Conditions: Cholestasis
Keywords: linerixibat PBC itch GSK2330672 GLIMMER primary biliary cholangitis pruritus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 147
Healthy volunteers: no

Brief summary:
This study is being conducted to evaluate the efficacy, safety and tolerability of GSK2330672 administration for the treatment of pruritus (itch) in participants with primary biliary cholangitis (PBC). Participants will receive either placebo or one of the 4 dose regimens of GSK2330672 (20 milligram \[mg\], 90 mg or 180 mg taken once daily or 90 mg twice daily). Participants on GSK2330672 will also receive placebo tablets to maintain blinding. The study has a prospectively defined adaptive design that will utilize interim data to further inform and potentially optimize the doses under investigation. Hence, additional dose regimen may be added during study. The total duration of a participant in the study will be up to 45 days of screening and 24 weeks of study including follow-up.

Detailed description:

Arms:
arm 1: Participants will receive matching placebo arm 2: Participants will receive GSK2330672 and matching placebo to maintain blind arm 3: Participants will receive GSK2330672 and matching placebo to maintain blind arm 4: Participants will receive GSK2330672 and matching placebo to maintain blind arm 5: Participants will receive GSK2330672 and matching placebo to maintain blind arm 6: Participants will receive GSK2330672 and matching placebo to maintain blind

Interventions: intervention 1: Placebo intervention 2: GSK2330672
Intervention descriptions: intervention 1: GSK2330672 matching placebo will be supplied as white film-coated tablets. intervention 2: GSK2330672 will be supplied in 2 dose strengths of 10 mg and 45 mg white film-coated tablets.

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A randomized, double-blind, multi-dose, placebo-controlled study to 
evaluate the efficacy, safety and tolerability of GSK2330672 administration for the 
treatment of pruritus in patients with primary biliary cholangitis.
(GLIMMER: GSK2330672 triaL of IBAT inhibition with Multidose Measurement for 
Evaluation of Response).
Protocol Number: 201000 / 02
Short Title: Dose response study of GSK2330672 for the treatment of pruritus in patients 
with primary biliary cholangitis.
Compound Number:
GSK2330672
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual.
Regulatory Agency Identifying Number(s): IND Number: 130391; EudraCT 
Number:  2016-002416-41
Approval Date: 06-DEC-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
06-Dec-2017
Amendment 1
15-Nov-2016
Original Protocol
26-Aug-2016
Amendment 2: 06-Dec-2017
Overall Rationale for the Amendment: To increase access to the trial for participants 
who will more closely reflect the intended treatment population of PBC patients while 
maintaining safety, to clarify some existing criteria and information, to make 
administrative changes, and to correct minor typographical and grammatical errors
 
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Section # and 
Name
Description of Change
Brief Rationale
2. Schedule of 
Activities
Addition of footnote 11 that in 
the event of a confirmed
baseline (run-in) failure, blood, 
urine, ECG, and Trial Slate 
assessments are not required
To minimize assessments that will not 
contribute to primary and secondary end 
points
2. Schedule of 
Activities
Addition of footnote 12 that 
highlights that randomization 
occurs at Visit 3
To point out that criteria for randomization 
are evaluated at Visit 3
3.3.1 Risk 
Assessment
Under “Investigational Product 
(GSK2330672),” first bullet 
point entitled “Gastrointestinal 
effects including diarrhea,” the 
mitigation strategy has changed 
from “Exclusion of participants 
with current symptomatic 
inflammatory bowel disease or 
malabsorption syndromes” to 
“Exclusion of participants with 
current diarrhea.” 
To clarify that only diarrhea constitutes an 
exclusion criterion
4. Objectives 
and Endpoints
First exploratory endpoint, 
second bullet:  time to 
worsening itch assessment 
changed to Weeks 17-20
To correct an error that incorrectly stated 
that time to worsening of itch would be 
assessed during Weeks 21-24
5.4 Scientific 
Rationale for 
Study Design,
7.7.1 Prohibited 
Medications,
7.7.2 Permitted 
Medications
Added the phrase, “…and 
during the Follow Up Period” to 
indicate when addition of or 
changes to certain medications 
may be made
To clarify that addition of and changes to 
restricted medications during Screening, 
the Initial Study Period, and the Main 
Study Period may be made during the 
Follow Up Period in addition to the Final 
Study Period
6.1 Inclusion 
Criteria
Revision of inclusion criterion 2, 
bullet 2 to read, “antinuclear dot 
and/or nuclear rim” instead of 
“antinuclear dot and rim”
To clarify that a potential participant may 
be positive for one or both PBC-specific 
antinuclear antibodies
6.1 Inclusion 
Criteria
Clarification in inclusion 
criterion 3 that “majority of time” 
means “more than half of the 
days, as recalled by the 
participant”
To define more specifically the recall 
period for itch severity that a participant 
must experience in order to be considered 
for the study
6.1 Inclusion 
Criteria
Clarification in inclusion 
criterion 3 that periods of low 
itch or no itch are acceptable as 
long as the worst daily itch 
score is ≥4 on the majority of 
days
To improve clarity and consistency of 
protocol implementation at screening, 
ensuring a population with moderate to 
severe itch on average is enrolled
 
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Section # and 
Name
Description of Change
Brief Rationale
6.2 Exclusion 
Criteria
Revision of exclusion criterion 1 
to permit potential participants 
with a screening total bilirubin 
up to 2xULN to participate
The trial population will more closely 
reflect the intended treatment population.
6.2 Exclusion 
Criteria
Revision of exclusion criterion 2 
to permit potential participants 
with a screening ALT up to 
6xULN to participate
The trial population will more closely 
reflect the intended treatment population.
6.2 Exclusion 
Criteria
Revision of exclusion criterion 5 
to permit potential participants 
who have other hepatic 
conditions in addition to PBC to 
participate.  PBC must be the 
dominant liver injury in the 
Investigator’s opinion.
The trial population will more closely 
reflect the intended treatment population. 
Actively replicating viral hepatitis B and C 
and confirmed hepatocellular or biliary 
cancer remain exclusions, as does history 
of hepatic decompensation.
6.2 Exclusion 
Criteria
Revision of exclusion criterion 6 
to clarify that only current 
diarrhea is an exclusion
The trial population will more closely 
reflect the intended treatment population.
6.2 Exclusion 
Criteria

Revision of exclusion 
criterion 9 to permit 
potential participants to 
take previously-
excluded 
immunosuppressant 
medications provided 
the medications have 
been at a stable (i.e., 
unchanged) dose for at 
least 2 months prior to 
the screening visit

Addition of a note 
beneath the newly 
revised exclusion 
criterion 9 that reads, 
“Note:  If a change in 
dose in any of these 
medications is 
anticipated during the 
course of the study, the 
participant should be 
excluded.  [Rationale:  
Limited evidence 
indicates these drugs 

The trial population will more 
closely reflect the intended 
treatment population.

The requirement for dose stability 
as detailed in the “note” that 
follows exclusion criterion 9 will 
minimize the risk that 
immunosuppressant medications 
could influence the secondary 
endpoint of change in ALP.
 
