on placebo treatment in 
regard to itch, sleep, health-related QoL, and safety.  
4.2.4. 
Rationale for Concomitant Medications 
Participants may be receiving concomitant therapy with UDCA or fibrates for treatment 
of PBC or with standard of care therapies for cholestatic pruritus, including bile acid 
binding resins, fibrates, rifampicin, naltrexone, naloxone, nalfurafine, pregabalin, 
gabapentin or SSRIs. Any of these therapies, as well as other medications that may affect 
itch such as opioids, systemic corticosteroids, or antihistamines that may be prescribed 
for other indications, must be stable, defined as no initiation, discontinuation, or dose 
changes within 8 weeks of Screening, during the Screening period and throughout the 
Intervention (treatment) period of the study, including both Part A and Part B (Please see 
Section 6.9.1). This is to ensure that evaluation of linerixibat’s effect on pruritus is not 
confounded by changes in background therapies that may affect itch.   
Eligible participants who are not receiving any standard of care therapies for cholestatic 
pruritus may participate in the study. For these participants only, if worsening pruritus 
develops then rescue medication (cholestyramine) may be permitted, provided they have 
been in the study for at least 12 weeks, a duration that was acceptable during the 
GLIMMER trial, and meet additional itch criteria (see Section 6.9.3). Participants who 
are receiving background cholestatic pruritus therapy are not eligible for rescue 
medication and, changes in their cholestatic pruritus medications (initiation, 
discontinuation, or change in dose) at any time during the study will be considered a 
protocol violation as described in Section 6.9.3.  
Obeticholic acid (OCA) use is not permitted at any time during the study due to its 
potential to confound assessment of efficacy and safety. OCA is approved for use in a 
subset of PBC participants with an inadequate response to or intolerance to UDCA 
[Ocaliva US Prescribing Information, and EU SmPC, 2021], and is associated with a dose 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
58 
dependent exacerbation in pruritus leading to treatment discontinuation in 1–10% of 
participants [EASL, 2017]. In Study 213688 evaluating pharmacokinetic drug-drug 
interaction with 5 and 10 mg OCA, linerixibat 40 mg BID demonstrated a 
protocol-defined meaningful reduction in total-OCA concentration. It is not 
recommended to co-administer linerixibat with OCA (IB, Section 6.4.4). 
4.2.5. 
Rationale for Use of Itch Numerical Rating Scale as the Primary 
Endpoint 
There are no well-established physical or physiological markers of treatment activity of 
pruritus associated with cholestatic liver disease that can be observed or measured. The 
rating of itch is subjective, and each participant is likely to have a distinct response to 
treatment for cholestatic pruritus. The aim of treatment with linerixibat is to provide the 
symptomatic relief of pruritus associated with primary biliary cholangitis. Therefore, 
patient-reported outcomes (PRO) are the best way to measure a treatment effect. Both the 
BAT117213 and the GLIMMER study reflected this, where individual participant 
responses clearly showed rapid and significant improvement of pruritus following 
linerixibat treatment using multiple PRO assessments [Hegade, 2017; data on file].  
The Symptom Questionnaire, which includes the itch, sleep and fatigue NRS items 
(described in Section 8.2.1.1), was developed by GSK with input from patients with PBC 
and psychometricians to detect the severity and variability of pruritus and associated 
symptoms, as well as the potential effects of treatment with the current standard of care 
on these symptoms. The itch and sleep NRS items assess symptoms that are relevant, 
important to, and well understood by PBC patients, and the patients are able to select 
responses that best reflect their disease experiences. NRS scales are widely used as a 
measure of severity as they are clear and simple and effective at measuring single 
constructs [Gries, 2017]. An external validation study was completed to collect 
quantitative data to assess the psychometric properties of the Mean Worst Daily Score 
(now referred to as the Weekly Itch Score), PBC-40, and Symptom Questionnaire and 
GSRS (GSK Health Outcomes Study 212144). The study along with analysis of the 
GLIMMER study provided psychometric validation of the PRO measures (0-10 Worst 
Itch NRS item, Symptom Questionnaire, and the weekly version of the PBC-40) with 
input from PBC-related pruritic study subjects (data on file). 
4.2.6. 
Rationale for Questionnaires 
Cholestatic pruritus in patients with PBC is a serious condition that causes significant 
impairment of day-to-day functioning, including fatigue, sleep disturbance, depression, 
and suicidality [Jin, 2016; Hegade, 2016; Younossi, 2000; Hönig, 2018]. Participants will 
complete questionnaires in both Part A and Part B of the study in order to assess the 
impact on these parameters. The PBC-40 is a patient-derived, disease specific health-
related quality of life measure developed and validated for use in PBC [Jacoby, 2005] as 
described in Section 8.2.1.2.  
Since depressive symptoms are prevalent in PBC patients [Shaheen, 2018] the BDI-II 
will assess symptoms of depression as described in Section 8.2.1.5.  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
59 
Cholestatic pruritus often interferes with sleep therefore participants will rate their sleep 
NRS in the eDiary and the ESS will assess daytime sleepiness as described in 
Section 8.2.1.4. 
GI symptoms are the most commonly reported adverse events associated with linerixibat. 
The GSRS as described in Section 8.2.1.3 will be used to systematically evaluate 
gastrointestinal symptoms. Management of GI symptoms should be based on adverse 
event reports (see Section 7.1.3). 
4.2.7. 
Patient Input into Study Design 
A small group of 5 patients with PBC were interviewed to gain insights on key study 
design elements from the perspective of a potential study participant. Patients provided 
feedback on the placebo-controlled design and follow-on study and how those may 
impact their interest in participating, their ability to maintain daily diaries, take study 
intervention daily, and complete the other assessments; overall study duration, and 
eligibility criteria.  
The patients provided feedback that more clarity was needed about excluded medications 
and stable background medication requirements. Patients also stated that it should be 
clarified that background medications would still be permitted throughout the study. This 
feedback has been incorporated into this protocol (as defined in Section 6.9.1) and will be 
incorporated along with other operational aspects as part of the SRM. 
4.3. 
Justification for Dose 
The dose to be included in this 24-week study will be linerixibat 40 mg BID based on the 
efficacy and tolerability results of the GLIMMER study and kinetic-pharmacodynamic 
(K-PD) modelling. In the GLIMMER study, doses of 20 mg once daily (QD), 90 mg QD, 
180 mg QD, 40 mg BID, and 90 mg BID were evaluated over a 12-week, double-blind 
period. When comparing the mean change from baseline in the Monthly Itch Score over 
the 12-week main study period, the doses of 40 mg and 90 mg BID and 180 mg QD were 
statistically different than placebo. The 40 mg BID dose trended with the greatest 
difference compared to placebo in Mean Worst Daily Itch score when considering the 
worst week of the month (Monthly Itch Score) as compared to 90 mg BID and 180 mg 
QD. Only 40 mg BID dose demonstrated significant improvements from baseline in the 
PBC-40 social and emotional domains. In addition to the dose-dependent decrease in 
Mean Worst Daily Itch scores, biomarkers of target engagement (serum C4 and FGF-19) 
measured in GLIMMER demonstrated a greater response with BID dosing as compared 
to QD dosing. 
There was a dose-dependent relationship with gastrointestinal-related adverse events with 
a greater rate of permanent discontinuation and poorer tolerability at the higher doses of 
study intervention (180 mg QD and 90 mg BID) compared to 40 mg BID. Common 
gastrointestinal-related AEs, including diarrhea, abdominal pain, nausea, and vomiting, 
all trended to favor the 40 mg BID dose as compared to the higher doses. The most 
frequently reported AE was diarrhea, which was mostly mild to moderate, there were no 
reported SAEs associated with diarrhea and no case of dehydration during the treatment 
period. There were no clinically significant consequences of diarrhea. These results 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
60 
support the use of 40 mg BID in Phase 3. Further details on dose rationale are available in 
the IB.  
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the 
study in the trial globally. 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit. For participants that will enroll into a 
follow-on study this last visit is Week 32 or completion of any required follow-up. If the 
participant will not enroll in a follow-on study, this would include completion of the 
follow-up phone call as shown in the SoA (see Section 1.3) or any required follow-up. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Sex and Age 
1. Male and female participants must be between 18 to 80 years of age inclusive, at the 
time of signing the informed consent. 
Note: if country/site age requirements for consent differ, the more stringent (e.g., 
higher age) restriction will be required for that country/site. 
Type of Participant and Disease Characteristics 
2. Participants who have proven PBC, as demonstrated by historically having at least 2 
of the following: 
• 
Documented history of sustained increased ALP levels greater than ULN first 
recognized at least 6 months prior to the Screening Visit (Note: Sustained ALP 
elevations at the time of Screening is not required, recognizing that the ALP 
may have decreased after initiation of UDCA therapy). 
• 
Documented positive anti-mitochondrial antibody (AMA) titer (>1:40 titer on 
immunofluorescence or M2 positive by enzyme linked immunosorbent assay 
[ELISA] or by an alternative validated assay) or PBC-specific antinuclear 
antibodies (antinuclear dot and/or nuclear rim positive). 
• 
Liver biopsy (documented at any time in the past) consistent with PBC. 
3. Participants who, during the Screening period, record their daily itch score by 
entering at least 40 of the 56 required itch entries, with an entry on at least 4 days in 
each week, during the 4-week period immediately preceding Randomization at Day 1 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
61 
and have a Monthly Itch Score of  ≥4 (i.e., at least 1 of the 4 Weekly Itch Scores 
must be ≥4), and no Weekly Itch Score can be <3 for any other week. 
Contraceptive/Barrier Requirements  
4.  Contraceptive/Barrier Requirements (applicable for female participants only): A 
female participant is eligible to participate if she is not pregnant or breastfeeding, and 
one of the following conditions applies: 
o 
Is a woman of non-childbearing potential (WONCBP) 
OR 
o Is a woman of childbearing potential (WOCBP) and using an acceptable 
contraceptive method as described in Section 10.4 during the study intervention 
period (at a minimum until 4 weeks after the last dose of study intervention). 
The investigator should evaluate the potential for contraceptive method failure 
(e.g., noncompliance, recently initiated in relationship to the first dose of study 
intervention. 
• 
A WOCBP must have a negative highly sensitive urine pregnancy test (or serum as 
required by local regulations) within 7 days before the first dose of study 
intervention, see Section 8.3.5, Pregnancy Testing. 
Note: If a serum pregnancy test is required by local regulations, sample collection 
must be arranged before Visit 3 to ensure the result confirming eligibility can be 
available before randomization. 
o 
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be excluded 
from participation if the serum pregnancy result is positive.  
• 
Additional requirements for pregnancy testing during and after study intervention are 
located in Section 8.3.5. 
• 
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Note: Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
Informed Consent 
5. Capable of giving signed informed consent as described in Section 10.1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
62 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Total bilirubin >2.0 x ULN using the average of two baseline measures.  
Note: Total bilirubin > 2x ULN but < 3x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin is < 35%. 
2. Screening ALT > 6x ULN in a single baseline measure or ALT > 5x ULN using the 
average of two baseline measures. 
3. Participants with abnormal liver biochemistry (ALT, aspartate aminotransferase 
[AST], ALP, or total bilirubin) during the Screening period (at Visit 1 or Visit 2) and 
the variance between these two samples for the abnormal parameter is >40%.  
Note: Variance will be calculated as the absolute value of [(Sample 1- Sample 
2)/average of Sample 1 and Sample 2) x100]. Sample 1 and Sample 2 must be 
collected at least 4 weeks apart. 
If variance of >40% is seen between Visit 1 and 2 samples, an additional sample 
may be taken and the variance between the additional sample (third sample) and the 
Screening (Visit 1) sample must be ≤ 40%. 
4. Screening estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 based on 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 
5. History or presence of hepatic decompensation (e.g., variceal bleeding, hepatic 
encephalopathy or ascites). 
6. Presence of viral hepatitis B (HBsAg positive) or C (anti-HCV positive and RNA 
detected) infection, primary sclerosing cholangitis (PSC), alcoholic liver disease 
and/or confirmed hepatocellular carcinoma or biliary cancer.  
7. Infection with human immunodeficiency virus (HIV).  
8. Current clinically significant diarrhea in the Investigator’s medical opinion. 
9. Active inflammatory ileal disease according to Investigator´s clinical judgment. 
10. Current symptomatic cholelithiasis or cholecystitis. (Participants with history of 
cholecystectomy ≥12 weeks before screening may be eligible for enrolment at the 
discretion of the investigator.) 
11. Current diagnosis of primary skin disorders with itch as a characteristic feature (e.g., 
atopic dermatitis, psoriasis). 
12. Primary sleep disorders such as but are not limited to sleep apnea, narcolepsy, 
hypersomnia. 
13. Any current malignancies (including hematologic and solid malignancies). 
14. History of bariatric surgery with ileal bypass at any time, or any bariatric surgery 
performed in the past 3 years.  
15. Any current uncontrolled psychiatric condition. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
63 
16. Any current medical condition (e.g., senility or dementia), which may affect the 
participant’s ability to comply with the protocol specified procedures. 
Prior/Concomitant Therapy 
17. Initiation, discontinuation or change in dose of UDCA in the 8 weeks prior to 
Screening. (Participants may join the study on stable doses of UDCA, but no 
initiation, discontinuation, or change in dose is permitted until completion of the 
Treatment Periods.) 
18. Use of obeticholic acid: within 8 weeks prior to Screening. (Participants may not 
initiate or restart during the study, please see Section 6.9.2.) 
19. Initiation, discontinuation, or change in dose of fibrates at any time during the 
8 weeks prior to Screening. (Participants may join the study on stable doses of these 
medications, but no initiation, discontinuation, or change in dose is permitted until 
completion of the Treatment Periods.) 
20. Initiation, discontinuation, or change in dose of any of the following in the 8 weeks 
prior to Screening: bile acid binding resins, rifampicin, naltrexone, naloxone, 
nalfurafine, pregabalin, gabapentin, sertraline or other SSRIs. (Participants may join 
the study on stable doses of these medications, but no change in dose nor addition of 
new treatment for cholestatic pruritus is permitted during the study.)  
Note: Dosing of linerixibat and bile acid binding resins should be staggered by at 
least 4 hours. 
21. Initiation, discontinuation or change in dose of opioids, regardless of indication, in 
the 8 weeks prior to Screening. (Participants may join the study on stable doses of 
these medications). 
22. Initiation, discontinuation or change in dose of colchicine, methotrexate, 
azathioprine, or systemic corticosteroids in the 8 weeks prior to Screening. 
Note: If a change in dose in any of these medications is anticipated during the course 
of the study, the participant should be excluded.   
23. Initiation, discontinuation, or change in dose of antihistamines used for the treatment 
of itching the 8 weeks prior to Screening. 
Note: Antihistamines used acutely for indications other than itch (e.g., for acute 
allergic reactions) are permitted. 
24. Administration of any other IBAT inhibitor in the 12 weeks prior to screening.  
25. Any planned procedures intended to treat cholestatic pruritus such as nasobiliary 
drainage or ultraviolet light therapy from Screening and throughout the study. 
Prior/Concurrent Clinical Study Experience 
26. Current enrolment or participation within the 8 weeks before start of the Screening, 
in any other clinical study involving an investigational study treatment. 
Diagnostic assessments 
27. QTc >480 msec  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
64 
Notes:  
The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-
read or manually over-read. 
The specific formula used to determine eligibility and discontinuation for an 
individual participant should be determined prior to initiation of the study and 
should be the only QT correction formula used during the study. In other words, 
several different formulas cannot be used to calculate the QTc for an individual 
participant and then the lowest QTc value used to include or discontinue the 
participant from the trial. 
Other Exclusions 
28. History of sensitivity or intolerance to the study treatment or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or GSK 
Medical Monitor, contraindicates their participation in the study.  
29. Subjects with moderate (or greater) alcohol consumption defined as one standard 
drink per day for women and two drinks per day for men; whereby one standard 
drink is equivalent to: 12 oz beer (5% alcohol); 5 ounces of wine (12% alcohol),or 
1.5 ounces of 80 proof spirits (40% alcohol).  
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
There are no specific dietary restrictions required for participation in the study. 
Laboratory samples should be taken in a fasted state; no food is permitted 6 hours prior to 
sample collection, though water, study interventions and other medications are permitted.  
Dosing of study intervention should be taken at least 30 minutes before food or beverage 
(other than water) for both the morning and evening doses to ensure optimal efficacy. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
Participants should abstain from alcohol for 24 hours prior to laboratory samples 
being taken and should not consume one standard drink or more per day for women 
and two drinks or more per day for men whereby one standard drink is equivalent to 
12 oz beer (5% alcohol), 5 oz of wine (12% alcohol), or 1.5 oz of 80 proof spirits 
(40% alcohol).  
5.3.3. 
Activity 
• 
Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. For the duration of the study, until final follow 
up, participants are encouraged to refrain from changing their activity beyond that 
which they normally perform.  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
65 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized in to the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, any protocol deviations 
and any SAEs. Information on prior and current treatment for cholestatic pruritus may 
also be collected for screen failures to provide information on/insight into the treatment 
history of the PBC population with pruritus. 
In the case of COVID-19 diagnosis during the Screening period, the decision whether to 
continue screening the participant will be at the discretion of the investigator. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened one time at the Investigator’s discretion. The participant may be 
rescreened one additional time in consultation with the GSK Medical Monitor. The 
second rescreening must be approved in writing by the GSK Medical Monitor. 
Rescreening decisions should be documented to indicate that rescreening the participant 
will not introduce additional risk factors and will not interfere with study procedures or 
ability to interpret results. 
The interval between screening visits for the same participant should be a minimum of 
1-week. Rescreened participants should be assigned a new participant number for every 
screening/rescreening event. Previously assigned participant numbers are to be recorded 
in the participants’ electronic CRF (eCRF). 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
The definition of study intervention is provided in the table of definitions. Linerixibat is 
not yet authorized in any region. 
6.1. 
Study Intervention(s) Administered 
Study Intervention Name 
GSK2330672/linerixibat 
Placebo 
Dose Formulation 
 film coated tablet 
 film coated tablet 
Unit Dose Strength(s) 
40 mg tablets 
N/A 
Dosage Level(s) 
1 tablet taken twice daily 
1 tablet taken twice daily 
CCI
CCI


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
66 
Study Intervention Name 
GSK2330672/linerixibat 
Placebo 
Route of Administration 
Oral 
Oral 
Use 
Experimental 
Placebo comparator 
Sourcing 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
 
6.2. 
Preparation/Handling/Storage/Accountability 
• 
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
• 
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. Please refer to 
Section 10.8.4 for home healthcare permissions. 
• 
All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labelled storage 
conditions with access limited to the investigator and authorized site staff. 
• 
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
• 
Participants will be instructed to commence study treatment with the evening dose 
on the day that study treatment is received.  
• 
Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM. 
• 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study 
contact. 
• 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK. 
• 
The contents of the Study Interventional label will be in accordance with all 
applicable regulatory requirements. If allowed by country regulation/ethics, study 
intervention (including rescue study medication) can be shipped from the 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
67 
investigational site, depot, or appropriately designated facility to the participant’s 
home address. Used and/or unused IMP can also be collected from the participant’s 
home address to the return/destruction location. The process for this shipment must 
be agreed with GSK who will provide operational details if this service is available. 
6.3. 
Assignment to Study Intervention 
All participants will be centrally assigned to randomized study intervention using an 
IVRS/IWRS. Before the study is initiated, the telephone number and call-in directions for 
the IVRS and/or the log-in information and directions for the IWRS will be provided to 
each site. 
Study intervention will be dispensed at the study visits as summarized in the SoA.  
Returned study intervention should not be re-dispensed to the participants. 
6.4. 
Blinding 
This is a double-blind study in which participants, investigators, site personnel (including 
site pharmacists), and the Sponsor are blinded to study intervention.  
The primary analysis will be performed when all randomized participants have completed 
the Part A intervention period (up to Week 24/Visit 9), as described in Section 9.4; at 
which point the study will become partially unblinded (core sponsor team unblinded, site 
blinded). GSK personnel involved in direct communication with the study 
sites/investigators continuing on Part B of GLISTEN will remain blinded to the 
randomized treatment assignment of individual participants in the study. The results of 
the primary analysis will not be disseminated to site personnel, investigators (except for 
the one investigator signatory of the clinical study report (CSR), under confidentiality), or 
study participants until the study (including Part B) is fully completed and the study is 
fully unblinded. All efforts will be taken to protect site facing sponsor personnel and site 
personnel from unblinding, which is described in a separate blinding plan. No impact on 
trial integrity is expected. 
Individual participant-level, de-identified (not associated with participant number), and 
unblinded exploratory biomarker (TSBA) and tolerability data (AEs of diarrhea and 
GSRS scores) will be analyzed prior to unblinding the study for population K-PD model 
development. Independent sponsor programmers and clinical pharmacology modeling 
and simulation (CPMS) analysts will have access to actual randomization and dosing 
information. In addition to the dosing information and pharmacodynamic (PD) endpoint 
records, variables to be investigated as predictive covariates in the K-PD models such as 
demographics, concomitant medication data, safety laboratory data, and exploratory 
biomarker concentrations (e.g. C4, FGF-19, autotaxin) at one or more timepoints (e.g., 
prior to the final analysis) throughout the study will be made available. Individuals 
unblinded early will have no involvement in the study conduct including any analysis of 
blinded PRO data described in Section 9.4.5. Procedures are described in a separate 
blinding plan, and no impact on trial integrity is expected. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
68 
The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participant’s intervention assignment is warranted. Participant safety must always be the 
first consideration in making such a determination. If the investigator decides that 
unblinding is warranted, the investigator should make every effort to contact GSK prior 
to unblinding a participant’s intervention assignment unless this could delay emergency 
intervention for the participant. If a participant’s intervention assignment is unblinded, 
GSK must be notified within 24 hours of this occurrence. The date and reason why the 
blind was broken must be recorded. 
A participant will be withdrawn from study intervention if the participant’s intervention 
code is unblinded by the investigator or treating physician, however the participant will 
be asked to remain in the study and complete all remaining study visits. The primary 
reason for discontinuation (the event or condition which led to the unblinding) will be 
recorded in the eCRF. 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy. 
6.5. 
Study Intervention Compliance 
• 
When participants self-administer study intervention(s) at home, they will be 
required to document administration of study treatment in a daily eDiary. 
Compliance with study treatment will be assessed by the number of returned tablets 
confirmed by site staff at each visit and supported by the medication eDiary data. 
Compliance will be documented in the source documents and eCRF. Deviations that 
impact overall compliance with the prescribed dosage regimen should be recorded. 
• 
A record of the quantity of linerixibat dispensed to and administered by each 
participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention 
delays and/or dose reductions will also be recorded. 
6.6. 
Dose Modification 
No modification of individual participant’s study intervention dose is permitted. 
6.7. 
Continued Access to Study Intervention after the End of the 
Study 
The sponsor will not provide treatment after the end of the study. However, participants 
who complete treatment in Part A and Part B will be given the opportunity to take part in 
an open-label, long-term follow-on study assessing safety and tolerability (and efficacy in 
participants transferring from this study), where linerixibat will be provided in an open-
label manner. This follow on study is expected to continue for approximately four years 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
69 
until study end, linerixibat can be lawfully made available to participants, or the study is 
terminated.  
Participants who wish to take part in this or any further follow-on studies must provide 
separate consent to those studies and meet the study-defined eligibility criteria. 
6.8. 
Treatment of Overdose 
For this study, any dose of linerixibat greater than 180 mg (greater than 4 tablets) per day 
will be considered an overdose. 
GSK does not recommend specific treatment for an overdose.  
In the event of an overdose, the investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
linerixibat can no longer be detected systemically. 
3. Obtain a plasma sample for PK analysis within 24-72 hour from the date of the last 
dose of study intervention if requested by the Medical Monitor (determined on a 
case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF. 
5. Decisions regarding dose interruptions or modifications will be made by the 
investigator in consultation with the Medical Monitor based on the clinical 
evaluation of the participant. 
6.9. 
Concomitant Therapy 
Any medication or vaccine (including over the counter or prescription medicines, 
recreational drugs, vitamins, and/or herbal supplements) or other specific categories of 
interest that the participant has received in the 12 weeks prior to screening, is receiving at 
the time of enrolment or receives during the study must be recorded in the eCRF along 
with: 
• 
reason for use  
• 
dates of administration including start and end dates 
• 
dosage information including dose, route and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.9.1. 
Permitted Medications 
Details concerning reasons for taking medications must be recorded in the eCRF for all 
concomitant medications whether prescription or non-prescription, including topical 
agents. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
70 
Guidance for permitted agents that may be used in the study population, provided all 
details are recorded in the eCRF, are provided below, however this list is not exhaustive 
and further concomitant medications should be discussed with the Medical Monitor: 
• 
Colchicine, methotrexate, azathioprine, or systemic corticosteroids: If there 
is a clinical need to start one of these medications during the study, it should be 
discussed with the medical monitor wherever possible. During Follow-Up 
Period systemic corticosteroids may be permitted.  
• 
Anti-diarrheals: Participants experiencing diarrhea, in consultation with the 
Investigator, may take anti-diarrheal treatments (loperamide or suitable local 
alternative as agreed by the Medical Monitor) obtained over the counter. Use of 
these treatments and their effect will be recorded at each review of concomitant 
medications (please see Section 7.1.3). 
Concomitant therapy for PBC or any medications that may affect itch as shown below are 
permitted but must be stable prior to Screening and throughout the Screening and 
Treatment Periods (i.e. no treatments in these categories may be initiated, 
discontinued or dose changed in the 8 weeks prior to Screening and throughout the 
study).  
• 
UDCA: Participants may be enrolled in the study on UDCA provided the dosing 
regimen is consistent with product labelling. Deviations from product labelling 
are permitted if medically necessary as judged by the Investigator. The UDCA 
dosing regimen must remain stable during the study 
• 
Bile acid binding resin medications: Dosing of bile acid binding resin 
medications such as cholestyramine, colesevelam, colestipol or colestimide 
should be altered so that dosing is separated from the study intervention 
(linerixibat) by at least 4 hours for the duration of study participation. 
• 
Rifampicin, naltrexone, naloxone, nalfurafine, gabapentin, pregabalin: Use 
of these agents is permitted during the study.  
• 
Fibrates: Use of these agents is permitted during the study.  
• 
Selective Serotonin Reuptake Inhibitors (SSRIs): Use of these agents is 
permitted during the study. 
• 
Opioid Medications: Use of these agents is permitted during the study. 
• 
Antihistamines (topical or systemic): Antihistamines may not be initiated for 
the treatment of itch, but antihistamines used regularly in the two months before 
screening may be continued without change in dose. Antihistamines used 
acutely for indications other than itch (e.g. for treatment of acute allergic 
reactions) may be initiated, discontinued, or dose changed as needed. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
71 
6.9.2. 
Prohibited Medications 
Other IBAT inhibitors: Use of any IBAT inhibitor except for the study intervention, is 
not permitted at any time during the study. 
Obeticholic acid: Use is not permitted at any time during the study. Obeticholic acid 
should not have been used for at least 8-weeks prior to the screening visit. 
6.9.3. 
Rescue Medication 
Rescue medication is permitted only for participants who are not receiving background 
cholestatic pruritus treatment when entering the study. If a participant reports 
experiencing worsening itch and requests rescue therapy, it may be considered only after 
12 weeks of randomized treatment. Rescue medication may be considered if either of the 
following criteria are met: 
1. Monthly itch score at or after Week 12 (Visit 6) has increased by at least 2 points 
compared to baseline AND is ≥ 7 
OR  
2. For participants with a baseline Monthly Itch Score > 8 Monthly itch score at or 
after Week 12 (Visit 6) is 10 
Once these criteria have been satisfied, the investigator may offer treatment with 
cholestyramine to the participant per treatment guidelines. Any use of rescue medications 
will be recorded in the eCRF. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
No replacement is planned for participants who discontinue/withdraw from the study. 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. In all cases, the participant should be encouraged to discuss any potential 
study intervention discontinuation with the investigator prior to stopping study 
intervention.  
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance or administrative reasons as described in Section 7.2. If study intervention is 
permanently discontinued following randomization and before the scheduled follow up, 
participants should not be withdrawn from the study and should complete the remaining 
scheduled visits and all required assessments, including the patient-reported Symptom 
Questionnaire and all other PRO assessments. Exploratory biomarkers, PK, and 
medication diaries are not required to be completed for participants remaining on the 
study but withdrawn from study treatment. Participants who have been withdrawn from 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
72 
study treatment but will remain in the study will not be required to complete an Early 
Discontinuation Visit but should complete a follow-up phone call 7-14 days after last 
dose of study treatment. 
If the participant is withdrawing from the study, they will be encouraged to complete 
Early Discontinuation Visit (please refer to Section 1.3, SoA) before their last dose of 
study intervention if possible. Table 1 below outlines the scenarios for participant 
discontinuation and the assessments required to be performed.  
Table 1 
Scenarios for Participant Discontinuation 
Discontinuing Study Treatment but will 
remain on the study 
Follow up phone call 7-14 days after last 
dose of study treatment; continue 
scheduled visits as planned. Early 
Discontinuation Visit is not required to be 
performed. 
Withdrawing from Study 
Early Discontinuation Visit conducted as 
soon as possible after withdrawal 
decision, and follow-up phone call 7-14 
days after last dose of study treatment. 
Note: If an Early Discontinuation Visit is 
completed between 7 and 14 days after 
last dose of study treatment, additional 
follow-up phone calls are not required 
 
7.1.1. 
Liver Chemistry Monitoring/Discontinuation Criteria 
Liver chemistry increased monitoring and stopping criteria have been designed to assure 
participants’ safety and evaluate liver event etiology. 
Participants will be informed on the signs and symptoms of potential liver injury such as 
abdominal pain, nausea, vomiting, loss of appetite, dark yellow urine, yellow eyes, or 
skin, or persistent fatigue, and report such symptoms immediately to the study center, 
even after the study has been concluded. The monitoring/discontinuation criteria outlined 
in the following sections should be used for participant monitoring. 
7.1.1.1. 
Increased monitoring: 
Increased safety monitoring is required under the circumstances listed below. The 
baseline defined below is described in Section 8.3.4.1. 
• 
Participants with normal baseline liver indices who develop elevations of any of 
the following:  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
73 
o ALT ≥3x ULN  
o AST ≥3x ULN 
o Total bilirubin ≥2x ULN 
o ALP ≥2x ULN and GGT ≥2x ULN 
• 
Participants with abnormal baseline liver indices who develop elevations of any 
of the following: 
o ALT ≥2x baseline  
o AST ≥2x baseline  
o Total bilirubin ≥1.5x baseline 
o ALP ≥2x baseline and GGT ≥2x baseline 
In the event of abnormal laboratory parameters as described above, repeat testing should 
be performed within 48-72 hours. If there are persistent elevations upon repeat testing of 
any of the criteria defined above, then close observation (see Section 7.1.1.3), and study 
intervention discontinuation should be considered (see Section 7.1.1.2).  
7.1.1.2. 
Stopping criteria 
Study intervention will be stopped (permanently or temporarily) for a participant if any of 
the following stopping criteria are met: 
• 
AST ≥8x ULN 
• 
ALT ≥8x ULN 
• 
ALT ≥3x baseline and ≥5x ULN 
• 
AST ≥3x baseline and ≥5x ULN 
• 
ALT≥3x ULN and INR > 1.5 and the participant is not receiving anticoagulants 
(if normal at baseline) 
• 
AST ≥3x ULN and INR > 1.5 and the participant is not receiving anticoagulants 
(if normal at baseline) 
• 
ALT≥2x BL and INR > 1.5 and the participant is not receiving anticoagulants (if 
abnormal at baseline) 
• 
AST ≥2x BL and INR > 1.5 and the participant is not receiving anticoagulants 
(if abnormal at baseline) 
• 
Total bilirubin ≥2x baseline and ≥1.5x ULN 
• 
Total bilirubin ≥3x ULN 
• 
ALP ≥2x ULN and GGT ≥2x ULN (if normal at baseline) or ALP ≥2x baseline 
and GGT ≥2x baseline (if abnormal at baseline) AND either: total bilirubin ≥2x 
baseline and ≥2x ULN, or direct bilirubin ≥2x baseline and ≥2x ULN, or new or 
worsening of liver-related symptoms*.  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
74 
• 
If there are liver chemistry elevations which, in the opinion of the investigator, are 
not attributable to the participant’s underlying PBC, or if there is worsening liver 
chemistry associated with appearance of new liver-related symptoms.  
*Liver-related symptoms, which may typically be associated with drug-induced liver 
injury, include fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, worsening pruritus and/or eosinophilia [>5%]. 
When liver stopping criteria are met, the study intervention should be immediately 
discontinued. Additional procedures and safety follow up will be required (see 
Section 10.6, Appendix 6) and close observation should be implemented (see 
Section 7.1.1.3). 
The GSK Medical Monitor must be notified within 24 hours of learning of the 
abnormality to confirm the participant’s study intervention cessation and follow-up.  
Upon completion of the liver safety follow-up, restart of study intervention (where there 
is a clear underlying non-Drug Induced Liver Injury [DILI] cause for the event) may be 
considered as outlined in Section 7.1.9.1. 
In all instances where study intervention is stopped due to meeting protocol-specified 
liver stopping criteria or investigator concern about possible deterioration in liver 
function, a formal adjudication of causality will be requested from the Hepatotoxicity 
Safety Panel. Details of this panel and the process of review will be provided in a 
separate charter. 
7.1.1.3. 
Close Observation 
If elevations persist upon repeat testing for participants who meet monitoring criteria or 
any participants who meet stopping criteria, the investigator should consult the medical 
monitor and the following ongoing monitoring should be performed: 
• 
Liver function tests (including AST, ALT, ALP, and direct bilirubin) should be taken 
two to three times weekly. Frequency of retesting can decrease to once a week or 
less if abnormalities stabilize or the study intervention has been discontinued and the 
subject is asymptomatic. 
• 
Obtaining additional tests to evaluate liver function, including international 
normalized ratio (INR) as appropriate. 
• 
Obtain a more detailed history of symptoms and prior or concurrent diseases.   
• 
Obtain a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets.   
• 
Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; Non-alcoholic Steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and 
biliary tract disease.   
• 
Obtain a history of exposure to environmental chemical agents.   


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
75 
7.1.2. 
Hepatic Encephalopathy  
Study intervention should be discontinued if the participant develops new clinically overt 
hepatic encephalopathy as per investigator clinical assessment against the published 
Westhaven 1-4 criteria [Vilstrup, 2014]. Under these circumstances, the liver event form 
should be completed in the eCRF, and the participant should be assessed for potential 
precipitants of encephalopathy.  
Study intervention can only be considered for restart following discussion with the 
Medical Monitor if an alternative (non-liver-related) cause of cognitive dysfunction is 
diagnosed and the episode is fully resolved and, in the investigator’s opinion unlikely to 
recur. 
7.1.3. 
Diarrhea Management Criteria and Stopping Criteria 
Diarrhea is an anticipated pharmacologic effect of linerixibat due to the increase in bile 
acid concentration in the colon and may be clinically similar to bile acid diarrhea. The 
most common clinical characteristics of bile acid diarrhea are loose (rarely watery) 
stools, stools without blood, and stools that are associated with urgency.  
Participants will be informed about diarrhea and will be instructed to contact the 
investigator if, at any time during the study, they are experiencing diarrhea that impacts 
their daily activities. In this study, the Common Terminology Criteria for Adverse Events 
(CTCAE), currently in version 5, will be used to quantitate the severity of diarrhea as 
well as the standard AE intensity grading defined in Section 10.3.4. This standard tool 
was initially developed by the National Cancer Institute.  
When study participants are experiencing diarrhea that is impacting their daily activities, 
investigators should instruct participants to use anti-diarrheal (loperamide or suitable 
local alternative as agreed by the Medical Monitor) for treatment (Details to be provided 
separately). Management of diarrhea with loperamide (or suitable local alternative as 
agreed by the Medical Monitor) following inhibition of IBAT has been previously 
described in the literature [Key, 2020] which supports its use in this study. 
7.1.3.1. 
Determination of diarrhea severity 
Diarrhea severity is determined in the context of normal stool frequency. At baseline, 
participants will be asked to describe their normal daily stool count and if they are 
currently experiencing diarrhea that is impacting their daily activities. This baseline stool 
frequency will be recorded for reference and calculation of diarrhea severity if needed 
and as described in the SRM.  
Participants should be asked about their experience with diarrhea at each visit as part of 
ongoing AE/SAE review. Diarrhea will be considered an AE of special interest (AESI) 
and will be recorded on a specific AESI eCRF page. AESIs are described in 
Section 8.4.7. 
Diarrhea severity will be assessed using the standard criteria in Section 10.3.4 and using 
CTCAE 5 criteria (as found in Table 2) in reference to their baseline stool frequency as 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
76 
mentioned above. For Activities of Daily Living (ADL) please see Section 10.9, 
Appendix 9. 
Table 2 
CTCAE 5 Severity Scale for Diarrhea 
 
Diarrhea should be managed as detailed in Section 7.1.3.2 and further details will be 
provided in the SRM.  
7.1.3.2. 
Stopping Criteria for Diarrhea (Grade 3 or 4) 
The criteria for decisions to permanently or temporarily discontinue study are shown in 
Table 3, as determined by the CTCAE criteria mentioned in Section 7.1.3.1, 
Determination of diarrhea severity. 
Table 3 
Study Intervention Actions for Severe Diarrhea (CTCAE 5 criteria) 
Study Intervention action 
Symptom Severity 
Temporary Discontinuation 
Grade 3 diarrhea 
Permanent Discontinuation 
≥ Grade 4 diarrhea 
 
Participants who have study intervention temporarily discontinued will be managed as 
clinically indicated until the participant returns to no more than Grade 2 diarrhea 
symptoms (i.e., ≤6 stools per day above baseline); at which time the study intervention 
may be restarted.  
Study intervention may be permanently discontinued, at the investigator’s discretion. 
7.1.4. 
QTc Stopping Criteria 
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the participant has been enrolled.  
• 
For example, if a participant is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual participant as well.  
• 
Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.   
Safety ECGs and other non-protocol specified ECGs are an exception. The QTc should 
be based on a single QTc value of an ECG obtained over a brief (e.g., 5-10 minute) 
recording period. If an automated reading is not available, the ECG should be manually 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
77 
over-read by the investigator or adequately trained physician. A participant who meets 
either of the criteria based on the single ECG reading will be withdrawn from study 
intervention:   
 