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Section # and 
Name
Description of Change
Brief Rationale
may alter disease 
progression in some 
PBC patients.]”
6.2 Exclusion 
Criteria
Addition of exclusion criterion 
14:  “Administration of any 
other IBAT inhibitor in the 3 
months prior to screening 
[Rationale:  Effects of another 
IBAT inhibitor may influence 
pruritus.]”
To ensure a thorough washout period for 
the use of another IBAT inhibitor well 
before possible administration of 
GSK2330672 to avoid confounding effects  
6.2 Exclusion 
Criteria
Revision of previous exclusion 
criterion 15, which in 
Amendment 02 is criterion 16, 
to permit potential participants 
with QTc up to 480 msec, 
regardless of the presence of 
bundle branch block, to 
participate
The trial population will more closely 
reflect the intended treatment population.
6.3 Criteria for 
Randomization
Revision of final paragraph to 
explain that participants who 
fail randomization criteria will 
be considered baseline (run-in) 
failures, and that the way to 
access the eligibility criteria is 
explained in the Study 
Reference Manual
To clarify how participants who fail 
randomization will be categorized within 
the trial data and to inform the reader how 
to access the eligibility information for a 
participant
6.5 Screen and 
Baseline 
Failures
Change of title of section from 
“Screen Failures” to “Screen 
and Baseline Failures”
To emphasize the differences between 
“screen failures” and “baseline failures” 
within the study
6.5.1 Screen 
Failures
Addition of Section 6.5.1
To clarify the differences between “screen 
failures” and “baseline failures” within the 
study
6.5.1 Screen 
Failures
Addition of permission to re-
screen participants who 
potentially become eligible as a 
result of a protocol amendment
The trial population will more closely 
reflect the intended treatment population.
Rescreening is only permitted where the 
participant would have met all the eligibility 
requirements of the amended protocol at 
the time of the first (original) screening 
visit.  The rescreened participants must 
meet all the eligibility requirements at the 
time of the rescreening (subsequent 
 
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Section # and 
Name
Description of Change
Brief Rationale
screening) visit to become eligible.
Rescreening is only permitted once for 
each relevant amendment.
6.5.2 Baseline 
(Run-In Failures)
Addition of Section 6.5.2 to 
differentiate screen failures 
from baseline failures

To clarify the differences between 
“screen failures” and “baseline 
failures” within the study

To clarify what assessments are 
required at Visit 3 when a 
baseline failure has been 
confirmed in order to minimize 
burden to a participant who will 
not complete the entire study
7.7 Concomitant 
Therapy

Addition of “topical 
agents including topical 
corticosteroids” to the 
list of medicines that 
must be recorded 
within the eCRF

Addition of “(including 
any topical medications 
and rescue therapy) to 
the “Note” in this 
section

To clarify that use of topical 
medications must be accounted 
for within the eCRF

To clarify that topical medications 
and rescue therapy used during 
the Final Study Period and 
reported in the Follow Up 
Telephone Contact will be 
recorded within the eCRF
7.7.1 Prohibited 
Medications
Deletion of immunosuppressant 
medications which are now 
permitted at stable doses 
according to the revised 
exclusion criterion 9 (Section 
6.2)
To ensure consistency with the revised 
exclusion criterion
7.7.1 Prohibited 
Medications
Addition of other IBAT inhibitors 
as a prohibited medication
To ensure consistency with the new 
exclusion criterion 14
7.7.2 Permitted 
Medications
Addition of the sentence, “All
use of any concomitant 
medications, including topical 
agents, must be recorded 
within the eCRF.”
To clarify that topical agents may be used 
and to emphasize that all concomitant 
medications must be recorded within the 
eCRF
7.7.2 Permitted 
Medications
Under “UDCA;” “Rifampicin, 
naltrexone, naloxone, 
nalfurafine, or sertraline;” and 
“Bezafibrate or fenofibrate;” the 
words “…and the Follow Up 
To clarify that during both the Final Study 
Period and the Follow Up Period use of 
these particular agents may be permitted
 
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Section # and 
Name
Description of Change
Brief Rationale
Period” were inserted after, 
“During the Final Study Period.”
7.7.2:  Permitted 
Medications
Addition of “Colchicine, 
methotrexate, azathioprine, or 
systemic corticosteroids may 
be used as long as the dose 
has remained stable for 2 
months prior to screening and 
that no change in dose is 
anticipated for the duration of 
the study.  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.”
The trial population will more closely 
reflect the intended treatment population.
7.7.3 Rescue 
Therapy
The words, “…and the Follow 
Up Period” were inserted after 
the phrase “During the Final 
Study Period” in the first 
sentence
To clarify that during both the Final Study 
Period and the Follow Up Period use of 
these particular agents may be permitted
7.7.3 Rescue 
Therapy
Clarification that use of rescue 
therapy should be recorded in 
the eCRF
To emphasize that rescue therapy, like 
any other therapy given during the trial, 
should be recorded in the eCRF
8.1.1 Liver 
Chemistry 
Stopping Criteria
Change of the section title from 
“Liver Chemistry Stopping 
Criteria” to “Liver Chemistry 
Increased Monitoring and
Stopping Criteria”
To clarify that this section contains both 
the increased monitoring and stopping 
criteria, and to emphasize that these 
criteria are different from each other
8.1.1 Liver 
Chemistry 
Increased 
Monitoring and 
Stopping Criteria

Insertion of Table 4 
heading for Liver 
Chemistry Criteria for 
Increased Monitoring; 
addition of an action 
column, and 
simplification of the 
table format

Insertion of Table 5 
heading for Liver 
Chemistry Criteria for 
Stopping Study 
Treatment; addition of 

To provide easier identification of 
the Tables within the protocol and 
provide clarity on follow-up 
actions

To ensure in this population with 
abnormal baseline liver chemistry 
that frequency of liver chemistry 
monitoring is increased or study 
treatment is stopped at the most 
appropriate time to maintain 
participant safety.  For most 
participants, this is a “fold 
increase from baseline” in ALT or 
 
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Section # and 
Name
Description of Change
Brief Rationale
an action column, and 
simplification of the 
table format

Revision of thresholds 
for increased 
monitoring of liver 
chemistry and for 
stopping study 
treatment to be defined 
principally in terms of 
“fold change from 
baseline values” while 
retaining some 
definitions in “fold of 
change from ULN 
values” in extreme 
cases.  Revision of 
section text to refer to 
liver chemistry criteria 
for increased 
monitoring and 
stopping of study 
treatment
total bilirubin values. For those 
with the largest baseline 
abnormalities, an absolute 
stopping threshold defined in 
multiples of ULN is retained.

To clarify that repeat testing 
applies to both increased 
monitoring and stopping criteria, 
and that “stopping” refers to 
stopping of study treatment

To improve clarity by aligning 
requirements for stopping criteria 
to Appendix 4
8.1.2 QTc 
Stopping Criteria

Amendment of 
threshold for stopping 
study treatment to QTc 
≥530 msec

Removal of criteria for 
bundle branch block
The trial population will more closely 
reflect the intended treatment population.  
Since the exclusion criteria was changed, 
the stopping criteria had to be changed 
accordingly to ensure that study treatment 
is stopped appropriately in the event of 
QTc prolongation.
As previously, an increase in QTc of >60 
msec will also trigger study treatment 
discontinuation.
9.1.1 Electronic 
Data Collection
Change of “eDevice” to 
“TrialMax Slate”
To clarify that the electronic device that is 
used in the clinic is called a “TrialMax 
Slate”
9.1.2.1 Patient 
Reported 
Symptom 
Questionnaires
Update of the interference of 
itch with sleep NRS to indicate 
that a score of 
 represents 
To correct an error and to align with the 
eDiary
9.2.1 Time 
Period and 
Frequency for 
Clarification that SAEs should 
be reported to the Sponsor 
immediately and reporting must 
Administrative update of Sponsor-required 
protocol text
 