• QTc ≥530 msec AND/OR increase from baseline of QTc >60 msec 
 
7.1.5. 
Renal Stopping Criteria 
A participant’s study intervention will be discontinued if the confirmed eGFR is <30 
mL/min/1.73m2 based on the CKD-EPI equation at any time during the study. 
The investigator should consult with designated sponsor personnel regarding the potential 
for restarting study intervention. If medical input is required, the Medical Monitor will be 
consulted for guidance. 
7.1.6. 
Diagnosis of Colon Cancer 
Participants who are diagnosed with colon cancer at any point in the study will be 
permanently discontinued from study intervention. 
7.1.7. 
Pregnancy 
Female participants who become pregnant during the study should discontinue study 
intervention immediately. 
7.1.8. 
Temporary Discontinuation due to AEs 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention (see Section 10.3, Appendix 3).  
The investigator will make an assessment of intensity for each AE reported during the 
study as described in Section 10.3, Appendix 3.  
For diarrhea AEs only, an assessment should also be made using the CTCAE v5 criteria 
as described in Section 7.1.3.1.  
In cases where participants discontinue study intervention due to an AE, the investigator 
should consult with the Medical Monitor to determine the appropriate evaluation and 
guidance on whether study intervention may be re-started. 
7.1.9. 
Restart of Study Intervention 
7.1.9.1. 
Study Intervention Restart after Meeting Liver Stopping Criteria 
Restart refers to resuming study intervention following liver stopping events in which 
there is a clear underlying cause (other than DILI) of the liver event (e.g., biliary 
obstruction, pancreatic events, hypotension, acute viral hepatitis). Furthermore, restart is 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
78 
not permitted following liver stopping event when the underlying cause was 
alcohol-related hepatitis. 
Approval by GSK for participants to restart study intervention may be considered where: 
o Investigator requests consideration for study intervention restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5x baseline and ALT <3x ULN). 
o Possible study intervention-induced liver injury has been excluded by the principal 
investigator and the study team. This includes the absence of markers of 
hypersensitivity (otherwise unexplained fever, rash, eosinophilia).  
o There is no evidence of alcohol-related hepatitis. 
o IRB/IEC approval of study intervention restart must be obtained, as required. 
o The participant is informed of any associated risks of restart and a separate ICF for 
study intervention restart is signed by the participant  
• 
If restart of study intervention is approved by GSK in writing: 
o The participant must be provided with a clear description of the possible benefits and 
risks of study intervention administration, including the possibility of recurrent, more 
severe liver injury or death.   
o The participant must also provide signed informed consent specifically for the study 
intervention restart. Documentation of informed consent must be recorded in the 
study file.   
o Study intervention must be administered at the dose specified by GSK. 
o Participants approved by GSK for restart of study intervention must return to the 
clinic once a week for liver chemistry tests until stable liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol.  
o If participant meets protocol-defined liver chemistry stopping criteria after study 
intervention restart, study intervention should be permanently discontinued.  
o GSK Medical Monitor, and the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) must be informed of the participant’s outcome following study 
intervention restart.  
o GSK must be notified of any adverse events.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request for any 
reason (or without providing any reason).  
• 
A participant may be discontinued/withdrawn at any time at the discretion of the 
investigator for the occurrence of any condition that, in the opinion of the 
Investigator, significantly jeopardizes the wellbeing and safety of the participant 
(including serious or intolerable AE that prevents the participant from continuing 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
79 
with study participant). Discontinuation/withdrawal may also occur at the discretion 
of the investigator for any behavioral or compliance reasons. It is expected that these 
situations will be uncommon. 
• 
At the time of discontinuation from the study, if possible, an early termination visit 
should be conducted as soon as possible, as shown in the SoA (Section 1.3). See SoA 
for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed. 
• 
The participant will be permanently discontinued both from the study intervention 
and from the study at that time. 
• 
All data and samples collected up to and including the date of withdrawal of/last 
contact with the participant will be included in the study analysis. If the participant 
withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
• 
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
• 
Participants may be withdrawn from study intervention but encouraged to continue 
participation in the study (including collection of PRO/eDiary data) as described in 
Section 7.1. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
80 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timings are summarized in the SoA (see Section 1.3).  
• Protocol waivers or exemptions are not allowed  
• Where applicable country and local regulations and infrastructure for home 
healthcare allow, home healthcare may take place at a location other than the clinical 
trial site to perform study assessments (at the discretion of the investigator). The site 
may work with GSK to use a centrally appointed home nursing vendor for conduct of 
study assessments. Please refer to Section 10.8 for further details on home healthcare 
availability. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA. 
• Laboratory results that could unblind the study will not be reported to investigative 
sites or other blinded personnel. 
• The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 
mL. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Administrative Procedures 
8.1.1. 
Collection of demographic data 
Demographic data such as year of birth, sex, race, and ethnicity will be recorded in the 
participant’s eCRF. 
Collection of sex, race and ethnicity data is necessary to assess and monitor the diversity 
of the trial participants, and to determine if the trial participants are truly representative of 
the impacted population. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
81 
8.2. 
Efficacy Assessments 
An eDiary will be used to electronically collect a number of PROs as described in this 
section. All participants will receive sufficient training on PRO completion using 
electronic devices.  
The SoA (Section 1.3) defines the timepoints and visits at which PROs are to be 
collected.   
8.2.1. 
Patient Reported Outcomes (PROs) 
8.2.1.1. 
Symptom Questionnaire/eDiary 
A symptom questionnaire will be used to measure impact of linerixibat on itch, sleep, and 
fatigue as described below. In addition, the eDiary will prompt participants to record 
whether they are taking the study treatment, and details of any missed doses. 
Itch Numerical Rating Scale (NRS) 
Itch will be assessed throughout this study using an NRS scale. At the screening visit 
(Visit 1) itch severity will be assessed retrospectively based on participant recall. The 
participant will be asked to rate their overall itch severity in the 2 months preceding 
screening to establish whether their baseline itch is severe enough prior to entering the 
screening period.  
Following the Screening Visit (Visit 1), participants will enter the Screening period and 
begin completing the eDiary to establish their baseline itch for eligibility purposes. The 
eDiary is to be completed twice each day; once in the morning and once in the evening. 
Participants will score the severity of their itching using the same scale described above. 
The NRS recorded in the morning will characterize the worst itch experienced during the 
night-time, whilst the NRS recorded in the evening will characterize the worst itch 
experienced during the day-time hours.   
During the screening period, participants must complete at least 40 of the 56 itch entries, 
with an entry on at least 4 days in each week, in the 28 days immediately preceding the 
Randomization visit on Day 1. For the 28 days prior to Randomization, the Monthly Itch 
Score must be ≥4 (i.e., at least 1 of the 4 Weekly Itch Scores must be ≥4), and no Weekly 
Itch Score can be <3 for any other week. Please see exclusion criteria in Section 5.2. 
After randomization, participants will continue to complete the symptom questionnaire in 
the eDiary throughout the study and will be completed twice each day; once in the 
morning and once in the evening approximately at the time of study intervention dosing. 
Sleep Interference and Fatigue NRS 
Participants will be asked to score the severity of how itch interfered with their sleep 
using an NRS from 0 to 10 where 0 represents no sleep interference and 10 is complete 
sleep interference according to the SoA (Section 1.3). The sleep NRS is recorded once 
daily in the morning.  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
82 
Participants will also be asked to score their fatigue using an NRS from 0 to 10 where 0 
represents no fatigue and 10 represents the worst possible fatigue. The fatigue NRS is 
recorded once daily in the evening. 
8.2.1.2. 
PBC-40 Health Related Quality of Life Scale 
The PBC-40 is a patient-derived, disease specific health-related quality of life measure 
with data to support its validity in PBC [Jacoby, 2005]. The PBC-40 assesses a variety of 
symptoms including itch, fatigue, memory and concentration and impact on social life 
and daily living. The PBC-40 was developed and validated with a 4 week recall period, 
which was modified to a recall period of “the past 7 days” to ensure more accurate recall 
of the impacts associated with PBC pruritus in the GLIMMER study. The revised recall 
period version has undergone cognitive interviewing and has been validated in a blinded 
interim analysis of GLIMMER and an external validation study (data on file). This 
revised PBC-40 will be used in this study at the timepoints specified in the SoA 
(Section 1.3). 
8.2.1.3. 
Gastrointestinal Symptom Rating Scale (GSRS) 
The GSRS is a validated scale that will be assessed for all participants at the timepoints 
indicated in the SoA (see Section 1.3). The GSRS assesses 15 items combined in to five 
symptom clusters, representing reflux, abdominal pain, indigestion, diarrhea, and 
constipation and will assess gastrointestinal symptoms experienced by participants over 
the preceding 5 to 7 days [Svedlund, 1988]. 
8.2.1.4. 
Epworth Sleepiness Scale (ESS) 
The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire that assesses 
daytime sleepiness. The ESS is comprised of 8 questions with respondents rating on a 4-
point scale (0-3) their usual chances of having dozed off or fallen asleep while engaged in 
eight different activities that differ widely in their somnificity. The total ESS score (the 
sum of 8 item-scores, range 0-24) gives an estimate of a more general characteristic, the 
person’s average sleep propensity (ASP), across a wide range of activities in their daily 
lives [Johns, 2002]. The higher the ESS score, the higher that person’s ASP in daily life, 
or their ‘daytime sleepiness’. These ESS item-scores provide estimates of eight different 
situational sleep propensities (SSP) for that person [Johns, 1994; Johns, 2010]. 
General cut-points for sleepiness severity are: 0-5 Lower Normal Daytime Sleepiness; 
6-10 Higher Normal Daytime Sleepiness; 11-12 Mild Excessive Daytime Sleepiness; 
13-15 Moderate Excessive Daytime Sleepiness; 16-24 Severe Excessive Daytime 
Sleepiness. 
The ESS will be administered at the timepoints specified in the SoA (Section 1.3).  
8.2.1.5. 
Beck Depression Inventory (BDI-II) 
The Beck Depression Inventory (BDI-II) is a 21-item questionnaire used to assess the 
intensity of depression in clinical and normal patients. The questionnaire will be 
administered at the timepoints specified in the SoA (Section 1.3).  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
83 
8.2.1.6. 
Patient’s Global Impression of Severity (PGI-S) 
This questionnaire will be used to understand how participant’s itch score over the past 
week using the 0-10 NRS relates to overall participant-reported itch severity. The 
primary role of the PGI-S is as an anchor for the psychometric analysis of the Itch NRS. 
The PGI-S uses a 5-level response scale and will be collected at the timepoints specified 
in the SoA (Section 1.3). 
8.2.1.7. 
Patient’s Global Impression of Change (PGI-C) 
This questionnaire will be used to understand how the participant’s daily itch score using 
the 0-10 NRS relates to overall participant-reported change in itch severity. The primary 
role of the PGI-S is as an anchor for the psychometric analysis of the Itch NRS. The 
PGI-C comprises a 7-level response scale to evaluate the participant’s assessment of 
change since baseline and a dichotomous (Yes/No) question on whether the change is 
considered meaningful by the participant. The PGI-C will be collected at the timepoints 
specified in the SoA (Section 1.3). 
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3).  
8.3.1. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded. 
• 
A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• 
In cases where visits may be performed at locations other than a trial site, such as by 
a home healthcare provider, physical exams may be performed as symptom directed 
exams or by other means as agreed with the investigator. Please refer to Section 10.8 
for home healthcare activities. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.3.2. 
Vital Signs 
• 
Temperature, pulse rate, and blood pressure will be assessed. 
• 
Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
• 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell 
phones). 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
84 
• 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 
pulse and 3 blood pressure measurements (3 consecutive blood pressure readings 
will be recorded at intervals of at least 1 minute). The first reading should be 
rejected. The second and third readings should be averaged to give the measurement 
to be recorded. 
8.3.3. 
Electrocardiograms (ECGs) 
• 
Single 12-lead ECGs will be obtained as outlined in the SoA (see Section 1.3) using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals. Refer to Section 7.1.4 for QTc withdrawal criteria and 
additional QTc readings that may be necessary. 
• 
ECGs will be reviewed locally by the investigator or an adequately trained physician. 
8.3.4. 
Clinical Safety Laboratory Assessments 
• 
Clinical Safety Laboratory Assessments are performed at the relevant laboratories 
provided in the List of Clinical Laboratories. 
• 
See Section 10.2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.  
• 
The investigator must review the laboratory report, document this review, and record 
any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents.  
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered significantly abnormal by the investigator or 
medical monitor.  
• 
If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified and the 
sponsor notified. 
• 
All protocol-required laboratory tests, as defined in Section 10.2, must be conducted 
in accordance with the laboratory manual/Study Reference Manual and the SoA 
(Section 1.3). 
• 
If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE), then the 
results must be recorded. 
• 
All available liver function tests (including liver enzymes, ALP, GGT, INR, total and 
direct bilirubin, CPK, LDH, and albumin) done by local laboratories must be 
recorded in the eCRF. 
• 
All local laboratory results for Liver Event/other safety follow-up must be recorded 
in the eCRF. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
85 
8.3.4.1. 
Baseline Liver Biochemistry/Variance During Screening 
Given that participants may have abnormal screening values for liver biochemistry, 
baseline serum AST, ALT, ALP, and total bilirubin (TB) values will be established using 
an average of two sets of laboratory values obtained at least 4 weeks apart. If both values 
(Sample 1 and Sample 2) are within normal range, no further assessment is required.  
Variance will be calculated as the absolute value of [(Sample 1- Sample 2)/average of 
Sample 1 and Sample 2) x100]. 
In order to ensure stability of liver disease and for participant safety, if any of the four 
liver parameters is above ULN in either Sample 1 or Sample 2, the variance between the 
two samples for the abnormal parameter(s) should be ≤ 40%. Should the variance 
between the two samples be > 40%, a third measure (Sample 3) may be obtained prior to 
the randomization visit. These participants would be eligible for enrollment provided the 
variance between Samples 1 and 3 for the parameter(s) is ≤ 40%. The baseline value will, 
therefore, be established using the average of Samples 1 and 2 or in the event that a third 
measure was obtained, the average of Samples 1 and 3.  
8.3.4.2. 
Fecal Occult Blood Test (FOBT) 
FOBT will be obtained at the timepoints outlined in Section 1.3 (SoA) in line with risk 
monitoring as described in Section 2.3.1.  
Participants with a positive FOBT should be referred to their healthcare provider for 
follow up according to local standard of care. 
8.3.5. 
Pregnancy Testing 
• 
Refer to Section 5.1, Inclusion Criteria for pregnancy testing entry criteria. 
• 
Pregnancy testing (urine or serum as required by local regulations) will be conducted 
at all on-treatment visits for women of child bearing potential during study 
intervention period. 
• 
Pregnancy testing (urine or serum as required by local regulations) will be conducted 
for women of child bearing potential at the end of relevant systemic exposure.  
• 
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study. 
8.3.6. 
Study Safety Monitoring 
• 
Participant safety will be continuously monitored by the GSK Medical Monitor, and 
the designated Safety Lead (or delegate) throughout the study. Pertinent findings and 
conclusions are shared with the product’s Safety Review Team (SRT) for review of 
the overall benefit risk profile of the product. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
86 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of AEs or SAEs can be found in Section 10.3. 
All events meeting permanent stopping criteria described in Section 7.1 except for 
pregnancy will be recorded as a (S)AE. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, are considered related to the study intervention or the 
study, that caused the participant to discontinue the study intervention (see Section 7).  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All SAEs will be collected from the signing of the ICF until the last scheduled visit, 
follow-up phone call (if performed), or completion of any required follow-up in the 
study (if applicable), whichever is later, at the time points specified in the SoA 
(Section 1.3).  
• All AEs will be collected from the start of intervention until the last scheduled visit, 
the follow-up phone call (if performed), or completion of any required follow-up in 
the study (if applicable), whichever is later, at the time points specified in the SoA 
(Section 1.3). 
• If a participant is found to have met increased monitoring or stopping criteria at 
Week 32 requiring additional follow-up after being enrolled in the follow-on study 
212358 (LLSAT), AEs and SAEs that occur after the Week 32 Visit will be recorded 
as follows: 
o AEs and SAEs considered by investigator to be part of the safety event 
requiring additional follow-up in GLISTEN: Record in GLISTEN eCRF. 
o AEs and SAEs that are considered by investigator NOT to be part of the safety 
event requiring additional follow-up in GLISTEN: Record in LLSAT eCRF. 
• Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions not as AEs. 
• All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
87 
• Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 10.3, Appendix 3: AEs and SAEs: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting ), will be followed until 
the event is resolved, stabilized, otherwise explained, or the participant is lost to follow-
up (as defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 3, Section 10.3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study intervention under clinical investigation are met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IECs, and 
investigators. 
• 
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the sponsor 
will review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary. 
8.4.5. 
Pregnancy 
• 
Details of all pregnancies in female participants will be collected after the start of 
study intervention and until the final follow up visit. 
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the female 
participant’s pregnancy. While pregnancy itself is not considered to be an AE or 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
88 
SAE, any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, 
and the information will be forwarded to the sponsor. 
• 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.5. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
• 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention immediately but will be encouraged to continue to 
attend study visits and undergo assessments. 
8.4.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Section 10.3.3 and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.  
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its 
completion.   
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
8.4.7. 
Adverse Events of Special Interest  
Adverse events of special interest for this study include: 
• 
Diarrhea reported as an AE 
• 
Elevated ALT reported as a Liver Event 
AESIs will be recorded on separate AESI forms within the eCRF in addition to the 
AE/SAE eCRFs. 
8.4.8. 
Participation Card 
The investigator (or designee) must provide the participant with a “participant card” 
containing information about the clinical study. The participant must be instructed to 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
89 
always keep the participant card in their possession for the duration of the study. In an 
emergency, this card serves to inform the responsible attending physician/ caregiver/ 
family member that the participant is in a clinical study and that relevant information may 
be obtained by contacting the investigator(s) or their back up. 
8.5. 
Pharmacokinetics 
Whole blood samples will be collected for measurement of plasma concentrations of 
linerixibat as specified in the SoA (Section 1.3).  
• 
The timing of sampling may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma concentrations) 
to ensure appropriate monitoring. In addition, PK sample collection and/or analysis 
may be terminated when sufficient data has been collected, and any remaining 
samples may be discarded if not required. 
• 
Dosing instructions for visits at which PK assessments are drawn will be specified in 
the SRM. 
• 
Instructions for the collection and handling of biological samples will be provided by 
the sponsor. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
• 
Samples collected for analyses of linerixibat plasma concentration may also be used 
to evaluate safety or efficacy aspects related to concerns arising during or after the 
study. 
• 
Genetic analyses will not be performed on these plasma samples unless consent for 
this was included in the informed consent. Participant confidentiality will be 
maintained.  
• 
Intervention concentration information that may unblind the study will not be 
reported to investigative sites or blinded personnel until the study has been 
unblinded. 
8.6. 
Genetics  
A blood and/or saliva sample for deoxyribonucleic acid (DNA) isolation will be collected 
from participants who have consented to participate in the genetics analysis component of 
the study. Participation is optional. Participants who do not wish to participate in the 
genetic research may still participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood and/or saliva sample 
may be requested from the participant. Signed informed consent will be required to 
obtain a replacement sample unless it was included in the original consent. 
See Section 10.5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples will be found in a separate laboratory manual. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
90 
8.7. 
Biomarkers 
Blood samples will be collected to measure the levels exploratory biomarkers, including 
markers of bile acid synthesis and re-uptake (total serum bile acids, autotaxin, serum C4 
and FGF-19). Biomarker sample collection and/or analysis may be terminated when 
sufficient data has been collected, and any remaining samples may be discarded if not 
required. 
The levels of biomarkers in PBC subjects at baseline, the effect of linerixibat treatment 
on biomarker levels and impact of background therapies (e.g. bile acid binding resins) 
will be assessed. Samples will be collected according to the schedule described in the 
SoA (see Section 1.3) and as detailed in the laboratory manual provided separately to 
sites.  
GSK may store samples for up to 15 years after the end of the study to achieve study 
objectives (please see China specific requirements in Section 10.7.1). Additionally, with 
participants consent, samples may be used for further research by GSK or others such as 
universities or other companies to contribute to the understanding of PBC, cholestatic 
pruritus, other diseases or the development of related or new treatments or research 
methods. Further research will only be conducted in countries where permitted by local 
regulation and guidelines. 
8.7.1. 
Biomarkers of Disease Progression 
Disease progression can occur even when patients are receiving adequate treatment (e.g., 
UCDA), with a risk of liver-related complications. In GLIMMER, results demonstrated 
that linerixibat does not result in an increase in plasma ALP confirming the lack of 
detrimental impact on PBC itself or clinically relevant interaction between linerixibat and 
UDCA (for more details see IB, Section 5.2.2).   
However, in order to continue to assess the hallmarks of PBC progression over a longer 
period, serum surrogate markers of liver fibrosis and liver function, ELF, and transient 
elastography (TE) utilizing Fibroscan will be obtained at timepoints outlined in 
Section 1.3. In addition, investigators are advised to implement hepatocellular 
carcinoma screening for patients with cirrhosis according to standard of care and country 
guidelines and/or local practices. Any liver biopsies that may be performed during the 
course of the study will be collected in the eCRF pages. 
8.7.1.1. 
Enhanced Liver Fibrosis Test (ELF) 
Blood samples for the ELF should be obtained at timepoints outlined in Section 1.3 
(SoA). These samples may not be collected from participants in China due to operational 
or logistical difficulties.  
8.7.1.2. 
Fibroscan 
Transient Elastography (TE) using Fibroscan should be performed at timepoints outlined 
in Section 1.3 (SoA). This is applicable only for sites that where Fibroscan is available 
and is performed regularly. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
91 
9. 
STATISTICAL CONSIDERATIONS 
Unless otherwise specified, all objectives/endpoints/hypotheses compare treatment with 
oral linerixibat with background itch therapy, if applicable, against placebo with 
background itch therapy, if applicable. Hereafter this comparison will be referred to as 
“linerixibat vs placebo”.  
9.1. 
Statistical Hypotheses 
9.1.1. 
Primary endpoint 
The primary objective is to investigate the superiority of 24 weeks of treatment with oral 
linerixibat compared with placebo on itch in PBC patients with cholestatic pruritus. The 
primary endpoint is Change from Baseline in Monthly Itch Scores over 24 weeks using a 
0-10 numerical rating scale (NRS). The primary estimand is the difference in means 
between linerixibat and placebo in the change from baseline in itch score over 24 weeks 
in PBC patients with cholestatic pruritus. For details of intercurrent events, see 
Section 9.4. The primary analysis will be a mixed model approach based on Monthly Itch 
score over 24 weeks (Weeks 4, 8, 12, 16, 20, and 24). The primary hypothesis is that 
linerixibat reduces itch score over 24 weeks compared to placebo. A negative change 
from baseline (or reduction) represents an improvement in itch. 
The null hypothesis (H0) assumes that there is no difference in the reduction of itch score 
over 24 weeks between linerixibat and placebo groups. The alternate hypothesis (H1) 
assumes that there is difference in the reduction of itch score over 24 weeks between 
linerixibat and placebo groups.  
The overall significance level for the primary endpoint analysis is set at the two-sided 
0.05 level. 
9.1.2. 
Secondary endpoints 
Formal multiplicity-controlled testing will be conducted for the key secondary endpoints 
of change from baseline in Weekly Itch Score (WIS) at Week 2, change from baseline in 
Monthly Sleep Score over 24 weeks, as well as responder endpoint defined as achieving 
≥2, ≥3, and ≥4-point reduction from Baseline in the Monthly Itch Score at Week 24. 
Additional testing not multiplicity controlled will be conducted for other secondary 
endpoints including change from baseline in PBC-40 domain score at Week 24, change 
from baseline in PGI-S over 24 weeks, PGI-C over 24 weeks, change from baseline in 
ALP at Week 24, and Change from baseline in bilirubin at Week 24.  
A step-down/hierarchical approach will be used to test the following key secondary 
endpoints if statistical significance is achieved for the primary endpoint: 
• Change from Baseline in WIS at Week 2 
• Change from Baseline in Monthly Sleep Score over 24 weeks 
• Responders defined as achieving a ≥2-point reduction from Baseline in the 
Monthly Itch score at Week 24. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
92 
• Responders defined as achieving a ≥3 -point reduction from Baseline in the 
Monthly Itch score at Week 24. 
• Responders defined as achieving a ≥4 -point reduction from Baseline in the 
Monthly Itch score at Week 24. 
These tests will be conducted sequentially at a 5% two-sided significance level. Other 
secondary endpoints will also be tested but outside this formal hierarchy. 
9.2. 
Sample Size Determination 
Approximately 230 participants (115 per group) who pass the screening eligibility criteria 
will be randomized in a 1:1 ratio to linerixibat or placebo groups. The sample size of 230 
was obtained and evaluated assuming that 10% of participants discontinue from the study 
at random and the data from the discontinuation week through week 24 are missing. This 
sample size allows approximately 90% power for a two-sided test with an alpha level of 
0.05 when the expected overall difference in change from baseline in Monthly Score 
across 24 weeks is ~-0.9 (based on BAT117213 and GLIMMER data) between the 
linerixibat and placebo groups (assuming a between subject standard deviation [SD] of 
2.07 for both groups based on GLIMMER data).  
9.2.1. 
Sample size assumptions 
Change from baseline in the WIS was simulated for each week from week 1 to week 24 
after randomization. It was assumed that the mean change from baseline in the WIS of 
placebo group reaches its plateaued effect size of -1.5 by week 12 in a linear relationship 
against treatment week. It was also assumed that delta between linerixibat and placebo 
reaches plateau of -1 by week 4 in a linear relationship against treatment week, and the 
mean change from baseline in the WIS of linerixibat group is the sum of placebo and 
delta as shown in Figure 3.  


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
93 
Figure 3 
Expected Change from Baseline in MWDI* 
 
* MWDI now referred to as the Weekly Itch Score (WIS). 
The expected weekly means are listed in Table 4 below. 
Table 4 
Expected Change from Baseline in Weekly Itch Score (WIS) 
Group 
N 
Expected Change from Baseline in 
WIS by Week  
(week 1 – week 11) 
Expected 
Change from 
Baseline WIS 
(Week 12 - 24) 
Dropout 
Rate 
Placebo 
115 {-0.125, -0.250, -0.375, -0.500, -0.625, 
-0.750, -0.875, -1.000, -1.125, -1.250, 
-1.375}  
-1.5 
10% 
Linerixibat 115 {-0.375, -0.750, -1.125, -1.500, -1.625, 
-1.750, -1.875, -2.000, -2.125, -2.250, 
-2.375} 
-2.5 
10% 
 
For each iteration of simulation, change from baseline data for each week was generated 
for 115 subjects per group using a truncated multivariate normal distribution within the 
interval of [-10, 10] with the mean vectors presented above. The variance covariance 
matrix was assumed to have a compound symmetry (CS) structure with standard 
deviation of 2.25 and correlation of 0.85 which corresponds to a between subjects SD of 
~2.07 and a within subject SD of ~0.87, based on the GLIMMER data.  
The rates of study withdrawal that resulted in missing values from withdrawals for 
placebo group and linerixibat 40 mg BID group after randomization were 1/36 and 1/23, 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
94 
respectively, in the GLIMMER study. Therefore, it was expected to have ~10% study 
withdrawal rate for each arm and the study withdrawal can occur at any week after 
randomization. Missing data was assumed to be missing at random in the simulation.    
Simulations were based on planned visits at week 4, 8, 12, 16, 20, and 24. For visit on 
week 4, the worst change from baseline in WIS from week 1 to 4 was reported as the 
change from baseline in Monthly Itch Score. Similarly, the change from baseline in 
Monthly Itch Scores were obtained for other visits. Mixed model repeated measure 
analysis was then applied to change from baseline in Monthly Itch Scores and the model 
included treatment, visit, and treatment by visit interaction as fixed effect. The 
comparison of active and placebo arms was based on the simple average of LS means of 
all visits, i.e., the main effect of treatment averaged across the 6 visits with equal weight 
at each visit.  
9.3. 
Analysis Sets 
For purposes of analysis, the following populations are defined: 
Population  
Description  
Screening 
All participants who sign the ICF 
Enrolled  
All participants who sign the ICF and pass screening 
(meet the eligibility criteria) 
ITT Population  
This population will comprise all randomized 
participants. Participants in the ITT Population will be 
classified according to the treatment as randomized.  
Non-bile acid binding resin 
ITT (Intent to Treat) 
Population  
The Non-bile acid binding resin ITT Population is a 
subset of the ITT population who are not receiving 
concomitant bile acid binding resin therapy at 
randomization (e.g., cholestyramine).  
Safety  
All randomized participants who take at least 1 dose of 
study intervention. Participants will be analyzed 
according to the treatment they actually received.  
9.4. 
Statistical Analyses 
The primary statistical analysis to assess the primary, secondary, and safety objectives 
will be performed when all randomized participants have completed the Part A 
intervention period (up to Week 24/Visit 9). In addition, available data for exploratory 
endpoints in Part A and Part B will be analyzed as part of this primary statistical analysis. 
By the time the last participant completes the Part A intervention period, it is anticipated 
that the majority of participants will have also completed the Part B intervention period 
(Week 24 through Week 32). Therefore, all available Part B data will also be assessed 
and reported as part of the primary statistical analysis.  
A final analysis will then be performed when all participants have completed the Part B 
intervention period, and the follow-up period, if applicable. This analysis will include 
complete Part B data and the full data for exploratory endpoints in Part A for which full 
datasets were not available at the time of the primary analysis. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
95 
The statistical analysis plan will be finalized prior to database lock (DBL) and it will 
include a more technical and detailed description of the statistical analyses described in 
this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. 
9.4.1. 
General Considerations 
The study will test at a 5% two-sided significance level the null hypotheses listed 
previously in Section 9.5. 
9.4.2. 
Primary and Secondary Endpoint(s) 
Endpoint  
Statistical Analysis Methods  
Primary  
The primary objective is to evaluate the treatment 
effect of linerixibat compared to placebo on itch over 
24 weeks. The primary hypothesis is that linerixibat 
reduces itch score over 24 weeks compared to placebo. 
A negative change (or reduction) from baseline in 
monthly itch score averaged over 24 weeks represents 
an improvement in itch. 
 
The Monthly Itch Score, based on a 0-10 NRS, will be 
determined from the worst weekly average available 
for the month. A week will have a Weekly Itch Score if 
at least 4 days in the week have a score. Otherwise, the 
Weekly Itch Score for the week will be missing. If one 
or more weekly scores is missing, then the worst of the 
non-missing weekly scores is selected as the worst for 
that month. If no week scores are available for a 
month, the Month Itch Score will be missing.  
 
The following intercurrent events have been 
considered for the evaluation of the primary endpoint 
of Monthly Itch Score: 
o Permanent treatment discontinuation, 
disruptions in treatment, treatment delays 
unrelated to the COVID-19 pandemic, 
addressed with treatment policy strategy 
o Permanent treatment discontinuation, 
disruptions in treatment, treatment delays 
related to the COVID-19 pandemic, 
addressed with hypothetical strategy 
o Change in background itch therapy or use 
of rescue medication, addressed with 
treatment policy strategy 
The summary measure will be mean difference 
between treatment groups. The primary analysis will 
be a mixed model for repeated measures (MMRM) of 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
96 
Endpoint  
Statistical Analysis Methods  
change from baseline in Monthly Itch score over the 
24-week treatment period. The model will include 
main effects for treatment, visit (Weeks 4, 8, 12, 16, 
20, and 24), concomitant use of itch medications at 
baseline, and baseline itch severity as continuous as 
well as treatment by visit interaction and baseline by 
visit interaction. An unstructured covariance structure 
will be assumed; if this does not converge then CS will 
be used, followed by an autoregressive [AR] 
covariance structure if CS does not converge.   
 
The change from baseline over 24-week treatment 
period will use a treatment policy strategy for the 
intercurrent events unrelated to the COVID-19 
pandemic, in which data following intercurrent events 
will be included as available and participants will be 
classified according to assigned treatment (regardless 
of treatment actually received) according to ITT 
principles. For intercurrent events related to the 
COVID-19 pandemic, hypothetical strategy will be 
used. The outcomes impacted by the COVID-19 
related intercurrent events will be discarded, and the 
MMRM then fitted. This assumes that unobserved 
outcomes of subjects who withdrew from the study or 
who experienced a COVID-19 related intercurrent 
event are missing at random (MAR). Full details will 
be provided in the Statistics Analysis Plan.   
 
A sensitivity analysis will be conducted to evaluate the 
impact of the MAR assumption on the conclusions of 
the primary analysis if the primary endpoint is 
significant in favor of linerixibat. In this sensitivity 
analysis, a tipping point approach will be used. This is 
akin to progressive stress-testing to assess how severe 
departures from the MAR assumption must be in order 
to change the overall conclusion of the primary 
analysis. Missing data will first be imputed for all 
visits under the MAR assumption, and then a shift will 
be applied. This will be repeated until the result is no 
longer statistically significant. The plausibility of the 
set of assumptions required for conclusions to change 
provides context for the interpretation of the trial 
results. The tipping point analysis will be two-
dimensional, which allows assumptions about the 
missing outcomes on the two arms to vary 
independently and includes scenarios where dropouts 
on linerixibat have worse outcomes than dropouts on 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
97 
Endpoint  
Statistical Analysis Methods  
placebo. Full details will be provided in the Statistics 
Analysis Plan. 
 
As a supplementary estimand for the primary 
objective, the hypothetical treatment effect of 
linerixibat will be compared to placebo in the absence 
of any intercurrent events. Hypothetical strategy will 
be applied to all the intercurrent events defined above, 
including treatment discontinuation, disruptions in 
treatment or treatment delays, changes in itch therapy 
or use of rescue medication. The outcomes impacted 
by the intercurrent events will be discarded, and the 
MMRM then fitted. This assumes that unobserved 
outcomes of subjects who withdrew from the study or 
who experienced an intercurrent event are MAR. 
The main analytical approach will also be repeated 
using the non-bile acid binding resin ITT population. 
Any participant taking bile acid binding resin as the 
background itch therapy at baseline will be excluded 
from the non-bile acid binding resin ITT population 
and any data from these excluded participants will not 
contribute to the analysis. 
Secondary  
Change from baseline in Weekly Itch Score at Week 2 
 
The change from baseline WIS at Week 2 will be 
evaluated. Similar to the primary estimand framework, 
treatment policy strategy will be used for the 
intercurrent events unrelated to the COVID-19 
pandemic, whereas hypothetical strategy will be used 
for the intercurrent events related to the COVID-19 
pandemic. 
 
Change from baseline WIS at Week 1 and 2 will be 
analyzed by a MMRM model including baseline itch 
severity as a continuous covariate, treatment, week 
(Weeks 1 and 2), concomitant use of itch medications 
at baseline, treatment by week interactions, and 
baseline by week interaction as fixed effects. The 
comparison at Week 2 will be estimated from the 
MMRM model.   
• 
Change from Baseline in Monthly Sleep score 
over 24 weeks: 
Change from baseline in Monthly Sleep score over 24 
weeks will be evaluated. 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
98 
Endpoint  
Statistical Analysis Methods  
Similarly, treatment policy strategy will be used for the 
intercurrent events unrelated to the COVID-19 
pandemic, whereas hypothetical strategy will be used 
for the intercurrent events related to the COVID-19 
pandemic. 
 
Change from baseline of Monthly Sleep score 
averaged over 24 weeks will be analyzed using a 
repeated measure mixed model including baseline 
Monthly Sleep score as covariate, treatment, visit, 
concomitant use of itch medications at baseline, 
treatment by visit interaction, and baseline by visit 
interaction as fixed effects.  
 
Responder defined as achieving a ≥2-point reduction 
from baseline in the Monthly Itch score at Week 24; 
Responder defined as achieving a ≥3-point reduction 
from baseline in the Monthly Itch score at Week 24; 
Responder defined as achieving a ≥4-point reduction 
from baseline in the Monthly Itch score at Week 24: 
The proportion of participants who are responders at 
Week 24 will be evaluated. 
 
Similarly, treatment policy strategy will be used for the 
intercurrent events unrelated to the COVID-19 
pandemic, whereas hypothetical strategy will be used 
for the intercurrent events related to the COVID-19 
pandemic. Data impacted by a COVID-19 related 
intercurrent event will be discarded and multiple 
imputation will be applied to impute itch data using 
available data for all subjects. The imputed data will 
then be used to derive the responder endpoint. 
 
The summary measure will be the difference in 
responder rates between linerixibat and placebo 
groups, analyzed using a stratified analysis with 
Cochran-Mantel-Haenszel (CMH) weights, adjusting 
for baseline itch severity and concomitant use itch 
medications.  
• 
Change from Baseline in PBC-40 domain scores at 
week 24: 
Change from baseline in the domain scores of PBC-40 
at week 24 will be evaluated. Similarly, treatment 
policy strategy will be used for the intercurrent events 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
99 
Endpoint  
Statistical Analysis Methods  
unrelated to the COVID-19 pandemic, whereas 
hypothetical strategy will be used for the intercurrent 
events related to the COVID-19 pandemic. Change 
from baseline in the domain scores of PBC-40 -over 24 
weeks will be analyzed using a mixed model including 
baseline domain scores of PBC-40 as covariate, 
treatment, visit , concomitant use of itch medications at 
baseline, treatment by visit interaction, and baseline by 
visit interaction as fixed effects. The comparison at 
Week 24 will then be estimated from the MMRM 
model.  
 
Change from baseline in PGI-S over 24 weeks 
Change from baseline in PGI-S over 24 weeks will be 
evaluated. Similarly, treatment policy strategy will be 
used for the intercurrent events unrelated to the 
COVID-19 pandemic, whereas hypothetical strategy 
will be used for the intercurrent events related to the 
COVID-19 pandemic. Change from baseline in PGI-S 
averaged over week 24 will be analyzed using a mixed 
model including baseline PGI-S as covariate, 
treatment, visit, concomitant use of itch medications at 
baseline, treatment by visit interaction, and baseline by 
visit interaction as fixed effects.  
 
PGI-C over 24 weeks 
Change from baseline in PGI-C over 24 weeks will be 
evaluated. Similarly, treatment policy strategy will be 
used for the intercurrent events unrelated to the 
COVID-19 pandemic, whereas hypothetical strategy 
will be used for the intercurrent events related to the 
COVID-19 pandemic. Change from baseline in PGI-C 
averaged over week 24 will be analyzed using a mixed 
model including treatment, visit, concomitant use of 
itch medications at baseline, and treatment by visit 
interaction as fixed effects.  
 
Change from baseline in ALP at Week 24 
Change from baseline in ALP at Week 24 will be 
evaluated. Similarly, treatment policy strategy will be 
used for the intercurrent events unrelated to the 
COVID-19 pandemic, whereas hypothetical strategy 
will be used for the intercurrent events related to the 
COVID-19 pandemic. Change from baseline in ALP -


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
100 
Endpoint  
Statistical Analysis Methods  
over 24 weeks will be fitted by a mixed model 
including baseline ALP as covariate, treatment, visit, 
concomitant use of itch medications at baseline, 
treatment by visit interaction, and baseline by visit 
interaction as fixed effects. The comparison at Week 
24 will be estimated from the MMRM model.  
 
Change from baseline in bilirubin at Week 24 
Change from baseline in bilirubin at Week 24 will be 
evaluated. Similarly, treatment policy strategy will be 
used for the intercurrent events unrelated to the 
COVID-19 pandemic, whereas hypothetical strategy 
will be used for the intercurrent events related to the 
COVID-19 pandemic. Change from baseline in 
bilirubin -over 24 weeks will be fitted by a mixed 
model including baseline bilirubin as covariate, 
treatment, visit, concomitant use of itch medications at 
baseline, treatment by visit interaction, and baseline by 
visit interaction as fixed effects. The comparison at 
Week 24 will be estimated from the MMRM model. 
 
9.4.3. 
Safety Endpoint(s) 
Endpoint  
Statistical Analysis Methods  
Safety  
Overall safety evaluations will be descriptive using the 
Safety Population. Graphical and tabular displays will 
be presented to facilitate safety data review.  
 
AEs and SAEs will be summarized, sorted by system 
organ class and preferred term assigned by MedDRA, 
and presented as number and percent by treatment 
group. Additional summaries of AEs leading to 
discontinuation of study intervention and study 
intervention related AEs will also be generated. AESI 
including diarrhea and elevated ALT reported as a 
liver event will be presented separately. 
 
Change from baseline for laboratory values including 
liver chemistry panel and for ECG values will be 
summarized by visit and treatment group. In addition, 
the number and percentage of participants with values 
outside the potential clinical importance range will also 
be summarized.  
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
101 
Endpoint  
Statistical Analysis Methods  
All vital sign data and change from baseline will be 
summarized by visit and treatment group. For systolic 
and diastolic blood pressure and heart rate, the number 
and percentage of participants with values of potential 
clinical importance will be summarized by treatment 
group. 
 
Criteria for potential clinical importance will be 
specified in the statistical analysis plan (SAP).  
 
9.4.4. 
Exploratory Endpoint(s) 
Details of analysis methods to be used for exploratory endpoints, including the endpoints 
for part B, are provided in the SAP. 
9.4.5. 
Other Analyses 
Blinded PRO data (Itch NRS, PGI-S, PGI-C) from the ITT population will be accessed 
during study conduct to establish a clinically meaningful within-patient change threshold 
or range of thresholds for the Itch NRS, specifically as it relates to change in scores at 
Week 24. Following FDA guidance [FDA, 2023], both distribution-based and 
anchor-based methods will be used for determining clinically meaningful within-patient 
change. An external vendor will be used to conduct these analyses, the details of which 
are provided separately. 
9.5. 
Interim Analysis 
The study has a planned futility analysis to be conducted after approximately 100 
participants reach 24 weeks of treatment (or discontinued early). The analysis will be 
overseen by an IDMC with non-binding futility guidelines as documented in the IDMC 
Charter. The study may be terminated following this analysis if the probability of 
demonstrating clinical efficacy based on observed data is too low to support continuing 
or following the safety review if the overall risk-benefit is assessed to be unfavorable. In 
the event of the study being discontinued, GSK processes will be followed to ensure the 
best interests and the safety of the participants. The trial will not be stopped for early 
benefit at this point and no alpha-spend is incurred. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
102 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements, PRO) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as required 
by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations. 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
103 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study.  
• Potential participants must be informed that their participation is voluntary. 
Participants will be required to sign a statement of informed consent that meets 
the requirements of 21 Code of Federal Regulations (CFR) 50, local regulations, 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• A copy of the ICF(s) must be provided to the participant 
• Participants who are rescreened are required to sign a new ICF 
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about linerixibat or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have linerixibat approved for 
medical use or approved for payment coverage.  
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorized designee 
will explain to each participant the objectives of the exploratory research. Participants 
will be told that they are free to refuse to participate and may withdraw their consent at 
any time and for any reason during the storage period. A separate signature will be 
required to document a participant's agreement to allow any participant data and/or 
remaining leftover samples to be used for further research not related to the study/disease. 
Participants who decline further research will tick the corresponding “No” box.  
In case of unexpected pregnancy, participant must be informed that Personal Information 
such as date of birth and sex of the baby will be collected as part of safety follow-up. 
Consent for the baby may be obtained from the participant and/or their partner as per 
local regulations. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
104 
10.1.4. 
Recruitment Strategy 
A competitive recruitment strategy is utilized for this study. Prior to selecting a site for 
inclusion in the study, data may be gathered to understand the number of participants that 
might be enrolled from the current patient population and existing networks.  
Supportive materials (if permitted locally and approved by the appropriate Ethics 
Committee or equivalent), such as leaflets and flyers may also be prepared and provided 
in digital format by recruitment third parties for use by investigator sites to provide 
information and awareness to participants and other healthcare providers/patient 
advocacy groups. These may be provided as paper printouts, which may be displayed in 
clinics or at patient events or provided to interested parties.  
A digital GLISTEN website and pre-screener tool may be created in certain countries in 
accordance with local regulations to provide information and awareness on the trial in a 
digital format, as well as enable digital prescreening of participants and establish a 
connection with investigator sites for further screening activities as applicable. This will 
only be implemented where permitted locally and once all applicable Ethics Committee 
approvals are in place.  
10.1.5. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• GSK will ensure protection of the personal data of the investigator and site staff 
which is collected within the framework of and for the purpose of the study. 
• The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• The contract between sponsor and study sites specifies responsibilities of the 
parties related data protection, including handling of data security breaches and 
respective communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related 
data are secured by technical and organizational security measures designed to 
protect such data against accidental or unlawful loss, alteration, or unauthorized 
disclosure or access. GSK and/or trusted third parties working on behalf of GSK 
and/or institutions working with GSK for the purposes of this study are 
contractually bound to protect participant coded data. GSK will protect participant 
coded data and will only share it as described in the ICF. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
105 
10.1.6. 
Committee Structure 
10.1.6.1. 
Safety Review Team (SRT) 
An SRT is in place for each GSK product. It comprises of a global cross-functional team 
responsible for the ongoing assessment of benefit-risk for a product. The SRT contribute 
to the continual assessment of incoming new efficacy and safety information. 
10.1.6.2. 
Independent Data Monitoring Committee  
An IDMC will perform a futility analysis of efficacy at the planned interim analysis for 
the study and evaluate the safety of participants. Details of the structure and function of 
the IDMC, and analysis plan for IDMC reviews, are outlined in the IDMC Charter.  
10.1.7. 
Dissemination of Clinical Study Data  
• The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study Register in compliance with 
applicable regulations/GSK policy. GSK will aim to register protocols summaries 
prior to study start and target results summaries submission within 12 months of 
primary/ study completion date. Where external regulations require earlier 
disclosure, GSK will follow those timelines.  
• Where required by regulation, summaries will also be posted on applicable 
national or regional clinical study registers. 
• Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report. The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports. GSK will also provide the investigator with the full summary of the study 
results including a summary of trial results understandable to laypersons.  
• The investigators are encouraged to share the plain language summary with the 
study participants, as appropriate. The full study report will be made available 
upon request, after decision on marketing authorization by regulatory authorities. 
• Under the framework of the SHARE initiative, GSK intends to make anonymized 
participant-level data from this study available to external researchers for 
scientific analyses or to conduct further research that can help advance medical 
science or improve patient care. This helps ensure the data provided by study 
participants are used to maximum effect in the creation of knowledge and 
understanding.  
• GSK will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis. 
• The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
106 
10.1.8. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.  
• Guidance on completion of eCRFs will be provided separately to investigators. 
• Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues 
that can impact participant safety and/or reliability of study results. These pre-
defined parameters will be monitored during and at the end of the study and all 
deviations from the QTLs and remedial actions taken will be summarized in the 
clinical study report. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• Monitoring details describing strategy including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about study data 
collection and management process including systems used can be found in the 
Data Management Plan or equivalent.  
• The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
CSR/ equivalent summary unless local regulations or institutional policies require 
a longer retention period. No records may be destroyed during the retention 
period without the written approval of the sponsor. No records may be transferred 
to another location or party without written notification to the sponsor.  
10.1.9. 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
107 
• Definition of what constitutes source data and its origin can be found in the 
Source Data Acknowledgment. 
• The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF. 
• The sponsor or designee will perform monitoring to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements.  
10.1.10. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first participant’s first visit (FSFV) will be the study start date. 
Study/Site Termination 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate or no recruitment of participants (evaluated after a reasonable amount 
of time) by the investigator 
• Total number of participants included earlier than expected 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
108 
investigator shall promptly inform the subject and should assure appropriate 
participant therapy and/or follow-up. 
10.1.11. 
Publication Policy 
• The results of this study may be published in peer reviewed scientific literature 
and/or presented at scientific meetings.   
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
109 
10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 5 will be performed by the central laboratory unless medically 
necessary as judged by the Investigator in consultation with the GSK Medical Monitor or 
designee. 
Local laboratory results are only required if the central laboratory results are not available 
in time for either study intervention administration and/or response evaluation. If a local 
sample is required, it is important that the sample for central analysis is obtained at the 
same time if possible. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Investigators must document their review of each laboratory safety report. 
Table 5 
Protocol Required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
Red Blood Cell (RBC) 
Count 
Hemoglobin 
Hematocrit 
RBC Indices: 
Mean Corpuscular 
Volume (MCV) 
Mean Corpuscular 
Hemoglobin (MCH) 
%Reticulocytes 
White Blood Cell 
(WBC) count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Coagulation 
Prothrombin Time (PT) / International Normalized Ration (INR) 
Clinical 
Chemistry1 
Blood Urea Nitrogen (BUN) 
Bicarbonate  
Creatinine 
eGFR (CKD-EPI) 
Potassium 
Sodium 
Calcium 
Glucose (fasting)2 
Total Cholesterol (fasting) 2  
Direct Low Density Lipoprotein (LDL) 
Cholesterol (fasting) 2 
Direct High Density Lipoprotein (HDL) 
Cholesterol (fasting) 2 
Triglycerides (Fasting) 2 
Alanine Aminotransferase (ALT) 
Aspartate Aminotransferase 
(AST) 
Alkaline phosphatase (ALP)  
Gamma Glutamyl Transferase  
Total and direct bilirubin 
Total Protein 
Albumin 
 
Other  
Vitamins A, D, E and K 
Fecal Occult Blood Test (FOBT) 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
110 
Laboratory 
Assessments 
Parameters 
Biomarkers 
Enhanced Liver Fibrosis (ELF)3, Serum C4, FGF-19. Autotaxin, Total 
Serum Bile Acids 
Pregnancy 
testing 
• 
Highly sensitive urine (Serum if required locally) human chorionic 
gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential)5 
Other 
Screening Tests • 
Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) 
• 
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody) 
NOTES: 
1. Details of liver chemistry stopping criteria and required actions and follow-up assessments after 
liver stopping or monitoring event are given in Section 7.1 and Section 10.6. 
2. Laboratory samples should be taken fasted (water, study intervention and other medications are 
permitted) for all visits. 
3. ELF may not be performed in China due to limitations in testing. 
4. Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or IRB/IEC. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
111 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE.  
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
112 
Events NOT Meeting the AE Definition  
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
10.3.2. 
Definition of SAE 
An SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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 were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
113 
An SAE is defined as any serious adverse event that, at any dose: 
• This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) 
g. Other situations: 
• Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, 
intensive treatment for allergic bronchospasm, blood dyscrasias, 
convulsions, or development of intervention dependency or intervention 
abuse. 
 