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Section # and 
Name
Description of Change
Brief Rationale
Collecting AE 
and SAE 
Information
not exceed 24 hours from the 
time that the site is notified
9.4.4 Clinical 
Safety 
Laboratory 
Assessments
Deletion of final bullet requiring 
collection in the eCRF of non-
protocol specified local 
laboratory values that are 
considered clinically significant 
or that result in a change in the 
participant’s management. 
(Note AEs/SAEs associated 
with laboratory findings 
continue to be reported in the 
eCRF).
Administrative update of Sponsor-required 
protocol text
10.1 Sample 
Size 
Determination
Change from “Table 4” to 
“Table 6”
To realign the table numbers within the 
protocol after providing numbers to other 
tables within the document
10.3.4 Interim 
Analyses
Removal of the word 
“Sponsor’s”
To clarify that trial leadership will review 
the results of the analysis
12.2. Appendix 
2:  
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information

Change from “Table 5” 
to “Table 7”

Removal of footnote “b” 
superscript

To realign the table numbers 
within the protocol after providing 
numbers to other tables within the 
document

No footnote “b” exists in the table.
12.3. Appendix 
3: Study 
Governance 
Considerations

Sub-section on 
Informed Consent 
Process:  deletion of 
paragraph beneath 
bullets

Included in error since use of 
remaining mandatory biomarker 
samples for optional exploratory 
research does not apply

Added section called 
“Dissemination of 
Clinical Study Data”

Administrative update of Sponsor-
required protocol text
12.4 Appendix 4: 
Liver Safety: 
Required 
Actions and 

Insertion of Figures 3 
and Figures 4 

To facilitate understanding of how 
to implement the liver criteria for 
increased monitoring and for 
stopping study treatment
 
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Section # and 
Name
Description of Change
Brief Rationale
Follow-up 
Assessments

Insertion of Section 
header 12.4.1 
(Procedures When 
Liver Stopping Criteria 
are Met) above pre-
existing text 
(unchanged).

To improve clarity

Reordering of bulleted 
list under 12.4.1

To list the actions in the likely 
order they will be conducted
12.5 Appendix 5: 
Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, 
Follow-up, and 
Reporting
Under SAE Reporting to GSK 
via Electronic Data Collection 
Tool:  revision of second bullet 
to clarify that if the electronic 
system is unavailable, the 
paper reporting tool should be 
used to ensure SAE reporting 
within 24 hours.
Administrative update of Sponsor-required 
protocol text
12.6 Appendix 6:  
Clinical 
Laboratory Tests
Change Table from Table 6 to 
Table 8
To realign the table numbers within the 
protocol after providing numbers to other 
tables within the document
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
TABLE OF CONTENTS ................................................................................................12
1.
SYNOPSIS.............................................................................................................15
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................19
3.
INTRODUCTION....................................................................................................24
3.1.
Study Rationale ..........................................................................................24
3.2.
Background ................................................................................................24
3.3.
Benefit/Risk Assessment ............................................................................25
3.3.1.
Risk Assessment .........................................................................26
3.3.2.
Benefit Assessment.....................................................................28
3.3.3.
Overall Benefit:Risk Conclusion...................................................28
4.
OBJECTIVES AND ENDPOINTS...........................................................................28
5.
STUDY DESIGN ....................................................................................................32
5.1.
Overall Design ............................................................................................32
5.2.
Number of Participants ...............................................................................33
5.3.
Participant and Study Completion...............................................................34
5.4.
Scientific Rationale for Study Design ..........................................................34
5.5.
Dose Justification........................................................................................35
6.
STUDY POPULATION...........................................................................................36
6.1.
Inclusion Criteria.........................................................................................36
6.2.
Exclusion Criteria........................................................................................37
6.3.
Criteria for Randomization ..........................................................................39
6.4.
Lifestyle Restrictions...................................................................................39
6.4.1.
Meals and Dietary Restrictions ....................................................39
6.4.2.
Caffeine, Alcohol, and Tobacco ...................................................39
6.4.3.
Activity .........................................................................................40
6.5.
Screen and Baseline Failures .....................................................................40
6.5.1.
Screen Failures............................................................................40
6.5.2.
Baseline (Run-In) Failures ...........................................................40
7.
TREATMENTS.......................................................................................................41
7.1.
Treatments Administered............................................................................41
7.1.1.
Study Treatment Administration...................................................41
7.2.
Dose Modification .......................................................................................42
7.3.
Method of Treatment Assignment ...............................................................43
7.3.1.
Treatment Assignment in the Study Periods ................................43
7.4.
Blinding.......................................................................................................44
7.5.
Preparation/Handling/Storage/Accountability..............................................44
7.6.
Treatment Compliance................................................................................45
7.7.
Concomitant Therapy..................................................................................45
 
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7.7.1.
Prohibited Medications.................................................................45
7.7.2.
Permitted Medications .................................................................46
7.7.3.
Rescue Therapy ..........................................................................47
7.8.
Treatment after the End of the Study ..........................................................47
8.
DISCONTINUATION CRITERIA.............................................................................47
8.1.
Discontinuation of Study Treatment ............................................................47
8.1.1.
Liver Chemistry Increased Monitoring and Stopping 
Criteria.........................................................................................47
8.1.2.
QTc Stopping Criteria ..................................................................49
8.1.3.
Renal Stopping Criteria................................................................49
8.1.4.
Other Stopping Criteria ................................................................49
8.1.5.
Temporary Discontinuation ..........................................................49
8.1.6.
Rechallenge.................................................................................50
8.1.6.1.
Study Treatment Restart or Rechallenge....................50
8.2.
Withdrawal from the Study..........................................................................50
8.3.
Lost to Follow Up........................................................................................50
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................51
9.1.
Efficacy Assessments.................................................................................51
9.1.1.
Electronic Data Collection............................................................51
9.1.2.
Patient Reported Outcomes (PROs)............................................52
9.1.2.1.
Patient Reported Symptom Questionnaire..................52
9.1.2.2.
PBC-40 Health-Related Quality of Life Scale..............52
9.1.2.3.
5-D Itch Scale.............................................................53
9.1.2.4.
Gastrointestinal Symptom Rating Scale 
(GSRS).......................................................................53
9.1.2.5.
Other PRO Measures.................................................53
9.1.3.
Actigraphy Sub-Study ..................................................................54
9.2.
Adverse Events...........................................................................................54
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................54
9.2.2.
Method of Detecting AEs and SAEs.............................................55
9.2.3.
Follow-up of AEs and SAEs.........................................................55
9.2.4.
Regulatory Reporting Requirements for SAEs .............................55
9.2.5.
Cardiovascular and Death Events................................................56
9.2.6.
Pregnancy ...................................................................................56
9.3.
Treatment of Overdose...............................................................................56
9.4.
Safety Assessments ...................................................................................57
9.4.1.
Physical Examinations.................................................................57
9.4.2.
Vital Signs....................................................................................57
9.4.3.
Electrocardiograms......................................................................58
9.4.4.
Clinical Safety Laboratory Assessments ......................................58
9.5.
Pharmacokinetics .......................................................................................58
9.6.
Pharmacodynamics ....................................................................................60
9.7.
Genetics .....................................................................................................60
9.8.
Biomarkers .................................................................................................60
9.9.
Medical Resource Utilization and Health Economics ..................................61
10. STATISTICAL CONSIDERATIONS........................................................................61
10.1.
Sample Size Determination ........................................................................61
10.2.
Populations for Analyses ............................................................................63
 
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10.3.
Statistical Analyses.....................................................................................64
10.3.1.
Efficacy Analyses.........................................................................64
10.3.2.
Safety Analyses...........................................................................65
10.3.3.
Other Analyses ............................................................................65
10.3.4.
Interim Analyses ..........................................................................66
11. REFERENCES.......................................................................................................67
12. APPENDICES........................................................................................................68
12.1.
Appendix 1: Abbreviations and Trademarks................................................68
12.2.
Appendix 2: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................72
12.3.
Appendix 3: Study Governance Considerations..........................................75
12.4.
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................79
12.4.1.
Procedures When Liver Stopping Criteria are Met .......................80
12.5.
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................83
12.6.
Appendix 6: Clinical Laboratory Tests.........................................................89
12.7.
Appendix 7: Genetics..................................................................................90
12.8.
Appendix 8: Country-specific requirements.................................................91
12.9.
Appendix 9: Protocol Amendment History...................................................92
 