10.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the eCRF for the 
following AEs and SAEs: 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
114 
10.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK required form. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe. 
• An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
Diarrhea AEs will also be assessed based on the CTCAE criteria as defined in 
Section 7.1.3.1. 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
115 
Assessment of Causality 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
• New or updated information will be recorded in the originally submitted 
documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
Follow-up of pregnancies 
• Pregnant participants will be followed to determine the outcome of the pregnancy. 
At the end of the pregnancy, whether full-term or premature, information on the 
status of the mother and child will be forwarded to GSK using the paper pregnancy 
follow-up report and the AE Report if applicable. Generally, the follow-up period 
does not need to be longer than 6 to 8 weeks after the estimated date of delivery. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
116 
Follow-up of AE and SAE 
• Regardless of the reporting period for SAEs in this study, if the pregnancy outcome 
is an SAE, it should always be reported as such. 
• Furthermore, the investigator must report any SAE occurring as a result of a 
poststudy pregnancy that is considered by the investigator to be reasonably related 
to the study intervention, to GSK as described in Section 8.4.5. 
 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the GSK Medical Monitor by telephone. 
• 
Contacts for SAE reporting can be found in the Study Reference Manual. 
 
SAE Reporting to GSK via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the case management group. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in the Study Reference Manual. 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
117 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below) 
Notes: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required.  
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrolment. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
118 
10.4.2. 
Contraception Guidance: 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) b 
Bilateral tubal occlusion 
Vasectomized partner 
Note: Vasectomized partner is a highly effective contraceptive method provided that the partner is 
the sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.  
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
• oral 
• intravaginal 
• transdermal 
• injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• oral 
• injectable 
Sexual abstinence 
• 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
• 
Effective Methodsd That Are Not Considered Highly Effective Failure rate of ≥ 1% per year 
when used consistently and correctly. 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action 
Male or female condom with or without spermicidee 
Cervical cap, diaphragm, or sponge with spermicide 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
119 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods)c 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
d. 
Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic abstinence (calendar, 
sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method (LAM) are not acceptable methods of contraception.  
e. 
Male condom and female condom should not be used together (due to risk of failure from friction). 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
120 
10.5. 
Appendix 5: Genetics 
USE/ANALYSIS OF DNA 
• Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity, and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood and/or saliva sample will be collected 
for DNA analysis 
• DNA samples will be used for research related to linerixibat or PBC, cholestatic 
pruritus and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to linerixibat, other IBAT inhibitors and PBC or cholestatic 
pruritus. Genetic research may consist of the analysis of one or more candidate genes 
or the analysis of genetic markers throughout the genome or analysis of the entire 
genome (as appropriate) 
• Additional analyses of DNA samples may be conducted if it is hypothesized that this 
may help further understand the clinical data.  
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to linerixibat or study interventions of this class to 
understand the study disease or related conditions. 
• The results of genetic analyses may be reported in the CSR or in a separate study 
summary. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained while research on linerixibat or study interventions of 
this class or indication continues but no longer than the data retention period of the 
study or other period as per local requirements. 
 
 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
121 
10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments  
Procedures When Liver Stopping Criteria are Met 
The procedures listed below are to be followed if a participant meets any of the liver 
chemistry stopping criteria defined in Section 7.1.1. 
Immediately withdraw the participant from study intervention (see Section 7.1.1.2). 
Make every reasonable attempt to have the participant return to the clinic within 24-72 
hrs. for repeat liver chemistries and additional testing. 
Notify the GSK Medical Monitor or designee within 24 hours of learning of the 
abnormality to confirm the participant’s study intervention cessation and follow-up. 
Complete the “Safety Follow-Up Procedures” listed below. 
Complete the liver event eCRFs. If the event also meets the criteria of an SAE, the SAE 
data collection tool will be completed separately with the relevant details. 
Upon completion of the liver safety follow-up, the participant should remain in the study, 
restart of study intervention (where there is a likely non-DILI cause for the event) might 
be considered upon discussion with medical monitor (see Section 7.1.9.1). 
Monitor participants at least weekly until liver chemistries (ALT, AST, ALP, TB, 
PT/INR) resolve, stabilize or return to within baseline values and the subject is 
asymptomatic. 
Additional Safety Follow-Up Procedures for participants who meet any of the liver 
stopping criteria: 
Viral hepatitis serology including: 
• 
Hepatitis A Immunoglobulin (IgM) antibody; 
• 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);  
• 
Hepatitis C RNA;  
• 
Cytomegalovirus IgM antibody;   
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing);   
• 
Hepatitis E IgM antibody. 
Blood sample for PK analysis, obtained within 12 hours of last dose. Record the 
date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to blood sample draw on the eCRF. If the date or time of the last dose 
is unclear, provide the participant’s best approximation. If the date/time of the last dose 
cannot be approximated OR a PK sample cannot be collected in the time period indicated 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
122 
above, do not obtain a PK sample. Instructions for sample handling and shipping are 
included in the SRM. 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
Serum and plasma samples for biomarkers of liver injury 
Fractionate bilirubin, if total bilirubin 2xULN. 
Assess eosinophilia. 
Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) as relevant 
on the AE eCRF. 
Record use of concomitant medications, acetaminophen, herbal remedies, other over the 
counter medications, or putative hepatotoxins on the Concomitant Medications eCRF. 
Record alcohol use on the Liver Events eCRF. 
The following are required for participants who meet liver stopping criteria for both 
ALT and total bilirubin:  
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins). 
Serum acetaminophen adduct high performance liquid chromatography (HPLC) assay 
(where available) to assess potential acetaminophen contribution to liver injury unless 
acetaminophen use is very unlikely in the preceding week).  
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate 
liver disease. 
The Liver Imaging and/or Liver Biopsy eCRFs are also to be completed if these tests are 
performed. 
 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
 
123 
10.7. 
Appendix 7: Country-Specific Requirements 
10.7.1. 
China 
10.7.1.1. 
Biomarkers and Exploratory Laboratory Samples 
For China, collection of all exploratory biomarker samples (Serum C4, FGF-19, 
Autotaxin, Total Serum Bile Acids) will be contingent on agreements with China 
regulatory (HGRAC). Depending on the agreements with the China regulatory and ethics 
committees, all or some of these biomarkers will be made optional for participants from 
China.  
These exploratory biomarkers are all biomarkers of bile acid synthesis and reuptake and 
will be analyzed to help inform about the pharmacodynamics of linerixibat. 
In addition, the optional genetics sample described in Section 8.6, ELF and Fibroscan as 
described in Section 8.7.1.2 will be contingent on agreements with HGRAC. ELF and 
serum acetaminophen Adduct HPLC assay for liver event testing may not be performed 
in China due to operational or logistical difficulties. 
For any biological samples taken, samples will be analyzed and stored within China 
according to local storage and retention regulations and requirements. 
Further research as described in Section 8.6 and Section 8.7 will not be applicable for 
samples from China. 
10.7.1.2. 
Visit 9 Questionnaire 
A questionnaire consisting of four questions will be administered to participants in China 
in order to support PRO validation for participants in China. Three of the questions have 
categorical based responses with one question open for free text response. The 
questionnaire is to be administered to participants from China at Visit 9 (end of Part A).  
 
 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
124 
10.7.1.3. 
China Schedule of Assessments (SoA) 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
 
 
Part A 
Part B 
 
 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial 
site to perform study assessments 
(Please see Section 10.8). 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit widow 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to -
6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Recheck clinical status before 
randomization. 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Including height and weight. 
Brief physical 
examination  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Please see Section 8.3.1; physical 
exams may be performed as symptom 
directed exams or by other means if 
assessment performed at locations 
other than the clinical site. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
125 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
 
 
Part A 
Part B 
 
 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial 
site to perform study assessments 
(Please see Section 10.8). 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit widow 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to -
6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Medical history 
and prior/current 
conditions  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Including substance usage (drugs, 
alcohol, tobacco and caffeine), family 
history of premature cardiovascular 
(CV) disease and PBC specific 
Medical History and past-PBC-related 
procedures 
Any change in medical history since 
screening should be reviewed at Day 
1, and a baseline stool frequency 
should be recorded as described in 
Section 7.1.3. 
Background Itch 
Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
The investigator will ask participants 
to rate their overall itch severity for 
the 2 months preceding the screening 
visit as described in Section 8.2.1.1. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
126 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
 
 
Part A 
Part B 
 
 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial 
site to perform study assessments 
(Please see Section 10.8). 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit widow 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to -
6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Urine Pregnancy 
test (Women of 
Childbearing 
Potential 
[WOCBP] only) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Refer to Section 8.3.5, serum 
pregnancy may be required locally in 
some locations. 
Human 
Immunodeficiency 
Virus (HIV), 
Hepatitis B and C 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Laboratory tests  
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Refer to Section 10.2, Clinical 
laboratory tests at Visit 2 refer to liver 
biochemistry parameters only. 
Fecal Occult 
Blood Test 
(FOBT) 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Please see Section 8.3.4.2. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
127 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
 
 
Part A 
Part B 
 
 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial 
site to perform study assessments 
(Please see Section 10.8). 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit widow 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to -
6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Exploratory 
Biomarkers 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Please see Section 8.7.  
Sample on Day 1 should be taken 
prior to any study intervention 
administration. 
Assessment is not required if study 
treatment is permanently discontinued. 
Enhanced Liver 
Fibrosis (ELF) 
Test 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
ELF may not be performed in China 
due to operational limitations. 
Fibroscan 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
To be performed only where site 
availability permits; please see 
Section 8.7.1.2. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
128 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
 
 
Part A 
Part B 
 
 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial 
site to perform study assessments 
(Please see Section 10.8). 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit widow 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to -
6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Pharmacokinetics 
(PK) 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
PK samples are required at a total of 3 
timepoints, 1 sample is required prior 
to first dose of study treatment at Visit 
3 and 2 further samples will be 
required at any 2 additional visits 
between weeks 8 and 24. 
Assessment is not required if study 
treatment is permanently discontinued.  
12-lead ECG 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
Vital signs 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention 
dispensing 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Study intervention 
administration 
 
 
 
======================================→ 
 
 
Day 1 is the day on which the first 
study intervention administration 
takes place and may differ from the 
randomization date. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
129 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
 
 
Part A 
Part B 
 
 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial 
site to perform study assessments 
(Please see Section 10.8). 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit widow 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to -
6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Medication diary 
 
 
 
======================================→  
 
Study medication diary to be 
completed daily throughout the study. 
The medication diary is not required if 
study treatment is permanently 
discontinued. 
Study intervention 
return/compliance 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Event 
(AE) review 
 
 
 
=====================================→ 
X 
X 
AEs will be collected from the start of 
study intervention.  
Serious Adverse 
Event (SAE) 
review 
=======================================================→ 
X 
X 
 
Concomitant 
medication review 
=======================================================→ 
X 
X 
Including PBC-specific Medications 
(past and present). 
Symptom 
Questionnaire 
=======================================================→ 
X 
 
Symptom Questionnaire includes the 
itch, sleep and fatigue NRS. Please see 
Section 8.2.1.1. 


TMF-16740250 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
130 
 
Screening  
(up to 56 days 
before Day 1) 
Intervention Period 
ED 
Follow-
up 
(7 -14 
days 
post 
last 
dose) 
Notes 
E.D = Early 
Discontinuation/Withdrawal (as 
described in Section 7.2). 
 
 
Part A 
Part B 
 
 
Where applicable country and local 
regulations and infrastructure allow, 
home healthcare may take place at a 
location other than the clinical trial 
site to perform study assessments 
(Please see Section 10.8). 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Day number  
-56 to 
-42 
-28 
to -14 
1 
28 
56 
84 
112 
140 
168 
196 
224 
Visit widow 
(days) 
NA 
NA 
NA 
3 
3 
3 
3 
3 
3 
3 
3 
Week number 
-8 to -
6 
-4 to -2 
(>V1 + 
4Wks) 
1 
4 
8 
12 
16 
20 
24 
28 
32 
Gastrointestinal 
Symptom Rating 
Scale 
 
 
================================================→ X 
 
Questionnaire on GI symptoms to be 
completed weekly in eDiary with a 
seven day recall as described in 
Section 8.2.1.3. 
PGI-C 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient Global Impression of Change 
Questionnaire 
PGI-S 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient Global Impression of Severity 
PBC-40  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PBC-40 Health Related Quality of 
Life Scale 
BDI-II 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
Beck Depression Inventory II 
ESS 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
Epworth Sleepiness Scale 
Visit 9 
Questionnaire 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
131 
10.7.2. 
Israel 
10.7.2.1. 
Genetics 
For Israel, due to operational challenges, sample collection for optional genetic research 
described in Section 8.6 and Section 10.5 will not be performed.  


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
132 
10.7.3. 
France 
This appendix includes all applicable requirements of French Public Health Code/specific 
local GSK requirements and identified, item per item, the mandatory modifications or 
additional information to the study protocol. 
10.7.3.1. 
Concerning the Selection of Study Population and Withdrawal Criteria 
The following vulnerable subject populations will be excluded; minors, protected 
subjects, adult subjects not in condition to express their consent, subjects deprived of 
liberty, subjects receiving psychiatric cares, subjects hospitalized in a Health and Social 
Establishment for other purpose than the participation to the study. 
A subject will be eligible for inclusion in this study if he/she is either affiliated to or 
beneficiary of a social security category (French Public Health Code law L.1121-8-1). 
(exception for a participant to a non-interventional study or to a participant to an 
interventional study if authorised by the Ethics Committee). It is the investigator’s 
responsibility to ensure and to document (in the source document - subject notes) that the 
subject:  
• 
is either affiliated to or beneficiary of a social security category 
• 
has got an authorisation by the Ethics Committee. 
10.7.3.2. 
Concerning the Study Governance Considerations  
• 
In section “Regulatory and Ethical Considerations, including the Informed Consent 
Process” of study protocol; Concerning the process for informing the subject and/or 
his/her legally authorized representative, the following text is added:  
French Patient Informed Consent is a document which summarizes the main features 
of the study and allows collection of the subject and/or his/her legally authorized 
representative written consent. It also contains a reference to the authorisation of 
ANSM and the approval from the French Ethics Committee. 
• 
Concerning the management of the Patient Informed Consent Forms, the following 
text is added:  
French Patient Informed Consent Form is in duplicate (triplicate for minor subject). 
The first page of the Patient Informed Consent Form is given to the investigator. The 
copy is kept by the patient or legally authorized representative. 
• 
Notification to the Hospital Director 
In accordance with Article L1123-13 of the French Public Health Code, the Hospital 
Director is informed of the commitment to the trial in her/his establishment. The Hospital 
Director is supplied with the protocol and any information needed for the financial 
disposition, the name of the investigator(s), the number of sites involved in his 
establishment and the estimated time schedule of the trial (R.1123-69). 
• 
Information to the Hospital Pharmacist 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
133 
In accordance with Article R.1123-70 of the French Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in her/his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows her/him to dispense the 
drug(s) of the trial according to the trial methodology), all information concerning the 
product(s) of the trial (e.g., included in the IB), the name of the investigator(s), the 
number of sites involved in her/his establishment and the estimated time schedule of the 
trial 
• 
Ethnic Origin 
In accordance with the data privacy regulation, the ethnic origin, as any personal data, 
can only be collected if the collection of this data is strictly necessary and relevant for the 
purpose of the study. 
• 
Testing of Biological Samples 
In accordance with the French Public Health Code law – article L1211-2, a biological 
sample without identified purpose at the time of the sample and subject’s preliminary 
information is not authorized. 
10.7.3.3. 
Concerning the DATA MANAGEMENT 
The following text is added: 
Within the framework of this clinical trial, data regarding the identity of the investigators 
and/or co-investigators and/or the pharmacists if applicable, involved in this clinical trial, 
and data regarding the subjects recruited in this clinical trial (subject number, treatment 
number, subjects status with respect to the clinical trial, dates of visit, medical data) will 
be collected and computerized in GSK data bases by GSK or on its behalf, for reasons of 
follow up, clinical trial management and using the results of said clinical trial. According 
to the data privacy regulation, each of these people aforesaid has a right of access, 
correction and opposition on their own data through GSK (Clinical Operations 
Department). 
10.7.3.4. 
Concerning Data Privacy 
In accordance with the applicable data privacy regulation, personal data are processed in 
a manner that ensures appropriate security, including protection against unauthorized or 
unlawful processing and against accidental loss, destruction, or damage, using 
appropriate technical or organizational measures. The processing is whether deemed to be 
compliant with one of the methodology of reference (MR-001) or has been the subject of 
a request for authorization to the CNIL. The Investigator has, regarding the processing 
data related to her/him, a right of access, of rectification, erasure and of opposition with 
GSK in accordance with the legal provisions. 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
134 
10.8. 
Appendix 8: Home Healthcare/Remote Activities  
10.8.1. 
Overall Rationale for this Appendix  
This protocol appendix outlines measures to be considered for any country/site where 
home healthcare options may be implemented for participants as permitted by country 
and local regulations and infrastructure.  
Activities may be performed remotely either to ensure study continuity during periods of 
significant challenge (e.g., pandemic, conflict), or if partial or fully remote study 
activities are permitted locally to support participant burden with visit scheduling. 
Where required due to study continuity issues, clinical investigators should document in 
participant notes appropriately how restrictions related to the event led to the changes in 
study conduct and duration of those changes and indicate which trial participants were 
impacted and how those trial participants were impacted (as per the current local 
regulatory guidance). Missing protocol required data/visits due to study continuity issues 
should be noted in participant notes and recorded as a protocol deviation. 
The purpose of the appendix is to provide information on the measures to be taken to 
protect participants’ safety, welfare, and rights, and promote data integrity. 
10.8.2. 
Home Healthcare Provisioning 
If allowed by country regulation/ethics, study assessments may be conducted remotely at 
some visits during this study, the details of which are provided separately. Remote 
activities for these applicable visits, such as those described in the below section, can be 
conducted by a home healthcare professional either as arranged and overseen by the 
investigator site or by a sponsor delegated third party such as 
, which has been 
contracted to perform these activities in many countries if requested using virtual 
technologies (telemedicine, secure video conferences, phone calls, or a web portal and/or 
mobile application).  
In addition, a fully remote metasite, wherein all visits are conducted fully remotely will 
be implemented with 
, where permitted by regulation/ethics. 
CCI
CCI


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
135 
10.8.3. 
Protocol Defined Procedures/Visits 
• It is the responsibility of the investigator or designee to inform GSK when remote 
assessments are required and occur and to document in the source notes. 
• Measurement of vital signs and weight, as well as conduct of a brief physical 
exam may be conducted remotely. In some cases, brief physical exams may be 
performed as symptom directed exams or by other means as agreed with the 
investigator. 
• Clinical safety laboratory sampling, PK, biomarkers and genetic sampling and 
processing may all be conducted remotely by a home healthcare professional. 
Ancillary materials for the above laboratory sampling may also be shipped direct 
to the participant’s home address from the investigational site/depot or delegated 
third party. Collected laboratory samples can also be collected direct from the 
participant’s home address to the central laboratory.  
• The process for laboratory sample shipments must be agreed with GSK if 
performed by the clinical site or details can be provided if performed by an agreed 
third party. 
• Additional unscheduled safety assessments such as routine blood sampling may 
be performed at the discretion of the Investigator including in the participant’s 
home, if deemed necessary Biological samples should not be collected if they 
cannot be processed in a timely manner or appropriately stored until the intended 
use.  
• If visits to a site/home are not feasible, then medical evaluation may take place by 
telemedicine which will use secure video conferences, phone calls, and a web 
portal and/or mobile application as a way of communicating with and monitoring 
the participant’s progress. GSK will be accountable for working with third party 
vendors to ensure the site has the required equipment, training and support for this 
model and should be notified as soon as possible by the investigator that the 
service is required. 
• As part of this model, study visits may be completed on a virtual platform that 
connects participants to their investigators and study teams through either a study-
issued smartphone or participant’s own device (BYOD) model. This technology 
may be used in combination with visits from mobile study personnel (e.g. mobile 
nurses) to participants’ homes for various lab collections and designated study 
procedures.  
• The study investigator is responsible for ensuring that the identification, 
management, and reporting of AEs and SAEs are completed in accordance with 
the protocol and applicable regulations. AEs are first reported by participants to 
the investigator/study team or may be identified by the study team during 
interactions with the participants via telemedicine encounters. In addition, mobile 
nurses may identify AEs as well and report them to the investigator for 
evaluation. Additionally, AEs may be identified from lab reports, imaging or ECG 
reports, and other records. As determined by the investigator, the appropriate 
medical intervention, therapeutic intervention, and/or support measures are 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
136 
instituted, as necessary. Participants can also request a timely secure 
videoconference with the investigator and/or site staff. 
• The participant should be informed of the plan and any potential risks associated 
with the virtual medium and sign a revised Informed Consent Form if required. 
IRB/Ethics committee should be informed and/or approve of this change in 
approach and the process documented in study files. 
• 
Note: If the Investigator wishes to conduct a trial visit at a location that has not been 
previously assessed by GSK, it is the investigator’s responsibility to identify an 
adequate alternate location and to notify GSK of the alternate location. The 
investigator should ensure that this alternate location meets ICH GCP requirements, 
is well-equipped to perform study procedures and covered by an adequate insurance. 
Furthermore, the investigator should have sufficient oversight to ensure that the staff 
at the alternate location are trained to perform study procedures.  
10.8.4. 
Study Intervention(s) 
• 
If allowed by country regulation/ethics, then study intervention (including rescue 
study medication and ancillary supplies related to Investigational Medicinal Product 
(IMP) administration) can be shipped direct-to-participant (DTP) from the 
investigational site or delegated third party, as arranged by the sponsor, to the 
participant’s home address. The process for this shipment must be agreed with GSK 
who will provide the relevant documentation and links to courier sites required to 
ensure shipments are adequately temperature controlled (if required) throughout 
transportation. 
• 
Used and/or unused IMP can also be collected from the participant’s home address to 
the return/destruction location, either the investigational site or agreed location of 
destruction. The process for this shipment must be agreed with GSK who will 
provide operational details if this service is available. 
• 
Staff at each clinical study center or the home healthcare professional (if provided by 
sponsor delegated third party) will be responsible for supply of study intervention 
according to procedures detailed in the SRM. No special procedures for the safe 
handling of study intervention are required. 
• 
The Principal Investigator assumes Good Clinical Practice (GCP) responsibilities for 
IMP handling and the medical control for dispensing to participants. Site Staff 
should document the dispensing in the Dispensing/Accountability Logs adding a 
comment that this was a DTP dispensing.  
• 
Compliance with study intervention administration will be verified through 
observation by study staff or trained home healthcare professionals if performed by 
sponsor delegated third party. 
• 
In some cases, trial participants who no longer have access to investigational product 
or the investigational site may need additional safety monitoring (e.g., on withdrawal 
of an active investigational treatment). 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
137 
10.8.5. 
Data Management/Monitoring 
• 
If on-site monitoring is no longer permitted, GSK will consider remote Source Data 
Verification/Source Document Review (SDV/SDR) where permitted by local 
regulations and the clinical site/institution. Remote SDV/SDR will be proposed to 
study sites to meet a participant and/or critical quality need, e.g., to assess participant 
safety or to ensure data integrity. In case of remote SDV/SDR, GSK will work with 
the site to ensure subject privacy.  
• 
eCRF/CRF Final or Interim Sign off Process: The Principal Investigator (PI) is 
responsible for ensuring that the data within the eCRF casebook and any other data 
sources utilized during the study for each study participant is complete and 
consistent with source documents throughout the study (ICH GCP 4.9.1 4.9.2). The 
PI may sign/re-sign the eCRF from any computer/location by accessing the eDC 
platform (Veeva CDMS) using his/her unique eCRF log-in credentials. The PI may 
delegate this activity to another medically qualified and trained sub-investigator and 
this must be documented on the Delegation of Responsibilities (DoR) Log. It is 
recommended that the PI identifies a sub-investigator as a back-up for eCRF 
signatures. The sub-investigator must be appropriately trained on the protocol and 
eCRF requirements (with training documented), and the DoR log updated 
accordingly.  
• 
Essential Document Sign Off Process: If an investigator is unable to print and sign 
essential documents such as Protocol /Amendment signature page then Email 
approval can be accepted by replying to the relevant email that is sent by GSK. 
 
 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
138 
10.9. 
Appendix 9: Activities of Daily Living (ADLs) 
Basic ADLs* 
Instrumental ADLs** 
1. Bathing 
1. Using the telephone 
2. Dressing 
2. Shopping 
3. Toileting 
3. Doing housework 
4. Transferring 
4. Doing laundry 
5. Maintaining continence 
5. Preparing meals 
6. Feeding 
6. Driving 
 
7. Taking medications 
 
8. Managing money 
*Basic ADLS: self-care activities that an individual must accomplish in order to remain 
self-sufficient 
**Instrumental ADLs: higher-level activities that individuals must perform or have help with to 
remain independent in their homes  
 
 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
139 
10.10. 
Appendix 10: Abbreviations, Definitions of Terms, and 
Trademarks 
ABBREVIATION 
DEFINITION 
AASLD 
American Association for the Study of Liver Diseases 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AMA 
Anti-mitochondrial antibody 
AR 
Autoregressive 
ASBT 
Apical Sodium-Dependent Bile Acid Transporter 
ASP 
Average Sleep Propensity 
AST 
Aspartate Aminotransferase 
BDI-II 
Beck Depression Inventory-II 
BID 
Bis in die (twice daily) 
BUN 
Blood Urea Nitrogen 
C4 
7-α-hydroxy-4-cholesten-3-one 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CMH 
Cochran-Mantel-Haenszel  
CONSORT 
Consolidated Standards of Reporting Trials 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
140 
ABBREVIATION 
DEFINITION 
COVID-19 
SARS-CoV-2 Virus 
CPK 
Creatine Phosphokinase 
CPMS 
Clinical Pharmacology Modeling and Simulation 
CRF 
Case Report Form 
CS 
Compound Symmetry 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Event 
CV 
Cardiovascular Disease 
DBL 
Database Lock 
DILI 
Drug Induced Liver Injury 
DNA 
Deoxyribonucleic Acid 
DoR 
Delegation of Responsibilities 
DTP 
Direct to Participant 
EASL 
European Association for the Study of the Liver 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ED 
Early Discontinuation 
eDiary 
Electronic Diary 
eGFR 
Estimated Glomerular Filtration Rate 
ELF 
Enhanced Liver Fibrosis 
ELISA 
Enzyme-linked Immunosorbent Assay 
EMA 
European Medicines Agency 
ESS 
Epworth Sleepiness Scale 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
141 
ABBREVIATION 
DEFINITION 
FDA 
Food and Drug Administration 
FGF-19 
Fibroblast Growth Factor-19 
FOBT 
Fecal Occult Blood Test 
FSFV 
First Subject, First Visit 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GGT 
Gamma Glutamyl Transferase 
GI 
Gastrointestinal 
GSK 
GlaxoSmithKline 
GSRS 
Gastrointestinal Symptom Rating Scale 
GWAS 
Genome-wide Association Study 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B 
hCG 
Human chorionic Gonadotropin 
HCV 
Hepatitis C 
HDL 
High Density Lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 
IBAT 
Inhibitor of the Human Ileal Bile Acid Transporter 
ICF 
Informed Consent Form 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
142 
ABBREVIATION 
DEFINITION 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intend to Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
IWRS 
Interactive Web Response System 
K-PD 
Kinetic-Pharmacodynamic 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
LFT 
Liver Function Test 
LOF 
Loss of Function 
MAR 
Missing at Random 
MCH 
Mean Corpuscular Hemoglobin 
MCV 
Mean Corpuscular Volume 
mg 
Milligram 
MMRM 
Mixed Model Repeated Measure 
MSDS 
Material Safety Data Sheet 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
143 
ABBREVIATION 
DEFINITION 
MWDI 
Mean Worst Daily Itch (now referred to as Weekly Itch) 
NASH 
Nonalcoholic Steatohepatitis 
NRS 
Numerical Rating Scale 
OCA 
Obeticholic Acid (Ocaliva) 
PBC 
Primary Biliary Cholangitis 
PBC-40 
Primary Biliary Cholangitis-40 Health Related Questionnaire 
PD 
Pharmacodynamics 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PheWAS 
Phenome-wide Association Study 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PRO 
Patient Reported Outcome 
PSC 
Primary Sclerosing Cholangitis 
PT 
Prothrombin Time 
QD 
Quaque die (once daily) 
QoL 
Quality of Life 
QTcB 
QT interval Bazett’s Formula 
QTcF 
QT interval Fredericia’s Formula 
QTL 
Quality Tolerance Limit 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
144 
ABBREVIATION 
DEFINITION 
SD 
Standard Deviation 
SDR 
Source Document Review 
SDV 
Source Data Verification 
SE 
Standard Error 
SoA 
Schedule of Assessments 
SRM 
Study Reference Manual 
SSP 
Situational Sleep Propensities 
SSRI 
Selective Serotonin Reuptake Inhibitor 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T2D 
Type 2 Diabetes 
TB 
Total Bilirubin 
UDCA 
Ursodeoxycholic Acid 
UK 
United Kingdom 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WIS 
Weekly Itch Score (formerly referred to as Mean Worst Daily 
Itch [MWDI] Score) 
WOCBP 
Women of Childbearing Potential 
WONCBP 
Women of non-Childbearing Potential 
WSS 
Weekly Sleep Score (formerly referred to as Mean Daily Sleep 
Score) 
 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
145 
Term 
Definition 
Adverse drug reaction 
An adverse event where a causal relationship between a 
medicinal product and the adverse event is at least a 
reasonable possibility, i.e., the relationship cannot be 
ruled out. 
a. In the context of a clinical trial, an ADR can be 
serious or non-serious. Serious ADRs may be subject to 
expedited reporting if they are considered unexpected 
(see SUSAR definition). 
Background therapy 
Type of medicinal product administered to each of the 
clinical trial participant, regardless of randomization 
group, to treat the indication that is the object of the 
study. Background treatment is generally considered to 
be the current standard care for the particular indication. 
In these trials, the IMP is given in addition to the 
background treatment and safety efficacy are assessed. 
The protocol may require that the IMP plus the 
background treatment is compared with an active 
comparator or with placebo plus background treatment.  
Blinding 
A procedure in which 1 or more parties to the study are 
kept unaware of the intervention assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
study, and only when the data are cleaned to an 
acceptable level of quality will appropriate personnel be 
unblinded or when required in case of a SAE. 
In a double-blind study, the participant, the investigator 
and sponsor staff who are involved in the treatment or 
clinical evaluation of the participants and the review or 
analysis of data are all unaware of the intervention 
assignment. 
Certified copy 
A copy (irrespective of the type of media used) of the 
original record that has been verified (i.e. by a dated 
signature or by generation through a validated process) 
to have the same information, including data that 
describe the context, content, and structure, as the 
original. 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
146 
Term 
Definition 
Comparator 
Any product used as a reference (including placebo, 
marketed product, GSK or non-GSK) for an 
investigational product being tested in a clinical trial. 
This is any product that is being used to assess the 
safety, efficacy, or other measurable value against the 
test product (IMP). 
Direct-from-Participant 
Shipments 
Home pickup of collected biological specimens, or 
pickup and return of unused/partially used/expired trial 
materials for return to investigator site. 
Direct-to-Participant 
Shipments 
Shipping of Investigational Product, lab kits, devices, 
etc., to the participant’s residence under secure and 
controlled conditions. 
eDiary 
Electronically registered patient data and automated data 
entries on, for example, a handheld mobile device, tablet 
or computer. 
Eligible 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Essential documents 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of 
the data produced. 
Home Healthcare Services  
Deployment of mobile health care professional(s) 
(nurses or phlebotomists) to perform study activities 
remotely. 
Investigational Product 
A pharmaceutical form of an active substance or 
placebo being tested or used as a reference in a clinical 
trial, including products already with a marketing 
authorization but used or assembled (formulated or 
packaged) in a way different from the authorized form, 
or when used for an unauthorized indication, or when 
used to gain further information about the authorized 
form. 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
147 
Term 
Definition 
Investigator 
A person responsible for the conduct of the clinical 
study at a study site. If a study is conducted by a team of 
individuals at a study site, the investigator is the 
responsible leader of the team and may be called the 
principal investigator.  
The investigator can delegate study-related duties and 
functions conducted at the study site to qualified 
individual or party to perform those study-related duties 
and functions. 
Participant number 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Participant 
Term used throughout the protocol to denote an 
individual who has been contacted to participate or who 
participates in the clinical study as a recipient of the 
study intervention (vaccine(s)/product(s)/control). 
Synonym: subject 
Pharmacogenomics 
The ICH E15 Guidance for Industry defines 
pharmacogenomics as the “Study of variation of DNA 
and RNA characteristics as related to drug or treatment 
response.”  
Pharmacogenetics, a subset of pharmacogenomics, is 
“the study of variations in DNA sequence as related to 
drug response.” Pharmacogenomic biomarkers include 
germline (host) DNA and RNA as well as somatic 
changes (e.g., mutations) that occur in cells or tissues.  
Pharmacogenomic biomarkers are not limited to human 
samples but include samples from viruses and infectious 
agents as well as animal samples. The term 
pharmacogenomic experiment includes both the 
generation of new genetic or genomic (DNA and/or 
RNA) data with subsequent analysis as well as the 
analysis of existing genetic or genomic data to 
understand drug or treatment response (PK, safety, 
efficacy or effectiveness, mode of action).  
Proteomic and metabolomic biomarker research is not 
pharmacogenomics. 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
148 
Term 
Definition 
Placebo 
An inactive substance or treatment that looks the same 
as, and is given in the same way as, an active drug or 
intervention/treatment being studied. 
Randomization 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Remote visit 
This term refers to the visit conducted in the place other 
than the study site. 
Rescue medication 
Medicines identified in the protocol as those that may be 
administered to the participants when the efficacy of the 
IMP is not satisfactory, or the effect of the IMP is too 
great and is likely to cause a hazard to the patient, or to 
manage an emergency situation. 
Source data 
All information in original records and certified copies 
of original records of clinical findings, observations, or 
other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data 
are contained in source documents (original records or 
certified copies). 
Standard of care 
Medicine(s) for a specific indication, or a component of 
the standard care for a particular medical indication, 
based on national and/or international consensus; there 
is no regulatory significance to this term. 
1. Products/regimens considered standard of care may 
differ country to country, depending on consensus in 
individual countries. 
Study intervention 
Term used throughout the clinical study to denote a set 
of investigational product(s) or marketed product(s) or 
placebo intended to be administered to a participant. 
Note: “Study intervention” and “study treatment” are 
used interchangeably unless otherwise specified. 
Study completion date 
The date on which the last participant in a clinical study 
was examined or received an intervention/treatment to 
collect final data for the primary outcome 
measures, secondary outcome measures, and AEs (that 
is, the last participant's last visit or LSLV). 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
149 
Term 
Definition 
Study monitor  
An individual assigned by the sponsor and responsible 
for assuring proper conduct of clinical studies at 1 or 
more investigational sites. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction; in a 
clinical trial, a serious adverse reaction that is 
considered unexpected, i.e., the nature or severity of 
which is not consistent with the reference safety 
information (e.g., Investigator's Brochure for an 
unapproved investigational medicinal product). All 
adverse drug reactions (ADRs) that are both serious and 
unexpected are subject to expedited reporting. 
Telemedicine 
The use of electronic information and 
telecommunications technologies (both video-based and 
audio-only) to facilitate remote health care delivery, 
participant and professional health-related education, 
public health and health administration. 
Virtual visit 
This term refers to study visits conducted using 
multimedia or technological platforms. 
 
TRADEMARK INFORMATION 
Trademarks of the GSK group of 
companies 
 
Trademarks not owned by the GSK 
group of companies 
None 
 
Enhanced Liver Fibrosis  
 
 
Fibroscan 
 
 
Ocaliva 
 
 
Questran 
 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
150 
10.11. 
Appendix 11: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment [03-ISR-01]: 24-MAR-2022 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.  
Overall Rationale for the Amendment:  
Introduction of country-specific requirement for Israel. 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Assessments (SoA) 
Note added to indicate that 
sample for optional genetic 
research will not be collected 
in Israel. 
In line with study strategy 
New Section 10.7.2 
Israel  
Country-specific requirement 
for Israel added: sample 
collection for optional genetic 
research will not be performed. 
In line with study strategy 
 
Amendment [03]: 02-SEP-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.  
Overall Rationale for the Amendment:  
Inclusion of additional stopping criteria, liver biochemistry triggers for monitoring of 
drug induced cholestatic liver injury and clarifications on exclusion criteria. 
Section # and Name 
Description of 
Change 
Brief Rationale 
Section 1.1. Synopsis 
Text amended 
referring to questions 
within the PBC-40 
questionnaire 
Clarification of question 
domains 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
151 
Section # and Name 
Description of 
Change 
Brief Rationale 
Section 1.1. Synopsis 
Addition of text 
related to 
administrative 
stratification factors 
Addition of text for 
clarification purposes in 
alignment with SAP. 
Section 1.1. Synopsis 
IDMC reference text 
amended to include 
safety monitoring of 
patients in the study 
Clarification of text 
Section 2.1. 
Text amended 
referring to questions 
within the PBC-40 
questionnaire 
Clarification of question 
domains 
Section 2.3.1. Risk 
Assessment 
Addition of reference 
to abdominal pain in 
relation to 
gastrointestinal 
effects including 
diarrhea 
Added for alignment with 
Investigator’s Brochure 
Section 3. Objectives and 
Endpoints/Estimands 
Text amended 
referring to questions 
within the PBC-40 
questionnaire 
Clarification of question 
domains 
Section 4.1. Overall Design 
Addition of text 
related to 
administrative 
stratification factors 
Addition of text for 
clarification purposes in 
alignment with SAP. 
Section 5.2. Exclusion 
Criteria 
Text added to clarify 
that participants with 
positive COVID-19 
tests will also be 
excluded from the 
study 
Text amended in line with 
updated guidance 
Section 5.2. Exclusion 
Criteria 
Text amended to 
clarify alcohol 
restriction 
requirements for the 
study 
Text amended in line with 
regulatory feedback 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
152 
Section # and Name 
Description of 
Change 
Brief Rationale 
Section 5.4. Screen Failures 
Text clarified that 
screen failures do not 
ultimately enrol in the 
study 
Clarification of text 
Section 6.1. Study 
Intervention(s) Administered 
Changes to colour of 
tablet and 
clarification of 
dosage level text 
Correction of text 
New Section 6.3.1. 
Unblinding Procedures   
Addition of text 
indicating unblinding 
procedures 
Clarification of text 
6.4. Study Intervention 
Compliance 
Clarification that 
deviations will be 
recorded for impacted 
compliance 
Clarification of text 
Section 7.1.1.1. Increased 
Monitoring 
Liver 
monitoring/stopping 
criteria amended  
Text amended in line with 
regulatory feedback 
Section 7.1.1.2. Stopping 
Criteria 
Additional ALP 
criteria added 
Text amended in line with 
regulatory feedback 
Section 7.1.1.3 Close 
Observation 
Additional ALP test 
added 
Text amended in line with 
regulatory feedback 
Section 7.1.3. Diarrhea 
Management Criteria and 
Stopping Criteria 
Removal of text 
requiring participant 
request for anti-
diarrheal treatment 
Clarification of text 
New Section 7.1.5. Renal 
Stopping Criteria 
Added stopping 
criteria related to 
renal function 
Text added in line with 
regulatory feedback 
New Section 7.1.6. Diagnosis 
of Colon Cancer 
Added stopping 
criteria related to 
diagnosis of colon 
cancer 
Text added in line with 
regulatory feedback 
Section 7.2. Participant 
Discontinuation/Withdrawal 
from the Study 
Text added to clarify 
occasions for 
Clarification of text 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
153 
Section # and Name 
Description of 
Change 
Brief Rationale 
discontinuation by 
the investigator 
Section 8.6.1. Biomarkers of 
Disease Progression 
Text added to include 
expectation of 
screening for 
hepatocellular 
carcinoma 
Text added in line with 
regulatory feedback 
Section 9.1.2. Secondary 
endpoints 
Text amended in 
relation to additional 
testing 
Clarification of statistical 
approach 
Section 9.4.2. Primary and 
Secondary Endpoint(s) 
Text clarified with 
regards to how 
imputed data 
impacted by COVID-
19 will be addressed 
Clarification of text 
New Section 9.4.5. Other 
Analyses 
Text added to clarify 
approach to 
validation of PRO 
data 
Clarification of text 
Section 10.1.5.1. Independent 
Data Monitoring Committee 
Text amended to 
clarify that safety of 
participants will be 
evaluated at IDMC 
Clarification of text  
 
Amendment [02]: 12-JUL-2021 
This amendment was considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it neither significantly impacts the safety or physical/mental 
integrity of participants nor the scientific value of the study 
Overall Rationale for the Amendment:  
Clarification of text and correction of typographical errors across the document 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
154 
Section # and Name 
Description of 
Change 
Brief Rationale 
Section 1.3. Schedule of 
Assessments 
Removal of Visit 
Number, Day 
Number and Week 
Number 
 Administrative error 
corrected for clarification: 
Follow up phone calls are not 
linked to a specific visit 
Section 1.3. Schedule of 
Assessments 
Text added to clarify 
that 3 total 
pharmacokinetic 
samples are required 
for the study 
 Additional text added for 
clarification purposes 
Section 3: Objectives and 
Endpoints/Estimands 
Removal of word 
“with” from 
exploratory endpoint 
#2 
 Correction of typographical 
error 
Section 3.1. Primary 
Estimand 
Text amended to 
clarify analysis of 
intercurrent event 
data 
Text clarified to describe how 
to discard data impacted by 
intercurrent events 
Section 1.1 Synopsis 
Section 3.3. Supplementary 
Estimand 
 