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1.
SYNOPSIS
Protocol Title: A randomized, double-blind, multi-dose, placebo-controlled study to 
evaluate the efficacy, safety and tolerability of GSK2330672 administration for the 
treatment of pruritus in patients with primary biliary cholangitis.
(GLIMMER: GSK2330672 triaL of IBAT inhibition with Multidose Measurement for 
Evaluation of Response).
Short Title: Dose response study of GSK2330672 for the treatment of pruritus in 
patients with primary biliary cholangitis.
Rationale:
This study is being conducted to evaluate the efficacy, safety, and tolerability of a range 
of doses of GSK2330672 for the treatment of adults with moderate to severe pruritus 
associated with primary biliary cholangitis (PBC). 
Objectives and Endpoints:
Objective
Endpoint
Primary

To investigate the dose response of oral 
GSK2330672 on itch in PBC patients with 
moderate to severe pruritus at Baseline.

Mean change from Baseline at Week 16 in 
the Mean Worst Daily Itch Score1.
Key Secondary

To characterize the effects of GSK2330672 
compared to placebo on impact of 
symptoms and quality of life in PBC patients 
with moderate to severe pruritus at 
Baseline.

Mean change from Baseline at Week 16 in 
PBC-40 Scale.

To evaluate the effects of GSK2330672 
compared to placebo on markers of disease 
among participants at high risk of PBC 
progression (i.e., those with serum alkaline 
phosphatase [ALP] concentrations 1.67x
upper limit of normal [ULN] and/or total 
bilirubin concentrations >ULN at Day 1).
In participants meeting the criteria for high risk 
of PBC progression:

Mean change from Baseline at Week 16 in 
serum ALP concentrations. 

Proportion of participants having serum ALP 
concentrations <1.67x ULN and total 
bilirubin concentrations ULN at Week 16.

Mean change from Baseline at Week 16 in 
serum alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), gamma-
glutamyl transferase (GGT), total bilirubin 
and albumin concentrations, and 
prothrombin time/international normalised 
ratio (PT/INR).
 
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Objective
Endpoint
Other Secondary

To determine the safety and tolerability of 
GSK2330672 compared to placebo in PBC 
patients with moderate to severe pruritus at 
Baseline.

Adverse events (AEs), clinical laboratory 
parameters, electrocardiograms (ECGs) 
and vital signs and the Gastrointestinal 
Symptoms Rating Scale (GSRS).

To evaluate to the effects of GSK2330672 
compared to placebo on itch response rates 
in PBC patients with moderate to severe 
pruritus at Baseline.

Proportion of participants who are 
responders at Week 16 based on each of 
the following separate definitions:

Mean Worst Daily Itch Score1 of <4.

At least a 30% reduction from 
Baseline in the Mean Worst Daily Itch 
Score1.

At least a 2-point reduction from 
Baseline in the Mean Worst Daily Itch 
Score1.

Mean number of responder days during 
Weeks 5 to 16 based on each of the 
following separate responder day2
definitions:

Worst Daily Itch Score of <4.

Worst Daily Itch Score at least 30% 
lower than the Baseline Mean Worst 
Daily Itch Score.

Worst Daily Itch Score at least 
2-points lower than the Baseline Mean 
Daily Score. 

To further characterize the effects of 
GSK2330672 compared to placebo on 
symptoms and quality of life in PBC patients 
with moderate to severe pruritus at 
Baseline.
Change from Baseline at Week 16 in:

Mean Daily Sleep Score3.

Mean Daily Fatigue Score4.

5-D Itch scale

To evaluate the effects of GSK2330672 
compared to placebo on total serum bile 
acid concentrations and on bile acid 
synthesis in PBC patients with moderate to 
severe pruritus at Baseline.

Mean change from Baselineat Week 16 in 
serum concentrations of total bile acids and 
serum 7--hydroxy-4-cholesten-3-one (C4) 
as a marker of bile acid synthesis. 
 
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Objective
Endpoint

To investigate the pharmacokinetics (PK) 
of oral GSK2330672 in PBC patients with 
moderate to severe pruritus at Baseline.

Plasma concentrations of GSK2330672 
after sparse sampling (PK parameters will 
be reported if data permit).
1.
Mean Worst Daily Itch Score: participant’s itch severity is recorded on an electronic diary (eDiary) each morning 
and evening using a 0-10 numerical rating scale (NRS), the Worst Daily Itch Score is averaged over the 7 days 
preceding randomization at Visit 3 (Baseline) and over the 7 days preceding Visit 6 (Week 16). 
2.
A responder day is based on the Worst Daily Itch Score recorded using the 0-10 NRS for that day. When the 
responder day definition is relative to Baseline, the Worst Daily Itch Score is compared to the Mean Worst Itch 
Daily Score for Baseline (see 1 above).
3.
Mean Daily Sleep Score: participant’s sleep quality is recorded on the eDiary each morning using a 0-10 NRS and 
the Daily Sleep Score is averaged over the 7 days preceding randomization at Visit 3 (Baseline) and over the 7 
days preceding Visit 6 (Week 16).
4.
Mean Daily Fatigue Score: participants fatigue level is recorded on the eDiary each evening using a 0-10 NRS 
and the Daily Fatigue Score is averaged over the 7 days preceding randomization at Visit 3 (Baseline) and over 
the 7 days preceding Visit 6 (Week 16).
Note: 
For all other endpoints Baseline is defined as the Visit 3 assessment and Week 16 is defined as the Visit 6 
assessment.
In addition to Week 16, which is the primary time point of interest, other intermediate time points will also be 
assessed.
Overall Design:
This is a phase IIb, multicenter, randomized, double-blind, placebo-controlled, parallel 
group, five arm dose-finding study in adults with moderate to severe pruritus associated 
with PBC.  The study has an adaptive design which aims to utilize interim data to further 
inform and potentially optimize the doses under investigation. 
Following the Screening Visit, there will be four study periods: 

Initial Study Period: Single-blind placebo treatment for 4 weeks during which 
participant’s symptoms will be recorded in the electronic diary (eDiary) to establish 
baseline symptoms and assess eligibility for randomization and compliance with 
study procedures.

Main Study Period: Eligible participants will be randomized to receive 12 weeks 
double-blind treatment with either placebo or one of 4 doses of GSK2330672 
administered either once daily or twice daily.  Randomization will be stratified based 
on participant’s risk of PBC disease progression based on serum alkaline 
phosphatase (ALP) and total bilirubin concentrations at Day 1. Participants will 
attend study visits every 4 weeks.

Final Study Period: Single-blind placebo treatment for 4 weeks to assess symptoms 
and safety post-completion of double-blind treatment.

Follow-up Period: to assess symptoms and use of anti-pruritus medications by 
telephone visit.
 
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Eligible participants may continue to receive some therapies for the treatment of PBC 
provided these are maintained at stable doses and there is no plan to discontinue them
during the study.  Concomitant use of cholestyramine, colesevalem, colestimide or
colestipol is not permitted until after completion of the Main Study Period.  Obeticholic 
acid use is not permitted at any time during the study.
In addition, an exploratory Actigraphy Sub-study will be conducted in a sub-set of 
participants who give consent.
Number of Participants:
Approximately 150 adult participants with PBC and moderate to severe pruritus will be 
screened to achieve approximately 118 randomized and approximately 100 evaluable 
participants overall. Should emerging data diverge significantly from protocol 
assumptions, the total sample size will be adjusted to include up to 160 randomized 
participants, and approximately 200 screened participants.
If during the study screen failure rates are higher than anticipated, the number of screened 
participants may be increased.
Treatment Groups and Duration:

Following the Screening Visit (Visit 1) eligible participants will enter the Initial 
Study Period within 45 days.

Initial Study Period: Single-blind placebo treatment for 4 weeks.  Participants will 
commence single-blind study treatment at Visit 2 (Day 1).

Main Study Period: Eligible participants will be randomized to receive 12 weeks 
double-blind treatment with either placebo or one of 4 dose regimens of 
GSK2330672 (20 mg, 90 mg or 180 mg taken once daily or 90 mg twice daily).  

Final Study Period: Single-blind placebo treatment for 4 weeks.

Follow-up Period: 4 weeks.
A participant’s total duration of study participation will be approximately 24 weeks from 
Visit 2 (Day 1) of the Initial Period to completion of the Follow-up Telephone Visit.
All study treatment will be administered orally twice daily, using placebo tablets as 
necessary to blind dose and regimen. During the Initial, Main and Final Study Periods it 
is important that participants remain blind to changes in study treatment e.g. from single-
blind placebo to randomized double-blind treatment and subsequently to single-blind 
placebo.  Investigator and study site staff communication with participants should ensure 
maintenance of each participant’s blinding to treatment throughout the study.
Based on interim data, the study may be adapted to remove or add dose regimens of 
GSK2330672 up to a maximum total daily dose of 360 mg.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Schedule of Activities
Screening
Initial 
Study 
Period
Main Study Period
Final Study 
Period
Follow-up
Period (FU)
Early End of 
Treatment or
Study 
Withdrawal
Assessments1
Visit Name
Visit 1
(Screening)
Visit 2
(Day 1)
Visit 311
(Baseline/
Week 4)
Visit 4
(Week 8)
Visit 5 
(Week 12)
Visit 6
(Week 16)
Visit 7
(Week 20)
Visit 8
(End of FU 
Phone Visit/ 
Week 24)
Day number
(window)
Day -45 to -1
Day 1
Day 28
(Day 28 to 35)
Day 56
(Day 56 to 63)
Day 84
(Day 84 to 91)
Day 112
(Day 112 to 
119)
Day 140
(Day 140 to
147)
Day 168
(Day 168 to 
175)
Procedure
Screening procedures
X2
Brief physical exam 
inc. weight
X
X
X
X
X
X
X
Concomitant 
medications
X2
X
X
X
X
X
X
X
12-lead ECG
X2
X
X
X
X
X
X
X
Vital signs (HR and 
BP)
X2
X
X
X
X
X
X
X
Pregnancy test (urine 
dipstick) in WOCBP
X2
X3
X
X
X
X
X
X
Clinical laboratory 
tests4
X2
X
X
X
X
X
X
X
AE Assessment
X
X
X
X
X
X
X
Study treatment 
dispensing
X
X
X
X
X
Study treatment 
administration 
<---------------------Participants administer morning and evening each day------------------------>
Study treatment 
compliance
X
X
X
X
X
Final eligibility and 
Randomization
X12
 
 
 
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Screening
Initial 
Study 
Period
Main Study Period
Final Study 
Period
Follow-up
Period (FU)
Early End of 
Treatment or
Study 
Withdrawal
Assessments1
Visit Name
Visit 1
(Screening)
Visit 2
(Day 1)
Visit 311
(Baseline/
Week 4)
Visit 4
(Week 8)
Visit 5 
(Week 12)
Visit 6
(Week 16)
Visit 7
(Week 20)
Visit 8
(End of FU 
Phone Visit/ 
Week 24)
Day number
(window)
Day -45 to -1
Day 1
Day 28
(Day 28 to 35)
Day 56
(Day 56 to 63)
Day 84
(Day 84 to 91)
Day 112
(Day 112 to 
119)
Day 140
(Day 140 to
147)
Day 168
(Day 168 to 
175)
PD/Biomarker blood 
samples4
X
X
X
X
X
X
FOBT5
X
X
Genetics sample6
X
PK samples7
X
X
X
Symptom eDiary
<-----------------------------------------------Morning and evening each day---------------------------------->
GSRS and GI 
symptoms on eDiary
<--------------------------------------------------------Once weekly------------------------------------------------->
PBC-40 Scale
X2
X
X
X
X
X
X
X
5D-Itch Scale
X
X
X
X
X
EuroQOL 5D-5L
X
X
X
X
PGI-S
X
X
X
X
X
X
X
PGI-C
X
X
X
X
X
X
BDI-II
X2
X
X
X
Actigraphy8
X
X
X
Participant Treatment 
Experience 
Assessment
X
X9
Telephone review10
X
Footnotes:
1.
Early End of Treatment Assessments to be completed for participants who prematurely discontinue study treatment following randomization (see Section 8.1).  Study Withdrawal 
Assessments to be completed for participants who withdraw consent for any further participation in the study following randomization (see Section 8.2). Note: If a participant 
discontinues study treatment at the same time they withdraw from the study, only the End of Treatment Assessments are required.
2.
See Table 2 for detailed description of Screening Procedures.
3.
Urine dipstick pregnancy test will be standard unless serum testing is required by local regulation or IRB/IEC.  Urine dipstick test at Visit 2 not required if the screening test was 
 
 
 
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performed <1 week of Visit 2.
4.
For clinical laboratory tests see Section 9.4.4 and biomarkers see Section 9.8. All laboratory and biomarker assessments will be fasting (water, study treatment and other 
medications are permitted) except for Screening Visit.
5.
FOBT (card test on 2 different stool/fecal samples) will be performed by participant at home prior to the visit. 
6.
Genetics sample in randomized participants only, to be collected preferably at Visit 3, but may be collected at Visit 4.
7.
PK sample at Visit 3 for participants on UDCA only. At other visits, two plasma samples will be collected on each PK occasion in all participants (see Section 9.5).  If PK sample 
collection is not collected at Visit 5 it may alternatively be collected at Visit 6. Note: PK sample collection is not required for participants who have prematurely discontinued study 
treatment and have not taken study treatment on the 3 or more days prior to the Visit.
8.
Participants who give consent for the Actigraphy Sub-study will be given actigraphy monitors at Visit 2, Visit 4 and Visit 5 with activity measurements performed over at least 5 
nights during Weeks 2 or 3, 9 or 10, and 13 or 14 respectively (see Section 9.1.3).
9.
Participant Treatment Experience Assessment only required for Early End of Treatment Assessments.
10. End of Follow Up Telephone Visit to review participant’s itch and anti-pruritus medications.
11. In the event of a confirmed baseline (run-in) failure at Visit 3, blood, urine, ECG, and TrialMax Slate assessments are not required, and no further study treatment will be 
dispensed.  If the FOBT has been collected and returned by the participant, it should be sent to the laboratory for evaluation.  Refer to Section 6.5.2 for more information.
12. Randomization criteria must be met at this visit for a participant to be randomized.  Refer to Section 6.3.
Abbreviations:
AE= Adverse Event; BDI-II= Beck Depression Inventory-II; BP= Blood Pressure; ECG= Electrocardiogram; EQ-5D= EuroQOL 5D-5L; FOBT= Fecal Occult Blood Test; GI= 
gastrointestinal; GSRS= Gastrointestinal Symptoms Rating Scale; HR= Heart Rate; IEC= Independent Ethics Committee; IRB= Institutional Review Board; PD= Pharmacodynamic; 
PGI-S= Patient Global Impression of Severity; PGI-C= Patient Global Impression of Change; PK= Pharmacokinetics; UDCA= Ursodeoxycholic acid; WOCBP= Women of Child Bearing 
Potential

For assessments scheduled at the same visit, where possible they should be performed in the following order: fasting blood tests and 
pharmacokinetic (PK) sample (1-3 hour post-dose), patient reported outcomes (PROs) [i.e., PGI-S, PGI-C, PBC-40, 5D-Itch, EQ-5D, 
BDI-II, Participant Treatment Experience Assessment], ECGs, vital signs, physical exam, other assessments, PK sample (5-8 hours 
post-dose). See Section 9 for further details.