Text amended to 
clarify analysis of 
intercurrent event 
data 
Text clarified to describe how 
to discard data impacted by 
intercurrent events 
Section 1.1 Synopsis 
Section 4.1. Overall Design 
Text added to clarify 
circumstances for 
follow up phone call 
 Text added to clarify that 
follow up phone calls should 
also be performed after study 
treatment withdrawal 
Section 5.1. Inclusion Criteria 
Text added to clarify 
additional validated 
assays may be used in 
Inclusion Criteria #2 
Text added to align with local 
requirements of different 
validated assays used for 
diagnosis of PBC 
Section 5.1. Inclusion Criteria 
Removal of “not” 
from inclusion 
criteria #4 
 Correction of typographical 
error for clarification 
purposes 
Section 4.2.4 Rationale for 
Concomitant Medications 
Section 6.8.3. Rescue 
Medication 
Correction of term 
“intolerable” to 
“worsening” 
Text has been amended to 
clarify conditions in which 
rescue medication can be 
considered 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
155 
Section # and Name 
Description of 
Change 
Brief Rationale 
Section 7.1. Discontinuation 
of Study Intervention and 
Participant 
Discontinuation/Withdrawal 
Additional text added 
to clarify 
circumstances of 
follow-up phone call 
 Text added to clarify that 
follow up phone calls should 
also be performed after study 
treatment withdrawal 
Section 7.1.3.1. 
Determination of Diarrhea 
Severity 
Text removed 
indicating diarrhea 
that is interfering 
with the participant’s 
daily activities will be 
considered an AESI 
Text removed to clarify that 
all diarrhea will be considered 
an AESI 
Section 7.1.7.1. Study 
Intervention Restart after 
Meeting Liver Stopping 
Criteria 
Removal of text 
referring to identified 
genetic markers for 
liver injury 
Text removed as not 
applicable for this study  
Section 8.1.1.5 Beck 
Depression Inventory (BDI-
II) 
 Removal of 
administrative text 
Text removed to clarify that 
questionnaires do not need to 
be completed during the visit 
Section 8.2.4. Clinical Safety 
Laboratory Assessments 
Removal of text 
referring to dose 
modification 
Text removed as dose 
modification is not applicable 
for this study 
Section 8.3.1. Time Period 
and Frequency for Collecting 
AE and SAE Information 
Additional text added 
to clarify that AEs 
and SAEs will be 
collected until the 
follow up phone call 
or the final scheduled 
GLISTEN visit 
Text added to clarify the 
duration of AE and SAE 
collection in relation to 
follow-up phone call (if 
applicable) 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
156 
Section # and Name 
Description of 
Change 
Brief Rationale 
Section 8.3.5. Pregnancy 
Removal of text 
requiring female 
partners of male 
participants requiring 
consent for 
pregnancy reporting 
Text was originally included 
in error, text has been 
removed as not necessary for 
study based on very low 
estimated exposure via semen 
in female partners of male 
participants due to minimal 
systemic absorption of 
linerixibat. Additionally, 
linerixibat was not genotoxic 
and was not associated with 
developmental toxicity in 
definitive embryofetal 
development studies in rats 
and rabbits or effects on 
female fertility and early 
embryonic development in 
rats at large exposure 
multiples. 
Section 8.5. Genetics 
Removal of “and 
destruction” 
Removed due to 
inconsistency, details of 
destruction is not provided in 
the laboratory manual 
Section 9.4.2. Primary and 
Secondary Endpoint(s) 
Text modified to 
clarify handling of 
data impacted by 
intercurrent event 
Text clarified to highlight 
how data impacted by 
intercurrent events will be 
handled 
Section 9.4.3.: Safety 
Endpoint (s) 
Text removed and 
clarified regarding 
analysis of AESI and 
safety data 
Text clarified and further 
safety analyses will be 
specified in the Statistical 
Analysis Plan  
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
Duplicated 
“Calcium” removed 
Removed as duplicated in 
error 
Section 10.3.5. Reporting of 
SAE to GSK 
 Removal of text 
requiring investigator 
to document causality 
review in eCRF 
within 72 hours. 
 Text has been removed as 
eCRF review within 72 hours 
is no longer required 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
157 
Section # and Name 
Description of 
Change 
Brief Rationale 
Section 10.6. Appendix 6: 
Liver Safety: Required 
Actions and Follow-Up 
Assessments 
Text added to clarify 
that acetaminophen 
adduct assay should 
only be performed 
where available 
 Text clarified as assay not 
currently available in some 
locations 
 Section 10.7. Appendix 7: 
Country-Specific 
Requirements 
Text added to clarify 
that acetaminophen 
adduct assay will not 
be performed in 
China 
Text clarified as additional 
Adduct HPLC assay not 
currently available in China 
New Section 10.7.2 Visit 9 
Questionnaire 
Additional 
questionnaire added  
Additional questionnaire 
added to supplement PRO 
validation for participants in 
China 
New section 10.7.3 China 
Schedule of Assessments 
China specific 
Schedule of 
Assessment added 
Schedule of Assessments 
added for clarity for China 
participants 
 
Amendment [01] 01-MAR-2021 
This amendment was considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment:  
Change to AE grading criteria and change in randomization strategy.  
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
References to re-
randomization or 
randomized withdrawal 
replaced with description 
of randomization in to 4 
different arms at Week 1 
Randomization strategy has 
changed so that treatment 
assignment for Part A and Part B 
occurs at Day 1 
Section 1.2 Schema 
Schema updated to reflect 
randomization at Week 1 
only 
Randomization strategy has 
changed so that treatment 
assignment for Part A and Part B 
occurs at Day 1 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
158 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3. 
Schedule of 
Assessments 
Randomization removed 
at Week 24, and note 
removed indicating that 
randomization could 
occur earlier than Week 
24 
Randomization strategy has 
changed so that treatment 
assignment for Part A and Part B 
occurs at Day 1 
Section 1.3 Schedule 
of Assessments 
Note added that Symptom 
Questionnaire will also 
contain fatigue NRS. 
Fatigue NRS omitted from 
original protocol in error. 
Section 2.1. Study 
Rationale 
References to randomized 
withdrawal removed 
Randomization strategy has 
changed so that treatment 
assignment for Part A and Part B 
occurs at Day 1 
Section 3 Objectives 
and 
Endpoints/Estimands 
Addition of exploratory 
endpoint for fatigue 
Fatigue NRS omitted from 
original protocol in error. 
Section 4.1 Overall 
Design 
References to re-
randomization and 
randomized withdrawal 
replaced with description 
of randomization in to 4 
different arms at Day 1 
Randomization strategy has 
changed so that treatment 
assignment for Part A and Part B 
occurs at Day 1 
Section 4.2.2. 
Rationale for 
Stratification Factors 
Reference to 
Randomization at Week 
24 removed 
Randomization strategy has 
changed so that treatment 
assignment for Part A and Part B 
occurs at Day 1 
Section 4.2.3. 
Rationale for Part B 
Reference to Re-
Randomization removed 
from heading title and text 
amended to reflect 
randomization only at Day 
1 
Randomization strategy has 
changed so that treatment 
assignment for Part A and Part B 
occurs at Day 1 
Section 4.2.5 
Rationale of Using 
Itch Numerical 
Rating Scale as 
Primary Endpoint 
Description of symptom 
questionnaire clarified 
that it includes itch, sleep 
and fatigue NRS 
Fatigue NRS omitted from 
original protocol in error. 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
159 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.2. 
Exclusion Criteria 
Exclusion Criteria #2 
updated to reflect that 
assessment is relative to 
the average baseline 
measure 
Update required for consistency 
with other sections detailing liver 
biochemistry baseline. 
Section 6.3 
Measures to 
Minimize Bias: 
Randomization and 
Blinding 
References to re-
randomization at Week 24 
removed 
Randomization strategy has 
changed so that treatment 
assignment for Part A and Part B 
occurs at Day 1 
Section 6.4. Study 
Intervention 
Compliance 
Clarification that 
compliance is measured 
using participant eDiary, 
and not just by counting 
returned tablets 
Compliance should be tracked 
using eDiary 
Section 6.8.2. 
Prohibited 
Medications 
OCA restricted from 8 
weeks from baseline 
Updated for consistency with 
Exclusion Criteria #20. 
Section 7.1.3. 
Diarrhea 
Management 
Criteria and 
Stopping Criteria 
Note added that diarrhea 
AEs should be graded 
against the standard 
grading as well as 
CTCAE v5 
All AEs should be assessed using 
existing guidance as described in 
Appendix 3. AEs for diarrhea 
should also be assessed using 
CTCAE v5 criteria. 
Section 7.1.3.1 
Text added to clarify that 
diarrhea AEs should be 
graded against the 
standard criteria in 
Appendix 10.3.4 
All AEs should be assessed using 
existing guidance as described in 
Appendix 3. AEs for diarrhea 
should also be assessed using 
CTCAE v5 criteria. 
Section 7.1.6 
Temporary 
Discontinuation due 
to AEs 
Specific text to CTCAE 
v5 criteria removed, and 
cross referenced to other 
relevant sections. 
Only AEs for diarrhea should be 
assessed using CTCAE v5 criteria, 
all other AEs should be assessed 
using existing guidance as 
described in Appendix 3. 
Section 8.1.1.1 New  
Sub-heading: 
Symptom 
Questionnaire 
Clarification text added 
that fatigue NRS and 
missed doses of study 
treatment is included with 
symptom diary 
Fatigue NRS omitted from 
original protocol in error. 
Compliance should be tracked 
using eDiary 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
160 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.1.1.2 
Sleep Interference 
Questionnaire NRS 
Clarification text added 
that fatigue NRS is 
included with symptom 
diary 
Fatigue NRS omitted from 
original protocol in error. 
Section 8.5. Genetics 
Additional saliva option 
added 
Flexibility to sample type added 
Section 9.2.1. 
Sample Size 
Assumptions 
Figure 3 Updated 
Figure 3 updated to reflect 
linerixibat in a blue color 
Section 10.2 
Appendix 2: Clinical 
Laboratory Tests 
Indirect LDL Cholesterol 
and Indirect HDL 
Cholesterol removed 
Tests removed as not required 
Section 10.3.4. 
Recording and 
Follow-Up of AE 
and SAE 
Assessment of Intensity: 
Grading criteria amended 
from CTCAE v5 to 
standard 
mild/moderate/severe 
grading. 
Only AEs for diarrhea should be 
assessed using CTCAE v5 criteria, 
all other AEs should be assessed 
using existing guidance as 
described in Appendix 3 
Section 10.5 
Appendix 5 Genetics 
Additional saliva option 
added 
Flexibility to sample type added 
 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
161 
11. 
REFERENCES 
Acosta A and Camilleri M. Elobixibat and its potential role in chronic idiopathic 
constipation. Ther. Adv. Gastroenterol. 2014; 7: 167-75. 
Buchwald H, Varco RL, Matts JP. Effect of partial ileal bypass surgery on mortality and 
morbidity from coronary heart disease in patients with hypercholesterolemia. Report of 
the Program on the Surgical Control of the Hyperlipidemias (POSCH). NEJM 1990; 
323:946-55. 
Campbell J, et al. A loss-of-function mutation in the ileal bile acid transporter SLC10A2 
is associated with gallbladder disease but not with colorectal cancer in a phenome-wide 
association study of 379337 UK Biobank participants. Hepatology. 2018; 68 (suppl.1), 
1100A. 
Carey E, Levy C, Mayo M.J, et al. Patient Reported Indicators of Health and Symptoms 
in US Patients with Primary Biliary Cholangitis (PBC). Hepatology 2018. 68 (suppl 1). 
Carey E, Smith H, McLaughlin M, et al. The Pervasive Impact of Pruritus on Quality of 
Life in Patients with Primary Biliary Cholangitis (PBC): Real World Experience in 
TARGET-PBC. Target RWE; The Liver Meeting; 2020. 
Chengwei C, Jun C, Xiaoguang D, et al. China consensus on the diagnosis and treatment 
of primary biliary cirrhosis (also known as primary biliary cholangitis). J Clin Hepatol. 
2015; 31(12), 1980-1909. doi:10.3969/j.issn.1001-5256.2015.12.004. 
EASL Clinical Practice Guidelines: The diagnosis and management of patients with 
primary biliary cholangitis. J Hepatol. 2017; 67(1):145-72. https://easl.eu/wp-
content/uploads/2018/10/PBC-English-report.pdf. 
Food and Drug Administration (FDA). Patient-Focused Drug Development: 
Incorporating Clinical Outcome Assessments into Endpoints for Regulatory Decision-
Making. Draft Guidance. April 2023. Available at: 
https://www.fda.gov/media/166830/download. 
GSK2330672/Linerixibat Investigator’s Brochure, V10.0, 21 August 2023.  
Gries KP, Berry M, Harrington M, at al. Literature review to assemble the evidence for 
response scales used in patient-reported outcome measures. J Patient Rep Outcomes. 
2017; 2: 41. 
Hegade VS, Kendrick SF, Dobbins RL, et. al. BAT117213: Ileal bile acid transporter 
(IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: Study protocol 
for a randomised controlled trial. BMC Gastroenterol 2016 16(1): 71. 
Hegade VS, Kendrick SF, Dobbins RL, et. al. Effect of ileal bile acid transporter inhibitor 
GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, 
placebo-controlled, crossover, phase 2a study. Lancet. 2017; 389: 1114-23. 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
162 
Hegade VS, Mells GF, Beuers U, et al. Patient Experience and Characteristics of 
Cholestatic Pruritus in the UK-PBC Research Cohort. Hepatology. 2014; 60:339A–69. 
Hegade VS, Mells GF, Fisher H, et al., the UK-PBC Consortium. Pruritus is Common 
and Under-treated in Patients with Primary Biliary Cholangitis in the United Kingdom. 
Clinical Gastroenterology and Hepatology. 2019; 17:1379–1387. 
Hönig. S, Herder B, Kautz A, et al. Pruritus strongly reduces quality of life in PBC 
patients – real life data from a large national survey. Journal of Hepatology 2018 68(1): 
S216. 
Huyghe J, Bien S, Harrison T, et al. Discovery of common and rare genetic risk variants 
for colorectal cancer. Nat Genet. 2019 Jan;51(1):76. 
Jacoby A, Rannard A, Buck D. et al. Development, validation, and evaluation of the 
PBC-40, a disease specific health related quality of life measure for primary biliary 
cirrhosis. Gut. 2005; 54:1622-1629. 
Jin XY and Khan TM. Quality of Life Among Patients Suffering from Cholestatic Liver 
Disease-Induced Pruritus: A Systematic Review. Journal of the Formosan Medical 
Association; 2016, 115 (9): 689-702. 
Johns MW. A new perspective on sleepiness. Sleep Biol Rhythm, 2010; 8: 170-179. 
Johns MW. Sleep propensity varies with behaviour and the situation in which it is 
measured: the concept of somnificity. J Sleep Res, 2002; 11: 61-67. 
Johns MW. Sleepiness in different situations measured by the Epworth Sleepiness Scale. 
Sleep, 1994; 17: 703-710. 
Karpen SJ, Kelly D, Mack C, et al. Ileal bile acid transporter inhibition as an 
anticholestatic therapeutic target in biliary atresia and other cholestatic disorders. 
Hepatology International, 2020; 14, 677-689. 
Key CC, McKibben A, Chien E, et al. A Phase 1 dose-ranging study assessing fecal bile 
acid excretion by volixibat, an apical sodium-dependent bile acid transporter inhibitor, 
and coadministration with loperamide. Hepatology. 2020;72(Suppl):Abstract 1221. 
Komori A, et al. Guidelines for the management of primary biliary cirrhosis, The 
Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, 
Labour and Welfare of Japan. Hepatology Research 2014; 44 (Suppl. 1): 71–90. 
Levy C. Management of Pruritus in Patients with Cholestatic Liver Disease Gastroenterol 
Hepatol 2011 7(9). 
Lindor KD, Bowlus CL, Boyer J, et al. Primary Biliary Cholangitis: 2018 Practice 
Guidance from the American Association for the Study of Liver Diseases. Hepatology. 
2019;69(1):394-419. https://doi.org/10.1002/hep.30145|. 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
163 
Mayo MJ, Pockros PJ, Jones D, et. al. A Randomized, Controlled, Phase 2 Study of 
Maralixibat in the Treatment of Itching Associated with Primary Biliary Cholangitis. 
Hepatology Communications 2019 3(3) pg 365-381. 
McLaughlin M., 23andMe Research Team, Chu AY. Loss-of-function mutations in the 
ileal bile acid transporter, SLC10A2, are associated with gallbladder disease but not with 
colorectal cancer in a phenome-wide association study of up to 2.5 million 23andMe 
participants, Hepatology 2020; 72; 361A. 
Ocaliva US Prescribing Information/Summary of Product Characteristics, 2021. 
Questran (cholestyramine powder, for suspension) Summary of Product Characteristics 
(SmPC). Cheplapharm Arzneimittel GmbH; Date of first authorisation: 01 April 1979; 
Date of last renewal: 01 April 2009; Revised March 2023. Available at: 
https://www.hpra.ie/img/uploaded/swedocuments/Licence_PA2239-005-
001_02032023145829.pdf. Accessed 10-Oct-2023. 
Questran (cholestyramine powder, for suspension) US Prescribing Information. Chestnut 
Ridge, NY: Par Pharmaceutical; 2019. Available at: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=362ddd91-a63f-4ec6-841a-
75785dd208c8. Accessed 10-Oct-2023. 
Shaheen AA, Kaplan GG, Almirshri W, et. al. The impact of depression and 
antidepressant usage on primary biliary cholangitis clinical outcomes. PlosOne 2018 
13(4). 
Svedlund J, Sjodin I, Dotevall G. GSRS--a clinical rating scale for gastrointestinal 
symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis 
Sci. 1988; 33:129-134. 
Tanaka A, Miura K, Yagi M, et. al. The assessment of subjective symptoms and patient-
reported outcomes in patients with primary biliary cholangitis using PBC-40. The Japan 
Society of Hepatology 2016. 57: 457-467. 
Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 
2014 Practice Guideline by the American Association for the Study of Liver Diseases and 
the European Association for the Study of the Liver. Hepatology 2014;60:715—735. 
Wu Y, Aquino CJ, Cowan DJ, et al. Discovery of a highly potent, nonabsorbable apical 
sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 
diabetes. J Med Chem. 2013; 56:5094-5114 
Yagi M, Tanaka A, Masanori M, et. al. Pruritus, dryness, fatigue and health-related 
quality of life in Japanese patients with primary biliary cholangitis. Hepatology, 2017 66 
(suppl 1). 
Younossi ZM, Kiwi ML, Boparai N, et al. Cholestatic liver diseases and health-related 
quality of life. Am J Gastroenterol. 2000; 95(2): 497-502. 


TMF-16740250- 
CONFIDENTIAL 
212620 
 
 
Protocol amendment 04 
164 
Zakharia K, Tabibian A, Lindor KD, et al. Complications, symptoms, quality of life and 
pregnancy in cholestatic liver disease Liver Int. 2018;38(3):399-411. 
 


Signature Page for  212620 TMF-16740250 v1.0
Signature Page for TMF-16740250 v1.0
Reason for signing: Approved
Name: 
Role: A
Date of signature: 20-Nov-2023 13:08:52 GMT+0000
PPD

SAP_001.pdf: 
Statistical Analysis Plan Amendment 4
Study ID:  212620
Official Title of Study: A two-part, randomized, placebo controlled, double 
blind, multicenter, Phase 3 study to evaluate the efficacy and safety of linerixibat 
for the treatment of cholestatic pruritus in participants with primary biliary 
cholangitis (PBC).
NCT ID: NCT04950127
Date of Document: 08 Nov 2024


CONFIDENTIAL 
The GlaxoSmithKline group of companies 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 1 of 102 
Information Type: 
Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: 
A two-part, randomized, placebo controlled, double blind, 
multicenter, Phase 3 study to evaluate the efficacy and safety 
of linerixibat for the treatment of cholestatic pruritus in 
participants with primary biliary cholangitis (PBC).  
Study Number: 
212620 
Compound Number: GSK2330672 (linerixibat) 
Abbreviated Title: 
Global Linerixibat Itch STudy of Efficacy and Safety iN PBC 
[Acronym:] 
GLISTEN 
Sponsor Name: GlaxoSmithKline Research & Development Limited  
Regulatory Agency Identifier Number(s)  
IND: 130391 
EudraCT: 2021-000007-21 
Registry 
ID 
Clintrials.gov 
NCT04950127 
Copyright 2024 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 2 of 102 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
VERSION HISTORY ....................................................................................................... 7 
1. 
INTRODUCTION .................................................................................................... 16 
1.1. 
Objectives, Estimands and Endpoints ......................................................... 17 
1.2. 
Study Design .............................................................................................. 23 
2. 
STATISTICAL HYPOTHESES ............................................................................... 27 
2.1. 
Primary Endpoint ........................................................................................ 27 
2.2. 
Secondary Endpoints and Multiplicity Control ............................................. 28 
3. 
ANALYSIS SETS ................................................................................................... 28 
4. 
STATISTICAL ANALYSES ..................................................................................... 30 
4.1. 
General Considerations .............................................................................. 30 
4.1.1. 
General Methodology .................................................................. 30 
4.1.2. 
Baseline Definition ....................................................................... 31 
4.2. 
Primary Endpoint Analyses ......................................................................... 33 
4.2.1. 
Definition of Endpoint/Estimands ................................................. 33 
4.2.2. 
Main Analytical Approach ............................................................ 34 
4.2.3. 
Sensitivity Analyses ..................................................................... 35 
4.2.4. 
Additional Estimands ................................................................... 37 
4.3. 
Secondary Endpoints Analyses .................................................................. 37 
4.3.1. 
Key/Confirmatory Secondary Endpoints ...................................... 37 
4.3.1.1. 
Definition of Endpoints/Estimands .............................. 37 
4.3.1.2. 
Main Analytical Approach of Secondary 
Endpoints ................................................................... 38 
4.3.2. 
Supportive Secondary Endpoint(s) .............................................. 41 
4.4. 
Exploratory Endpoints Analyses ................................................................. 44 
4.4.1. 
Overview of Planned Analyses of Exploratory Endpoints ............. 44 
4.4.2. 
Statistical Analyses of Exploratory Endpoints .............................. 46 
4.5. 
Safety Analyses .......................................................................................... 49 
4.5.1. 
Extent of Exposure ...................................................................... 49 
4.5.2. 
Adverse Events............................................................................ 49 
4.5.2.1. 
Adverse Events of Special Interest ............................. 51 
4.5.2.2. 
COVID-19 Assessment and COVID-19 AEs ............... 52 
4.5.3. 
Additional Safety Assessments (if applicable) .............................. 52 
4.5.3.1. 
Laboratory Data .......................................................... 52 
4.5.3.2. 
Vital Signs .................................................................. 53 
4.5.3.3. 
ECG ........................................................................... 53 
4.5.3.4. 
Fecal Occult Blood Test (FOBT) ................................. 53 
4.6. 
Other Analyses ........................................................................................... 54 
4.6.1. 
Covariate/Subgroup analyses ...................................................... 54 
4.6.2. 
Subpopulation Analyses .............................................................. 55 
4.6.2.1. 
Analysis Sets for Subpopulation Analyses .................. 55 
4.6.2.2. 
China Subpopulation Analyses ................................... 57 
4.6.2.3. 
Japan Subpopulation Analyses .................................. 58 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 3 of 102 
4.6.2.4. 
East Asia Subpopulation Analyses ............................. 59 
4.6.3. 
Operating model analyses ........................................................... 59 
4.6.4. 
Shrinkage Analysis ...................................................................... 61 
4.7. 
Interim Analyses ......................................................................................... 61 
4.7.1. 
Interim Analysis Set ..................................................................... 62 
4.7.2. 
Interim Study Population Analyses............................................... 62 
4.7.3. 
Interim Efficacy Analyses ............................................................. 62 
4.7.3.1. 
Primary analyses ........................................................ 62 
4.7.3.2. 
Supplementary analyses ............................................ 63 
4.7.4. 
Interim Safety Analyses ............................................................... 63 
4.8. 
Changes to Protocol Defined Analyses ....................................................... 63 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 65 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 66 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 66 
6.1.1. 
Participant Disposition ................................................................. 67 
6.1.2. 
Demographic and Baseline Characteristics .................................. 67 
6.1.3. 
Protocol Deviations ...................................................................... 67 
6.1.4. 
Prior and Concomitant Medications ............................................. 68 
6.1.5. 
Study Intervention Compliance .................................................... 68 
6.2. 
Appendix 2 Electronic Patient-reported Outcome (ePRO) 
Compliance ................................................................................................. 68 
6.2.1. 
Study Level Compliance .............................................................. 68 
6.2.2. 
Endpoint Level Compliance ......................................................... 70 
6.3. 
Appendix 3 Data Derivations Rule .............................................................. 71 
6.3.1. 
Criteria for Potential Clinical Importance ...................................... 71 
6.3.1.1. 
Laboratory Values ...................................................... 71 
6.3.1.2. 
Vital Signs .................................................................. 72 
6.3.2. 
Study Period ................................................................................ 72 
6.3.2.1. 
Classification Related to Study Period ........................ 72 
6.3.2.2. 
Classification Related to Study Intervention 
State ........................................................................... 72 
6.3.2.3. 
Classification of Concomitant Medication ................... 73 
6.3.3. 
Study Intervention Emergent Flag for Adverse Events ................. 74 
6.3.4. 
Study Day and Reference Dates .................................................. 74 
6.3.5. 
Analysis Window .......................................................................... 74 
6.3.6. 
Study Population Data ................................................................. 75 
6.3.6.1. 
Treatment Compliance ............................................... 75 
6.3.6.2. 
Chronic Kidney Disease (CKD) Stage ........................ 77 
6.3.7. 
Efficacy Data ............................................................................... 77 
6.3.7.1. 
Itch Score ................................................................... 77 
6.3.7.1.1. 
Worst Daily Itch Score ............................ 77 
6.3.7.1.2. 
Weekly Itch score ................................... 77 
6.3.7.1.3. 
Monthly Itch Score .................................. 78 
6.3.7.2. 
Sleep Score ................................................................ 79 
6.3.7.2.1. 
Daily Sleep Score ................................... 79 
6.3.7.2.2. 
Weekly Sleep Score ............................... 79 
6.3.7.2.3. 
Monthly Sleep Score............................... 80 
6.3.7.3. 
Fatigue Score ............................................................. 81 
6.3.7.3.1. 
Daily Fatigue Score ................................ 81 
6.3.7.3.2. 
Weekly Fatigue Score ............................. 81 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 4 of 102 
6.3.7.3.3. 
Monthly Fatigue Score ............................ 82 
6.3.7.4. 
Itch Responder ........................................................... 82 
6.3.7.5. 
Itch Response Day ..................................................... 83 
6.3.7.6. 
PBC-40 ....................................................................... 84 
6.3.7.7. 
Patient Global Impression of Severity ......................... 85 
6.3.7.8. 
Patient Global Impression of Change ......................... 85 
6.3.7.9. 
Epworth Sleepiness Scale .......................................... 85 
6.3.7.10. Beck Depression Inventory –II .................................... 86 
6.3.7.11. Discard of Data based on Hypothetical 
Estimand Strategy ...................................................... 87 
6.3.8. 
Safety Data .................................................................................. 87 
6.3.8.1. 
Exposure calculation .................................................. 87 
6.3.8.2. 
Exposure adjusted incidence rate ............................... 88 
6.3.8.2.1. 
Exposure adjusted incidence rate 
for the Main Safety Estimand .................. 88 
6.3.8.2.2. 
Exposure adjusted incidence rate 
for Supplementary Safety 
Estimand ................................................ 89 
6.3.8.3. 
Gastrointestinal Symptoms Rating Scale .................... 90 
6.3.8.4. 
ECG Parameters ........................................................ 91 
6.3.8.4.1. 
RR Interval ............................................. 91 
6.3.8.4.2. 
Corrected QT Intervals ........................... 92 
6.3.8.5. 
Adverse Events of Special Interest ............................. 92 
6.3.8.5.1. 
Diarrhea reported as an AE  .................... 92 
6.3.8.5.2. 
Elevated ALT reported as a Liver 
Event (meets Liver Monitoring or 
Stopping criteria) .................................... 92 
6.3.8.6. 
Liver related SMQs ..................................................... 92 
6.3.8.7. 
Rescue Medication ..................................................... 93 
6.3.9. 
Laboratory Parameters ................................................................ 93 
6.3.10. 
Pharmacokinetic Concentrations ................................................. 93 
6.3.11. 
Analysis Variables / Covariates Derivation ................................... 94 
6.3.12. 
Intercurrent Events ...................................................................... 97 
6.3.13. 
Multiple measurements at One Analysis Time Point .................... 98 
6.3.14. 
Handling of Partial Dates ............................................................. 99 
6.3.15. 
Trademarks ............................................................................... 101 
7. 
REFERENCES ..................................................................................................... 102 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 5 of 102 
LIST OF TABLES 
PAGE 
Table 1 
Baseline definition .................................................................................. 32 
Table 2 
Overview of planned analyses of exploratory endpoints ......................... 44 
Table 3 
List of covariate/subgroup ...................................................................... 54 
Table 4 
Changes to Protocol Defined Analysis Plan ........................................... 64 
Table 5 
Expected Change from Baseline in Weekly Itch Score (WIS) ................. 66 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 6 of 102 
LIST OF FIGURES 
PAGE 
Figure 1 
Expected Change from Baseline in MWDI* ............................................ 65 
 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 7 of 102 
VERSION HISTORY 
SAP 
Version 
Approval 
Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
SAP 
01 
November 
2021 
Protocol 
amendment [03] 
(02-Sep-2021) 
Not Applicable 
Original 
version 
SAP 
Amendme
nt 1 
28 June 2022 Protocol 
amendment [03] 
(02-Sep-2021) 
Added non-Metasite 
ITT analysis set 
In line with 
regulatory 
feedback 
Text added to clarify 
how LS means are 
averaged in MMRM 
analysis 
In line with 
regulatory 
feedback 
Added MMRM analysis 
of non-Metasite ITT 
population for the 
primary endpoint 
In line with 
regulatory 
feedback 
Clarified the definition 
of COVID 19 related 
intercurrent events and 
that hypothetical 
strategy will not be 
applied to supportive 
secondary endpoints 
In line with 
regulatory 
feedback 
Added empirical 
cumulative distribution 
function (eCDF) graph 
for primary, week 2, and 
responder endpoints.  
In line with 
regulatory 
feedback 
Added exposure 
adjusted incidence rate 
for safety analyses 
In line with 
regulatory 
feedback 
Added analyses of 
exploratory endpoints, 
including PK for China, 
Japan and East Asia 
subpopulations 
Not 
previously 
addressed  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 8 of 102 
SAP 
Version 
Approval 
Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
Added baseline bile acid 
binding resin (BABR) 
covariate 
Added for 
biomarker 
exploratory 
analysis 
Added study population 
analyses 
Not 
previously 
addressed  
Added data derivation 
rule 
Not 
previously 
addressed  
SAP 
Amendme
nt 2 
19 April 
2024 
Protocol 
amendment [04] 
(20-Nov-2023) 
Updated the baseline 
definition for safety 
assessments to be the 
last assessment prior to 
first dose, instead of 
Visit 3. 
In line with 
regulatory 
feedback 
Updated baseline 
definition for 
biomarkers to be the 
average of screening 2 
and last assessment 
prior to first dose (or 
either value in cases 
where only one of these 
values is present). 
Not 
previously 
addressed 
Updated list of regions 
in Covariate/Subgroup 
analyses Section.  
Not 
previously 
addressed 
Added the predictive 
probability of success 
and the conditional 
power under the Interim 
Efficacy Analysis 
Section. 
To align 
with IDMC 
Charter 
Clarified the 
calculations of exposure 
In line with 
regulatory 
feedback 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 9 of 102 
SAP 
Version 
Approval 
Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
for the exposure 
adjusted incidence rate. 
Removed empirical 
cumulative distribution 
function (eCDF) graph 
for change from 
baseline MWDI score at 
week 2 as it is not 
required. Additional 
eCDF graphs for the 
other endpoints added, 
using imputed data. 
Not 
previously 
addressed 
Mexico specific analysis 
removed. 
No longer 
required 
In the Subpopulation 
Analyses Section; 
defined a Non-BABR 
ITT East Asia 
population and clarified 
the definition of the 
China and East Asia 
populations. 
Not 
previously 
addressed 
Renamed the primary 
interim analysis set and 
clarified in the 
definition that it will 
include approximately 
100 subjects, in line 
with the study protocol. 
Also updated the 
definition of the interim 
safety population to be 
analyzed according to 
treatment as 
randomized, rather than 
actually received. 
Not 
previously 
addressed 
Updated Prior and 
Concomitant 
Medications Section to 
specify that the WHO 
Not 
previously 
addressed 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 10 of 102 
SAP 
Version 
Approval 
Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
drug dictionary will be 
used for all summaries, 
and summaries will be 
reported by ATC 
classification. 
Updates to Analysis 
Window Section for 
unscheduled and 
withdrawal visits.  
In line with 
regulatory 
feedback 
Removed RoW Metasite 
from Study Design 
Section since no RoW 
metasites will be 
included in this study. 
No longer 
required 
Clarified estimands for 
safety endpoints and 
added a supplementary 
safety estimand. 
Not 
previously 
addressed 
Updated Handling of 
Partial Dates section, to 
allow imputation of 
partial dates when 
calculating disease 
duration. 
Not 
previously 
addressed 
Clarified definitions of 
treatment states for AEs, 
and intervention 
emergent flag for AEs. 
Not 
previously 
addressed 
Clarified derivation of 
Adverse Events of 
Special Interest (AESI). 
Not 
previously 
addressed 
Updated baseline 
definition for 
Laboratory data to 
consider cases where 
only 1 sample is 
available. Added criteria 
for handling values 
below LOQ. 
Not 
previously 
addressed 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 11 of 102 
SAP 
Version 
Approval 
Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
Clarified the list of 
Liver related SMQs. 
Not 
previously 
addressed 
Added calculation of 
exposure adjusted 
incidence rate for 
Supplementary Safety 
Estimand (while-on-
treatment strategy) to 
Section 6.3.8.2. 
Not 
previously 
addressed 
Derivation of baseline 
concomitant medication 
variables clarified in 
Section 6.3.10. 
Not 
previously 
addressed 
Clarified the derivations 
of Intercurrent Events in 
Section 6.3.11. 
Not 
previously 
addressed 
The terminology of 
Mean Worst Daily Itch 
(MWDI) Score was 
changed to Weekly Itch 
Score (WIS). The 
calculation remains the 
same. 
In line with 
Protocol 
amendment 
04 
Clarification of 
previously omitted Part 
B endpoints:  
In exploratory 
endpoints, added the 
Quality of Life and 
Patient-Reported 
Outcomes (PROs) 
endpoints for Part B on 
MSS, MFS, ESS, BDI-
II, PGI-S, and PGI-C.  
Clarified that 
exploratory biomarker 
endpoints and the effect 
of bile acid binding 
In line with 
Protocol 
amendment 
04 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 12 of 102 
SAP 
Version 
Approval 
Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
resins on linerixibat 
pharmacodynamics will 
be assessed in Part B.  
In exploratory markers 
of liver fibrosis 
endpoints, clarified that 
ELF will be assessed in 
Part B. 
Additional details added 
to Sensitivity Analysis 
to clarify multiple 
imputation model. 
Clarificatio
n of 
imputation 
model 
Added details for the 
new statistical analysis 
strategy involving a 
primary analysis after 
all participants have 
completed the Part A 
intervention period and 
a final analysis after all 
participants have 
completed the Part B 
intervention period, and 
the follow-up period. 
In line with 
Protocol 
amendment 
04 
Additional e-DISH plots 
added. 
Not 
previously 
addressed 
Added ranges for 
Chronic Kidney Disease 
Stage, for use in PK 
summaries. 
Not 
previously 
addressed 
New analysis added for 
PGI-C, where the 
percentage of 
participants with 
improved PGI-C will be 
reported. 
Not 
previously 
addressed 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 13 of 102 
SAP 
Version 
Approval 
Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
Additional analysis of 
ALP and Bilirubin 
added for participants 
with ALP ≥1.67x ULN 
at baseline. 
Not 
previously 
addressed 
Updated the analyses 
required for each 
subpopulation (China, 
Japan, East Asia). 
To align 
with 
requiremen
ts for each 
region 
Additional covariates 
added to Section 4.6.1. 
And clarified which 
covariates are to be 
included in the 
subgroup analysis. 
Not 
previously 
addressed 
Clarified handing of 
participants in the 
Safety population who 
receive incorrect 
treatment (Section 3). 
Not 
previously 
addressed 
Clarified that AE/SAEs 
starting in Part A that 
last to Part B will be 
counted in Part A only. 
Correction 
due to how 
the data is 
recorded 
Removed table for pre-
treatment SAEs, these 
will be reported in 
listing only. Also 
removed table for post-
treatment SAEs, since 
these will now be 
captured in the 
supplementary safety 
estimand. 
Not 
previously 
addressed 
Criteria for Potential 
Clinical Importance 
updated (Section 6.3.1). 
Not 
previously 
addressed 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 14 of 102 
SAP 
Version 
Approval 
Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
SAP 
Amendme
nt 3 
05 August 
2024 
Protocol 
amendment [04] 
(20-Nov-2023) 
Included IL-31 
biomarker in list of 
biomarkers to be 
analysed. 
Clarificatio
n that IL-31 
will also be 
analyzed as 
part of the 
exploratory 
biomarker 
objective 
Clarified that ITT 
population for Part B 
will be all participants 
randomized who do not 
withdraw in Part A. And 
the Safety population 
for Part B will be all 
subjects who take a least 
one dose in Part B. 
Not 
previously 
addressed 
Removed Child Pugh 
derivation since it is not 
possible to derive at 
baseline for all subjects. 
Not 
previously 
addressed 
Clarified that all AEs 
will be reported using 
the supplementary 
estimand. 
Not 
previously 
addressed 
Added explanation 
regarding process for 
de-identification of 
participant data for 
public disclosure 
(Section 6.1.2) 
Not 
previously 
addressed 
Added a new section for 
Electronic Patient-
reported Outcome 
(ePRO) Compliance. 
Based on 
updated 
internal 
guidance 
Clarified derivation of 
study period. 
Not 
previously 
addressed 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 15 of 102 
SAP 
Version 
Approval 
Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
SAP 
Amendme
nt 4 
08 Nov 2024 
Protocol 
amendment [04] 
(20-Nov-2023) 
Subgroup analyses by 
sex, age, race, and 
ethnicity will be 
performed for the 
primary efficacy 
endpoint, and for 
common AEs. 
In line with 
FDA 
feedback 
Specified the planned 
shift parameters for the 
tipping point analysis. 
In line with 
FDA 
feedback 
Additional details 
provided for shrinkage 
estimation. 
In line with 
FDA 
feedback 
Clarified multiple 
imputation model. 
In line with 
FDA 
feedback 
Clarified that MedDRA 
and WHO dictionaries 
available at the time of 
the primary analysis 
will be used for the final 
analysis also. 
Not 
previously 
addressed 
Clarified Part B 
treatment start date for 
cases of treatment 
switch on the same day. 
Not 
previously 
addressed 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 16 of 102 
1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report (CSR) for Study 212620. Details of the planned interim analysis, as well as 
the final analyses, are provided. 
This Phase 3 study will investigate the efficacy and safety of 24 weeks of 40 mg BID oral 
linerixibat, for the treatment of pruritus in PBC patients with moderate to severe 
cholestatic pruritus (Part A), as well as assess the return of itch over 8 weeks after 
withdrawal of 40 mg BID oral linerixibat compared to placebo (Part B).  
Participants will record itch scores twice daily using an electronic Diary (eDiary). A 0-10 
Numerical Rating Scale (NRS), which has been validated in the PBC population, will be 
used to assess itch with a response option of 0 representing no itching and 10 
representing the worst imaginable itching. Every morning the participant will record the 
worst itch experienced the night before and every evening, the participant will record the 
worst itch experienced that day. 
The itch scores for any day, week, and month will then be determined as follows: 
• 
Worst Daily Itch (WDI) score: the worst of the two scores recorded daily will be 
considered the score for that day 
• 
Weekly Itch Score (WIS) (formerly referred to as the Mean Worst Daily Itch 
[MWDI]): the average of the WDI scores in one week 
• 
Monthly Itch Score (MIS): the worst WIS for that month (i.e., worst week score of 
the 4 weeks) 
Participant’s sleep will also be evaluated using the daily eDiary. Participants will record a 
sleep interference score each morning using a 0-10 NRS, where 0 represents no sleep 
interference and 10 represents complete sleep interference. For each week, the average of 
the Daily Sleep Scores (DSS) will be used to calculate the Weekly Sleep Score (WSS). 
The Monthly Sleep Score (MSS) is the worst WSS for that month (i.e., worst week score 
of the 4 weeks). 
The Primary Biliary Cholangitis-40 Questionnaire (PBC-40) is a disease-specific health-
related QoL instrument consisting of 6 domains: social, emotional, symptoms, fatigue, 
itch (including an item on sleep disturbance from itching), and cognitive. This study will 
further evaluate the effect of linerixibat on the PBC-40 domains. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 17 of 102 
1.1. 
Objectives, Estimands and Endpoints 
Objectives* 
Endpoints 
Primary 
To investigate the effect of treatment 
with oral linerixibat compared with 
placebo on itch in PBC patients with 
cholestatic pruritus over 24 weeks (Part 
A) 
• 
Change from Baseline in Monthly Itch 
Scores over 24 weeks using a 0-10 
numerical rating scale (NRS) 
Secondary 
To evaluate the early effects of oral 
linerixibat compared to placebo on itch 
in PBC patients with cholestatic 
pruritus (Part A) 
• 
Change from baseline in Weekly Itch 
score at Week 2 
To characterize the effects of treatment 
with oral linerixibat compared with 
placebo on health related QoL (Part A) 
• 
Change from Baseline in Monthly Sleep 
Score as measured by 0-10 NRS over 24 
weeks 
• 
Change from Baseline in PBC-40 
domain scores at Week 24 
To evaluate the effects of 24 weeks of 
treatment with oral linerixibat 
compared to placebo on itch response 
rates in PBC patients with cholestatic 
pruritus (Part A) 
• 
Responder defined as achieving a ≥2-
point reduction from Baseline in the 
Monthly Itch score at Week 24.  
• 
Responder defined as achieving a ≥3-
point reduction from Baseline in the 
Monthly Itch score at Week 24.  
• 
Responder defined as achieving a ≥4-
point reduction from Baseline in the 
Monthly Itch score at Week 24.  
To investigate the treatment effect of 
oral linerixibat compared with placebo 
on Patient’s Global Impression of 
Severity (PGI-S) and Patient’s Global 
Impression of Change (PGI-C) 
throughout the treatment period (Part 
A) 
• 
Change from baseline in Patient's Global 
Impression of Severity (PGI-S) over 24 
weeks 
• 
PGI-C over 24 weeks 
To evaluate the effects of treatment 
with linerixibat on markers of PBC 
disease activity and progression (Part 
A) 
• 
Change from baseline in ALP at Week 
24 
• 
Change from baseline in bilirubin at 
Week 24 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 18 of 102 
Objectives* 
Endpoints 
Safety 
• 
To evaluate the safety of oral 
linerixibat compared with placebo 
(Part A and Part B) 
Clinical assessments including, but not 
limited to:  
• 
Adverse Events (AEs) and Serious 
Adverse Events (SAEs) 
• 
Vital signs 
• 
12-lead Electrocardiogram (ECG) 
• 
Clinical laboratory evaluation (including 
liver chemistry panel and fasting lipids) 
Exploratory 
• 
To evaluate the gastrointestinal 
(GI) tolerability of oral linerixibat 
compared with placebo on 
gastrointestinal symptoms (Part A 
and Part B) 
• 
Change from Baseline in 
Gastrointestinal Symptom Rating Scale 
(GSRS) over time 
• 
To evaluate the effects of oral 
linerixibat compared to placebo on 
the percentage of itch response 
days (Part A) 
• 
Percentage of days participant achieves 
a ≥2-point reduction from Baseline in 
the Worst Daily Itch score over 24 
weeks. 
• 
Percentage of days participant achieves 
a ≥3-point reduction from Baseline in 
the Worst Daily Itch score over 24 
weeks. 
• 
Percentage of days participant achieves 
a ≥4-point reduction from Baseline in 
the Worst Daily Itch score over 24 
weeks. 
• 
To investigate the improvement, 
maintenance, or return of itch (Part 
B)  
• 
Change from Baseline (Part A) in 
Weekly Itch Score at 8 weeks 
• 
Change from Baseline (Part B) in 
Monthly Itch Score over 8 weeks 
(maintenance) 
• 
To investigate the improvement, 
maintenance, or decline of health-
related quality of life (QoL) and 
other patient-reported outcomes 
(Part B) 
• 
Change from Baseline in  
• PBC-40 domain scores at 8 weeks 
• Monthly Sleep Score at 8 weeks 
• Monthly Fatigue Score at 8 weeks  
• Epworth Sleepiness Scale at 8 weeks  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 19 of 102 
Objectives* 
Endpoints 
• BDI-II at 8 weeks  
• PGI-S at 8 weeks 
• 
PGI-C at 8 weeks 
• 
To evaluate the effects of oral 
linerixibat compared with placebo 
on exploratory biomarkers (Part A 
and Part B) 
• Change from Baseline in concentrations 
of exploratory biomarkers including#: 
• Serum C4 
• Total serum bile acids 
• Autotaxin  
• Fibroblast Growth Factor-19 (FGF-
19)  
• 
Explore the effect of bile acid 
binding resins on linerixibat 
Pharmacodynamics (PD) (Part A 
and Part B) 
• Linerixibat serum biomarkers including#: 
• Serum C4 
• Total serum bile acids  
• Autotaxin,  
• FGF-19 
• 
To characterize the PK in PBC 
participants (Part A) 
• 
Determination of PK parameters by 
population PK analysis.† 
• 
To evaluate the effect of linerixibat 
compared to placebo on non-
invasive markers of liver fibrosis 
(where available) (Part A and Part 
B, if applicable) 
• 
Change from Baseline (Part A) in 
Enhanced Liver Fibrosis (ELF) at Week 
24 
• 
Change from Baseline (Part B) in ELF 
at week 8 
• 
Change from Baseline in Transient 
Elastography (Fibroscan) at Week 24 
• 
To further characterize the effects 
of oral linerixibat compared with 
placebo on symptoms and health-
related quality of life (Part A) 
• 
Change from Baseline in Epworth 
Sleepiness Scale (ESS) over 24 weeks 
• 
Change from Baseline in Beck 
Depression Inventory-II (BDI-II) at 24 
weeks 
• 
Change from Baseline in Monthly 
Fatigue Score as measured by 0 – 10 
NRS over 24 weeks. 
*Linerixibat refers to linerixibat with stable background itch therapy if applicable. 
Placebo refers to placebo with stable background itch therapy if applicable. 
# IL-31, a cytokine recently proposed to be associated with pruritus in PBC will also be 
included. 
†See Section 4.8 which provides the rationale for changes related to this endpoint.   


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 20 of 102 
Estimands for Primary and Secondary Objectives: 
Unless otherwise specified, all primary and key secondary (as detailed in Section 2.2) 
study objectives will be assessed using estimands defined with the following common 
elements in terms of population, treatment comparison and approach for managing 
intercurrent events. 
 
Primary and key Secondary 
Endpoints 
Supportive Secondary 
Endpoints 
Population 
• 
PBC patients with cholestatic pruritus 
Treatment 
• 
Linerixibat + background itch therapy if applicable 
• 
Placebo + background itch therapy if applicable 
Intercurrent events: 
Permanent treatment 
discontinuation, 
disruptions in 
treatment or treatment 
delays unrelated to the 
COVID-19 pandemic 
Addressed with treatment 
policy strategy, i.e., regardless 
of the intercurrent event 
occurring. 
Addressed with treatment 
policy strategy, i.e., 
regardless of the 
intercurrent event 
occurring. 
Permanent treatment 
discontinuation, 
disruptions in 
treatment, or treatment 
delays related to the 
COVID-19 pandemic 
Addressed with hypothetical 
strategy, i.e., the outcomes 
impacted by the COVID-19 
pandemic related intercurrent 
events will be discarded. 
Addressed with treatment 
policy strategy, i.e., 
regardless of the 
intercurrent event 
occurring. 
Change in background 
itch therapy* or use of 
rescue medication 
Addressed with treatment 
policy strategy, i.e., regardless 
of the intercurrent event 
occurring. 
Addressed with treatment 
policy strategy, i.e., 
regardless of the 
intercurrent event 
occurring. 
*Change in background itch therapy is defined as any change in dose of background 
therapy, addition of a new background therapy, or stopping an existing background 
therapy. 
For supportive secondary endpoints (as defined in Section 2.2), treatment policy will be 
used for all the intercurrent events.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 21 of 102 
Summary Measures for the study objectives are as follows: 
Endpoint 
Summary Measure 
Primary objective 
Change from Baseline in Monthly Itch 
Scores over 24 weeks using a 0-10 NRS 
Difference in means averaged over 24 
weeks between treatment groups 
Secondary objectives 
Change from baseline in Weekly Itch 
Score at week 2 
Difference in means between treatment 
groups 
Change from Baseline in Monthly Sleep 
Score as measured by 0-10 NRS over 24 
weeks 
Difference in means averaged over 24 
weeks between treatment groups 
Responder defined as achieving a ≥2-
point reduction from Baseline in the 
Monthly Itch score at Week 24 
Difference in proportions between 
treatment groups 
 
Responder defined as achieving a ≥3-
point reduction from Baseline in the 
Monthly Itch score at Week 24 
Difference in proportions between 
treatment groups 
 
Responder defined as achieving a ≥4-
point reduction from Baseline in the 
Monthly Itch score at Week 24 
Difference in proportions between 
treatment groups 
Change from Baseline in PBC-40 domain 
scores at Week 24 
Difference in means between treatment 
groups 
Change from baseline in PGI-S over 24 
weeks 
Difference in means averaged over 24 
weeks between treatment groups 
PGI-C over 24 weeks 
 
Difference in means averaged over 24 
weeks between treatment groups 
Change from baseline in ALP at Week 24 Difference in means between treatment 
groups 
Change from baseline in bilirubin at 
Week 24 
Difference in means between treatment 
groups 
Rationale for estimand: Interest lies in the treatment effect when medication is taken for 
the entire study duration.  For participants discontinuing randomized medication, having 
disruptions in treatment or treatment delays unrelated to the COVID-19 pandemic, 
changing background itch therapy, or using rescue medication, the use of a treatment 
policy strategy recognises that this could be due to an unfavourable cause. The study is 
designed to evaluate treatment effects attributable to linerixibat and it is important that 
this effect is not confounded by site closure or lockdown caused by the COVID-19 
pandemic. Therefore, for participants who have permanent treatment discontinuation, 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 22 of 102 
disruptions in treatment, or treatment delays related to the COVID-19 pandemic (see 
Section 4.2.1 for definition), a hypothetical strategy will be used. The definition of 
COVID-19 pandemic related intercurrent events and the corresponding strategy are 
subject to change to be consistent with regulatory agencies’ evolving recommendations.   
Supplementary Estimand for the Primary Objective 
A supplementary estimand for the primary objective will be defined to assess the 
hypothetical treatment effect of linerixibat compared to placebo in the absence of 
intercurrent events including treatment discontinuation, disruptions in treatment or 
treatment delays, changes in itch therapy or use of rescue. In this case, all daily itch score 
data impacted by the intercurrent events will be discarded. 
Estimands for Safety Objective: 
Unless otherwise specified, Safety endpoints will be assessed using estimands defined 
with the following common elements in terms of population, treatment comparison and 
approach for managing intercurrent events. 
 
Safety Endpoints 
Including: 
• 
Adverse Events (AEs) 
and Serious Adverse 
Events (SAEs) 
Safety Endpoints 
Including: 
• 
Vital signs 
• 
12-lead ECG 
• 
Clinical laboratory 
evaluation (including liver 
chemistry panel and 
fasting lipids) 
Population 
• 
PBC patients with cholestatic pruritus 
Treatment 
• 
Linerixibat + background itch therapy if applicable 
• 
Placebo + background itch therapy if applicable 
Intercurrent events: 
Permanent 
treatment 
discontinuation 
due to any reason 
Addressed with while on-
treatment strategy, i.e., 
considering data prior to 
intercurrent event. This 
strategy is to summarise the 
events while the participants 
are exposed to the treatment. 
Addressed with treatment policy 
strategy, i.e., regardless of the 
intercurrent event occurring 
Disruptions in 
treatment or 
treatment delays 
due to any reason 
(related or 
unrelated to the 
Addressed with treatment 
policy strategy, i.e., regardless 
of the intercurrent event 
occurring 
Addressed with treatment policy 
strategy, i.e., regardless of the 
intercurrent event occurring 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 23 of 102 
 
Safety Endpoints 
Including: 
• 
Adverse Events (AEs) 
and Serious Adverse 
Events (SAEs) 
Safety Endpoints 
Including: 
• 
Vital signs 
• 
12-lead ECG 
• 
Clinical laboratory 
evaluation (including liver 
chemistry panel and 
fasting lipids) 
COVID-19 
pandemic) 
Change in 
background itch 
therapy or use of 
rescue medication 
Addressed with treatment 
policy strategy, i.e., regardless 
of the intercurrent event 
occurring 
Addressed with treatment policy 
strategy, i.e., regardless of the 
intercurrent event occurring 
Supplementary Estimand for the Safety Objective 
A supplementary estimand for the safety endpoints Adverse Events (AEs) and Serious 
Adverse Events (SAEs) will be defined to assess treatment discontinuation for any reason 
with the treatment policy strategy, i.e., regardless of the intercurrent event occurring.  
1.2. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
This study is a Phase 3, multicenter, 2-part (Part A and Part B), 
randomized, double-blind, placebo-controlled study in PBC patients 
with moderate to severe pruritus. Part A will evaluate the efficacy, 
linerixibat 40 mg BID
6 to 8 weeks
8 weeks
24 weeks
Screening
Period
Intervention Period
Part B
2 weeks
*The follow-up period will only apply to participants who do not enrol into a follow-on study
Part A
Follow Up
Period*
placebo
Placebo
linerixibat 40 mg BID
R
Day 1
Week 24
linerixibat 40 mg BID
Placebo
R = Randomization


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 24 of 102 
Overview of Study Design and Key Features 
safety and impact on health-related quality of life of linerixibat 
compared with placebo over 24 weeks, while Part B will assess the 
return of itch over 8 weeks after withdrawal of linerixibat. In both Part 
A and Part B, participants may be treatment naïve, have had prior itch 
therapy and/or may take stable background itch therapy at the discretion 
of the physician in the best interest of the patient, or rescue medication 
where applicable.   
This study consists of four Periods: Screening, Intervention (Part A and 
Part B) and Follow-up.  
Screening Period: Participants will attend two screening visits to assess 
eligibility as described below: 
Screening 1 (Visit 1): Assessments to be performed as described in the 
schedule of assessments (SoA). Itch severity will be assessed 
retrospectively based on participant recall and then prospectively for 
eligibility purposes using a twice daily eDiary throughout the screening 
period. 
Screening 2 (Visit 2): Additional liver biochemistry assessments to be 
performed at least 4 weeks after screening visit 1 to ensure stability of 
liver disease for participant safety and eligibility purposes. 
Intervention (Treatment) Period: will start with Part A (Day 1 through 
Week 24) followed by Part B (Week 24 through Week 32). Eligible 
participants will be randomized in a 1:1:1:1 ratio to receive linerixibat 
40 mg BID in Part A and Part B, linerixibat 40 mg BID in Part A and 
placebo in Part B, placebo in Part A and Part B, or placebo in Part A 
and linerixibat 40 mg BID in Part B.  
Follow-up Period or Follow-on Study:  
Participants who complete treatment in Part A and Part B will be 
offered the opportunity to take part in a separate long-term follow-on 
study, where linerixibat will be provided in an open-label manner. This 
open-label, long-term study will assess safety and tolerability (and 
efficacy in participants transferring from this study). Participants who 
do not enter the follow-on study will have a follow-up phone call 
approximately 7-14 days after the last dose of study drug. 
This study will be delivered through a partially decentralized clinical 
trial approach. Decentralized clinical trials (DCTs) are defined as trials 
executed through telemedicine, mobile/local healthcare providers and/or 
mobile technologies [Apostolaros, 2020]. This study will employ a 
combination of two types of sites: 1) Metasite, and 2) brick and mortar 
sites, which may employ decentralized methodologies. The sites and 
operating models are defined as follows: 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 25 of 102 
Overview of Study Design and Key Features 
Metasite: Participants at the Metasite will complete all visits remotely 
(Metasite model). The Metasite model uses telemedicine-based clinical 
research to allow all trial visits to be conducted remotely.  
Brick and mortar sites: Brick and mortar sites may offer participants the 
opportunity to complete all visits at the site (brick and mortar model) or 
to complete some visits remotely (flexible model). Under the flexible 
model, consenting/initial screening and dispensing visits will be 
performed in clinic. All other visits may be performed remotely as 
described in the Study Reference Manual (SRM). The flexible model 
will be available worldwide in sites/countries where the regulations and 
infrastructure allow. 
This study plans to randomize approximately 230 participants with PBC 
and moderate to severe cholestatic pruritus. Participants receiving 
concomitant bile acid binding resins may comprise up to 15% of the 
overall Phase 3 study population. 
Study 
interventio
n 
After a Screening period, eligible participants will be enrolled in the 
study and start the 24-week Treatment Period Part A followed by 8 
weeks of Treatment Period Part B. Finally, participants will be offered 
enrolment in a long-term follow-up study after Treatment Period Parts 
A and B. Participants who do not enter the follow-up study will have a 
2-week follow-up.   
The total expected duration of study participation for each participant is 
approximately 40-42 weeks.  
Permanent Discontinuation: If study intervention is permanently 
discontinued following randomization and before the scheduled follow-
up, participants should not be withdrawn from the study and should 
complete the remaining scheduled visits and all required assessments, 
including the eDiary. 
If the participant is withdrawing from the study, they will be 
encouraged to complete Early Discontinuation Visit (please refer to 
Schedule of Activities (SoA) in the study protocol) before their last dose 
of study intervention if possible.  
Restart of Study Intervention: Restart refers to resuming study 
intervention following liver stopping events in which there is a clear 
underlying cause (other than drug induced liver injury [DILI]) of the 
liver event (e.g. biliary obstruction, pancreatic events, hypotension, 
acute viral hepatitis). Furthermore, restart is not permitted following 
liver stopping event when the underlying cause was alcohol-related 
hepatitis.  
Concomitant Therapy: Concomitant therapy for PBC or any 
medications that may affect itch as shown in the study protocol are 
permitted but must be stable prior to Screening and throughout the 
Screening and Intervention Periods. Rescue medication is permitted 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 26 of 102 
Overview of Study Design and Key Features 
only for participants who are not receiving background cholestatic 
pruritus treatment when entering the study. If a participant reports 
experiencing worsening itch and requests rescue therapy, it may be 
considered only after 12 weeks of randomized treatment. Once the 
criteria for using rescue medication have been satisfied, the investigator 
may offer treatment with cholestyramine to the participant per treatment 
guidelines. 
Study 
interventio
n 
Assignment 
Intervention (treatment) period will start with Part A (Day 1 through 
Week 24) followed by Part B (Week 24 through Week 32). Day 1 is the 
day on which the first study intervention administration takes place and 
may differ from the randomization date. Eligible participants will be 
randomized in a 1:1:1:1 ratio to receive linerixibat 40 mg BID in Part A 
and Part B, linerixibat 40 mg BID in Part A and placebo in Part B, 
placebo in Part A and Part B, or placebo in Part A and linerixibat 40 mg 
BID in Part B. Participants who had initially been taking linerixibat in 
Part A will either continue on linerixibat or switch to placebo at Week 
24 for Part B. Participants who had been taking placebo in Part A will 
either continue on placebo or switch to linerixibat at Week 24 for Part 
B.  
Randomization will be stratified by:  
• 
Severity of pruritus based on Monthly Itch Score for the 28 days 
preceding randomization: 
• 
Moderate: ≥ 4 and < 7  
• 
Severe: ≥ 7 
• 
Concomitant cholestatic pruritus treatment regimen (definitions of 
cholestatic pruritus treatments can be found in the main protocol 
text):  
• 
Bile acid binding resin (BABR)-containing regimen 
• 
Regimen that does not contain BABRs 
• 
No defined cholestatic pruritus treatment  
• 
Region/site: 
• 
US Brick and Mortar 
• 
US Metasite 
• 
Rest of world (RoW) Brick and Mortar 
Region/site will serve as an administrative stratification factor and will 
not be used in the analysis. 
Interim 
Analyses 
The study has a planned futility analysis to be conducted after 
approximately 100 participants reach 24 weeks of treatment (or 
discontinue early). The analysis will be overseen by an Independent 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 27 of 102 
Overview of Study Design and Key Features 
Data Monitoring Committee (IDMC) with non-binding futility 
guidelines as documented in the IDMC Charter (current version: 
GlaxoSmithKline Document Number TMF-16125967). The study may 
be terminated following this analysis if the probability of demonstrating 
clinical efficacy based on observed data is too low to support continuing 
or following the safety review if the overall risk-benefit is assessed to 
be unfavorable. In the event of the study being discontinued, GSK 
processes will be followed to ensure the best interests and the safety of 
the participants. The trial will not be stopped for early benefit at this 
point and no alpha-spend is incurred. 
Primary 
and Final 
Analyses 
The primary statistical analysis to assess the primary, secondary, and 
safety objectives will be performed when all randomized participants 
have completed the Part A intervention period (up to Week 24/Visit 9). 
In addition, available data for exploratory endpoints in Part A and Part 
B will be analyzed as part of this primary statistical analysis. By the 
time the last participant completes the Part A intervention period, it is 
anticipated that the majority of participants will have also completed the 
Part B intervention period (Week 24 through Week 32). Therefore, all 
available Part B data will also be assessed and reported as part of the 
primary statistical analysis.  
A final analysis will then be performed when all participants have 
completed the Part B intervention period, and the follow-up period, if 
applicable. This analysis will include complete Part B data and the full 
data for exploratory endpoints in Part A for which full datasets were not 
available at the time of the primary analysis. 
2. 
STATISTICAL HYPOTHESES  
2.1. 
Primary Endpoint 
The primary objective is to investigate the superiority of 24 weeks of treatment with oral 
linerixibat compared with placebo on itch in PBC patients with cholestatic pruritus.  The 
primary endpoint is Change from Baseline in MIS over 24 weeks using a 0-10 NRS. The 
primary estimand is the difference in means between linerixibat and placebo in the 
change from baseline in itch score over 24 weeks in PBC patients with cholestatic 
pruritus. The primary analysis will be a mixed model approach based on MIS over 24 
weeks (Weeks 4, 8, 12, 16, 20, and 24). The primary hypothesis is that linerixibat reduces 
itch score over 24 weeks compared to placebo. A negative change from baseline (or 
reduction) represents an improvement in itch. 
The null hypothesis (H0) assumes that there is no difference in the reduction of itch score 
over 24 weeks between linerixibat and placebo groups. The alternate hypothesis (H1) 
assumes that there is a difference in the reduction of itch score over 24 weeks between 
linerixibat and placebo groups.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 28 of 102 
The overall significance level for the primary endpoint analysis is set at the two-sided 
0.05 level. 
2.2. 
Secondary Endpoints and Multiplicity Control 
Formal multiplicity-controlled testing will be conducted for the key secondary endpoints 
of change from baseline in WIS at Week 2, change from baseline in MSS over 24 weeks, 
as well as responder endpoints defined as achieving ≥2, ≥3, and ≥4-point reduction from 
Baseline in the MIS at Week 24. Additional non-controlled testing will be conducted for 
supportive secondary endpoints including change from baseline in PBC-40 domain scores 
at Week 24, change from baseline in PGI-S over 24 weeks, PGI-C over 24 weeks, change 
from baseline in ALP at Week 24, and change from baseline in bilirubin at Week 24.  
A step-down/hierarchical approach will be used to test the following key secondary 
endpoints if statistical significance is achieved for the primary endpoint: 
• 
Change from Baseline in WIS at Week 2 
• 
Change from Baseline in MSS over 24 weeks 
• 
Responders defined as achieving a ≥2-point reduction from Baseline in the MIS at 
Week 24. 
• 
Responders defined as achieving a ≥3 -point reduction from Baseline in the MIS at 
Week 24. 
• 
Responders defined as achieving a ≥4 -point reduction from Baseline in the MIS at 
Week 24. 
These tests will be conducted sequentially at a 5% two-sided significance level. Other 
secondary endpoints will also be tested but outside this formal hierarchy. 
3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screening 
• 
All participants who sign the 
Informed Content Form (ICF) 
• 
Study Population 
Enrolled  
• 
All participants who sign the ICF 
and pass screening (meet the 
eligibility criteria) 
• 
Study Population 
Intent to Treat 
(ITT)  
• 
This population will comprise all 
randomized participants. 
Participants in the ITT Population 
will be classified according to the 
treatment as randomized. 
• 
Study Population 
• 
Efficacy 
• 
Biomarker 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 29 of 102 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
• 
For Part B, this will be all 
participants in the ITT who do not 
withdraw in Part A. 
Non-BABR ITT  • 
The Non-BABR ITT Population is 
a subset of the ITT population 
who are not receiving concomitant 
bile acid binding resin therapy 
(cholestyramine, colesevalem, 
colestimide, and/or colestipol) at 
randomization. 
• 
Efficacy 
Non-Metasite 
ITT 
• 
The non-Metasite ITT population 
is a subset of the ITT population 
who are not enrolled at the 
Metasite. 
• 
Efficacy 
Ursodeoxycholic 
acid (UDCA) 
ITT 
• 
A subset of the ITT population 
who are receiving UDCA at 
randomization 
• 
ALP 
ALP ≥1.67x 
ULN ITT 
• 
A subset of the ITT population 
who have serum alkaline 
phosphatase [ALP] concentrations 
≥1.67x upper limit of normal 
[ULN] at baseline. 
• 
ALP 
• 
Total Bilirubin 
Safety 
• 
All randomized participants who 
take at least 1 dose of study 
intervention. Participants will be 
analyzed according to the 
treatment they actually received.* 
• 
For Part B, this will be all 
participants in the safety 
population who take at least 1 
dose in Part B. 
• 
Safety 
• 
Study Population 
PK 
• 
Any randomized participant who 
had at least 1 PK sample. 
Participants will be analyzed 
according to the treatment they 
actually received. 
• 
PK  
* In cases where incorrect treatment was received for the duration of a treatment period 
(i.e., entire Part A or entire Part B), then the participant will be analyzed according to the 
treatment received. If the participant received incorrect treatment for only part of a 
treatment period and therefore received both treatments during the same treatment period, 
then analysis will be based on active treatment.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 30 of 102 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
Planned treatment will be used for the analyses except safety and PK, which will use 
actual treatment. Participants who prematurely withdrew from study will not be replaced. 
In the case of wrong stratification assigned at the time of randomization, the analyses will 
be performed based on the actual stratum per data collected in the CRF. 
Confidence intervals (CIs) will use 95% CIs unless otherwise specified. Where requested, 
t-type confidence limits will be constructed for LS means estimates, unless otherwise 
specified. The alpha level for all the tests is at two sided 0.05 unless otherwise specified.  
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation (SD), median, minimum and maximum. 
Categorical data will be summarized as the number and percentage of participants in each 
category.  
For descriptive analyses, intercurrent event strategy will not be applied. In other words, 
data impacted by an intercurrent event will not be discarded for descriptive summary 
displays that have no statistical model involved.  
For descriptive summary of responder rate, the responder at Week 4, 8, 12, 16, 20, 24 
will be dichotomized from the corresponding MIS. Participants with missing responder 
data at the Week of interest due to the missing of MIS for the 4 weeks prior will be 
classified as non-responders for that Week.  
It is anticipated that participant accrual will be spread thinly across centers; therefore, 
summaries of data by center are unlikely to be informative and will not be provided. 
For all the analyses using MMRM, an unstructured covariance structure will be assumed; 
if this does not converge then compound symmetry (CS) will be used, followed by an 
autoregressive [AR(1)] covariance structure if CS does not converge. The degrees of 
freedom will be computed using the Kenward-Roger (KR) method. Distributional 
assumptions underlying the MMRM will be examined by obtaining a normal probability 
plot of the residuals and a plot of the residuals versus the fitted values (i.e. checking the 
normality assumption and constant variance assumption of the model, respectively) to 
gain confidence that the model assumptions are reasonable.  If there are any clear 
departures from the distributional assumptions, alternative models will be explored using 
appropriate transformed data. When the least-squares (LS) means over multiple 
timepoints are estimated for each treatment group and the difference from placebo is 
derived, equal weight is applied to each timepoint and simple average of LS means at 
each time point is used.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 31 of 102 
4.1.2. 
Baseline Definition 
The summary of baseline definitions for all the study endpoints, except aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), 
total bilirubin (TB), Total serum bile acids, Serum C4, Serum autotaxin, and FGF-19 is 
shown in Table 1.  
Baseline serum AST, ALT, ALP and TB values will be established using an average of 
two sets of laboratory values as detailed in protocol Section 8.3.4.1. The two samples are 
expected to be obtained at least 4 weeks apart; however, in cases where this was not 
feasible, both samples will still be used for the calculation of the baseline value. The 
baseline value will be established using the average of Samples 1 and 2. In cases where at 
least one of the two samples is abnormal and the variance between Sample 1 and Sample 
2 was > 40% and a third sample was obtained confirming eligibility prior to 
randomization, then the average of Samples 1 and 3 will be used, as described in Section 
8.3.4.1 of the protocol. In cases where only one value is present, then this value will be 
used as baseline. If any values are below the LOQ and are therefore reported as a non-
numeric value (e.g., < 3), the rules in Section 6.3.9 will be applied. 
For PD/Biomarker samples (Total serum bile acids, Serum C4, Serum autotaxin, FGF-19, 
and IL-31) baseline value will be established using the average of the Screening 2 and 
last assessment prior to the first dose values. In cases where only one of these values is 
present then this value will be used as baseline. For analysis of PD/Biomarker samples in 
Part B, the same baseline as Part A will be used. 
For other laboratory results, vital signs, GSRS, PBC-40, PGI-S, ESS, BDI-II, ELF, 
Fibroscan, and ECG endpoints in Part A, the baseline assessment will be the last 
assessment conducted prior to the first dose of randomized medication. For the analysis 
of PBC-40, PGI-S, ESS, BDI-II, ELF during Part B, the baseline will be the assessment 
performed at Visit 9. 
For safety related endpoints in Part B, including vital signs, ECG, clinical laboratory 
evaluations, and GSRS, the same baseline for Part A will be used.  
For daily data collected on the eDiary, the baseline will be as follows: 
• 
WIS at baseline will be the average of the WDI scores i.e. the higher of the AM and 
PM score each day, in the 7 days prior to randomization 
• 
MIS at baseline for Part A will be the worst WIS in the 28 days immediately 
preceding randomization. More specifically, for each week of the 4 weeks 
immediately preceding randomization, the WIS will be calculated, and the worst 
WIS of the 4 weeks will be the baseline. 
• 
MIS at baseline for Part B will be the worst WIS of the 28 days immediately 
preceding Part B. More specifically, for each week of the 4 weeks immediately 
preceding Part B, the WIS will be calculated, and the worst WIS of the 4 weeks will 
be the baseline. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 32 of 102 
• 
MSS at baseline for Part A will be the worst WSS of the 28 days immediately 
preceding randomization. More specifically, participant’s sleep quality is recorded 
on the eDiary each morning using a 0-10 NRS. For each week of the 4 weeks 
immediately preceding randomization, the WSS will be calculated, and the worst 
MSS of the 4 weeks will be the baseline. 
• 
MSS at baseline for Part B will be the worst WSS of the 28 days immediately 
preceding Part B. More specifically, for each week of the 4 weeks immediately 
preceding Part B, the WSS will be calculated, and the worst WSS of the 4 weeks will 
be the baseline. 
• 
Monthly Fatigue Score (MFS) at baseline for Part A will be the worst Weekly 
Fatigue Score (WFS) of 28 days immediately preceding randomization. More 
specifically, fatigue is recorded on the eDiary each evening using a 0-10 NRS. For 
each week of the 4 weeks immediately preceding randomization, the average of the 
Daily Fatigue Scores (DFS) in one week will be used to calculate WFS. The worst of 
WFS of the 4 weeks will be the baseline. 
• 
MFS at baseline for Part B will be the worst WFS of the 28 days immediately 
preceding Part B. More specifically, for each week of the 4 weeks immediately 
preceding Part B, the WFS will be calculated, and the worst WFS of the 4 weeks will 
be the baseline. 
Table 1 
Baseline definition 
Parameter 
Study Assessments Considered as Baseline 
Last 
assessment 
prior to the 
first dose of 
Part A1 
Mean of 7 days 
prior to 
randomization 
Monthly Score 
for 28 days prior 
to randomization 
Monthly 
Score for 28 
days prior to 
day 1 of Part 
B 
Visit 9 (Week 
24)  
MIS, MSS, MFS at 
Part A 
 
 
X 
 
 
MIS, MSS, MFS at 
Part B 
 
 
 
X 
 
WIS 
 
X 
 
 
 
PBC-40, PGI-S, 
ESS, BDI-II at Part 
A 
X 
 
 
 
 
PBC-40, PGI-S, 
ESS, BDI-II at Part 
B 
 
 
 
 
X 
GSRS 
X 
 
 
 
 
ECGs 
X 
 
 
 
 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 33 of 102 
Parameter 
Study Assessments Considered as Baseline 
Last 
assessment 
prior to the 
first dose of 
Part A1 
Mean of 7 days 
prior to 
randomization 
Monthly Score 
for 28 days prior 
to randomization 
Monthly 
Score for 28 
days prior to 
day 1 of Part 
B 
Visit 9 (Week 
24)  
Laboratory data 
excluding AST, 
ALT, ALP, and TB2 
X 
 
 
 
 
Vital signs 
X 
 
 
 
 
ELF (Part A) 
Fibroscan 
X 
 
 
 
 
ELF at Part B 
 
 
 
 
X 
1 If time is not collected, Day 1 assessments are assumed to be taken prior to first dose. 
2 Please see the baseline definition of AST, ALT, ALP, and TB in the text above. 
4.2. 
Primary Endpoint Analyses 
4.2.1. 
Definition of Endpoint/Estimands 
The primary endpoint is Change from Baseline in MIS over 24 weeks using a 0-10 NRS. 
The MIS will be determined from the worst WIS for the month (4 weeks). A week will 
have a WIS if there are at least 4 WDI scores in the week, where a WDI score needs at 
least 1 entry for that day. Otherwise, the WIS for the week will be missing. If one or 
more WIS are missing, then the worst of the non-missing WIS is selected as the MIS. If 
no WIS are available for a month, the MIS will be missing.  
The following intercurrent events have been considered for the evaluation of the primary 
endpoint of MIS: 
• 
Permanent treatment discontinuation, disruptions in treatment, treatment delays 
unrelated to the COVID-19 pandemic, addressed with treatment policy strategy 
• 
Permanent treatment discontinuation, disruptions in treatment, treatment delays 
related to the COVID-19 pandemic, addressed with hypothetical strategy 
• 
Change in background itch therapy or use of rescue medication, addressed with 
treatment policy strategy 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 34 of 102 
The number and percentage of participants experiencing each intercurrent event will be 
summarized. 
The COVID-19 pandemic related intercurrent events are defined as permanent treatment 
discontinuation, disruptions in treatment, or treatment delays related to study treatment 
supply interruption due to COVID-19 pandemic, such as site closure, lockdowns, and 
other drug supply issues. The intercurrent events caused by COVID-19 infection or 
concern of COVID-19 are not included in the above definition of COVID-19 pandemic 
related and will be treated the same manner as the other COVID-19 pandemic unrelated 
intercurrent events.  
Data following intercurrent events that are unrelated to COVID-19 will be included as 
available. WDI scores impacted by COVID-19 pandemic related intercurrent events will 
be discarded. For example, if treatment is disrupted during Day 28 to Day 30 due to 
COVID-19, the WDI scores collected during this period will be discarded to construct the 
corresponding WIS. If treatment is permanently discontinued from Day 30 due to 
COVID-19, the data from Day 30 onwards will be discarded, thus leading to missing 
WIS and consequently missing MIS.  
The summary measure will be mean difference between treatment groups. 
4.2.2. 
Main Analytical Approach 
The primary analysis will be a mixed model for repeated measures (MMRM) of change 
from baseline in MIS over the 24-week treatment period. The MMRM will be fitted after 
the outcomes impacted by COVID-19 pandemic related intercurrent events have been 
discarded. This assumes that unobserved outcomes of participants who withdrew from 
the study or who experienced a COVID-19 pandemic related intercurrent event are 
missing at random (MAR). 
Endpoint / Variables 
• 
Change from Baseline in Monthly Itch Scores (MIS) over 24 weeks using a 0-10 numerical rating scale (NRS) 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑉𝑖𝑠𝑖𝑡+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑉𝑖𝑠𝑖𝑡+ 𝐵𝐿𝐼𝑡𝑐ℎ+ 𝐵𝐿𝐼𝑡𝑐ℎ∗𝑉𝑖𝑠𝑖𝑡
+ 𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑+ 𝐸𝑟𝑟𝑜𝑟 
o 
Response (Y): change from baseline in MIS at Visits 4 – 9 of the study intervention during Part A. 
o 
Categorical: treatment group, visit, baseline concomitant itch therapy (3-level; Regimen contains 
BABR, Regimen that does not contain BABR, No defined anti-cholestatic pruritus treatment) 
o 
Continuous: baseline MIS 
o 
Interaction: treatment group*visit, baseline MIS*visit 
o 
Repeated: visit 
Visit refers to the planned visits (V4 – V9) at week 4, 8, 12, 16, 20, and 24 of the study intervention during 
Part A. See Section 6.3.7.1. 
• 
Baseline is defined in Section 4.1.2 
Model Results Presentation 
• 
The LS means and the corresponding 95% confidence intervals of change from baseline in MIS over 24 
weeks (equal weight for each time point, i.e., average of Weeks 4, 8, 12, 16, 20 and 24 LS means) for 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 35 of 102 
linerixibat and placebo will be reported. The LS mean, 95% CI, and p-value for the difference from placebo 
will be reported in the same table.  
• 
The LS means and 95% confidence intervals for change from baseline in MIS at each visit (Weeks 4, 8, 12, 
16, 20, and 24) will be reported for linerixibat and placebo, as well as the LS means and corresponding 95% 
CIs for the difference from placebo at each visit.  
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Subgroup/covariate Analyses 
o 
The MMRM analysis will be repeated by including each of the covariates indicated in Section 4.6.1, 
respectively in separate models, along with its interaction with treatment group. For continuous covariates, the 
model estimates are obtained for the median, lower, and upper quartiles of the covariate. For covariates 
concomitant background itch therapy (Yes vs. No), baseline concomitant fibrates (Yes vs. No), baseline 
concomitant BABR and baseline cholestyramine use, baseline concomitant itch therapy (3-level) will not be 
included in the model (i.e., we will remove the baseline concomitant itch therapy [3-level] variable in place of 
these variables in each respective model to avoid confounding). 
o 
The LS mean of change from baseline and its corresponding 95% CI will be reported for each treatment 
group, as well as the LS mean and its 95% CI of difference from placebo. The p-values for treatment group, 
covariate, and interaction between treatment group and covariate will be reported.  
o 
Additionally, a shrinkage estimation may be applied to the estimate and confidence intervals for the 
subgroups, further details are provided in Section 4.6.4. 
Supplementary Analyses 
• 
The same MMRM analysis will be applied after discarding data impacted by the intercurrent events. The LS 
means and the corresponding 95% confidence intervals of change from baseline in MIS over 24 weeks for 
linerixibat and placebo will be reported. The LS mean, 95% CI, and p-value for the difference from placebo 
will be reported in the same table. See Section 4.2.4 for more details.  
• 
The same MMRM analysis will be applied to the non-bile acid binding resin ITT Population. The LS means 
and the corresponding 95% confidence intervals of change from baseline in MIS over 24 weeks for linerixibat 
and placebo will be reported. The LS mean, 95% CI, and p-value for the difference from placebo will be 
reported in the same table. See Section 4.2.4 for more details. 
• 
The same MMRM analysis will also be applied to the non-Metasite ITT Population. The LS means and the 
corresponding 95% confidence intervals of change from baseline in MIS over 24 weeks for linerixibat and 
placebo will be reported. The LS mean, 95% CI, and p-value for the difference from placebo will be reported 
in the same table. See Section 4.2.4 for more details. 
• 
The impact of operating model will be tested by including operating model and the interaction between 
operating model and treatment group into the MMRM. See Section 4.6.3 for the details of operating model 
definition, analysis model, and displays. 
• 
The empirical cumulative distribution function (eCDF) graph by treatment group of change from baseline in 
non-missing MIS averaged over Week 4, 8, 12, 16, 20, and 24 (equal weight for the timepoints) will be 
provided. The observed number of observations will be used as the denominator.  
• 
Additionally, the empirical cumulative distribution function (eCDF) graph by treatment group of change from 
baseline in Imputed MIS averaged over Week 4, 8, 12, 16, 20, and 24 (equal weight for the timepoints) will be 
provided. Multiple imputation will be applied to impute the missing MIS by treatment groups. Please see step 
1 in Section 4.2.3 for details of the imputation model. 
4.2.3. 
Sensitivity Analyses 
A sensitivity analysis will be conducted to examine the sensitivity of inferences to 
departure from the MAR assumption if the primary endpoint is significant in favor of 
linerixibat. In this sensitivity analysis, a tipping point approach will be used. This is akin 
to progressive stress-testing to assess how severe departures from the MAR assumption 
must be in order to change the overall conclusion of the primary analysis.  The following 
steps will be taken: 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 36 of 102 
1. Missing MIS for Week 4, 8, 12, 16, 20, and 24, including data discarded due to 
COVID 19 related intercurrent events, will be imputed under the MAR assumption.  
i. Briefly, the first step of imputation will use SAS MI procedure to impute the 
intermitted missing values and the variables to be used are MIS at baseline, 
Week 4, 8, 12, 16, 20, and 24, and treatment group. Treatment group will be 
included in the SAS by statement in the first instance (i.e., imputed separately 
for each treatment group), in case of non-convergence then it may be included as 
a covariate (using the SAS PROC MI var statement). The seed number for the 
imputation is 212620. The number of imputations is 100. Since the MIS NRS 
has a 0-10 range, any imputed values that are less than 0 will be set to 0, and any 
values greater than 10 will be set to 10.   
ii. The 2nd step of imputation will use the regression method to impute the 
monotone missing values, for each of the monotone missing dataset (out of the 
100 imputed as indicated above). The variables to be used are baseline 
concomitant itch therapy, as well as MIS at baseline, Week 4, 8, 12, 16, 20, and 
24, and treatment group. Treatment group will be included in the SAS by 
statement in the first instance (i.e., imputed separately for each treatment group), 
and a categorical covariate in the case of non-convergence (using the SAS 
PROC MI class statement). The seed number for the imputation is 212620. 
Since the MIS NRS has a 0-10 range, any imputed values that are less than 0 
will be set to 0, and any values greater than 10 will be set to 10. Then, change 
from baseline MIS will be calculated. 
2. The 100 complete data sets generated from step 1 will be analyzed by the MMRM 
model specified in Section 4.2.2, respectively. 
3. The results from the MMRM analyses of 100 complete data sets, including the LS 
mean and its standard error of difference from placebo in change from baseline in 
MIS over 24 weeks, will be combined using SAS PROC MIANALYZE based on 
Rubin’s rules to have a pooled estimate of LS mean and 95% CI of difference from 
placebo, as well as the p-value.  
4. Repeat step 1, with a pair of shift parameters applied to the imputed datapoints for 
linerixibat and placebo groups, respectively. As described above, any values that are 
less than 0 will be set to 0, and any values greater than 10 will be set to 10. 
5. Repeat steps 2 – 3 to obtain the combined estimate of difference from placebo with 
95% CI and associated p-value. 
6. Repeat steps 4 – 5 with another pair of shift parameters.  
Overall, a sequence of shift parameters ranging from -3 to 3 by 0.5 increments will be 
applied to find the tipping point where the result is no longer statistically significant. The 
shift parameters will vary independently for each arm and will include scenarios where 
participants in the linerixibat arm have worse outcomes following withdrawal from the 
study than participants in the placebo arm. The shift parameters will only be applied to 
the imputed monotone missing values, but not to the intermittent missing values. The 
tipping point results will be reported in a 2-dimensional table that includes the combined 
estimate of difference from placebo in change from baseline in MIS over 24 weeks, as 
well as its 95% CI and corresponding p-value, for each pair of shift parameters.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 37 of 102 
4.2.4. 
Additional Estimands 
As a supplementary estimand for the primary objective, the hypothetical treatment effect 
of linerixibat will be compared to placebo in the absence of any intercurrent events. 
Hypothetical strategy will be applied to all the intercurrent events defined in Section 
4.2.1, including treatment discontinuation, disruptions in treatment or treatment delays, 
changes in itch therapy or use of rescue medication, regardless of whether an intercurrent 
event is related to COVID-19 or not. The WDIs impacted by any intercurrent events will 
be discarded in the same way as detailed in Section 4.2.1, and the MMRM will then be 
fitted. This assumes that unobserved outcomes of participants who withdrew from the 
study or who experienced an intercurrent event are MAR. 
The main analytical approach will be repeated using the non-bile acid binding resin ITT 
population. Any participant taking bile acid binding resin as the background itch therapy 
at baseline will be excluded from the non-bile acid binding resin ITT population and any 
data from these excluded participants will not contribute to the analysis. 
The main analytical approach will also be repeated by using the non-Metasite ITT 
population. Any participants enrolled at Metasite will be excluded from the non-Metasite 
ITT population and any data from these excluded participants will not contribute to the 
analysis. 
4.3. 
Secondary Endpoints Analyses 
4.3.1. 
Key/Confirmatory Secondary Endpoints 
4.3.1.1. 
Definition of Endpoints/Estimands 
• 
Change from baseline in Weekly Itch score at Week 2 
The WIS defined earlier at Week 2 will be evaluated. Similar to the primary endpoint, 
treatment policy strategy will be used for the intercurrent events unrelated to the COVID-
19 pandemic, whereas hypothetical strategy will be used for the intercurrent events 
related to the COVID-19 pandemic.  The discard of data impacted by COVID-19 
intercurrent events is detailed in Section 4.2.1.  
• 
Change from Baseline in Monthly Sleep Score over 24 weeks: 
The MSS, based on a 0-10 NRS, will be the worst WSS available for the month (4 
weeks). A week will have a WSS if at least 4 days in the week have a score. Otherwise, 
WSS will be missing. If one or more WSS are missing, then the worst of the non-missing 
WSS is selected as the worst for that month. If no WSS are available for a month, the 
MSS will be missing. 
Treatment policy strategy will be used for the intercurrent events unrelated to the 
COVID-19 pandemic, whereas hypothetical strategy will be used for the intercurrent 
events related to the COVID-19 pandemic. The DSS affected by the COVID-19 
pandemic related intercurrent events will be discarded to construct the corresponding 
WSS, which may lead to missing WSS and consequently missing MSS.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 38 of 102 
• 
Responder defined as achieving a ≥2-point reduction from baseline in the Monthly 
Itch score at Week 24; 
• 
Responder defined as achieving a ≥3-point reduction from baseline in the Monthly 
Itch score at Week 24; 
• 
Responder defined as achieving a ≥4-point reduction from baseline in the Monthly 
Itch score at Week 24: 
Responder will be evaluated using three different thresholds based on change from 
baseline in MIS at Week 24, which is the worst WIS of weeks 21 - 24. Treatment policy 
strategy will be used for the intercurrent events unrelated to the COVID-19 pandemic, 
whereas hypothetical strategy will be used for the intercurrent events related to the 
COVID-19 pandemic. WDI scores affected by COVID-19 pandemic related intercurrent 
events will be discarded, which may lead to missing WIS and consequently missing MIS. 
If there are missing MIS, multiple imputation will be applied to impute MIS using 
available data for all participants. The imputed MIS at Week 24 and the corresponding 
baseline score will then be dichotomized to form the responder endpoint. 
4.3.1.2. 
Main Analytical Approach of Secondary Endpoints 
Change from baseline WIS at Week 1 and 2 will be fitted to a MMRM model including 
baseline WIS as a continuous covariate, treatment, week (Weeks 1 and 2), concomitant 
use of itch medications at baseline, treatment by week interactions, and baseline WIS by 
week interaction as fixed effects. The comparison at Week 2 will be estimated from the 
MMRM model.   
Endpoint / Variables 
• 
Change from baseline in Weekly Itch score at Week 2 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑊𝑒𝑒𝑘+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑊𝑒𝑒𝑘+ 𝐵𝐿𝐼𝑡𝑐ℎ+ 𝐵𝐿𝐼𝑡𝑐ℎ∗𝑊𝑒𝑒𝑘+
𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑+ 𝐸𝑟𝑟𝑜𝑟  
o 
Response (Y): change from baseline in WIS at Week 1 and 2 of the study intervention during part A. 
o 
Categorical: treatment group, week, baseline concomitant itch therapy (3-level) 
o 
Continuous: baseline WIS 
o 
Interaction: treatment group*week, baseline WIS*week 
o 
Repeated: week 
In this model Week is used rather than visit since Week 2 does not correspond to a visit.  
• 
Baseline is defined in Section 4.1.2. 
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Model Results Presentation 
• 
The LS means and the corresponding 95% confidence intervals of change from baseline in WIS at Week 1 
and 2 for linerixibat and placebo will be reported. The LS mean, 95% CI, and p-value for the difference from 
placebo will be reported in the same table.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 39 of 102 
Supplementary Analyses 
• 
The same MMRM analysis will be applied to the Non-bile acid binding resin ITT Population. The same model 
results display as the ITT population will be produced.  
Change from baseline of MSS at planned Visits 4 - 9 will be analyzed using a MMRM 
model including baseline MSS as covariate, treatment, visit, concomitant use of itch 
medications at baseline, treatment by visit interaction, and baseline MSS by visit 
interaction as fixed effects. The comparison of effects averaged over the visits will be 
estimated from the MMRM.  
Endpoint / Variables 
• 
Change from baseline in Monthly Sleep score over 24 weeks 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑉𝑖𝑠𝑖𝑡+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑉𝑖𝑠𝑖𝑡+ 𝐵𝐿𝑆𝑙𝑒𝑒𝑝+ 𝐵𝐿𝑆𝑙𝑒𝑒𝑝∗𝑉𝑖𝑠𝑖𝑡+
𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑+ 𝐸𝑟𝑟𝑜𝑟  
o 
Response (Y): change from baseline in MSS at Visits 4 – 9 of the study intervention during part A. 
o 
Categorical: treatment group, visit, baseline concomitant itch therapy (3-level) 
o 
Continuous: baseline MSS 
o 
Interaction: treatment group*visit, baseline MSS*visit 
o 
Repeated: visit 
Visit refers to the planned visits (V4 – V9) at week 4, 8, 12, 16, 20, and 24 of the study intervention during part 
A. 
• 
Baseline is defined in Section 4.1.2. 
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Model Results Presentation 
• 
The LS means and the corresponding 95% confidence intervals of change from baseline in MSS over 24 
weeks for linerixibat and placebo will be reported. The LS mean, 95% CI, and p-value for the difference from 
placebo will be reported in the same table.  
• 
The LS means and 95% confidence intervals for change from baseline in MSS at each visit (Weeks 4, 8, 12, 
16, 20, and 24) will be reported for linerixibat and placebo, as well as the LS means and corresponding 95% 
CIs for the difference from placebo.  
Supplementary Analyses 
• 
The same MMRM analysis will be applied to the Non-bile acid binding resin ITT Population. The same model 
results display as the ITT population will be produced.  
• 
A figure displaying Bland-Altman repeated measures correlations of change from baseline in MSS and MIS 
across all treatment groups will be produced, including all visits in Part A. The correlation coefficient will be 
displayed within the figure. 
The summary measure for the responder endpoint will be the difference in responder 
rates (proportion of responders) between linerixibat and placebo groups, analyzed using a 
stratified analysis with Cochran-Mantel-Haenszel (CMH) weights, adjusting for baseline 
itch severity and concomitant use of itch medications.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 40 of 102 
Endpoint / Variables 
• 
Responder defined as achieving a ≥2-point reduction from baseline in the Monthly Itch score at Week 24; 
• 
Responder defined as achieving a ≥3-point reduction from baseline in the Monthly Itch score at Week 24; 
• 
Responder defined as achieving a ≥4-point reduction from baseline in the Monthly Itch score at Week 24 
Model Specification 
• 
Each responder endpoint will be analyzed using a stratified analysis with Cochran-Mantel-Haenszel (CMH) 
weights, adjusting for itch severity at baseline (moderate: ≥ 4 and < 7; severe: ≥ 7) and concomitant therapy 
use at baseline (BABR-containing regimen, regimen that does not contain BABR, No cholestatic pruritus 
treatment). 
• 
The CMH estimate of the adjusted treatment difference will be calculated as a weighted average of strata-
specific estimates of the treatment difference calculated within each of the following six Baseline analysis 
strata: 
o 
Moderate itch severity AND BABR-containing regimen  
o 
Moderate itch severity AND non-BABR-containing regimen  
o 
Moderate itch severity AND no cholestatic pruritus treatment  
o 
Severe itch severity AND BABR-containing regimen  
o 
Severe itch severity AND non-BABR-containing regimen  
o 
Severe itch severity AND no cholestatic pruritus treatment  
• 
The CMH estimate is given by 
 
where yk and xk are the number of responder in linerixibat and placebo arms, respectively, in the kth strata; nk 
is the number of participants in the linerixibat arm, mk is the number of participants in the placebo arm, and Nk 
= nk + mk is the total number of participants in the kth stratum; 
  
are the CMH weight for the kth strata; and  
𝑑̂𝑘= 𝑦𝑘
𝑛𝑘
−𝑥𝑘
𝑚𝑘
 
are the estimates of the differences in response proportions between the two treatment arms, for the kth 
strata.  
• 
The corresponding two-sided 95% CI will be calculated as 
 
where the variance estimator is consistent in both sparse data and large strata and is given below   
(
)
(
)
(
)
(
)
(
)2
2
ˆ
ˆ
ˆ
raˆ
v