All reasonable attempts should be made to ensure compliance with the visit schedule, however participants will not be considered out 
of compliance if visit windows extend because of extraordinary events that make it impossible for participants to complete a visit 
within the required window. Determination of the maximum visit window deviation is at the discretion of the Medical Monitor.

The timing and number of planned study assessments specifically PK or pharmacodynamic (PD)/biomarkers assessments 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. 
 
 
 
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
Any changes in the timing or addition of time points for any planned study assessments specified above must be documented and 
approved by the relevant study team member and then archived in the sponsor and site study files, but will not constitute a protocol 
amendment. The Institutional Review Boards (IRB)/ Independent Ethics Committees (IEC) will be informed of any safety issues that 
require alteration of the safety monitoring scheme or amendment of the informed consent form (ICF).
 
 
 
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Table 2
Screening Procedures
Screening
Notes
Visit 1
Window
Day -45 to -1
Procedure
Informed Consent
X
Inclusion/Exclusion Criteria
X
Demography
X
Full physical examination including height 
and weight
X
Medical history (includes substance usage, 
family history of liver disease, cancer and 
cardiovascular disease)
X
Substances: alcohol and tobacco 
Past and current medical conditions, 
including PBC and pruritus history, and 
associated medications
X
Includes use and response to 
UDCA, cholestyramine, 
colesevalem and other anti-pruritus 
medications
PBC-40 Scale
X
BDI-II
X
12-lead ECG
X
Vital signs
X
Laboratory assessments (non-fasting), 
including liver chemistries
X
Urine dipstick pregnancy test (WOCBP 
only)1
X
Hepatitis B and C screening
X
Footnotes:
1.
Urine testing will be standard unless serum testing is required by local regulation or IRB/IEC.
Abbreviations
BDI-II= Beck Depression Inventory-II
ECG= electrocardiogram
PBC= Primary Biliary Cholangitis
WOCBP = Women Of Child Bearing Potential
UDCA = Ursodeoxycholic acid
 
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3.
INTRODUCTION
GSK2330672 is a selective inhibitor of the human ileal bile acid transporter (IBAT) that 
is being developed as a novel, oral treatment for pruritus associated with primary biliary 
cholangitis (PBC).
3.1.
Study Rationale
This study is being conducted to evaluate the efficacy, safety and tolerability of a range 
of doses of GSK2330672 for the treatment of adults with moderate to severe pruritus
associated with PBC. A secondary objective is to evaluate the potential of GSK2330672 
to improve markers of disease progression in PBC patients at increased risk of 
developing advanced disease.
3.2.
Background
Primary biliary cholangitis is a rare, chronic condition caused by the inflammatory 
destruction of the intrahepatic bile ducts giving rise to impaired bile acid flow and 
retention in the liver, leading to hepatic scarring, fibrosis and ultimately cirrhosis and 
liver failure. A major symptom associated with PBC is pruritus, which is an intense 
itching that can occur anywhere on the body, often resulting in disturbed sleep and 
having a significant impact on a patient’s quality of life.  Currently there are few 
therapies that provide effective relief of pruritus.
Located in the distal ileum of the gastrointestinal tract, IBAT is responsible for the active
reuptake of bile acids from the gut lumen that are then returned to the liver via the portal 
vein, resulting in efficient enterohepatic conservation of bile acids, and negative feedback 
regulation of hepatic bile acid synthesis. 
For patients with PBC, inhibition of IBAT by GSK2330672 is anticipated to increase 
excretion of bile acids and reduce bile acid concentrations in the liver and systemic 
circulation, resulting in reduced pruritus and associated symptoms. The associated
alterations in hepatic bile acids have the potential to reduce liver damage and slow PBC 
disease progression.
A previous study in 22 PBC patients with pruritus (GSK study BAT117213) 
demonstrated an improvement in patient-reported itch symptoms during 14 days 
treatment with GSK2330672 90mg twice daily compared to placebo. Where 
improvements in itch were observed, they were evident by 7 days of treatment and 
continued through the treatment period. Most itch scores began to worsen following end 
of treatment with the majority not returning to baseline within 2 weeks. The present study 
is designed to further assess the drug’s therapeutic potential in terms of efficacy, 
durability of effect, dose-response relationship, safety and tolerability.
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK2330672 is provided in the Investigator’s Brochure (IB).
 
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3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of GSK2330672 may be found in the IB and 
Participant Information Leaflet.
 
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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product [GSK2330672]

Gastrointestinal effects including 
diarrhea.

Animal studies including altered bowel 
motions (see IB Section 4.5).

AEs in humans including loose stools 
(see IB Section 5.3).

Exclusion of participants with current 
diarrhea (see Section 6.2).

Potential gallstones due to interruption 
of enterohepatic recirculation of bile 
acids.

Report of gallstone-related AE in 
human studies (see IB Section 5.3).

Exclusion of participants with current 
symptomatic cholelithiasis or
inflammatory gall bladder disease (see 
Section 6.2).

Hypertriglyceridemia due to 
interruption of enterohepatic 
recirculation of bile acids.

Slight increases in triglycerides seen in 
humans (See IB Section 5.3).

Monitoring of lipid profiles (see
Section 9.4.4).

Increase in alanine aminotransferase 
(ALT).

Minor reversible ALT elevations 
reported in healthy volunteers and 
patients with type 2 diabetes (see IB 
Section 5.3).

Stopping rules for liver chemistry (see 
Section 8.1.1).

Monitoring of liver chemistry (see 
Section 9.4.4).
Study Procedures

Potential risk the participant does not 
follow the correct study treatment 
administration due to the number of 
bottles dispensed.

To maintain the blind across study 
treatment groups and study periods, 
participants will be dispensed several 
bottles of study treatment and are 

Bottles are clearly labelled for morning 
and evening dosing, and the number of 
tablets to take (see Section 7.1.1).  A 
dosing card with instructions will also 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
required to take tablets from each bottle 
(see Section 7.1.1). If the participant 
misunderstands the instructions or 
confuses the bottles, study treatment 
may be administered incorrectly.
be given to the participant.

Investigator and site staff training, and 
a pharmacy manual will be provided.
 
 
 
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3.3.2.
Benefit Assessment
Potential benefits of study participation include:

Possible improvement in symptoms of pruritus associated with PBC during study 
treatment.

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.
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with GSK2330672 are justified by the anticipated 
benefits that may be afforded to participants with pruritus associated with PBC.
4.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary

To investigate the dose response of oral 
GSK2330672 on itch in PBC patients with 
moderate to severe pruritus at Baseline.

Mean change from Baseline at Week 16 in 
the Mean Worst Daily Itch Score1.
Key Secondary

To characterize the effects of GSK2330672 
compared to placebo on impact of symptoms 
and quality of life in PBC patients with 
moderate to severe pruritus at Baseline.

Mean change from Baseline at Week 16 
in PBC-40 Scale.