+
=
+
=
k
k
k
cmh
k
k
k
k
k
cmh
cmh
W
Q
P
d
N
m
n
Q
P
d
d
  
where 
 
) 
ˆ
r(
a ˆ 
v 
96 
.1
ˆ
cmh
cmh
d 
d 

 
  
k 
k 
k 
k 
N
m 
n 
W = 
 


=
k
k 
k 
cmh
W 
d
W 
d
ˆ 
ˆ 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 41 of 102 
2
2
2
2
/)
(
k
k
k
k
k
k
k
k
k
k
N
n
m
m
n
x
m
y
n
P
−
+
−
=
 
2
/)
(
/)
(
k
k
k
k
k
k
k
k
k
N
x
n
y
N
y
m
x
Q
−
+
−
=
 
Confidence intervals are readily available in SAS software (SAS Help Center: Common Risk Difference) 
Multiple Imputation 
• 
Multiple imputation will be applied to impute the missing MIS by treatment groups before the dichotomization 
of change from baseline in MIS at Week 24 to responder. Please see step 1 in Section 4.2.3 for details. The 
100 complete data sets will then be analyzed by CMH method detailed above, and subsequently combined to 
estimate the CMH adjusted difference in responder rates between linerixibat and placebo groups.  
Model Results Presentation 
• 
The CMH estimate of the difference in the proportion of responders between the two treatment groups, 
corresponding 95% confidence interval, and p-value will be displayed for each responder definition. 
Supplementary Analyses 
• 
The same analysis will be applied to the Non-bile acid binding resin ITT Population. The same model results 
display as the ITT population will be produced.  
• 
The empirical cumulative distribution function (eCDF) graph by treatment group of change from baseline in 
non-missing MIS at Week 24 will be provided. The observed number of observations will be used as the 
denominator. 
• 
Additionally, the empirical cumulative distribution function (eCDF) graph by treatment group of change from 
baseline in Imputed MIS at Week 24 will be provided. Multiple imputation will be applied to impute the missing 
MIS by treatment groups. Please see step 1 in Section 4.2.3 for details of the imputation model. 
4.3.2. 
Supportive Secondary Endpoint(s) 
For supportive secondary endpoints, all the intercurrent events will be treated with 
treatment policy strategy. 
• 
Change from Baseline in PBC-40 domain scores at Week 24 
Change from baseline in PBC-40 domain scores at Visits 4 – 9 in Part A will be analyzed 
using a MMRM. The comparison at week 24 (V9) by domain will then be estimated from 
the MMRM model. Please refer to Section 1.1 for estimand strategies. 
Endpoint / Variables 
• 
Change from Baseline in PBC-40 domain scores at Week 24 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑉𝑖𝑠𝑖𝑡+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑉𝑖𝑠𝑖𝑡+ 𝐵𝐿𝑃𝐵𝐶40 + 𝐵𝐿𝑃𝐵𝐶40 ∗𝑉𝑖𝑠𝑖𝑡+ 𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑
+ 𝐸𝑟𝑟𝑜𝑟 
o 
Response (Y): change from baseline in PBC-40 domain scores at Visits 4 – 9 of the study intervention 
during Part A. 
o 
Categorical: treatment group, visit, baseline concomitant therapy (3-level) 
o 
Continuous: baseline PBC-40 domain score 
o 
Interaction: treatment group*visit, baseline PBC-40 domain scores*visit 
o 
Repeated: visit 
• 
 Baseline is defined in Section 4.1.2 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 42 of 102 
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Model Results Presentation 
• 
The LS means and the corresponding 95% confidence intervals of change from baseline in PBC-40 at Week 
24 (V9) for linerixibat and placebo, as well as the LS mean, 95% CI, and p-value for the difference from 
placebo will be reported. 
• 
Change from baseline in PGI-S over 24 weeks  
Change from baseline in derived PGI-S at visits 4 - 9 will be analyzed using MMRM. 
The comparison averaged over the 6 visits (24 weeks) will be estimated from the 
MMRM. Please refer to Section 1.1 for estimand strategies.  
Endpoint / Variables 
• 
Change from Baseline in PGI-S over 24 weeks 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑉𝑖𝑠𝑖𝑡+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑉𝑖𝑠𝑖𝑡+ 𝐵𝐿𝑃𝐺𝐼−𝑆+ 𝐵𝐿𝑃𝐺𝐼−𝑆∗𝑉𝑖𝑠𝑖𝑡+
𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑+ 𝐸𝑟𝑟𝑜𝑟  
o 
Response (Y): change from baseline in PGI-S at Visits 4 – 9 of the study intervention during Part A. 
o 
Categorical: treatment group, visit, baseline concomitant itch therapy (3-level) 
o 
Continuous: baseline PGI-S 
o 
Interaction: treatment group*visit, baseline PGI-S*visit 
o 
Repeated: visit 
• 
Baseline is defined in Section 4.1.2 
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Model Results Presentation 
• 
The LS means and the corresponding 95% confidence intervals of change from baseline in PGI-S over 24 
weeks for linerixibat and placebo, as well as the LS mean, 95% CI, and p-value for the difference from 
placebo will be reported. 
• 
PGI-C over 24 weeks 
Derived PGI-C at Visits 4 – 9 will be analyzed using MMRM. The comparison averaged 
over the 6 visits (24 weeks) will be estimated from the MMRM. Please refer to Section 
1.1 for estimand strategies. 
Endpoint / Variables 
• 
PGI-C over 24 weeks 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑉𝑖𝑠𝑖𝑡+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑉𝑖𝑠𝑖𝑡+  𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑+ 𝐸𝑟𝑟𝑜𝑟  
o 
Response (Y): PGI-C at Visits 4 – 9 of the study intervention during Part A. 
o 
Categorical: treatment group, visit, baseline concomitant itch therapy (3-level) 
o 
Interaction: treatment group*visit 
o 
Repeated: visit 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 43 of 102 
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Model Results Presentation 
• 
The LS means and the corresponding 95% confidence intervals of PGI-C over 24 weeks for linerixibat and 
placebo, as well as the LS mean, 95% CI, and p-value for the difference from placebo will be reported. 
Supplementary analysis 
• 
The percentage of participants with improved PGI-C will be reported by visit. Improved PGI-C will be defined 
as those who reported minimally improved, moderately improved, or very much improved. The number and 
percentage of participants will be reported for linerixibat and placebo, as well as the percentage difference, 
95% CI, and p-value for the difference from placebo will be reported. 
• 
Change from baseline in ALP at Week 24 
Change from baseline in ALP at Visits 4 - 9 will be fitted by MMRM. The comparison at 
Visit 9 (week 24) will be estimated from the MMRM model. Please refer to Section 1.1 
for estimand strategies. 
Endpoint / Variables 
• 
Change from Baseline in ALP at Week 24 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑉𝑖𝑠𝑖𝑡+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑉𝑖𝑠𝑖𝑡+ 𝐵𝐿𝐴𝐿𝑃+ 𝐵𝐿𝐴𝐿𝑃∗𝑉𝑖𝑠𝑖𝑡
+ 𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑+ 𝐸𝑟𝑟𝑜𝑟 
o 
Response (Y): change from baseline in ALP at Visits 4 – 9 of the study intervention during part A. 
o 
Categorical: treatment group, visit, baseline concomitant itch therapy (3-level) 
o 
Continuous: baseline ALP 
o 
Interaction: treatment group*visit, baseline ALP*visit 
o 
Repeated: visit 
• 
Baseline is defined in Section 4.1.2 
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Model Results Presentation 
• 
The LS means and the corresponding 95% confidence intervals of change from baseline in ALP at Week 24 
for linerixibat and placebo, as well as the LS means, 95% CI, and p-value for the difference from placebo will 
be reported.   
Supplementary analysis 
• 
ALP and change from baseline ALP will be summarized descriptively by visit and treatment group for the 
participants with UDCA.  
• 
The same MMRM analysis will be applied to the participants in the ALP ≥1.67x ULN ITT Population. The LS 
means and the corresponding 95% confidence intervals of change from baseline in ALP at Week 24 for 
linerixibat and placebo will be reported. The LS mean, 95% CI, and p-value for the difference from placebo 
will be reported in the same table. In the event of small sample size and/or convergence issues, then only 
summary statistics will be reported. 
• 
Change from baseline in bilirubin at Week 24 
Change from baseline in bilirubin at Visits 4 – 9 will be fitted by MMRM. The 
comparison at visit 9 (week 24) will be estimated from the MMRM model. Please refer to 
Section 1.1 for estimand strategies. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 44 of 102 
Endpoint / Variables 
• 
Change from Baseline in bilirubin at Week 24 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑉𝑖𝑠𝑖𝑡+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑉𝑖𝑠𝑖𝑡+ 𝐵𝐿𝑏𝑖𝑙𝑖𝑟𝑢𝑏𝑖𝑛+ 𝐵𝐿𝑏𝑖𝑙𝑖𝑟𝑢𝑏𝑖𝑛∗𝑉𝑖𝑠𝑖𝑡
+ 𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑+ 𝐸𝑟𝑟𝑜𝑟 
o 
Response (Y): change from baseline in bilirubin at Visits 4 – 9 of the study intervention during Part A. 
o 
Categorical: treatment group, visit, baseline concomitant itch therapy (3-level) 
o 
Continuous: baseline bilirubin 
o 
Interaction: treatment group*visit, baseline bilirubin *visit 
o 
Repeated: visit 
• 
Baseline is defined in Section 4.1.2 
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Model Results Presentation 
• 
The LS means and the corresponding 95% confidence intervals of change from baseline in bilirubin at Week 
24 for linerixibat and placebo, as well as the LS mean, 95% CI, and p-value for the difference from placebo 
will be reported.   
Supplementary analysis 
• 
The same MMRM analysis will be applied to the participants in the ALP ≥1.67x ULN ITT Population. The LS 
means and the corresponding 95% confidence intervals of change from baseline in Bilirubin at Week 24 for 
linerixibat and placebo will be reported. The LS mean, 95% CI, and p-value for the difference from placebo 
will be reported in the same table. In the event of small sample size and/or convergence issues, then only 
summary statistics will be reported. 
4.4. 
Exploratory Endpoints Analyses 
4.4.1. 
Overview of Planned Analyses of Exploratory Endpoints 
The hypothetical estimand strategy will not be applied for the analyses of exploratory 
endpoints. All the intercurrent events will be treated with treatment policy strategy. The 
table below provides an overview of the planned analyses. The ITT population will be 
used for the analysis unless otherwise specified. The details of statistical analyses are 
provided in Section 4.4.2. 
Table 2 
Overview of planned analyses of exploratory endpoints 
Endpoints 
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Gastrointestinal symptoms (Part A and Part B) 
Change from baseline in 
GSRS over time 
 
 
 
Y 
 
 
 
 
 
 
Y 
Y 
 
 
Percentage of itch response days (Part A) 
≥2 point reduction  
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
≥3 point reduction  
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
≥4 point reduction  
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 45 of 102 
Endpoints 
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Improvement, maintenance, or return of itch (Part B) 
Change from baseline 
(Part A) in WIS at 8 
weeks 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
Y 
 
 
Change from baseline 
(Part B) in MIS over 8 
weeks 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
Improvement, maintenance or decline of quality of life (Part B) 
Change from baseline in 
PBC-40 domain scores 
at 8 weeks 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
Change from baseline in 
MSS over 8 weeks 
 
 
 
Y 
 
 
 
 
 
 
Y 
 
 
 
Change from baseline in 
PGI-S over 8 weeks 
 
 
 
Y 
 
 
 
 
 
 
Y 
 
 
 
PGI-C over 8 weeks 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Biomarkers (Part A) 
Change from baseline in 
biomarkers including 
serum C4, total serum 
bile acids, autotaxin, 
FGF-19, and IL-31 
 
 
 
Y[1] 
 
 
 
Y 
 
 
Y[1] 
Y 
 
 
Biomarkers (Part B) 
Change from baseline in 
biomarkers including 
serum C4, total serum 
bile acids, autotaxin, 
FGF-19, and IL-31 
 
 
 
Y[1] 
 
 
 
 
 
 
Y[1] 
Y 
 
 
Effect of BABR on linerixibat PD (Part A) 
Biomarkers including 
serum C4, total serum 
bile acids, autotaxin, 
FGF-19, IL-31 
 
 
 
Y[2] 
 
 
 
Y[2] 
 
 
Y[2] 
 
 
 
Effect of BABR on linerixibat PD (Part B) 
Biomarkers including 
serum C4, total serum 
bile acids, autotaxin, 
FGF-19, IL-31 
 
 
 
Y[2] 
 
 
 
 
 
 
Y[2] 
 
 
 
PK (Part A) 
PK concentration[3]  
 
 
 
Y[4,5] 
Y[4] 
 
 
 
 
 
 
 
 
 
Marker of liver fibrosis (Part A) 
Change from baseline in 
ELF at Week 24 
 
 
 
Y 
 
 
 
 
 
 
Y 
 
 
 
Change from baseline in 
Fibroscan at Week 24 
 
 
 
Y 
 
 
 
 
 
 
Y 
 
 
 
Marker of liver fibrosis (Part B) 
Change from baseline in 
ELF at Week 8 
 
 
 
Y 
 
 
 
 
 
 
Y 
 
 
 
Symptoms and quality of life (Part A) 
Change from baseline in 
ESS over 24 weeks 
 
 
 
Y 
 
 
 
Y 
 
 
Y 
 
 
 
Change from baseline in 
BDI-II at 24 weeks 
 
 
 
Y 
 
 
 
Y 
 
 
Y 
 
 
 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 46 of 102 
Endpoints 
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Change from baseline in 
MFS over 24 weeks 
 
 
 
Y 
 
 
Y 
Y 
 
 
Y 
Y 
 
 
Symptoms and quality of life (Part B) 
Change from baseline in 
ESS over 8 weeks 
 
 
 
Y 
 
 
 
 
 
 
Y 
 
 
 
Change from baseline in 
BDI-II at 8 weeks 
 
 
 
Y 
 
 
 
 
 
 
Y 
 
 
 
Change from baseline in 
MFS over 8 weeks 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
Symptoms and quality of life (Part A and Part B) 
Change from baseline in 
WIS 
 
 
 
 
 
 
Y 
 
 
 
 
Y 
 
 
Change from baseline in 
WSS  
 
 
 
 
 
 
Y 
 
 
 
 
Y 
 
 
Change from baseline in 
WFS 
 
 
 
 
 
 
Y 
 
 
 
 
Y 
 
 
NOTES : 
o 
T = Table, F = Figures, L = Listings, Y = Yes display generated 
o 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
o 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
o 
Individual = Represents FL related to any displays of individual participant observed raw or derived data. 
1. 
Descriptive summary tables will also be provided by the following covariates: Baseline cholestyramine use; 
Baseline concomitant UDCA, and Baseline concomitant cholestatic pruritus therapy.  
2. 
The descriptive analysis of these endpoints will be by baseline BABR. See the baseline BABR definition in Section 
4.6.1.  
3. 
Population PK analysis will be described in a separate report.  
4. 
PK population will be used in the analysis. 
5. 
Besides summarizing PK concentration by visit, PK concentration will also be summarized by baseline BABR (see 
Section 4.6.1 for details) and visit as well as presence or absence of cirrhosis (as collected on PBC history CRF) 
and visit, and baseline CKD category and visit (see Section 6.3.6.2 for details) in separate tables. 
4.4.2. 
Statistical Analyses of Exploratory Endpoints 
• 
Change from baseline in concentration of exploratory biomarkers  
The change from baseline in exploratory biomarkers at visits 4 – 9 will be fitted to 
MMRM. The comparison of effects averaged over the visits will be estimated from the 
model.   
Endpoint / Variables 
• 
Change from baseline in concentrations of exploratory biomarkers including: 
o 
Serum C4 
o 
Total serum bile acids 
o 
Autotaxin  
o 
Fibroblast Growth Factor-19 (FGF-19) 
o 
Interleukin 31 (IL-31) 
Data Transformation 
• 
The values of biomarkers will be natural log transformed to obtain log-transformed values at baseline, visits 4 
– 9 of the study intervention during Part A.  
• 
The estimated change from baseline in log-transformed value will be transformed back to obtain geometric 
ratio to baseline. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 47 of 102 
• 
The estimated difference vs placebo in log-transformed value will be transformed back to obtain geometric 
ratio to placebo. 
• 
The % coefficient of variation of estimate will be calculated as  
%𝐶𝑉𝑤= 100 ∗√exp(𝑆𝐸2) −1 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑉𝑖𝑠𝑖𝑡+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑉𝑖𝑠𝑖𝑡+ 𝐵𝐿𝐵𝑖𝑜𝑚𝑎𝑟𝑘𝑒𝑟+ 𝐵𝐿𝐵𝑖𝑜𝑚𝑎𝑟𝑘𝑒𝑟∗𝑉𝑖𝑠𝑖𝑡
+ 𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑+ 𝐸𝑟𝑟𝑜𝑟 
o 
Response (Y): change from baseline in log transformed biomarker data at visits 4 - 9 of the study 
intervention during Part A. 
o 
Categorical: treatment group, visit, baseline concomitant itch therapy (3-level) 
o 
Continuous: log transformed biomarker baseline value 
o 
Interaction: treatment group*visit, log transformed baseline biomarker*visit 
o 
Repeated: visit  
• 
Baseline is defined in Section 4.1.2 
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Model Results Presentation 
• 
The back transformed LS means and the corresponding 95% confidence intervals of geometric ratio to 
baseline in biomarkers over 24 weeks for linerixibat and placebo will be reported. The back transformed LS 
mean and 95% CI for the geometric ratio to placebo will be reported in the same table.  
• 
The back transformed LS means and 95% confidence intervals for geometric ratio to baseline in biomarkers 
at each visit (Weeks 4, 8, 12, 16, 20, and 24) will be reported for linerixibat and placebo, as well as the back 
transformed LS means and corresponding 95% CIs for the geometric ratio to placebo. A figure will be 
presented for the geometric ratio to placebo at each visit. 
Subgroup/covariate Analyses 
• 
The MMRM analysis will be repeated by including the covariates listed below and its interaction with treatment 
group: 
o 
Baseline cholestyramine use 
o 
Baseline concomitant UDCA 
o 
Baseline BABR 
Please refer to Section 4.6.1 on the details of covariates. When covariate baseline cholestyramine or baseline 
BABR use is included, baseline concomitant itch therapy will not be included in the model. 
• 
The back transformed geometric ratio to baseline and its corresponding 95% CI will be reported for each 
treatment group, as well as the back transformed geometric ratio to placebo and its 95% CI. The p-values for 
treatment group, covariate, and interaction between treatment group and covariate will be reported.  
• 
Change from baseline in ESS over 24 weeks 
Change from baseline in ESS at visits 6 and 9 will be fitted by MMRM. The comparison 
of effects averaged over visits 6 and 9 will be estimated from the MMRM model. 
Endpoint / Variables 
• 
Change from Baseline in ESS over 24 weeks 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑉𝑖𝑠𝑖𝑡+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑉𝑖𝑠𝑖𝑡+ 𝐵𝐿𝐸𝑆𝑆+ 𝐵𝐿𝐸𝑆𝑆∗𝑉𝑖𝑠𝑖𝑡
+ 𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑+ 𝐸𝑟𝑟𝑜𝑟 
o 
Response (Y): change from baseline in ESS at visits 6 and 9 of the study intervention during Part A. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 48 of 102 
o 
Categorical: treatment group, visit, baseline concomitant itch therapy (3-level) 
o 
Continuous: baseline ESS 
o 
Interaction: treatment group*visit, baseline ESS *visit 
o 
Repeated: visit 
• 
Baseline is defined in Section 4.1.2 
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Model Results Presentation 
• 
The LS means and the corresponding 95% confidence intervals of change from baseline in ESS over 24 
weeks for linerixibat and placebo, as well as the LS mean and 95% CI for the difference from placebo will be 
reported.   
• 
Change from baseline in BDI-II at 24 weeks 
Change from baseline in BDI-II at Visits 6 and 9 will be fitted by MMRM. The 
comparison at Visit 9 (week 24) will be estimated from the MMRM model. 
Endpoint / Variables 
• 
Change from Baseline in BDI-II at 24 weeks 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑉𝑖𝑠𝑖𝑡+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑉𝑖𝑠𝑖𝑡+ 𝐵𝐿𝐵𝐷𝐼−𝐼𝐼+ 𝐵𝐿𝐵𝐷𝐼−𝐼𝐼∗𝑉𝑖𝑠𝑖𝑡
+ 𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑+ 𝐸𝑟𝑟𝑜𝑟 
o 
Response (Y): change from baseline in BDI-II at visits 6 and 9 of the study intervention during Part A. 
o 
Categorical: treatment group, visit, baseline concomitant itch therapy (3-level) 
o 
Continuous: baseline BDI-II 
o 
Interaction: treatment group*visit, baseline BDI-II *visit 
o 
Repeated: visit 
• 
Baseline is defined in Section 4.1.2 
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Model Results Presentation 
• 
The LS means and the corresponding 95% confidence intervals of change from baseline in BDI-II at Week 24 
for linerixibat and placebo, as well as the LS mean and 95% CI for the difference from placebo will be 
reported.   
• 
Change from baseline in MFS as measured by 0 – 10 NRS over 24 weeks 
Change from baseline in MFS at visits 4 - 9 will be fitted by MMRM. The comparison of 
effects averaged over the visits will be estimated from the MMRM model. 
Endpoint / Variables 
• 
Change from Baseline in MFS over 24 weeks 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 49 of 102 
Model Specification 
• 
Mixed Models Repeated Measures (MMRM) analysis. 
• 
Terms in the model: 
𝑌=  𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 𝑉𝑖𝑠𝑖𝑡+ 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡∗𝑉𝑖𝑠𝑖𝑡+ 𝐵𝐿𝑀𝐹𝑆+ 𝐵𝐿𝑀𝐹𝑆∗𝑉𝑖𝑠𝑖𝑡
+ 𝐵𝐿𝐶𝑜𝑛𝑐𝑜𝑚𝑖𝑡𝑎𝑛𝑡 𝑖𝑡𝑐ℎ 𝑚𝑒𝑑+ 𝐸𝑟𝑟𝑜𝑟 
o 
Response (Y): change from baseline in MFS at visits 4 - 9 of the study intervention during Part A. 
o 
Categorical: treatment group, visit, baseline concomitant itch therapy (3-level) 
o 
Continuous: baseline MFS 
o 
Interaction: treatment group*visit, baseline MFS *visit 
o 
Repeated: visit 
• 
Baseline is defined in Section 4.1.2 
Model Checking & Diagnostics 
• 
See Section 4.1.1 
Model Results Presentation 
• 
The LS means and the corresponding 95% confidence intervals of change from baseline in MFS over 24 
weeks for linerixibat and placebo, as well as the LS mean and 95% CI for the difference from placebo will be 
reported.   
4.5. 
Safety Analyses 
The safety analyses will be based on the Safety Analysis Set, unless otherwise specified. 
The summary of data during study intervention will be presented by Part A and Part B 
separately, unless otherwise specified. For all the adverse events analyses where 
cumulative incidence proportions are summarized, the exposure adjusted incidence rates 
will also be provided.  
4.5.1. 
Extent of Exposure 
The number of days exposure to study drug during the study intervention period and the 
cumulative dose will be summarized.  
The formulas of calculation and the missing data rules are detailed in Section 6.3.8.1.  
4.5.2. 
Adverse Events 
Adverse event analyses, including adverse events (AEs), serious adverse events (SAEs) 
and adverse events of special interest (AESIs), will be based on GSK core data 
standards. Adverse events will be mapped to system organ classes (SOC) and preferred 
terms (PT) using the standard Medical Dictionary for Regulatory Affairs (MedDRA 
dictionary). The most recent MedDRA dictionary at the time of the primary analysis will 
be used. All AE and SAE summaries will be by SOC and PT unless otherwise 
specified. Liver related AEs will also be summarized by standardized MedDRA Queries 
(SMQs) and PT.  
An adverse event (AE) is considered study intervention emergent if the AE onset date is 
on or after study intervention start date unless otherwise specified (see Section 6.3.2). All 
AE summaries will be based on study intervention emergent events unless otherwise 
specified. AEs and SAEs will be summarized by Parts A and B separately. If an AE/SAE 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 50 of 102 
starts in Part A and lasts to Part B, it will be counted only in Part A. SAE summaries will 
be based on all SAEs reported regardless of whether they meet the definition of study 
intervention emergent or not.   
For all AE tables, counting will be by participant and not by event. In other words, if a 
participant has more than one event with the same preferred term, the participant will be 
counted once for that preferred term in the treatment group. If a participant has more than 
one event in the same system organ class, the participant will be counted once for that 
system organ class in the treatment group. All AE and SAE summaries will be exposure 
adjusted unless otherwise specified. 
AEs that are study intervention emergent will be summarized including:  
• 
counts and percentages of participants with any AE, 
• 
common AEs defined as AEs with ≥ 5% incidence in any treatment group by PT,  
• 
AEs by maximum severity or grade (not exposure adjusted),  
• 
AEs related to study treatment,  
• 
AEs leading to permanent discontinuation of study intervention,  
• 
AEs leading to study withdrawal 
All AEs at Part A will also be summarized by operating model.  
Common AEs defined as AEs with ≥ 5% incidence in any treatment group, will also be 
reported by PT for subgroups sex, age, race, and ethnicity, as defined in Section 4.6.1. 
Under the supplementary safety estimand strategy, all AEs, will also be reported 
including AE’s that occur after permanent treatment discontinuation. 
SAEs during on-treatment periods will be summarized including: 
• 
counts and percentages of participants with any SAE,  
• 
SAE related to study treatment,  
• 
fatal SAEs,  
• 
fatal SAEs related to study treatment, 
• 
number of participants and occurrences of SAE (not exposure adjusted) 
Under the supplementary safety estimand strategy, SAEs will also be reported including 
SAE’s that occur after permanent treatment discontinuation. 
A study treatment-related AE is defined as an AE for which the investigator classifies the 
possible relationship to study treatment as “Yes”. A worst-case scenario approach will be 
taken to handle missing relatedness data, i.e. the summary table will include events with 
the relationship to study treatment as ‘Yes’ or missing.   
Complete participant listings of all AEs will be provided. For each AE the following will 
be specified: treatment group, start and stop dates, time since study treatment 1st and last 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 51 of 102 
dose, severity grade, MedDRA system organ class and preferred term, duration, 
relationship to study treatment, action taken, outcome of the adverse event and 
seriousness. The Common Terminology Criteria for Adverse Events (CTCAE), currently 
in version 5, will be used to quantitate the severity of diarrhea as well as the standard AE 
intensity grading defined in protocol (TMF-16740250) Section 10.3.4. The severity 
evaluated by both criteria will be provided.   
4.5.2.1. 
Adverse Events of Special Interest 
The following will be considered adverse events of special interest (AESI) for the 
purpose of analyses:    
• 
Diarrhea reported as an AE  
o Definition: all study intervention emergent AEs with High Level Term (HLT) of 
“Diarrhoea (excl infective)” that have been marked as AESI by investigators 
• 
Elevated ALT reported as a Liver Event (meets Liver Monitoring or Stopping 
criteria) 
o Definition: study intervention emergent AEs with System Organ Class (SOC) of 
“Hepatobiliary disorders” or “Investigations” that have been marked as AESI by 
investigators 
The summary of event characteristics will be provided for each AESI respectively, 
including: 
• 
count and percentage of participants with any event,  
• 
number of events,  
• 
count and percentage of participants with any event that is serious,  
• 
count and percentage of participants with any event that is related to study treatment,  
• 
count and percentage of participants by number of occurrences (one, two, three or 
more), maximum severity or grade, maximum severity or grade for events related to 
study intervention, outcomes and the action taken for the event, 
• 
count and percentage of events requiring antidiarrheal therapies and the number of 
cases resolved by the antidiarrheal therapies.  
Under the supplementary safety estimand strategy, AESI will also be reported including 
AESI that occur after permanent treatment discontinuation. 
The worst-case approach will be applied at a participant level for the maximum 
severity, i.e. a participant will only be counted once as the worst case from all the events 
experienced by the participant. For action taken to an event, a participant will be counted 
once under each action, e.g. if a participant has an event leading to both study 
intervention discontinuation and study withdrawal, the participants will be counted once 
under both actions.  The maximum severity of diarrhea will be evaluated by 
both CTCAE and standard AE intensity grade and reported separately.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 52 of 102 
A Kaplan-Meier plot of time to first event of diarrhea reported as an AESI will be 
provided for Part B (a Kaplan-Meier plot of Part A data will be reported as part of the 
Integrated Safety Summary (ISS) and is described in the Project Data Analysis Plan for 
the ISS).  
4.5.2.2. 
COVID-19 Assessment and COVID-19 AEs 
The overall incidence of AEs and SAEs of COVID-19, COVID-19 AEs leading to study 
intervention discontinuation, COVID-19 AEs leading to study intervention interruption or 
delay will be summarized. The incidence of these events at individual PT level can be 
obtained from the standard AE/SAE summaries. 
4.5.3. 
Additional Safety Assessments (if applicable) 
4.5.3.1. 
Laboratory Data 
Summaries of worst-case changes from baseline with respect to potential clinical 
importance (PCI) range will be generated for haematology, coagulation, fat soluble 
vitamins, and chemistry (including liver function tests) laboratory tests, where a PCI 
range is specified in Section 6.3.1. Decreases to low, changes to within range or no 
changes from baseline, and increases to high will be summarized for the worst-case post-
baseline. If a participant has a decrease to low and an increase to high during the same 
time interval, then the participant is counted in both the “to Low” categories and the “to 
High” categories.    
The observed and change from baseline of haematology, coagulation, fat soluble 
vitamins, and chemistry laboratory tests will be produced by visit and by treatment group. 
Liver function laboratory tests will be included with chemistry lab tests. 
For haematology, coagulation, fat soluble vitamins, and chemistry (including liver 
function tests) laboratory tests, observed values will be compared to normal ranges and 
classified as “Low” (where applicable), “Normal”, or “High (if applicable). For each liver 
function test, 4x4 contingency tables (shift tables) will be displayed by treatment group 
and by visit that summarize the counts of participants who were classified as “Low”, 
“Normal”, “High” at Baseline vs. “Low”, “Normal”, “High” at Post-baseline time points, 
as well as the total. Worst-case post-baseline will also be reported. Summary and listing 
of abnormal laboratory results will be provided.   
An e-DISH plot of maximum post baseline total bilirubin versus maximum post baseline 
ALT will be created for each intervention period separately (Part A and Part 
B).  Similarly, e-DISH plots of maximum post baseline total bilirubin versus maximum 
post baseline AST, and maximum post baseline total bilirubin versus maximum post 
baseline ALP, will also be created for each study period.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 53 of 102 
For each of the respective plots, the following datapoints will be flagged: 
• 
Maximum postbaseline total bilirubin equal to or exceeding 2 x ULN within 30 days 
after a maximum postbaseline ALT equal to or exceeding 3 x ULN 
• 
Maximum postbaseline total bilirubin equal to or exceeding 2 x ULN within 30 days 
after a maximum postbaseline AST equal to or exceeding 3 x ULN 
• 
Maximum postbaseline total bilirubin equal to or exceeding 2 x ULN within 30 days 
after postbaseline ALP became equal to or exceeding 2 x ULN 
Plots will be generated using central data only and repeated using central plus local lab 
data. 
The count and percentage of participants who have met the liver increased monitoring 
criteria and participants who have met the liver stopping criteria as defined in the 
protocol will be summarized for each treatment group.  
4.5.3.2. 
Vital Signs 
Change from baseline in vital signs, including temperature, pulse rate 
(bpm), systolic blood pressure(mmHg) and diastolic blood pressure (mmHg), will be 
summarized by visit and by treatment group. Summary of worst-case change from 
baseline with respect to potential clinical importance range will be produced.  
4.5.3.3. 
ECG 
The QTc data analysis will use the collected values based on Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. Change from 
baseline in ECG will be summarized by visit and by treatment group.  
The QTc values based on Fridericia formula or Bazett’s formula will be rounded to the 
nearest integer and the values will be categorized into the following CTCAE grade and 
ranges: Grade 0 (<450 msec), Grade 1 (450-480 msec), Grade 2 (481-500 msec), and 
Grade 3 (≥501 msec). Summaries of grade increase will be provided. These summaries 
will display the number and percentage of participants with any grade increase, increase 
to grade 2 and increase to grade 3 for the worst-case post-baseline observation only. 
Missing baseline grade will be assumed as grade 0. 
The changes in QTc values will be categorized into the clinical concern ranges which are 
specific to changes in QTc: ≤30, 31-60, and >60 msec. A summary of change in QTc 
value will display the number and percentage of participants with a change within each 
range for the worst-case post-baseline observation only. Participants with missing 
baseline values will be excluded from this summary. 
4.5.3.4. 
Fecal Occult Blood Test (FOBT) 
Summary of count and percentage of participants with positive and negative FOBT at V3 
and V9 and a shift table will be reported.    


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 54 of 102 
4.6. 
Other Analyses 
4.6.1. 
Covariate/Subgroup analyses 
The list of covariates and other strata may be used in the statistical analyses of primary 
endpoint are shown below. Additional covariates and other strata of clinical interest may 
also be considered. 
Table 3 
List of covariate/subgroup 
Covariate/Subgroup 
Details 
Baseline cholestyramine use 
Previous cholestyramine use (no concomitant use at 
baseline) 
Baseline concomitant cholestyramine  
Baseline cholestyramine naive 
Region 
North America (US and Canada) 
Asia (China and Japan) 
Europe (Belgium, Bulgaria, Czechia, France, Germany, 
Greece, Italy, Israel, Poland, Spain, Switzerland, United 
Kingdom) 
Other Regions (Argentina, Brazil, Mexico, Russian 
Federation)  
Baseline ALP* 
Continuous 
Baseline ALP* 
(Categorical) 
≤ 1xULN 
> 1xULN to < 1.67xULN 
≥ 1.67xULN 
Baseline total bilirubin* 
Continuous 
Baseline total bilirubin (Categorical)* 
≤ 1xULN  
> 1xULN 
Baseline concomitant UDCA 
Yes 
No 
Baseline total serum bile acids 
Continuous 
Baseline itch severity group* 
≥4 - <7 
 
 ‘Moderate’ 
≥7 - ≤10           ‘Severe’ 
Baseline MIS* 
Continuous 
Baseline concomitant cholestatic pruritus therapy 
(Yes vs. No) 
Yes 
No 
Note: if a participant used any of the listed concomitant 
background itch therapy then yes, otherwise it is no. 
Baseline concomitant cholestatic pruritus therapy 
(3-level) 
Regimen contains BABR, including cholestyramine, 
colesevalem, colestimide and colestipol 
Regimen that does not contain BABR, including 
antihistamines#, bezafibrate, fenofibrate, rifampicin, 
naltrexone, naloxone, nalfurafine, gabapentin or sertraline 
No defined anti-cholestatic pruritus treatment. 
#Note: When antihistamines are used acutely for indications 
other than itch (e.g. for treatment of acute allergic reactions), 
it is not considered as an anti-cholestatic pruritus treatment, 
therefore, it is not considered as a regimen that doesn’t 
contain BABR.  
Please refer to protocol Section 6.9.1 for the list of anti-
cholestatic pruritus treatment. 
Baseline concomitant Fibrates (Yes vs. No) 
Yes 
No 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 55 of 102 
Covariate/Subgroup 
Details 
Note: if a participant used any Fibrates then yes, otherwise it 
is no. 
Baseline concomitant BABR (Yes vs. No) 
Yes 
No 
Note: if a participant used any of the BABR then yes, 
otherwise it is no. 
Sex 
Female 
Male 
Age Category (years) 
18-49 
50-64 
≥65 
Race  
Asian 
White  
Other 
Ethnicity 
Not Hispanic or Latino and Other 
Hispanic or Latino 
*Covariates will be included in the summary of baseline covariates only and will not be included in the subgroup 
analysis detailed in Section 4.2.2.  
4.6.2. 
Subpopulation Analyses 
4.6.2.1. 
Analysis Sets for Subpopulation Analyses 
The following analysis sets are defined for subpopulation analyses to support regional 
regulatory submission. Additional analysis sets may be considered if requested by 
regulators. 
Analysis 
Set 
Definition / Criteria 
Analyses 
Evaluated 
Screening 
China 
• 
This is a subset of the Screening analysis set 
enrolled at sites in China Mainland 
• 
Study 
Population 
Enrolled 
China 
• 
This is a subset of the Enrolled analysis set 
for participants enrolled at sites in China 
Mainland 
• 
Study 
Population 
ITT China 
• 
This is a subset of the ITT Population 
enrolled at sites in China Mainland 
• 
Efficacy 
Safety 
China 
• 
This is a subset of the Safety analysis set 
enrolled at sites in China Mainland 
• 
Safety 
Non-BABR 
ITT China 
• 
This is a subset of the Non-BABR ITT 
Population enrolled at sites in China 
Mainland 
• 
Efficacy 
PK China 
• 
This is a subset of the PK analysis set 
enrolled at sites in China Mainland 
• 
PK 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 56 of 102 
Analysis 
Set 
Definition / Criteria 
Analyses 
Evaluated 
Screening 
Japan 
• 
This is a subset of the Screening analysis set 
enrolled at sites in Japan whose race is 
Japanese 
• 
Study 
Population 
Enrolled 
Japan 
• 
This is a subset of the Enrolled analysis set 
for participants enrolled at sites in Japan 
whose race is Japanese 
• 
Study 
Population 
ITT Japan 
• 
This is a subset of the ITT Population 
enrolled at sites in Japan whose race is 
Japanese. 
• 
Efficacy 
Safety 
Japan 
• 
This is a subset of the Safety analysis set 
enrolled at sites in Japan whose race is 
Japanese 
• 
Safety 
PK Japan 
• 
This is a subset of the PK analysis set 
enrolled at sites in Japan whose race is 
Japanese 
• 
PK 
Screening 
East Asia 
• 
This is a subset of the Screening analysis set 
who are of East Asia subpopulation*  
• 
Study 
Population 
Enrolled 
East Asia 
• 
This is a subset of the Enrolled analysis set 
who are of East Asia subpopulation*  
• 
Study 
Population 
ITT East 
Asia 
• 
This is a subset of the ITT Population who are 
of East Asia subpopulation*  
• 
Efficacy 
Safety East 
Asia 
• 
This is a subset of the Safety analysis set who 
are of East Asia subpopulation*  
• 
Safety 
Non-BABR 
ITT East 
Asia 
• 
This is a subset of the Non-BABR ITT 
Population who are of East Asia 
subpopulation* 
• 
Efficacy 
PK East 
Asia 
• 
This is a subset of the PK analysis set who are 
of East Asia subpopulation*  
• 
PK 
* East Asia subpopulation: participants of a relevant Asian heritage (Asian – Japanese 
Heritage, Asian – East Asian Heritage) enrolled at sites in Japan, China mainland, Hong 
Kong, Taiwan, Macau, South Korea. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 57 of 102 
4.6.2.2. 
China Subpopulation Analyses 
The analyses of China subgroup are based on ITT China, Safety China and PK China 
analysis sets. The following endpoints will be evaluated: 
 
Endpoints 
Primary 
• 
Change from Baseline in Monthly Itch Scores over 24 weeks using a 
0-10 numerical rating scale (NRS) 
Secondary 
• 
Change from baseline in Weekly Itch score at Week 2 
• 
Change from Baseline in Monthly Sleep Score as measured by 0-10 
NRS over 24 weeks 
• 
Responder defined as achieving a ≥2-point reduction from Baseline 
in the Monthly Itch score at Week 24.  
• 
Responder defined as achieving a ≥3-point reduction from Baseline 
in the Monthly Itch score at Week 24.  
• 
Responder defined as achieving a ≥4-point reduction from Baseline 
in the Monthly Itch score at Week 24.  
• 
Change from Baseline in PBC-40 domain scores at Week 24 
Safety 
• 
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
• 
Clinical laboratory evaluation  
Exploratory • 
Change from Baseline in concentrations of exploratory biomarkers 
including: 
o Serum C4 
o Total serum bile acids 
o Autotaxin  
o Fibroblast Growth Factor-19 (FGF-19)  
• 
PK 
The analyses of these endpoints will be conditional on the primary endpoint results for all 
participants. If the primary endpoint for all participants is not significant (p > 0.05), the 
China subgroup analyses may not be produced.  
For responder analysis, if the sample size per stratum permits, CMH estimation will be 
applied. If the number of participants per stratum is small, an unadjusted estimation will 
be used. For primary and the other secondary endpoints, if data permits, the same 
MMRM as the main analytic approach will be applied to the China subpopulation using 
the same covariates. When there is statistical model involved, LS means and 95% CI will 
be reported, whereas p-value will not be provided. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 58 of 102 
4.6.2.3. 
Japan Subpopulation Analyses 
The analyses of Japan subgroup are based on ITT Japan, Safety Japan and PK Japan 
analysis sets. The following endpoints will be evaluated: 
 
Endpoints 
Primary 
• 
Change from Baseline in Monthly Itch Scores over 24 weeks using a 
0-10 numerical rating scale (NRS) 
Secondary 
• 
Change from baseline in Weekly Itch score at Week 2 
• 
Change from Baseline in Monthly Sleep Score as measured by 0-10 
NRS over 24 weeks 
• 
Responder defined as achieving a ≥2-point reduction from Baseline 
in the Monthly Itch score at Week 24.  
• 
Responder defined as achieving a ≥3-point reduction from Baseline 
in the Monthly Itch score at Week 24.  
• 
Responder defined as achieving a ≥4-point reduction from Baseline 
in the Monthly Itch score at Week 24.  
• 
Change from baseline in Patient's Global Impression of Severity 
(PGI-S) over 24 weeks 
• 
PGI-C over 24 weeks 
• 
Change from baseline in ALP at Week 24 
• 
Change from baseline in bilirubin at Week 24 
Safety 
• 
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
• 
Clinical laboratory evaluation (including liver chemistry panel and 
fasting lipids) 
Exploratory • 
Change from Baseline in concentrations of exploratory biomarkers 
including: 
o 
Serum C4 
o 
Total serum bile acids 
o 
Autotaxin  
o 
Fibroblast Growth Factor-19 (FGF-19)  
o 
Interleukin 31 (IL-31)   
• 
PK 
The analyses of these endpoints will be conditional on the primary endpoint for all 
participants. If the primary endpoint for all participants is not significant (p>0.05), the 
Japan subgroup analyses may not be produced.  
For responder analysis, if the sample size per stratum permits, CMH estimation will be 
applied. If the number of participants per stratum is small, an unadjusted estimation will 
be used. For primary and the other secondary endpoints, if data permits, the same 
MMRM as the main analytic approach will be applied to the Japan subpopulation using 
the same covariates. When there is a statistical model involved, LS means and 95% CI 
will be reported, whereas p-value will not be provided. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 59 of 102 
4.6.2.4. 
East Asia Subpopulation Analyses 
The analyses of East Asia subgroup are based on ITT East Asia, Safety East Asia and PK 
East Asia analysis sets. The following endpoints will be evaluated: 
The analyses of these endpoints will be conditional on the results of primary endpoint for 
all participants. If the primary endpoint for all participant is not significant (p > 0.05), the 
East Asia subgroup analyses may not be produced.  
For responder analysis, if the sample size per stratum permits, CMH estimation will be 
applied. If the number of participants per stratum is small, an unadjusted estimation will 
be used. For primary and the other secondary endpoints, if data permits, the same 
MMRM as the main analytic approach will be applied to the East Asia subpopulation 
using the same covariates. When there is statistical model involved, LS means and 95% 
CI will be reported, whereas p-value will not be provided. 
4.6.3. 
Operating model analyses 
There will be 3 operating models in this study: 
• 
Metasite model by Metasite (portion of US participants, currently none planned 
outside US) 
• 
Flexible model by brick & mortar site (global) 
• 
Brick & mortar model by brick & mortar site (global) 
The following definitions will be used to categorise participants by operating models: 
 
Endpoints 
Primary 
• 
Change from Baseline in Monthly Itch Scores over 24 weeks using a 
0-10 numerical rating scale (NRS) 
Secondary 
• 
Change from baseline in Weekly Itch score at Week 2  
• 
Change from Baseline in Monthly Sleep Score as measured by 0-10 
NRS over 24 weeks 
• 
Responder defined as achieving a ≥2-point reduction from Baseline 
in the Monthly Itch score at Week 24.  
• 
Responder defined as achieving a ≥3-point reduction from Baseline 
in the Monthly Itch score at Week 24.  
• 
Responder defined as achieving a ≥4-point reduction from Baseline 
in the Monthly Itch score at Week 24.  
• 
Change from Baseline in PBC-40 domain scores at Week 24 
Safety 
• 
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
• 
Clinical laboratory evaluation  
Exploratory • 
PK 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 60 of 102 
• 
Metasite model is defined as having all visits remotely for participants at Metasite. 
• 
Flexible model is defined as having at least one remote visit during the study 
intervention period of Part A for participants at brick & mortar sites.  
• 
Brick and mortar model is defined as having all visits onsite during the study 
intervention period of Part A for participants at brick & mortar sites. 
Visits conducted remotely will be captured via the eCRF at each visit using the question 
“visit conducted remotely” (Yes/No). This will be used to define the operating model for 
each participant as described above.  
The following summaries will be reported for Part A: 
• 
Participant disposition by site operating model (in addition to overall) 
• 
Important protocol deviations by site operating model (in addition to overall) 
• 
Adverse events by site operating model (in addition to overall) 
To assess the impact of the three operating models (Metasite vs Flexible vs Brick and 
Mortar) on the primary endpoint, the following MMRM analysis will be applied: 
• 
Response: change from baseline in MIS at Week 4, 8, 12, 16, 20, and 24 of the study 
intervention during Part A. 
• 
Categorical variables: treatment group, visit (Weeks 4, 8, 12, 16, 20, and 24), 
baseline concomitant therapy, country/region (US or RoW), operating model 
(Metasite, Flexible, or Brick and Mortar) 
• 
Continuous variable: baseline MIS 
• 
Interaction terms: treatment group*visit, treatment group*country/region, treatment 
group*operating model, baseline MIS*visit,  
• 
Repeated: visit 
In addition to the p-values of operating model and the interaction between treatment and 
operating model, the following estimates will be reported: 
• 
LS means and the corresponding 95% CI of change from baseline on MIS over 24 
weeks for each treatment group and between treatment group comparisons for 
Metasite vs Flexible vs Brick and Mortar operating models. 
• 
The same MMRM analysis will be applied to the participants in US region only 
(country/region terms will therefore be removed from the model). LS means of 
change from baseline over 24 weeks for each treatment group and between treatment 
group comparisons for Metasite vs Flexible vs Brick and Mortar will be reported, 
based on US region only.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 61 of 102 
4.6.4. 
Shrinkage Analysis 
Bayesian hierarchical modelling will be used to estimate treatment effect estimates for 
the subgroups in Table 3 of Section 4.6.1, as mentioned in Section 4.2.2. 
The primary endpoint in each subgroup-level will first be analyzed using the same 
method as per Section 4.2.2. For each subgrouping variable, each subgroup-level specific 
least square mean treatment difference estimates and their corresponding standard error 
will then be included in a Bayesian hierarchical model to obtain shrinkage estimates of 
the subgroup-specific treatment effects.  
The subgroup-specific treatment effects, 𝜇𝑗 (𝑗= 1, … , 𝐽 where 𝐽 is the number of 
subgroups for a particular subgrouping variable) will be assumed to be normally 
distributed as 𝜇𝑗∼𝑁(𝜇, 𝜏2) where 𝜇 is the overall treatment effect and 𝜏2 is the between-
subgroup variance. The following non-informative prior for 𝜇 and weakly-informative 
prior for 𝜏 will be used in the model:  
a. 
𝜇 ∼ U[-16, 16] 
b. 𝜏∼half-𝑁(𝑆𝐷=1) 
The selected prior for 𝜏 covers a very small to very large between subgroup heterogeneity 
given the assumed SD for the primary endpoint of 2.07 [Wang, 2024]. 
Models will be fitted using a Markov chain Monte Carlo (MCMC) algorithm with at least 
50,000 iterations, a thin of at least 5 and a burn-in of at least 1000. The posterior mean 
differences (𝜇𝑗) with 95% credible interval (CrI) will be presented by subgroup in a forest 
plot alongside the initial estimates. A posterior summary of 𝜏 will also be presented 
(median and CrI). 
4.7. 
Interim Analyses 
An interim analysis will be performed after approximately 100 participants reach 24 
weeks of treatment or discontinue early. The interim analysis will be evaluated by an 
Independent Monitoring Committee (IDMC) and conducted such that the ongoing study 
integrity is maintained. Only the independent statistical support group responsible for 
providing the interim analysis results to the IDMC will be unblinded to the individual 
treatment group assignments (current version: GlaxoSmithKline Document Number 
TMF-16125967). Individual and detailed interim analysis results will not be shared with 
investigators, participants, or the study team who are involved in the conduct of the study 
before the final database lock. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 62 of 102 
4.7.1. 
Interim Analysis Set 
The analysis sets used in the interim analysis are defined as below: 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
ITT Interim 
• 
All randomized participants through the data 
cut off of interim analysis. Participants will 
be classified according to the treatment as 
randomized.  
• 
Study 
Population 
• 
Efficacy 
ITT Interim 
Primary 
• 
The first approximately 100 randomized 
ITT participants who have completed 24 
weeks of treatment or who have 
discontinued treatment early.  
• 
Efficacy 
Safety Interim 
• 
All randomized participants through the data 
cut off of interim analysis who take at least 
1 dose of study intervention. Participants 
will be analyzed according to the treatment 
as randomized. 
• 
Study 
Population 
• 
Safety 
4.7.2. 
Interim Study Population Analyses 
Interim study population analyses will be based on ITT Interim and Safety Interim 
analysis sets. 
Summary of disposition, including study withdrawal and treatment discontinuation, will 
be provided. Demographic characteristics, including sex, age, age group, ethnicity, race, 
will be summarized. Summaries of the covariate/subgroups at baseline will be provided. 
See Section 4.6.1 for the full list of covariate/subgroups.  
Summary of disposition, including study withdrawal and treatment discontinuation will 
also be provided based on the ITT Interim Primary analysis set. 
4.7.3. 
Interim Efficacy Analyses 
4.7.3.1. 
Primary analyses 
The Interim analysis for the primary efficacy endpoint will use the ITT Interim Primary 
analysis set, using MMRM as described in Section 4.2.  
The LS means and 95% confidence intervals will be reported for change from baseline in 
MIS over 24 weeks. The LS mean, 95% CI, and p-value will be reported for the 
difference between placebo and linerixibat in change from baseline in MIS over 24 
weeks. The predictive probability of success with complete data given interim data, and 
the conditional power given interim data will be provided. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 63 of 102 
The futility assessment, the calculation of predictive probability of success and 
conditional power are detailed in the IDMC charter (TMF-16125967)Appendix 3: 
Statistical Guidance and Stopping Rule – Efficacy. 
4.7.3.2. 
Supplementary analyses 
The supplementary analyses of efficacy will be based on ITT Interim analysis set. 
• 
MIS 
The LS means and 95% CIs of change from baseline in MIS and difference from placebo 
over 24 weeks will be reported. The LS means and 95% CI of change from baseline in 
MIS and difference from placebo at each visit (Weeks 4, 8, 12, 16, 20, 24 since Day 1 of 
active treatment) from MMRM analysis described in Section 4.2 will also be reported. 
• 
MSS  
The MMRM analysis for the sleep endpoint described in Section 4.3.1 will be used for 
the interim analysis of MSS. The LS means and 95% CIs of change from baseline in 
MSS and difference from placebo over 24 weeks will be reported. The LS means and 
95% CIs of change from baseline in MSS and difference from placebo at each visit 
(Weeks 4, 8, 12, 16, 20, 24 since Day 1 of active treatment) will also be reported.  
4.7.4. 
Interim Safety Analyses 
The safety analyses at interim will be based on Safety Interim analysis set. 
Summaries of AEs of diarrhea or elevated ALT leading to permanent study drug 
discontinuation will be provided. The liver function test results (i.e., AST, ALT, total 
bilirubin, ALP, INR, and GGT) for participants meeting liver monitoring and/or stopping 
criteria will be listed, which will include participants with elevated ALT leading to 
permanent study drug discontinuation.  
As supplementary analyses, summaries of all AEs and SAEs, summary of AEs leading to 
permanent study drug discontinuation, and summary of participants meeting liver 
monitoring and/or stopping criteria will also be provided.  
4.8. 
Changes to Protocol Defined Analyses 
Changes from the originally planned statistical analysis specified in the protocol are 
detailed in Table 4. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 64 of 102 
Table 4 
Changes to Protocol Defined Analysis Plan 
Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes 
• 
Hypothetical strategy will be used 
for COVID-19 related intercurrent 
events for all primary and 
secondary endpoints.  
• 
Hypothetical strategy will be 
used for intercurrent events 
caused by COVID-19 related 
site closure, lockdowns, or 
other supply chain issues for 
the primary and key 
secondary endpoints. 
Treatment policy will be 
used for the supportive 
secondary endpoints.  
• 
In line with regulatory 
agency’s evolving 
recommendation on 
handling of “COVID-19 
related” intercurrent events 
since COVID-19 pandemic 
is no longer a temporary 
problem. Therefore, it is not 
necessary to apply this 
strategy to the supportive 
secondary endpoints. 
• 
PGI-C will be analyzed as a 
continuous variable using a 
MMRM model. 
• 
Additionally, the percentage 
of participants with improved 
PGI-C for each treatment 
group will be reported, as 
well as the percentage 
difference, 95% CI, and p-
value for the difference from 
placebo. 
• 
Analyzing PGI-C as a 
categorical variable may aid 
interpretation.  
• 
ALP and Bilirubin will be analyzed 
using the ITT population only. 
• 
Additionally, statistical 
analysis for ALP and 
Bilirubin will be repeating for 
the ALP ≥1.67x ULN ITT 
population (see Section 
4.3.2). 
• 
For demonstrating absence 
of worsening disease (PBC) 
progression. 
• 
Determination of PK parameters 
by population PK analysis. 
• 
Population PK analysis will 
no longer be performed.  
Only PK concentration data 
will be summarized in this 
study. 
• 
Due to the minimal 
absorption of linerixibat (oral 
bioavailability = 0.05%), 
plasma concentrations are 
intermittently measurable 
with a high degree of 
variability. Therefore, a 
population PK analysis is not 
feasible.  
• 
PRO compliance analysis not 
specified. 
• 
PRO compliance Section 6.2 
added. Summaries of 
compliance over all PROs 
will be performed and 
reported as a percentage of 
completed PROs out of the 
total number of expected 
PROs. 
• 
In line with updates to 
internal guidance and 
statistical analysis plan 
template. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 65 of 102 
5. 
SAMPLE SIZE DETERMINATION 
Approximately 230 participants (115 per group) who pass the screening eligibility criteria 
will be randomized in a 1:1 ratio to linerixibat or placebo groups. The sample size of 230 
was obtained and evaluated assuming that 10% of participants discontinue from the study 
at random and the data from the discontinuation week through Week 24 are missing. This 
sample size allows approximately 90% power for a two-sided test with an alpha level of 
0.05 when the expected overall difference in change from baseline in MIS across 24 
weeks is ~-0.9 (based on BAT117213 and GLIMMER data) between the linerixibat and 
placebo groups (assuming a between subject SD of 2.07 for both groups base on 
GLIMMER data).  
Change from baseline in the WIS was simulated for each week from Week 1 to Week 24 
after randomization. It was assumed that the mean change from baseline in the WIS of 
placebo group reaches its plateaued effect size of -1.5 by week 12 in a linear relationship 
against treatment week. It was also assumed that delta between linerixibat and placebo 
reaches plateau of -1 by week 4 in a linear relationship against treatment week, and the 
mean change from baseline in the WIS of linerixibat group is the sum of placebo and 
delta as shown in Figure 1. 
Figure 1 
Expected Change from Baseline in MWDI* 
 
*MWDI now referred to as the Weekly Itch Score (WIS). 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 66 of 102 
The expected weekly means are listed below: 
Table 5 
Expected Change from Baseline in Weekly Itch Score (WIS) 
Group 
N 
Expected Change from Baseline in WIS by Week  
(Week 1 – Week 11) 
Expected Change 
from Baseline in WIS 
(Week 12 - 24) 
Dropo
ut 
Rate 
Placebo 
115 
(-0.125, -0.250, -0.375, -0.500, -0.625, -0.750, -0.875, -1.
000, -1.125, -1.250, -1.375)  
-1.5 
10% 
Linerixibat 
115 
(-0.375, -0.750, -1.125, -1.500, -1.625, -1.750, -1.875, -2.
000, -2.125, -2.250, -2.375) 
-2.5 
10% 
For each iteration of simulation, change from baseline data for each week was generated 
for 115 subjects per group using a truncated multivariate normal distribution within the 
interval of [-10, 10] with the mean vectors presented above. The variance covariance 
matrix was assumed to have a compound symmetry (CS) structure with standard 
deviation of 2.25 and correlation of 0.85 which corresponds to a between subjects SD of 
~2.07 and a within subject SD of ~0.87, based on the GLIMMER data.  
The rates of study withdrawal that resulted in missing values from withdrawals for 
placebo group and linerixibat 40 mg BID group after randomization were 1/36 and 1/23, 
respectively, in the GLIMMER study. Therefore, it was expected to have ~10% study 
withdrawal rate for each arm and the study withdrawal can occur at any week after 
randomization. Missing data was assumed to be missing at random in the simulation.    
Simulations were based on planned visits at Week 4, 8, 12, 16, 20, and 24. For visit on 
Week 4, the worst change from baseline in WIS from Week 1 to 4 was reported as the 
change from baseline in MIS. Similarly, the change from baseline in MIS were obtained 
for other visits. Mixed model repeated measure analysis was then applied to change from 
baseline in MIS and the model included treatment, visit, and treatment by visit interaction 
as fixed effect. The comparison of active and placebo arms was based on the simple 
average of LS means of all visits, i.e., the main effect of treatment averaged across the 6 
visits with equal weight at each visit.  
6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, study population analyses will be based on the ITT 
Population and Safety analysis sets and summarized by Part A and Part B.  
A summary of the number of participants in each of the participant level analyses set will 
be provided. Enrolment will be presented by country and site based on the Enrolled 
analysis set. Screen status and reasons for screen failures will be based on Screening 
analysis set.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 67 of 102 
6.1.1. 
Participant Disposition 
A summary of the number and percentage of participants who completed the study as 
well as those who prematurely withdrew from the study will be provided. Reasons for 
study withdrawal will be summarized. Participant status and participant disposition at 
Part A will also be summarized by site operating model (see Section 4.6.3).  
6.1.2. 
Demographic and Baseline Characteristics 
The demographic characteristics including age, sex, ethnicity, height/weight at screening 
and race will be summarized with descriptive statistics. In addition, the following age 
categories will be summarized: 18-49, 50-64, and ≥65; and < 65, 65-74 and ≥75. 
Additionally, a de-identified high-level race variable will be defined for the purpose of 
public disclosure as White, Asian, and Other (De-identified), where the categories of 
American Indian or Alaska Native/Black or African American/Mixed 
Race/Unknown/Not Reported/Missing are collapsed into the Other (de-identified) 
category. Similarly, if the summary of any demographics and/or that of race and racial 
combinations meet the criteria for de-identification, then a de-identified version should be 
produced. 
A summary of baseline disease characteristics will be provided. This summary will 
include PBC, hepatitis, and cirrhosis diagnosis; liver biopsy; duration of pruritus; PBC 
historical stage; and prior liver transplant. 
Past medical conditions and current medical conditions as of screening will be 
summarized respectively. 
Substance use, including smoking history, tobacco use, alcohol and drug history will be 
summarized. 
Number and percentage of participants taking UDCA, anti-cholestatic pruritus treatment, 
and antihistamines as anti-cholestatic pruritus treatment at baseline will be summarized.  
6.1.3. 
Protocol Deviations 
Important protocol deviations will be summarized.  
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
• 
Data will be reviewed prior to freezing the database to ensure all important 
deviations (where possible without knowing the study intervention details) are 
captured and categorised in the protocol deviations dataset.  
• 
This dataset will be the basis for the summaries of important protocol deviations. 
In addition to the overall summary of protocol deviations, separate summaries of  
• 
important protocol deviations at Part A 
• 
important protocol deviations at Part A by operating model will also be produced.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 68 of 102 
6.1.4. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO Drug dictionary (the 
most recent dictionary at the time of the primary analysis will be used). The summary of 
concomitant medications will be provided by ingredient, i.e. multi-ingredient medications 
will be summarized for each individual ingredient rather than a combination of 
ingredients. The summary will be created using ingredient base names, i.e. ingredients 
with the same base name but different salt will appear under one base name in the 
summary. Anatomical Therapeutic Chemical (ATC) classifications will appear in the 
summary.  
The number and percentage of participants using rescue medication will be summarized 
by treatment group. 
6.1.5. 
Study Intervention Compliance  
Study intervention compliance (%) will be calculated as [Total cumulative actual dose / 
Total cumulative scheduled dose] *100 based on number of tablets dispensed and 
returned, as well as based on eDiary.  
Overall compliance will be summarized using descriptive statistics as well as the 
categories of <80%, 80%-105%, and >105%. Listing of compliance will be provided.  
6.2. 
Appendix 2 Electronic Patient-reported Outcome (ePRO) 
Compliance 
Compliance is the state of being in accordance with protocol-defined specifications.  
Evaluating compliance with the schedule of PRO assessments is important to understand 
the completeness of the PRO data in this study. Study level compliance will be calculated 
to evaluate compliance across all PRO assessments in the study (i.e., assessments 
supporting primary, secondary, and exploratory endpoints), while endpoint level 
compliance will be a targeted calculation to evaluate compliance with PRO assessments 
supporting the analysis of primary and important secondary endpoints. Details for each of 
these calculations are provided below. 
6.2.1. 
Study Level Compliance 
Overall PRO compliance (across all PROs and all participants) for the study is calculated 
for the ITT population as: 
∑
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑒 𝑃𝑅𝑂𝑠
𝑖=𝑛
𝑖=1
∑
𝐸𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑒 𝑃𝑅𝑂𝑠
𝑖=𝑛
𝑖=1
, 
Where i = participant and n = number of randomized participants. 
Compliance will be calculated for each treatment group and each respective study period 
(Part A and Part B separately). The ‘Number of complete PROs’ will be calculated across 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 69 of 102 
the study period for all participants in the ITT population. The definition for ‘Expected 
number of complete PROs’ is explained for each PRO below. 
For the itch eDiary, 2 entries per participant per day are expected. For the sleep eDiary 1 
entry per participant per day is expected, and for the fatigue eDiary 1 entry per participant 
per day is expected. For GSRS, 1 eDiary entry per participant per week is expected. 
For visit-based PRO data, an assessment is expected for each participant at each visit 
identified in the SoA of the protocol (Section 1.3). For PRO assessments with multiple 
questions (PBC-40, ESS, BDI-II), a participant will be considered to have completed the 
questionnaire for each respective visit if at least one question from the questionnaire is 
completed. Participants who initiate completion of a PRO assessment at a site visit will 
generally complete the PRO in its entirety. 
For Part A, a participant who completes Part A (including baseline) is anticipated to have 
the following PRO assessments: 
• 
Itch eDiary; approximately 394 diaries* (2 diaries x from Day -28 to Day 169 or 
Visit 9 – 1, whichever is earlier) 
• 
Sleep eDiary; approximately 197 diaries* (1 diary x from Day -28 to Day 169 or 
Visit 9 – 1, whichever is earlier) 
• 
Fatigue eDiary; approximately 197 diaries* (1 diary x from Day -28 to Day 169 or 
Visit 9 – 1, whichever is earlier) 
• 
GSRS; 25 eDiaries (baseline, plus 1 per week for 24 weeks) 
• 
PGI-C; 6 entries (V4 to V9) 
• 
PGI-S; 7 entries (V3 to V9) 
• 
PBC-40; 7 entries (V3 to V9) 
• 
BDI-II; 3 entries (V3, V6 and V9) 
• 
ESS; 3 entries (V3, V6 and V9) 
*for the purpose of this example the approximate number of eDiaries assumes that the 
subject had their Visit 9 on the planned day, but as per the formula the number of 
expected days is dependent on when Visit 9 actually occurs. 
Therefore, a participant who does not withdraw from study before completion of Part A 
would have an anticipated number of complete PROs of 839 (813 diaries from eDiaries, 
and 26 from visit-based PRO assessments). 
For Part B, a participant who completes Part B is anticipated to have the following PRO 
assessments: 
• 
Itch eDiary; approximately 112 diaries* (2 diaries x from Visit 9 + 1 to Visit 9 + 56 
or Visit 11 – 1, whichever is earlier) 
• 
Sleep eDiary; approximately 56 diaries* (1 diary x from Visit 9 + 1 to Visit 9 + 56 or 
Visit 11 – 1, whichever is earlier) 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 70 of 102 
• 
Fatigue eDiary;  approximately 56 diaries* (1 diary x from Visit 9 + 1 to Visit 9 + 56 
or Visit 11 – 1, whichever is earlier) 
• 
GSRS; 8 eDiaries (1 per week for 8 weeks) 
• 
PGI-C; 2 entries (V10 and V11) 
• 
PGI-S; 2 entries (V10 and V11) 
• 
PBC-40; 2 entries (V10 and V11) 
• 
BDI-II; 1 entry (V11) 
• 
ESS; 1 entry (V11) 
*for the purpose of this example the approximate number of eDiaries assumes that the 
subject had their Visit 9 on the planned day, but as per the formula the number of 
expected days is dependent on when Visit 9 actually occurs. 
Therefore, a participant who does not withdraw from study before completion of Part B 
would have an anticipated number of complete PROs of 240 (232 diaries from eDiaries, 
and 8 from visit-based PRO assessments). 
If a participant is lost to follow-up, PRO compliance will be calculated up to the last Visit 
attended (i.e., anticipated number of eDiaries is dependent on the time they are in the 
study). Similarly, if a participant withdraws from the study, compliance should be 
calculated through to the early discontinuation/withdrawal (ED) visit. 
The study level PRO compliance will be reported for each study period (Part A and Part 
B separately), for each treatment group and overall treatment groups. For Part A, the 
target compliance for eDiary assessments is 57% over all treatment groups (based on the 
requirement of only 4 daily scores per week, as described in Section 6.3.7). The target 
compliance for Part A visit-based PRO assessments is 80% over all treatment groups.  
The study level PRO compliance calculation for Part B will be produced at the end of the 
study when all participants have either completed or withdrawn from the study. 
6.2.2. 
Endpoint Level Compliance 
For the primary endpoint in Part A (MIS), a summary table will be produced displaying 
the frequency and percentage of participants who have 0, 1, 2, 3, or 4 Weekly Itch Scores 
(WIS) available at each month. This will be presented by treatment group and overall 
treatment groups. Similarly, a summary table will also be produced for the key secondary 
endpoint related to MSS in Part A. 
For the key secondary endpoint related to WIS in Part A, a summary table will be 
produced displaying the frequency and percentage of participants who have ≥4 or <4 
WDI scores in each week. This will be presented by treatment group and overall 
treatment groups. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 71 of 102 
6.3. 
Appendix 3 Data Derivations Rule 
6.3.1. 
Criteria for Potential Clinical Importance 
6.3.1.1. 
Laboratory Values 
Reference ranges for all laboratory parameters collected throughout the study are 
provided by the laboratory. A laboratory value that is outside the reference range is 
considered either high abnormal (value above the upper limit of the reference range) or 
low abnormal (value below the lower limit of the reference range). Note: a high abnormal 
or low abnormal laboratory value is not necessarily of clinical concern.  
Laboratory 
Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Haematology 
Haematocrit  
Ratio of 1 
 
Decrease from baseline >0.075. 
and 
is below LLN 
0.54 
Haemoglobin  
g/L 
 
Decrease from baseline >25g/L 
180 
Lymphocytes  
x109/ L 
 
0.8 
 
Neutrophil Count  
x109/ L 
 
1.5 
 
Platelet Count  
x109/ L 
 
100 
550 
While Blood Cell 
Count 
x109/ L 
 
3 
20 
Coagulation 
INR 
Ratio 
 
 
> 1.5 (absolute value) 
Clinical Chemistry 
Albumin 
g/L 
 
30 
 
∆ from BL 
>20% decrease from baseline 
 
Calcium 
mmol/L 
 
2 
2.75 
Creatinine 
umol/L 
∆ from BL 
 
Increase from baseline 
>26.5 
Glucose (fasting) 
mmol/L 
 
3 
9 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
eGFR (CKD-EPI) 
mL/min/ 
1.73m2 
 
30 
 
Liver Function 
ALT  
IU/L 
 
 
3x baseline 
AST  
IU/L 
 
 
3x baseline 
ALP 
IU/L 
 
 
2x baseline 
Total Bilirubin  
µmol/L 
 
 
1.5x baseline 
GGT 
IU/L 
 
 
2x baseline 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 72 of 102 
6.3.1.2. 
Vital Signs 
The following criteria will be used to flag potential clinical importance:  
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Pulse Rate 
bpm 
< 40 
> 110 
QRS interval 
Msec 
< 75 
> 110 
6.3.2. 
Study Period 
6.3.2.1. 
Classification Related to Study Period 
Assessments and events will be classified according to the time of occurrence relative to 
study period. 
Study Period 
Treatment Details 
Definition 
 
Notes 
Screening  
None 
Date < Date of 
Randomisation 
 
Part A 
Part A 
Date of Randomisation ≤ 
Date ≤ V9 
Date of Randomisation is collected as 
‘Date of Treatment Assignment’ on 
Treatment Assignment CRF page. 
Part B 
Part B 
V9 < Date ≤  Date of 
Study Completion (or 
Discontinuation) 
Date of Study Completion or 
Discontinuation as collected on Study 
Conclusion CRF page. 
Note: Visit 9 dates will be provided via the SDTM supplementary SV domain and refer to the exact date of the 
participants visit.  
Note: For visit-based assessment, the nominal visit name may be used to assign the treatment period (e.g., Visit 3 to 
Visit 9 to Part A, and Visit 10 and 11 to Part B). 
6.3.2.2. 
Classification Related to Study Intervention State 
Assessments and events will also be classified according to the time of occurrence 
relative to the study intervention period.  
Treatment State 
Definition 
Pre-Treatment 
Date < Date of start of study intervention  
On-Treatment 
(Intervention 
emergent) 
Date of start of study intervention ≤ Date ≤ Study intervention stop date (or Date of last dose 
of study intervention if lost to follow-up at the end of the study) 
If time of assessment or study intervention is not collected, the following assessment on the 
first dose date will be assumed to be taken prior to the first dose and therefore considered 
pre-intervention: ECG, Lab, and vital signs 
Post-Treatment 
Date of last dose of study intervention < Date  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 73 of 102 
The definitions of treatment states for AEs are provided below: 
Treatment State 
Definition  
Pre-Treatment 
AE start date < Date of start of study intervention 
On-Treatment Part A 
For participants that switched from Part A to Part B treatment without any gaps in 
between the switch 
• 
Part A Study Treatment Start Date ≤ AE Start Date ≤ Part A Study Treatment 
Stop Date. 
For participants that switched from Part A to Part B treatment with a gap of less 
than or equal to two days in between the switch 
• 
Part A Study Treatment Start Date ≤ AE Start Date < Part B Study Treatment 
Start Date. 
For participants that switched from Part A to Part B treatment with a gap of more 
than two days in between the switch (or entered Part B but never started Part B 
treatment) 
• 
Part A Study Treatment Start Date ≤ AE Start Date ≤ Part A Study Treatment 
Stop Date + 2 days. 
For participants that withdraw from the study or discontinue treatment during Part A 
of the study 
• 
Part A Study Treatment Start Date ≤ AE Start Date ≤ Part A Study Treatment 
Stop Date + 2 days. 
On-Treatment Part B 
Date of start of study intervention Part B ≤ AE start date ≤ Part B Study Treatment 
Stop Date (or Date of last dose of study intervention Part B if lost to follow-up at the 
end of the study) + 2 days 
Post-Treatment Part A 
For participants that switched from Part A to Part B treatment with a gap of more 
than two days in between the switch 
• 
Part A Study Treatment Stop Date + 2 days < AE Start Date < Date of first 
dose of study intervention Part B 
For participants that withdraw from the study or discontinue treatment during Part A 
of the study 
• 
Part A Study Treatment Stop Date + 2 days < AE Start Date < Withdrawal 
date if available (otherwise, follow-up visit date or last contact date [whichever 
is later]) 
Post-Treatment Part B 
Part B Study Treatment Stop Date (or Date of last dose of study intervention Part B 
if lost to follow-up at the end of the study) + 2 days < AE start date  
Onset Time Since 1st Dose 
If Date of start of study intervention ≤ AE start date: AE Start Date – Date of Start of 
Study Intervention +1 
Missing otherwise. 
Duration (Days)  
AE Resolution Date – AE Onset Date + 1 
6.3.2.3. 
Classification of Concomitant Medication 
Medication State 
Definition 
Prior 
Medication start date < Date of start of study intervention 
Concomitant Part A 
Medication start date ≤ Date of last dose of Part A study intervention, and  
Medication end date > Date of start of Part A study intervention.  
A medication could potentially be both prior and concomitant.  
Concomitant Part B 
Medication start date ≤ Date of last dose of Part B study intervention, and  
Medication end date > Date of start of Part B study intervention.  
A medication could potentially be both prior and concomitant. 
Notes:  
If the medication start date is missing but it is flagged as ongoing, then the medication will be assumed to be 
ongoing throughout the study. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 74 of 102 
6.3.3. 
Study Intervention Emergent Flag for Adverse Events 
Flag 
Definition 
Study Intervention 
Emergent Part A 
For participants that switched from Part A to Part B treatment without any gaps in between 
the switch 
• 
Part A Study Treatment Start Date ≤ AE Start Date ≤ Part A Study Treatment Stop 
Date. 
For participants that switched from Part A to Part B treatment with a gap of less than or equal 
to two days in between the switch 
o 
Part A Study Treatment Start Date ≤ AE Start Date < Part B Study Treatment Start 
Date. 
For participants that switched from Part A to Part B treatment with a gap of more than two 
days in between the switch (or entered Part B but never started Part B treatment) 
• 
Part A Study Treatment Start Date ≤ AE Start Date ≤ Part A Study Treatment Stop 
Date + 2 days. 
For participants that withdraw from the study or discontinue treatment during Part A of the 
study 
• 
Part A Study Treatment Start Date ≤ AE Start Date ≤ Part A Study Treatment Stop 
Date + 2 days. 
Study Intervention 
Emergent Part B 
• 
Part B Study Treatment Start Date ≤ AE Start Date ≤ Part B Study Treatment Stop 
Date + 2 days. 
Notes: 
• 
If the study treatment stop date is missing, then the AE will be considered to be intervention emergent. 
• 
The Part B treatment start date is defined as the first day where the participant received only Part B treatment. 
For participants who switch from Part A treatment to Part B treatment on the same day, the Part B treatment 
start date will be the day following the switch.  
• 
A gap is defined as a day where no treatment is taken. 
6.3.4. 
Study Day and Reference Dates 
The safety reference date is the study intervention start date and will be used to calculate 
study day for safety measures.  
The efficacy reference date is the study intervention start date and will be used to 
calculate study day for efficacy measures and efficacy durations. The baseline 
characteristics will be calculated based on the date of randomization.  
The study day is calculated as below with no day 0 defined: 
• 
Assessment Date = Missing              → Study Day = Missing  
• 
Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
• 
Assessment Data ≥ Reference Date → Study Day = Assessment Date – Ref Date + 1     
6.3.5. 
Analysis Window  
For data summaries by visit, the nominal visit description will be used. Unscheduled and 
withdrawal visit data will be slotted into a target visit based on analysis window defined 
in the table below. If there are multiple assessments within the same window, a scheduled 
visit will be prioritized over un-scheduled visits. If all assessments within the same 
window are from unscheduled visits, the earliest one will be taken in the slotting. The 
reference date is the start of study intervention.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 75 of 102 
Analysis 
Set / 
Domain 
Parameter 
(if 
applicable) 
Target  
Analysis Window 
Analysis Timepoint 
Beginning 
Timepoint 
Ending Timepoint 
Safety/ITT 
All 
Day 1 
Day 1 
Day 14 
Visit 3 
 
 
Day 28 
Day 15 
Day 42 
Visit 4 
 
 
Day 56 
Day 43 
Day 70 
Visit 5 
 
 
Day 84 
Day 71 
Day 98 
Visit 6 
 
 
Day 112 
Day 99 
Day 126 
Visit 7 
 
 
Day 140 
Day 127 
Day 154 
Visit 8 
 
 
Day 168 
Day 155 
Day 182 
Visit 9 
 
 
Day 196 
Day 183 
Day 210 
Visit 10 
 
 
Day 224 
Day 211 
Day 238 
Visit 11 
Note: Day 1 is the start of study intervention.   
6.3.6. 
Study Population Data 
6.3.6.1. 
Treatment Compliance 
• 
Compliance by number of tablets 
Compliance will be calculated based on the number of tablets dispensed and returned 
within Part A (dispensed at Visits 3, 4, and 6, and returned at Visits 4-9) and Part B 
(dispensed at Visit 9 and returned at Visits 10 - 11) 
Part A Compliance =100 * (total number of tablets dispensed from Visit 3 to Visit 6 – 
total number of tablets returned from Visit 4 to Visit 9 / (expected number of tablets to be 
taken), where expected number of tablets to be taken = 2 tablets per day * (Visit 9 – Day 
1 of study intervention). 
Part B Compliance =100 * (total number of tablets dispensed at Visit 9 – total number 
of tablets returned from Visit 9 to Visit 11 / (expected number of tablets to be taken), 
where expected number of tablets to be taken = 2 tablets per day * (Visit 11 – Visit 9). 
If a participant is lost to follow-up, compliance will be calculated up to the last Visit 
attended, assuming no tablets were taken from any bottles dispensed at this visit. These 
participants will be flagged, and a footnote added to any summaries of compliance to 
provide information on the number of participants where compliance has not been 
calculated over the entirety of the study part. 
For example, if a participant does not return for Visit 6 and is lost to follow-up, their 
compliance during Part A will be calculated as: 100 * (total number of tablets dispensed 
from Visits 3 to 4 – total number of tablets returned from Visits 3 to 5) / (expected 
number of tablets to be taken), where expected number of tablets to be taken = 2 tablets 
per day * (Visit 4 – Visit 3), with a flag added to say that the participant drops out after 
Visit 4. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 76 of 102 
Similarly, if a participant withdraws from the study, compliance should be calculated up 
to the ED visit.  
• 
Compliance by e-Dairy 
The compliance will be calculated based on the e-Dairy questions. 
For each day of Part A, from the evening of Day 1 of study intervention until the morning 
of Visit 9, the following will be calculated:   
CEQam = 1 if ‘Yes, I took both the morning and evening dose’ is selected; 
= 1 if ‘I took the morning dose only’ is selected; 
= 0 if otherwise 
CEQpm = 1 if ‘Yes, I took both the morning and evening dose’ is selected; 
= 1 if ‘I took the evening dose only’ is selected; 
= 0 if otherwise 
Total Part A CEQam = Number of days that CEQam = 1 between Day 2 of study 
intervention and Visit 9. 
Total Part A CEQpm = Number of days that CEQpm = 1 between Day 1 of study 
intervention and Visit 9 - 1. 
Part A AM Compliance = 100 * (Total CEQam)/expected days, where expected days is 
Visit 9 – Day 1 of study intervention 
Part A PM Compliance = 100 * (Total CEQpm)/ expected days, where expected days is 
Visit 9 – Day 1 of study intervention 
Part A Compliance =mean (Part A AM compliance, Part A PM Compliance) 
Similarly, for Part B,  
Total Part B CEQam = Number of days that CEQam = 1 between Visit 9 + 1 and Visit 
11. 
Total Part B CEQpm = Number of days that CEQpm = 1 between Visit 9 + and Visit 11 - 
1. 
Part A AM Compliance = 100 * (Total CEQam)/expected days, where expected days is 
Visit 11 – Visit 9 
Part B PM Compliance = 100 * (Total CEQpm)/ expected days, where expected days is 
Visit 11 – Visit 9 
Part B Compliance =mean (Part B AM compliance, Part B PM Compliance) 
If a participant is lost to follow-up, the compliance is calculated up to the date of the last 
visit, or the date of the last e-Dairy entry, whichever is later. If a participant withdraws 
from the study, the compliance is calculated up to the date of the ED visit. Similar as the 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 77 of 102 
compliance by number of tablet, these participants will be flagged, and a footnote added 
to any summaries of compliance to provide information on the number of participants 
where compliance has not been calculated over the entirety of the study part. 
6.3.6.2. 
Chronic Kidney Disease (CKD) Stage 
The following CKD ranges will be used: 
• 
Stage 1 (normal or high GFR): eGFR >=90 mL/min/1.73m2 
• 
Stage 2 (mild CKD): eGFR 60-89 mL/min/1.73m2 
• 
Stage 3a (moderate CKD): eGFR 45-59 mL/min/1.73m2 
• 
Stage 3b (moderate CKD): eGFR 30-44 mL/min/1.73m2 
• 
Stage 4 (severe CKD): eGFR 15-29 mL/min/1.73m2 
• 
Stage 5 (end stage CKD): eGFR <15 mL/min/1.73m2 
Note: eGFR forms an exclusion criterion for this study and therefore baseline values are 
expected to be ≥ 30. 
6.3.7. 
Efficacy Data 
6.3.7.1. 
Itch Score 
6.3.7.1.1. Worst Daily Itch Score 
The itch eDiary is to be completed twice each day to rate the worst bedtime itch 
(completed in the morning; AM score) and the worst daytime itch (completed during the 
evening; PM score) using 0-10 NRS score. The WDI score is the maximum (worst) of the 
AM and PM NRS scores.  
If there is missing data within a day: 
Missing bedtime Worst Itch score then                  
 
WDI = PM Worst Itch score 
Missing daytime Worst Itch score then                   
 
WDI = AM Worst Itch score 
Missing AM and PM Worst Itch score then           
 
WDI = Missing 
If there is more than one entry in the e-diary data for worst itch at a timepoint (AM or 
PM) of a given day, the worst (the highest) score from each duplicate record at that 
timepoint will be used in the derivation of WDI. 
6.3.7.1.2. Weekly Itch score 
The WIS is the average of the WDI scores in one week. The reference date of WIS during 
Part A (Week 1 – Week 24) is the start of study intervention (Day 1). The reference date 
of WIS during Part B (Week 25 – Week 32) is Visit 9. 
The WIS at each week of Part A and B is calculated as the average of WDI from start 
date to end date shown below:  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 78 of 102 
Analysis Time point 
Start Date  
End Date 
Week 1 
Day 2 
Day 8 
Week 2 
Day 9 
Day 15 
Week 3 
Day 16 
Day 22 
Week 4 
Day 23 
Day 29 
Week 5 
Day 30 
Day 36 
Same logic followed for Week 6 to Week 22 
Week 23 
Day 156 
Day 162 
Week 24 
Day 163 
 