To evaluate the effects of GSK2330672 
compared to placebo on markers of disease 
among participants at high risk of PBC 
progression (i.e., those with serum ALP 
concentrations 1.67xULN and/or total 
bilirubin concentrations >ULN at Day 1).
In participants meeting the criteria for high risk 
of PBC progression:

Mean change from Baseline at Week 16 in 
serum ALP concentrations. 

Proportion of participants having serum 
ALP concentrations <1.67x ULN and total 
bilirubin concentrations ULN at Week 16. 

Mean change from Baseline at Week 16 in 
serum ALT, AST, GGT, total bilirubin and
albumin concentrations and PT/INR.
 
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Objective
Endpoint
Other Secondary

To determine the safety and tolerability of 
GSK2330672 compared to placebo in PBC 
patients with moderate to severe pruritus at 
Baseline.

AEs, clinical laboratory parameters, ECGs,
vital signs and the GSRS.

To evaluate the effects of GSK2330672 
compared to placebo on itch response rates 
in PBC patients with moderate to severe 
pruritus at Baseline.

Proportion of participants who are 
responders at Week 16 based on each of 
the following separate definitions:

Mean Worst Daily Itch Score1 of <4.

At least a 30% reduction from 
Baseline in the Mean Worst Daily Itch 
Score1.

At least a 2-point reduction from 
Baseline in the Mean Worst Daily Itch 
Score1.

Mean number of responder days during 
Weeks 5 to 16 based on each of the 
following separate responder day2
definitions:

Worst Daily Itch Score of <4.

Worst Daily Itch Score at least 30% 
lower than the Baseline Mean Worst 
Daily Itch Score.

Worst Daily Itch Score at least 2-
points lower than the Baseline Mean 
Daily Score.

To further characterize the effects of 
GSK2330672 compared to placebo on 
symptoms and quality of life in PBC patients 
with moderate to severe pruritus at Baseline.
Change from Baseline at Week 16 in:

Mean Daily Sleep Score3.

Mean Daily Fatigue Score4.

5-D Itch Scale.

To evaluate the effects of GSK2330672 
compared to placebo on total serum bile acid 
concentrations and on bile acid synthesis in 
PBC patients with moderate to severe 
pruritus at Baseline.

Mean change from Baseline at Week 16 in 
serum concentrations of total bile acids 
and serum C4 as a marker of bile acid 
synthesis.
 
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Objective
Endpoint

To investigate the PK of oral GSK2330672 in 
PBC patients with moderate to severe 
pruritus at Baseline.

Plasma concentrations of GSK2330672
after sparse sampling (PK parameters will 
be reported if data permit).
Exploratory

To evaluate participant’s treatment 
experience and health status with 
GSK2330672 compared to placebo in PBC 
patients with moderate to severe pruritus at 
Baseline.

Treatment benefits and disadvantages as 
elicited in a Participant Treatment 
Experience Assessment at Week 16.

Time to worsening of itch during Weeks 
17-20 in participants with an improved 
Worst Daily Itch Score at Week 16 relative 
to Baseline.

Change from Baseline at Week 16 in 
EQ-5D-5L health dimensions and utility 
index. 

Change from Baseline at Week 16 in
Patient Global Impression of Severity 
(PGI-S) and Patient Global Impression of 
Change (PGI-C).

To evaluate the effect of GSK2330672 
compared to placebo on exploratory 
biomarkers of PBC and bile acid physiology
in PBC patients with moderate to severe 
pruritus at Baseline.

Change from Baseline at Week 16 in 
serum autotaxin, fibroblast growth factor-
19 (FGF-19), enhanced liver fibrosis (ELF) 
test and individual serum bile acid species.

To evaluate the effect of GSK2330672 
compared to placebo on serum lipids and 
absorption of fat-soluble vitamins in PBC 
patients with moderate to severe pruritus at 
Baseline.

Change from Baseline at Week 16 in 
fasting lipid profile, including direct low 
density lipoprotein (LDL) cholesterol. 

Change from Baseline at Week 16 in 
Vitamins A, D, E and K.

To evaluate the effect of GSK2330672 
compared to placebo on depressive 
symptoms associated with PBC in PBC 
patients with moderate to severe pruritus at 
Baseline.

Change from Baseline at Week 16 in the 
Beck Depression Inventory-II (BDI-II). 

To explore the effect of GSK2330672 on 
ursodeoxycholic acid (UDCA) concentrations 
in PBC patients with moderate to severe 
pruritus at Baseline.

Plasma concentrations of UDCA after 
sparse sampling (in participants on UDCA).
 
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Objective
Endpoint

To evaluate the pharmacogenomics of PBC 
and response to GSK2330672 in PBC 
patients with moderate to severe pruritus at 
Baseline.

Pharmacogenomics for genes related to 
PBC, pruritus and IBAT response (in 
consenting participants).

To evaluate the potential of actigraphy to 
quantify scratching activity and sleep quality 
due to pruritus associated with PBC and to 
assess the effect of GSK2330672 on these 
parameters in PBC patients with moderate to 
severe pruritus at Baseline.

Mean scratching event duration, and 
frequency (events/night) of specific 
scratching movements measured by wrist 
actigraphy and derived parameters (in 
participants in the Actigraphy Sub-study).
1.
Mean Worst Daily Itch Score: participant’s itch severity is recorded on an electronic diary (eDiary) each morning 
and evening using a 0-10 numerical rating scale (NRS), the Worst Daily Itch Score is averaged over the 7 days 
preceding randomization at Visit 3 (Baseline) and over the 7 days preceding Visit 6 (Week 16). 
2.
A responder day is based on the Worst Daily Itch Score recorded using the 0-10 NRS for that day. When the
responder day definition is relative to Baseline, the Worst Daily Itch Score is compared to the Mean Worst Itch 
Daily Score for Baseline (see 1 above).
3.
Mean Daily Sleep Score: participant’s sleep quality is recorded on the eDiary each morning using a 0-10 NRS and 
the Daily Sleep Score is averaged over the 7 days preceding randomization at Visit 3 (Baseline) and over the 7 
days preceding Visit 6 (Week 16).
4.
Mean Daily Fatigue Score: participants fatigue level is recorded on the eDiary each evening using a 0-10 NRS 
and the Daily Fatigue Score is averaged over the 7 days preceding randomization at Visit 3 (Baseline) and over 
the 7 days preceding Visit 6 (Week 16).
Note: 
For all other endpoints Baseline is defined as the Visit 3 assessment and Week 16 is defined as the Visit 6 
assessment.
In addition to Week 16, which is the primary time point of interest, other intermediate time points will also be 
assessed.
 
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5.
STUDY DESIGN
5.1.
Overall Design
Figure 1
Study Schematic
This is a phase IIb, multicenter, randomized, double-blind, placebo-controlled, parallel 
group, dose-finding study in adults with moderate to severe pruritus associated with PBC.  
The study has an adaptive design which aims to utilize interim data to further inform and 
potentially optimize the doses under investigation (see Section 10.3.4). 
Following the Screening Visit, there will be four study periods: 

Initial Study Period: Single-blind placebo treatment for 4 weeks during which 
participants’ symptoms will be recorded in the eDiary to establish baseline 
symptoms and assess eligibility for randomization and compliance with study 
procedures.

Main Study Period: Eligible participants will be randomized to receive 12 weeks 
double-blind treatment with either placebo or one of 4 dose regimens of 
GSK2330672 (20 mg, 90 mg or 180 mg taken once daily or 90 mg twice daily).  
Randomization will be stratified based on participant’s risk of PBC disease 
progression based on serum ALP and total bilirubin concentrations at Day 1 (see 
Section 7.3.1).