Day 169 or Visit 9 - 1, whichever is 
earlier 
Week 25 
Visit 9 + 1 
Visit 9 + 7 
Week 26 
Visit 9 + 8 
Visit 9 + 14 
Same logic followed for Week 27 – Week 31 
Week 32 
Visit 9 + 50 
Visit 9 + 56 or Visit 11 – 1, 
whichever is earlier 
Note: Day 1 is the start of study intervention in Part A.  
The reference date of Part A baseline WIS is randomization day. The WIS at Part A 
baseline weeks are calculated as the average of WDI from start date to end date shown 
below:  
Analysis Time point 
Start Date  
End Date 
Part A Baseline Week 1 
Day -28 
Day -22 
Part A Baseline Week 2 
Day -21 
Day -15 
Part A Baseline Week 3 
Day -14 
Day -8 
Part A Baseline Week 4 
Day -7 
Day -1 
Note: Day -1 is the day immediately preceding randomization date.  
At least 4 WDI scores are required for the calculation of WIS of that week. If more than 3 
of the WDI scores are missing in any week, then the WIS of that week will be set to 
missing. 
The WIS at Part A Baseline Week 4 is the baseline used for endpoints on change from 
baseline in WIS. Therefore, change from baseline in WIS at Week x = WIS at Week x – 
WIS at Part A Baseline Week 4.  
6.3.7.1.3. Monthly Itch Score 
The MIS is the worst WIS for that month (i.e., worst week score of the 4 weeks).  
The MIS at a visit is the worst (maximum) WIS of the weeks defined above in 6.3.7.1.2, 
as shown below:  
Analysis Time point 
Labels for 
Summaries 
Monthly Itch Score 
Visit 3 
Part A Baseline (V3) 
Maximum (WIS at Part A Baseline Week 1 – 4) 
Visit 4 / Week 4 
Week 4 (V4) 
Maximum (WIS at Week 1 – 4) 
Visit 5 / Week 8 
Week 8 (V5) 
Maximum (WIS at Week 5 – 8) 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 79 of 102 
Analysis Time point 
Labels for 
Summaries 
Monthly Itch Score 
Visit 6 / Week 12 
Week 12 (V6) 
Maximum (WIS at Week 9 – 12) 
Visit 7 / Week 16 
Week 16 (V7) 
Maximum (WIS at Week 13 – 16) 
Visit 8 / Week 20 
Week 20 (V8) 
Maximum (WIS at Week 17 – 20) 
Visit 9 / Week 24 
Week 24 (V9) 
Maximum (WIS at Week 21 – 24) 
Visit 10 / Week 28 
Week 28 (V10) 
Maximum (WIS at Week 25 – 28) 
Visit 11 / Week 32 
Week 32 (V11) 
Maximum (WIS at Week 29 – 32) 
If one or more WIS are missing, then the worst (maximum) of the non-missing WIS is 
selected as the MIS. If no WIS are available for the 4-week periods defined in the table 
above, the MIS at that Visit will be set to missing.  
The frequency and percentage of participants with 0, 1, 2, 3, or 4 weekly itch scores 
available at each month will be presented by treatment group. 
The change from baseline in MIS at Visit x during Part A = MIS at Visit x – MIS at Part 
A Baseline (V3).  
The baseline of MIS at Part B is Week 24 MIS. The change from baseline in MIS at Visit 
x during Part B = MIS at Visit x – MIS at Week 24 (V9) 
6.3.7.2. 
Sleep Score 
6.3.7.2.1. Daily Sleep Score 
The sleep eDiary is to be completed every morning to score the severity of how itch 
interfered with sleep using an NRS from 0 to 10.  
If there is more than one entry in the e-diary data for the sleep score on any given day, the 
worst score will be used as the DSS for that day. 
6.3.7.2.2. Weekly Sleep Score 
The WSS is the average of the DSS in one week. The reference date of WSS during Part 
A (Week 1 – Week 24) is the start of study intervention (Day 1).  
The WSS at each week of part A is calculated as the average of DSS from start date to 
end date shown below:  
Analysis Time point 
Start Date  
End Date 
Week 1 
Day 2 
Day 8 
Week 2 
Day 9 
Day 15 
Week 3 
Day 16 
Day 22 
Week 4 
Day 23 
Day 29 
Week 5 
Day 30 
Day 36 
Same logic followed for Week 6 to Week 22 
Week 23 
Day 156 
Day 162 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 80 of 102 
Analysis Time point 
Start Date  
End Date 
Week 24 
Day 163 
Day 169 or Visit 9 - 1, whichever is 
earlier 
Note: Day 1 is the start of study intervention in Part A.  
The reference date of Part A baseline WSS is randomization day. The WSS at Part A 
baseline weeks are calculated as the average of DSS from start date to end date shown 
below:  
Analysis Time point 
Start Date  
End Date 
Part A Baseline Week 1 
Day -28 
Day -22 
Part A Baseline Week 2 
Day -21 
Day -15 
Part A Baseline Week 3 
Day -14 
Day -8 
Part A Baseline Week 4 
Day -7 
Day -1 
Note: Day -1 is the day immediately preceding randomization date.  
If more than 3 of the DSS are missing in any week then the WSS of that week will be set 
to missing. 
The WSS at Part A Baseline Week 4 is the baseline used for endpoints on change from 
baseline in WSS. Therefore, the change from baseline in WSS at Week x= WSS at Week 
x – WSS at Part A Baseline Week 4.  
6.3.7.2.3. Monthly Sleep Score 
The MSS is the worst WSS for that month (i.e., worst week score of the 4 weeks). The 
MSS at a visit is the worst (maximum) WSS of the weeks defined above in 6.3.7.2.2, as 
shown below:  
Analysis Time point 
Labels for Summaries 
Monthly Sleep Score 
Visit 3 
Part A Baseline (V3) 
Maximum (WSS at Part A Baseline Week 1 – 4) 
Visit 4 / Week 4 
Week 4 (V4) 
Maximum (WSS at Week 1 – 4) 
Visit 5 / Week 8 
Week 8 (V5) 
Maximum (WSS at Week 5 – 8) 
Visit 6 / Week 12 
Week 12 (V6) 
Maximum (WSS at Week 9 – 12) 
Visit 7 / Week 16 
Week 16 (V7) 
Maximum (WSS at Week 13 – 16) 
Visit 8 / Week 20 
Week 20 (V8) 
Maximum (WSS at Week 17 – 20) 
Visit 9 / Week 24 
Week 24 (V9) 
Maximum (WSS at Week 21 – 24) 
If one or more WSS scores are missing, then the worst (maximum) of the non-missing 
WSS scores is selected as the MSS. If no WSS scores are available for the 4-week 
periods defined in the table above, the MIS at that Visit will be set to missing.  
The frequency and percentage of participants with 0, 1, 2, 3, or 4 weekly sleep scores 
available at each month will be presented by treatment group. 
The change from baseline in MSS at Visit x= MSS at Visit x – MSS at Part A Baseline 
(V3).  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 81 of 102 
6.3.7.3. 
Fatigue Score 
6.3.7.3.1. Daily Fatigue Score 
The fatigue eDiary is to be completed every evening to score the fatigue using an NRS 
from 0 to 10.  
If there is more than one entry in the e-diary data for the fatigue score on any given day, 
the worst score will be used as the DFS for that day. 
6.3.7.3.2. Weekly Fatigue Score 
The WFS is the average of the DFS in one week. The reference date of WFS during Part 
A (Week 1 – Week 24) is the start of study intervention (Day 1).  
The WFS at each week of part A is calculated as the average of DFS from start date to 
end date shown below:  
Analysis Time point 
Start Date  
End Date 
Week 1 
Day 2 
Day 8 
Week 2 
Day 9 
Day 15 
Week 3 
Day 16 
Day 22 
Week 4 
Day 23 
Day 29 
Week 5 
Day 30 
Day 36 
Same logic followed for Week 6 to Week 22 
Week 23 
Day 156 
Day 162 
Week 24 
Day 163 
Day 169 or Visit 9 - 1, whichever is 
earlier 
Note: Day 1 is the start of study intervention in Part A.  
The reference date of Part A baseline WFS is randomization day. The WFS at Part A 
baseline weeks are calculated as the average of DFS from start date to end date shown 
below:  
Analysis Time point 
Start Date  
End Date 
Part A Baseline Week 1 
Day -28 
Day -22 
Part A Baseline Week 2 
Day -21 
Day -15 
Part A Baseline Week 3 
Day -14 
Day -8 
Part A Baseline Week 4 
Day -7 
Day -1 
Note: Day -1 is the day immediately preceding randomization date.  
If more than 3 of the DFS are missing in any week then the WFS of that week will be set 
to missing. 
The WFS at Part A Baseline Week 4 is the baseline used for endpoints on change from 
baseline in WFS. Therefore, the change from baseline in WFS at Week x= WFS at Week 
x – WFS at Part A Baseline Week 4.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 82 of 102 
6.3.7.3.3. Monthly Fatigue Score 
The MFS is the worst WFS for that month (i.e., worst week score of the 4 weeks). The 
MFS at a visit is the worst (maximum) WFS of the weeks defined above in 6.3.7.3.2, as 
shown below:  
Analysis Time point 
Labels for Summaries 
Monthly Fatigue Score 
Visit 3 
Part A Baseline (V3) 
Maximum (WFS at Part A Baseline Week 1 – 4) 
Visit 4 / Week 4 
Week 4 (V4) 
Maximum (WFS at Week 1 – 4) 
Visit 5 / Week 8 
Week 8 (V5) 
Maximum (WFS at Week 5 – 8) 
Visit 6 / Week 12 
Week 12 (V6) 
Maximum (WFS at Week 9 – 12) 
Visit 7 / Week 16 
Week 16 (V7) 
Maximum (WFS at Week 13 – 16) 
Visit 8 / Week 20 
Week 20 (V8) 
Maximum (WFS at Week 17 – 20) 
Visit 9 / Week 24 
Week 24 (V9) 
Maximum (WFS at Week 21 – 24) 
If one or more WFS scores are missing, then the worst (maximum) of the non-missing 
WFS scores is selected as the MFS. If no WFS scores are available for the 4-week 
periods defined in the table above, the MFS at that Visit will be set to missing.  
The change from baseline in MFS at Visit x= MFS at Visit x – MFS at Part A Baseline 
(V3).  
6.3.7.4. 
Itch Responder 
Improvement in MIS score is the reduction of the score (10 is the highest and worst 
severity, 0 lowest and least severe).  
Responders at Visits 4 – 9 (Week 4, 8, 12, 16, 20, and 24) are evaluated by comparing the 
change from baseline in MIS at that visit against the responder threshold.  
For responder threshold of achieving a ≥2-point reduction from Baseline in the Monthly 
Itch score, 
Responder = 1, if change from baseline in MIS ≤ -2 
 
      = 0, if change from baseline in MIS > -2 
 
      = missing, if MIS is missing 
For responder threshold of achieving a ≥3-point reduction from Baseline in the Monthly 
Itch score, 
Responder = 1, if change from baseline in MIS ≤ -3 
 
      = 0, if change from baseline in MIS > -3 
 
      = missing, if MIS is missing 
For responder threshold of achieving a ≥4-point reduction from Baseline in the Monthly 
Itch score, 
Responder = 1, if change from baseline in MIS ≤ -4 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 83 of 102 
 
      = 0, if change from baseline in MIS > -4 
 
      = missing, if MIS is missing 
The missing MIS values will be imputed before dichotomized to responder for the CMH 
analysis as detailed in Section 4.3.1 
6.3.7.5. 
Itch Response Day 
Itch response at a day is defined by comparing the change from baseline WDI score at a 
day to an itch response threshold. Baseline is defined as the WIS of 7 days prior to 
randomization. 
For threshold of achieving a ≥2-point reduction from Baseline in WDI, 
WDI response = 1, if change from baseline in WDI score ≤ -2 
 
 
= 0, if change from baseline in WDI score > -2 
 
 
= missing, if WDI is missing 
For threshold of achieving a ≥3-point reduction from Baseline in WDI, 
WDI response = 1, if change from baseline in WDI score ≤ -3 
 
 
= 0, if change from baseline in WDI score > -3 
 
 
= missing, if WDI is missing 
For threshold of achieving a ≥4-point reduction from Baseline in WDI, 
WDI response = 1, if change from baseline in WDI score ≤ -4 
 
 
= 0, if change from baseline in WDI score > -4 
 
 
= missing, if WDI is missing 
The percentage of itch response days during part A is calculated, for each itch response 
threshold, as  
(Number of response days / total number days from Day 2 to V9 -1 for which a WDI 
score is available) * 100 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 84 of 102 
6.3.7.6. 
PBC-40 
The answers to the individual PBC-40 questions should be scored as in http://www.uk-
pbc.com/wp-content/uploads/2015/12/coded-PBC-40.pdf (summarized below). 
Question 1 is scored as: 
5 – Never 
4 – Rarely 
3 – Sometime 
2 – Most of the Time 
1 – Always 
Question 2 to 27 (inclusive) are scored as: 
1 – Never 
2 – Rarely 
3 – Sometime 
4 – Most of the Time 
5 – Always 
Questions 28 to 33 (inclusive) are scored as: 
1 – Not at all 
2 – A little 
3 – Somewhat 
4 – Quite a bit 
5 – Very much 
Questions 34-39 (inclusive) are scored as: 
5 – Strongly Agree 
4 – Agree 
3 – Neither Agree nor Disagree 
2 – Disagree 
1 – Strongly Disagree 
Question 40 is scored as: 
1 – Strongly Agree 
2 – Agree 
3 – Neither Agree nor Disagree 
4 – Disagree 
5 – Strongly Disagree 
For all questions, an answer of Does/Did not apply will be scored 0. 
For each visit the PBC-40 questionnaire should provide scores for 6 domains:  
PBC-Symptoms = sum of scores of questions 1 to 7 
PBC-Itch = sum of scores of questions 8 to 10 
PBC Fatigue = sum of scores of questions 11 to 21 
PBC-Cognitive = sum of scores of questions 22 to 27 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 85 of 102 
PBC-Emotional = sum of scores of questions 28, 30 and 33 
PBC-Social = sum of scores of questions 29, 31 and 32, and 34 to 40 
For each individual PBC domain (symptoms, itch, emotional, social, fatigue and 
cognitive), if more than 50% of the corresponding question scores for a participant are 
missing then the total score for that domain will be marked as missing.  If 50% or more 
of the corresponding question scores are complete, the median of these responses will be 
imputed for the missing values within the domain before calculating the domain score. 
6.3.7.7. 
Patient Global Impression of Severity 
Derived PGI-S scores will be on a scale of 1-5 from the PGI-S question: 
1 = Absent 
2 = Mild 
3 = Moderate 
4 = Severe 
5 = Very Severe 
6.3.7.8. 
Patient Global Impression of Change 
Derived PGI-C score will be on a scale of 1-7 from the PGI-C question: 
1 = Very Much Improved 
2 = Moderately Improved 
3 = Minimally Improved 
4 = No Change 
5 = Minimally Worse 
6 = Moderately Worse 
7 = Very Much Worse 
6.3.7.9. 
Epworth Sleepiness Scale 
The ESS consists of 8 questions using scales ranging from 0 to 3, where scale of 0 means 
“would never doze” and scale of 3 means “high chance of dozing”. The total ESS score is 
the sum of the scores of all questions and ranges from 0 to 24.  
If there is more than one score made for question, the mean score will be used.  
If there are decimal scores entered for questions, the scores will be taken at face value 
and added to compose the total score. If the total score includes a decimal, it will be 
rounded to form whole number.  
If one or more responses are missing, the total score is missing.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 86 of 102 
From the author, the total ESS scores can be interpreted as follows: 
• 
0-5: Lower Normal Daytime Sleepiness  
• 
6-10: Higher Normal Daytime Sleepiness 
• 
11-12: Mild Excessive Daytime Sleepiness 
• 
13-15: Moderate Excessive Daytime Sleepiness 
• 
16-24: Severe Excessive Daytime Sleepiness 
6.3.7.10. 
Beck Depression Inventory –II 
The BDI-II consists of 21 questions, with possible responses being scored from 0 (least 
severe response) to 3 (most severe response). The scores for all 21 questions are then 
added together to obtain an ‘observed total score’ on a scale of 0 to 63. 
If there are no missing responses then  
Total Score = Observed Total Score 
If there are 1 or 2 missing responses the Total Score can be adjusted to account for the 
missing responses by: 
Total Score = (21 / number of non-missing responses) * Observed Total Score 
If 3 or more responses are missing then: 
Total Score = missing. 
IMPORTANT NOTE: For questions 16 and 18, the collected code values must be 
adjusted as shown below to compute the item score:  
Question 16: 
Collection Code 
Label 
Item Score 
0 
0 - I have not experienced any change in my sleeping pattern 
 0 
1 
1a - I sleep somewhat more than usual 
 1 
2 
1b - I sleep somewhat less than usual 
 1 
3 
2a - I sleep a lot more than usual 
 2 
4 
2b - I sleep a lot less than usual 
 2 
5 
3a - I sleep most of the day 
 3 
6 
3b - I wake up 1-2 hours early and can't get back to sleep 
 3 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 87 of 102 
Question 18: 
Collection  
Code 
Label 
Item  
Score 
0 
0 - I have not experienced any change in my appetite 
 0 
1 
1a - My appetite is somewhat less than usual 
 1 
2 
1b - My appetite is somewhat greater than usual 
 1 
3 
2a - My appetite is much less than before 
 2 
4 
2b - My appetite is much greater than usual 
 2 
5 
3a - I have no appetite at all 
 3 
6 
3b - I crave food all the time 
 3 
6.3.7.11. 
Discard of Data based on Hypothetical Estimand Strategy 
• 
Hypothetical estimand strategy for COVID-19 pandemic related intercurrent events 
For the primary and key secondary endpoints where hypothetical strategy is applied to 
COVID-19 pandemic related intercurrent events (see Section 1.1 for more details), WDI 
scores or DSS impacted by study treatment interruption due to COVID-19 pandemic will 
be discarded and treated as missing. The corresponding WIS or WSS will then be 
constructed, followed by the derivation of MIS or MSS. See Section 4.2.1 for more 
details. 
• 
Hypothetical estimand strategy for any intercurrent events 
For the supplementary estimand of the primary endpoint, hypothetical strategy will be 
used for any intercurrent events, including treatment discontinuation, disruptions in 
treatment or treatment delays, changes in itch therapy or use of rescue medication. WDI 
scores impacted by these intercurrent events will be discarded and treated as missing. The 
corresponding WIS will then be constructed, followed by the derivation of MIS. 
6.3.8. 
Safety Data 
6.3.8.1. 
Exposure calculation 
Number of days of exposure to study drug during part A and B will be calculated based 
on the formula below regardless of temporary treatment interruption:     
Part A Duration of Exposure in Days = Part A Treatment Stop Date – Part A 
Treatment Start Date + 1   
Part B Duration of Exposure in Days = Part B Treatment Stop Date – Part B 
Treatment Start Date + 1 
Participants who were randomized but did not report a treatment start date will be 
categorized as having zero days of exposure. 
For participants with treatment stop date missing, if treatment stop occurs during Part A, 
the stop date will be imputed as Visit 9 date or early discontinuation/withdrawal (ED) 
date, whichever is earlier.  


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 88 of 102 
If there is no evidence that the treatment stops during Part A, the stop date will be 
imputed as Visit 11 date or ED date, whichever is earlier.  
Note that the Part B treatment start date is defined as the first day where the participant 
received only Part B treatment. For participants who switch from Part A treatment to Part 
B treatment on the same day, the Part B treatment start date will be the day following the 
switch. 
The cumulative dose will be based on the formula:   
Cumulative Dose = Sum of (Duration of Exposure x Total Daily Dose)   
6.3.8.2. 
Exposure adjusted incidence rate 
When cumulative incidence rate is reported for AE analyses, exposure adjusted incidence 
rate will also be reported. Exposure adjusted incidence rate will be calculated based on 
the formula below: 
𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒 𝑎𝑑𝑗𝑢𝑠𝑡𝑒𝑑 𝑖𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑟𝑎𝑡𝑒= 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠 𝑤𝑖𝑡ℎ 𝑡ℎ𝑒 𝑒𝑣𝑒𝑛𝑡
𝑇𝑜𝑡𝑎𝑙 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 𝑡𝑖𝑚𝑒 𝑖𝑛 𝑦𝑒𝑎𝑟 
 × 100 
6.3.8.2.1. Exposure adjusted incidence rate for the Main Safety Estimand 
For the main safety estimand, a while-on-treatment strategy will be used to address 
permanent treatment discontinuation. Exposure will be calculated as follows: 
For AEs reported in Part A, Total exposure time in year  = sum of participant total 
exposure duration in days during Part A for all safety population (across all 
participants)/365.25, where participant total exposure duration in days is calculated as 
follows:  
• 
if they DO experience the AE, then start date of first AE – Part A treatment start date 
+ 1. 
• 
if they DO NOT experience the AE and DO NOT Withdraw from the study during 
Part A, and they switched from Part A to Part B treatment without any gaps in 
between the switch, then Part A Duration of Exposure in Days (See Section 
6.3.8.1)  
• 
if they DO NOT experience the AE and DO NOT Withdraw from the study during 
Part A, and they switched from Part A to Part B treatment with a gap of less than or 
equal to two days in between the switch, then ([Part B treatment start date – 1 Day] – 
Part A treatment start date) + 1 
• 
if they DO NOT experience the AE and DO NOT Withdraw from the study during 
Part A, and they switched from Part A to Part B treatment with a gap of more than 
two days in between the switch (or entered Part B but never started Part B 
treatment), then Part A Duration of Exposure in Days (See Section 6.3.8.1) + 2 
Days. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 89 of 102 
• 
If they DO NOT experience the AE and DO Withdraw from the study during Part A, 
then Part A Duration of Exposure in Days (See Section 6.3.8.1) + 2 Days. 
Similarly, for AEs reported in Part B, Total exposure time in year  = sum of participant 
total exposure duration in days during Part B for all safety population (across all 
participants)/365.25, where participant total exposure duration in days is calculated as 
follows:   
• 
if they DO experience the AE, then start date of first AE – Part B treatment start date 
+ 1. 
• 
if they DO NOT experience the AE, then Part B Duration of Exposure in Days 
(See Section 6.3.8.1) + 2 Days. 
Note that if a participant experiences multiple AEs in the same System Organ Class and 
Preferred Term, exposure adjusted incidence rates are only calculated for the first instance 
of the AE. 
6.3.8.2.2. Exposure adjusted incidence rate for Supplementary Safety Estimand 
For the supplementary safety estimand, a treatment policy strategy (or ‘while-on-study’) 
will be used to address permanent treatment discontinuation (i.e., including AEs after  
permanent treatment discontinuation). Exposure is defined from first date of treatment to 
the end of participation in the study, regardless of the end of exposure to treatment. 
Exposure will be calculated as follows: 
For AEs reported in Part A, Total exposure time in year  = sum of participant total 
exposure duration in days during Part A for all safety population (across all 
participants)/365.25, where participant total exposure duration in days is calculated as 
follows:  
• 
If they DO experience the AE, then start date of first AE – Part A treatment start date 
+ 1. 
• 
if they DO NOT experience the AE and Withdraw from the study >2 days after Part 
A treatment stop date (but before end of visit 9), then withdrawal date – Part A 
treatment start date + 1 
• 
If they DO NOT experience the AE and Withdraw from the study ≤ 2 days after Part 
A treatment stop date (but before end of visit 9), then (Part A treatment stop date + 2 
– Part A treatment start date) + 1  
• 
if they DO NOT experience the AE and DO NOT Withdraw from the study and DO 
NOT Discontinue treatment prior to starting Part B, then ([Part B treatment start date 
– 1 Day] – Part A treatment start date) + 1 
• 
if they DO NOT experience the AE and DO NOT Withdraw from the study and DO 
Discontinue treatment before starting Part B (i.e., they never start Part B treatment), 
then Follow-up visit date or last contact (whichever is later) – Part A treatment start 
date + 1 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 90 of 102 
Similarly, for AEs reported in Part B, Total exposure time in year  = sum of participant 
total exposure duration in days during Part B for all safety population (across all 
participants)/365.25, where participant total exposure duration in days is calculated as 
follows:   
• 
if they DO experience the AE, then start date of first AE – Part B treatment start date 
+ 1 
• 
if they DO NOT experience the AE and Withdraw from the study >2 days after Part 
B treatment stop date, then withdrawal date – Part B treatment start date + 1 
• 
If they DO NOT experience the AE and Withdraw from the study ≤ 2 days after Part 
B treatment stop date, then (Part B treatment stop date + 2 – Part B treatment start 
date) + 1 
• 
if they DO NOT experience the AE and DO NOT Withdraw from the study, then 
Follow-up visit date or Visit 11 Completion date (whichever is later) – Part B 
treatment start date + 1 
Note that if a participant experiences multiple AEs in the same System Organ Class and 
Preferred Term, exposure adjusted incidence rates are only calculated for the first instance 
of the AE. 
6.3.8.3. 
Gastrointestinal Symptoms Rating Scale 
The responses to each question in the GSRS range from No discomfort at all (1) to Very 
severe discomfort (7). 
For each week, the GSRS questionnaire should provide scores for 5 domains: 
Diarrhoea Syndrome = average of scores for questions 11, 12 and 14 
Indigestion Syndrome = average of scores for questions 6, 7, 8 and 9 
Constipation Syndrome = average of scores for questions 10, 13 and 15 
Abdominal pain syndrome = average of scores for questions 1, 4 and 5 
Reflux Syndrome = average of scores for questions 2 and 3 
Total = average scores for questions 1-15 
For each individual GSRS domain (Diarrhoea, Indigestion, Constipation, Abdominal 
Pain, Reflux) if more than 50% of the corresponding question scores for a participant are 
missing then the total score for that domain will be marked as missing.  If 50% or more 
of the corresponding question scores are complete the mean of these responses will be 
imputed for the missing values within the domain before calculating the domain score.   
If there is more than one entry for the GSRS questionnaires on any given date or 
timepoint the worst score will be used for that date or timepoint as conservative 
approach. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 91 of 102 
As per the schedule of assessment, the GSRS will be completed at Visit 3 (prior to first 
dose), then every 7 days after the first dose of Part A treatment: 
Note: Day 1 is the start of study intervention in Part A.  
6.3.8.4. 
ECG Parameters 
6.3.8.4.1. RR Interval 
If RR interval (msec) is not provided directly, then RR can be derived based on QT and 
QTcF (or QTcB if available instead). 
If QTcB is machine read & QTcF is not provided, then : 
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐵)
2
] ∗1000 
Otherwise if QTcF is machine read, then:  
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐹)
3
] ∗1000 
If both QTcB and QTcF are available QTcF should be used. 
If ECGs are manually read, the RR value preceding the measurement QT interval will not 
be derived. 
Analysis Time point 
Start Date  
End Date 
Baseline 
Visit 3 
Visit 3 
Week 1 
Day 2 
Day 8 
Week 2 
Day 9 
Day 15 
Week 3 
Day 16 
Day 22 
Week 4 
Day 23 
Day 29 
Week 5 
Day 30 
Day 36 
Same logic followed for Week 6 to Week 22 
Week 23 
Day 156 
Day 162 
Week 24 
Day 163 
 
Day 169 or Visit 9 - 1, whichever is 
earlier 
Week 25 
Visit 9 + 1 
Visit 9 + 7 
Week 26 
Visit 9 + 8 
Visit 9 + 14 
Same logic followed for Week 27 – Week 31 
Week 32 
Visit 9 + 50 
Visit 9 + 56 or Visit 11 – 1, 
whichever is earlier 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 92 of 102 
6.3.8.4.2. Corrected QT Intervals 
When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of 
other measurements. 
If RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as:  
𝑄𝑇𝑐𝐵= 
𝑄𝑇
√𝑅𝑅
1000
 
𝑄𝑇𝑐𝐹= 
𝑄𝑇
3√𝑅𝑅
1000
 
6.3.8.5. 
Adverse Events of Special Interest  
6.3.8.5.1. Diarrhea reported as an AE  
Diarrhea AESI will be all study intervention emergent AEs with High Level Term (HLT) 
of “Diarrhoea (excl infective)” that have been marked as AESIs by investigators, reported 
via the Adverse Event eCRF. 
6.3.8.5.2. Elevated ALT reported as a Liver Event (meets Liver Monitoring or 
Stopping criteria) 
Elevated ALT reported as a Liver Event (meets Liver Monitoring or Stopping criteria) 
AESI will be all study intervention emergent AEs with System Organ Class (SOC) of 
“Hepatobiliary disorders” OR “Investigations” that have been marked as AESIs by 
investigators, as reported via the Adverse Event eCRF.  
The study team will monitor liver event reporting to ensure that elevated ALT liver 
events are correctly reported as an AE and marked as an AESI on the AE eCRF. 
6.3.8.6. 
Liver related SMQs 
Liver related AEs will be summarized by standardized MedDRA Queries (SMQs). The 
following SMQs will be reported: 
 
SMQ 
1 
Cholestasis and jaundice of hepatic origin (SMQ). 
2 
Drug related hepatic disorders-severe events only (SMQ) 
2a Hepatic failure, fibrosis and cirrhosis and other liver damage related conditions 
(SMQ) 
2b Hepatitis, non-infectious (SMQ) 
3 
Liver related investigations, signs and symptoms (SMQ) 
4 
Liver related coagulation and bleeding disturbance (SMQ) 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 93 of 102 
As per GSK SOP the MedDRA dictionary is reviewed and updated every 6 months. As a 
result, the list of terms that will be used to identify these SMQs will be updated on a 6 
monthly basis following the up versioning of the dictionary. The final list of terms to be 
used will be confirmed at end of study. 
6.3.8.7. 
Rescue Medication 
Rescue medication is permitted only for participants who are not receiving background 
cholestatic pruritus treatment when entering the study. Participants using protocol defined 
rescue medication will be defined as follows: 
Initiation of cholestyramine at or after Week 12, where; 
• 
their Monthly Itch Score at or after Week 12 (Visit 6) has increased by at least 2 
points compared to baseline AND their Monthly Itch Score is ≥ 7 
OR 
• 
their Baseline Monthly Itch Score > 8, AND their Monthly Itch Score at or after 
Week 12 (Visit 6) is 10 
6.3.9. 
Laboratory Parameters 
If a laboratory value which is expected to have a numeric value for summary purposes, 
has a non-detectable level reported in the database, where the numeric value is missing, 
but typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or 
greater than x in the comment field) is present, the number of decimal places in the 
observed values will be used to determine how much to add or subtract in order to impute 
the corresponding numeric value.   
Example 1: 2 Decimal Places   =  ‘< x ‘ becomes x – 0.001       e.g. <0.05 becomes 0.049 
Example 2: 1 Decimal Place     =  ‘< x’ becomes x – 0.01          e.g. <0.2 becomes 0.19 
Example 3: 0 Decimal Places   =  ‘> x’ becomes x + 0.1            e.g. >99 becomes 99.1 
6.3.10. 
Pharmacokinetic Concentrations 
If linerixibat PK concentration is reported as missing in the linerixibat treatment group, 
then this will be reported as missing, if a concentration at V5, V6, V7, V8 or V9 is 
reported as non-quantifiable (NQ), then this will be imputed as ½ lower limit of 
quantification (LLQ) when the sample time is after dosing time, for inclusion in plots and 
PK concentrations summary tables. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 94 of 102 
6.3.11. 
Analysis Variables / Covariates Derivation 
Variable/Covariate 
Derivation 
Baseline cholestyramine use  
(3 Levels: Previous 
cholestyramine use (no 
concomitant use at baseline); 
Baseline concomitant 
cholestyramine; Baseline 
cholestyramine naive) 
Previous cholestyramine use (no concomitant use 
at baseline): 
The Previous PBC/Pruritus Treatments eCRF will 
be used. Where “Cholestyramine” is selected from 
the Bile Acid Binding Resins medications, and 
“Yes” is selected for the “Subject Stopped 
Treatment” field. The Concomitant 
Medication/Therapy eCRF data will also be 
checked to ensure that the medication end date is 
prior to randomisation. 
Baseline concomitant cholestyramine: 
The Previous PBC/Pruritus Treatments eCRF will 
be used. Where “Cholestyramine” is selected from 
the Bile Acid Binding Resins medications, and 
“No” is selected for the “Subject Stopped 
Treatment” field. The Concomitant 
Medication/Therapy eCRF data will also be 
checked. 
Baseline cholestyramine naive: 
Participants will be considered baseline 
cholestyramine naive if they do not meet either of 
the above (i.e., no previous Cholestyramine use and 
no baseline Cholestyramine use). The Concomitant 
Medication/Therapy eCRF data will also be 
checked to ensure there is no reported 
cholestyramine use. 
Baseline concomitant 
cholestatic pruritus therapy 
(3 Levels: Regimen contains 
BABR; Regimen that does not 
contain BABR; No defined anti-
cholestatic pruritus treatment) 
Regimen contains BABR: 
The Previous PBC/Pruritus Treatments eCRF will 
be used. Where “Cholestyramine”, “Colesevelam”, 
“Colestipol” or “Colestilan/Colestimide” is selected 
from the Bile Acid Binding Resins medications, 
and “No” is selected for the “Subject Stopped 
Treatment” field. 
The Concomitant Medication/Therapy eCRF data 
will also be checked for any medications identified 
as: 
• 
Bile acid binding resins 
Regimen that does not contain BABR; 
The Previous PBC/Pruritus Treatments eCRF will 
be used. Where any medication that does not 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 95 of 102 
Variable/Covariate 
Derivation 
contain BABR is selected, and “No” is selected for 
the “Subject Stopped Treatment” field. 
The Concomitant Medication/Therapy eCRF data 
will also be checked for any medications identified 
as: 
• 
Antihistamines: Only when the indication is 
for Itch, as described in Section 4.6.1. 
• 
Fibrates 
• 
Rifampicin/rifampin 
• 
Selective serotonin reuptake inhibitors (e.g., 
sertraline, citalopram, fluoxetine, paroxetine, 
etc.):  
• 
Pregabalin 
• 
Gabapentin 
• 
Opiate antagonists (e.g., naltrexone, 
naloxone, nalfurafine, nalmefene) 
No defined anti-cholestatic pruritus treatment: 
All remaining participants where neither of the 
above are identified. 
Baseline concomitant 
cholestatic pruritus therapy 
(Yes vs. No) 
This will be derived using the “Baseline 
concomitant cholestatic pruritus therapy” variable 
above where: 
Yes: 
When Baseline concomitant cholestatic pruritus 
therapy = “Regimen contains BABR” OR 
“Regimen that doesn’t contain BABR”  
No: 
When Baseline concomitant cholestatic pruritus 
therapy = “No defined anti-cholestatic pruritus 
treatment” 
Baseline concomitant BABR 
(Yes vs. No) 
This will be derived using the “Baseline 
concomitant cholestatic pruritus therapy” variable 
above where: 
Yes: 
When Baseline concomitant cholestatic pruritus 
therapy = “Regimen contains BABR” 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 96 of 102 
Variable/Covariate 
Derivation 
No: 
When Baseline concomitant cholestatic pruritus 
therapy = “No defined anti-cholestatic pruritus 
treatment” OR “Regimen that doesn’t contain 
BABR” 
Baseline concomitant Fibrates 
(Yes vs. No) 
Yes: 
The Previous PBC/Pruritus Treatments eCRF will 
be used. Where "Fenofibrate", "Bezafibrate" or 
"Other" is selected from the "Fibrates" medications, 
and “No” is selected for the “Subject Stopped 
Treatment” field. 
The Concomitant Medication/Therapy eCRF data 
will also be checked for any medications identified 
as: 
• 
Fibrates 
No: 
All remaining participants where no Fibrate use at 
baseline is identified. 
Operating Model 
(3 Level: Metasite, Flexible, 
Brick and Mortar) 
Metasite:  
There is only one metasite planned for this study 
(site number= 251379), therefore any participants 
where ‘SITEID=251379’ will be classed as 
‘Metasite’. 
Flexible: 
Participants where SITEID ne 251379 AND have at 
least 1 study visit conducted remotely during Part A 
will be classed as ‘Flexible’.  
Brick and mortar: 
All remaining participants, where SITEID ne 
251379 AND who have conducted all visits onsite 
(i.e, no remote visits during Part A) will be 
considered ‘Brick and mortar’. 
The number of Visits conducted remotely will be 
captured via the Visit Conduct eCRF at each visit 
using the question “visit conducted remotely” 
(Yes/No). We will use the response to this question 
to flag if any remote visits have been conducted. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 97 of 102 
6.3.12. 
Intercurrent Events 
Intercurrent Event 
Derivation 
Permanent treatment 
discontinuation, disruptions in 
treatment or treatment delays 
unrelated to the COVID-19 
pandemic 
Permanent discontinuation unrelated to 
COVID-19 pandemic: 
• 
Permanent treatment discontinuation (i.e., 
treatment withdrawal or Study withdrawal) will 
be identified via the Study Conclusion eCRF 
and Study Treatment Discontinuation eCRF 
where they have also indicated that the 
discontinuation was not due to the COVID-19 
pandemic – via the question “Participant 
Discontinued From the Study/treatment Due to 
COVID-19 Pandemic”. 
• 
The Intercurrent event date will be the date of 
discontinuation. 
Disruptions or delays in treatment unrelated to 
COVID-19 pandemic: 
• 
Identified using the Study Treatment -
Continual Dosing eCRF. Missed treatment start 
and end dates will be provided. 
• 
A disruption will be considered if at least 1 day 
(both doses missed) of treatment is missed. 
• 
When 1 or more days of treatment are missed, 
the start and end date of the intercurrent event 
will correspond to the start and end dates of the 
missed treatment, respectively. 
Permanent treatment 
discontinuation, disruptions in 
treatment, or treatment delays 
related to the COVID-19 
pandemic 
Permanent discontinuation related to COVID-19 
pandemic: 
• 
Permanent treatment discontinuation (i.e., 
treatment withdrawal or Study withdrawal) will 
be identified via the Study Conclusion eCRF 
and Study Treatment Discontinuation CRF 
where they have also indicated that the 
discontinuation was due to the COVID-19 
pandemic – via the question “Participant 
Discontinued From the Study/treatment Due to 
COVID-19 Pandemic”. 
• 
The Intercurrent event date will be the date of 
discontinuation. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 98 of 102 
Intercurrent Event 
Derivation 
Disruptions or delays in treatment related to 
COVID-19 pandemic: 
• 
Identified using the Study Treatment Supply 
Interruption Due To COVID-19 Pandemic 
eCRF. Interruption start and end dates will be 
provided. 
• 
A disruption will be considered if at least 1 day 
(both doses missed) of treatment is missed. 
• 
When 1 or more days of treatment are missed, 
the start and end date of the intercurrent event 
will correspond to the start and end dates of the 
missed treatment, respectively. 
Change in background itch 
therapy or use of rescue 
medication 
• 
Concomitant Medication/Therapy eCRF will 
be used to identify Changes to background itch 
therapy or use of rescue since randomisation. 
• 
Starting/stopping or changing the dose of any 
itch medications will be considered as a change 
in background itch therapy. 
• 
The start date of the first change in background 
itch medication will be considered as the date 
of the intercurrent event (i.e., if there are 
multiple changes in background medication, 
then the first change will be considered, and 
Itch scores following this will be considered as 
being impacted). 
• 
If there is a partial start/end date, then dates 
will be imputed as per Section 6.3.14. 
6.3.13. 
Multiple measurements at One Analysis Time Point 
When triplicate ECG assessments are taken, mean of the measurement will be calculated 
first and summary statistics will be based on the calculated mean. This will apply to both 
baseline and post baseline assessments. 
For lab tests on a study day, if more than one assessment is taken on the same day, the 
test from a central lab will be taken over the test from a local lab. If multiple assessments 
are taken from the same type of lab test, the worst case will be used. 
Participants having both High and Low values versus Normal Ranges at any post-
baseline visits for safety parameters will be counted in both the High and Low categories 
of “Any visit post-baseline” row of related summary tables.  This will also be applicable 
to relevant Potential Clinical Importance summary tables. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 99 of 102 
If there is more than one entry in the e-diary data for itch, sleep, or fatigue on any 
timepoint (AM or PM) of a day, then the worst score for that day or timepoint will be 
used as described in Section 6.3.7.  
If there is more than one entry for the GSRS questionnaire on any given date or 
timepoint, the worst score will be used for that date or timepoint as conservative 
approach. 
6.3.14. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
• Partial dates will be displayed as captured in participant listing 
displays.   
• However, where necessary, display macros may impute dates as 
temporary variables for sorting data in listings only. In addition, partial 
dates may be imputed for ‘slotting’ data to study phases or for 
specific analysis purposes as outlined below. 
• For Adverse Events, imputed partial dates will not be used to derive 
study day, time to onset or duration (e.g., time to onset or duration of 
adverse events), or elapsed time variables (e.g., time since 
diagnosis). In addition, imputed dates are not used for deriving the 
last contact date in overall survival analysis dataset. 
• 
For Medical History, partial dates will be imputed for the calculation of 
disease duration. 
Adverse Events 
• Partial dates for AE recorded in the CRF will be imputed using the 
following conventions: 
Missing start 
day 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = 1st of month. 
Else if study intervention start date is not missing: 
• 
If month and year of start date = month 
and year of study intervention start date, 
then 
• 
If stop date contains a full date and 
stop date is earlier than study 
intervention start date, then set start 
date= 1st of month. 
• 
Else set start date = study 
intervention start date. 
Else set start date = 1st of month. 
Missing start 
day and month 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = January 1. 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 100 of 102 
Element 
Reporting Detail 
Else if study intervention start date is not missing: 
o 
If year of start date = year of study 
intervention start date, then 
▪ 
If stop date contains a full date and 
stop date is earlier than study 
intervention start date, then set start 
date = January 1. 
▪ 
Else set start date = study 
intervention start date.       
Else set start date = January 1. 
Missing end 
day  
A '28/29/30/31' will be used for the day (dependent 
on the month and year). 
Missing end 
day and month 
No Imputation 
Completely 
missing 
start/end date 
No imputation 
Concomitant 
Medications/Medical 
History 
o Partial dates for any concomitant medications recorded in the CRF 
will be imputed using the following convention: 
o For the calculation of Duration of PBC and Duration of Pruritus, 
partial dates will be imputed using the below convention: 
 
Missing start 
day 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = 1st of month. 
Else if study intervention start date is not missing: 
o 
If month and year of start date = month 
and year of study intervention start date, 
then 
▪ 
If stop date contains a full date and 
stop date is earlier than study 
intervention start date, then set start 
date= 1st of month. 
▪ 
Else set start date = study 
intervention start date. 
Else set start date = 1st of month. 
Missing start 
day and month 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = January 1. 
Else if study intervention start date is not missing: 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 101 of 102 
Element 
Reporting Detail 
o 
If year of start date = year of study 
intervention start date, then 
• 
If stop date contains a full date and 
stop date is earlier than study 
intervention start date, then set start 
date = January 1. 
• 
Else set start date = study. 
intervention start date.       
Else set start date = January 1. 
Missing end day A '28/29/30/31' will be used for the day (dependent 
on the month and year).  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used 
for the month. 
Completely 
missing 
start/end date 
No imputation 
6.3.15. 
Trademarks 
Trademarks of the 
GlaxoSmithKline Group of 
Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of 
Companies 
 
 
Fibroscan 
 
 
SAS 
NONE 
 
Enhanced Liver Fibrosis 


CONFIDENTIAL 
 
212620 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 102 of 102 
7. 
REFERENCES 
Apostolaros M, Babaian D, Corneli A, Forrest A, Hamre G, Hewett J, et al. Legal, 
regulatory, and practical issues to consider when adopting decentralized clinical trials: 
recommendations from the Clinical Trials Transformation Initiative. Therapeutic 
Innovation & Regulatory Science. 2020; 54:779-787. 
GlaxoSmithKline Document Number TMF-16125967: Study 212620 IDMC Charter V2. 
05 May 2023 
GlaxoSmithKline Document Number TMF-16740250: Study 212620 protocol 
amendment 04. 20 Nov 2023 
Wang Y, Tu W, Koh W, et al. Bayesian Hierarchical Models for Subgroup 
Analysis. Pharm Stat. Published online July 15, 2024. doi:10.1002/pst.2424