Final Study Period: Single-blind placebo treatment for 4 weeks to assess symptoms 
and safety post-completion of double-blind treatment.
 
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
Follow-up Period: to assess symptoms and use of anti-pruritus medications by 
telephone visit.
Eligible participants may continue to receive some therapies for the treatment PBC 
provided these are maintained at stable doses and there is no plan to discontinue them 
during the study.  Concomitant use of cholestyramine, colesevelam, colestipol or 
colestimide is not permitted until after completion of the Main Study Period.  Obeticholic 
acid use is not permitted at any time during the study.
All study treatment will be administered orally twice a day, using placebo tablets as 
necessary to blind dose and regimen. Participants will commence single-blinded study 
treatment at Visit 2 [Day1].  During the Initial, Main and Final Study Periods it is 
important that participants remain blind to changes in study treatment from single-blind 
placebo to randomized double-blind treatment and subsequently to single-blind placebo.  
Investigator and study site staff communication with participants should ensure 
maintenance of each participant’s blinding to treatment throughout the study.
A participant’s total duration in the study will be approximately 24 weeks from Day 1 to 
completion of the Follow-up Telephone Visit.
The study also includes an exploratory Actigraphy Sub-study which will be conducted at 
a limited number of study sites and in a sub-set of participants who give their consent.
5.2.
Number of Participants
Approximately 150 adult participants with PBC and moderate to severe pruritus will be 
screened to achieve 118 randomized and 100 evaluable participants overall.  Should 
emerging data diverge significantly from protocol assumptions, the total sample size will 
adjusted to include up to 160 randomized participants, and to approximately 200 screened 
participants (see Section 10.3.4).
If during the study the screen failure rate is higher than anticipated, the number of 
screened participants may be increased.
Participants are considered evaluable if they have taken at least one dose of double-blind 
study treatment and have both a Baseline and a Week 16 assessment for itch (see Section 
10.1).
If participants discontinue single-blind study treatment during the Initial Study Period or 
do not meet the additional criteria for randomization (see Section 6.3), they will not be 
randomized or continue in the study and may be replaced.  
Participants who prematurely discontinue double-blind study treatment after 
randomization will stay in the study and complete the remaining scheduled visits, if
possible.  Any participant who withdraws from the study after randomization will not be 
replaced.
 
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5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
periods of the study including the Follow-up Telephone Visit. A participant is considered 
to have completed study treatment if he/she has taken study treatment through to the end 
of the Final Study Period (Visit 7).
The end of the study is defined as the date of the last Follow-up telephone contact of the 
last participant in the study.
5.4.
Scientific Rationale for Study Design
The study is designed to evaluate the efficacy and safety of different doses of 
GSK2330672 and includes placebo to support the evaluation of treatment response.  
During the Main Study Period study treatment will be provided using randomized, 
double-blind methodology.  Previous studies have demonstrated that patient-reported itch 
may show some improvement on placebo treatment, so placebo control is used in this 
study to help distinguish the effect of GSK2330672 relative to no treatment.
The use of single-blind placebo in the Initial Study Period will establish each 
participant’s baseline level of itch, against which their response to GSK2330672 will be 
assessed.  Participants whose itch score at the end of single-blind placebo (i.e. baseline) is 
too low to reliably detect an improvement on blinded study treatment, or who do not 
complete sufficient daily eDiary entries, will be withdrawn from the study at the end of 
the Initial Study Period.
The Final Study Period uses single-blind placebo to support the evaluation of the 
recurrence of symptoms upon cessation of blinded study treatment.  
Assignment of randomized study treatment will be stratified according to the 
participant’s risk of PBC progression at baseline, with the treatment allocation ratios 
varying across the two strata (see Section 7.3.1). This is intended to increase the ability of 
the study to detect any difference in change in markers of PBC progression between 
placebo and GSK2330672 in participants whose liver chemistry indicates an increased 
risk of disease progression. 
The study duration has been chosen to ensure adequate time to assess the effect of 
GSK2330672, whilst minimizing the period of restrictions on use of concomitant 
medications and the associated inconvenience to participants with troublesome 
symptoms.
During the study, participants may continue to receive selected agents for the treatment of 
PBC (e.g. ursodeoxycholic acid [UDCA]), provided the dosage prior to and during the 
study, is stable.  Prohibited agents include those that bind bile acids (cholestyramine, 
colesevelam, colestipol or colestimide) or that may exacerbate symptoms of pruritus 
(obeticholic acid), since their use during the study may compromise the efficacy and 
safety evaluation of GSK2330672 (see also Section 6.2).  However, during the Final 
Study Period whilst receiving single-blind placebo, and during the Follow Up Period, if
 
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participants report their itch has recurred or persists they may receive previous or new 
anti-pruritus therapies as clinically indicated (see Section 7.7).
The use of an adaptive design, with the evaluation of interim efficacy and safety data, 
will facilitate characterisation of the dose-response relationship of GSK2330672 (see 
Section 10.3.4).  
5.5.
Dose Justification
To date PBC patients have received GSK2330672 at a dose of 45 mg twice daily
increased to 90 mg twice daily after 3 days and continued for 14 days in total.  The dose 
range for the current study is based on responses observed in these PBC patients and in 
the biomarkers total serum bile acids and 7--hydroxy-4-cholesten-3-one (C4) measured 
in Type II diabetic (T2DM) patients.  The IB provides further details on the findings in 
these studies.
The doses selected for the current study provide an initial range in order to characterize 
the effects of GSK2330672 on pruritus in PBC patients.  Since the ED50 was observed to 
be in the range of 30 to 60 mg for both biomarkers in T2DM, a lower, potentially 
minimally effective dose of 20 mg was selected to explore the GSK2330672 dose 
associated with a minimum effect on itch.  A 90 mg twice daily dose is included given its 
observed efficacy from the study in PBC patients.  A 180 mg once daily dose is also 
included to determine if once daily dosing would have a similar impact on itch as twice 
daily dosing.
The study treatment arms planned for this study are:

Placebo

20 mg once daily (anticipated minimally effective dose)

90 mg once daily

180 mg once daily (anticipated to identify plateau of efficacy)

90 mg twice daily (demonstrated efficacy in previous study)
Following the interim analysis, the GSK2330672 arms may be adapted up to a maximum 
total daily dose of 360mg (see Section 10.3.4). This dose has adequate nonclinical 
toxicology cover for local gastrointestinal tract exposure (based on administered oral 
dose, i.e., 7.2 mg/kg/day assuming 50 kg body weight): 139-fold No Observed Adverse 
Effect Level (NOAEL) in the rat and 69-fold NOAEL in the dog for local gastrointestinal 
tract exposure (mg/kg/day dose). Further information on nonclinical toxicology studies 
can be found in the IB.
 
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6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
To qualify for screening and enrollment, the prospective participant must present with 
pruritus associated with PBC.  Prior to requesting informed consent, the investigator will 
review (where practical) a prospective participant’s case notes or medical history, to 
evaluate his/her experience of itch and medications, to assess consistency with the 
inclusion/exclusion criteria. 
Following the investigator’s pre-screening assessment, potential participants will be 
asked to give their written informed consent prior to any study specific procedures being 
performed, and their eligibility assessed (see Section 6.1 and Section 6.2).
Screening procedures to be performed following completion of the informed consent 
process are listed in Table 2.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 80 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who have proven PBC, as demonstrated by having at least 2 of the 
following:

History of sustained increased ALP levels >upper limit of normal (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 institution of UDCA therapy as described in inclusion 
number 4). 

Documented positive anti-mitochondrial antibody (AMA) titer (>1:40 titer on 
immunofluorescence or M2 positive by ELISA) or PBC-specific antinuclear 
antibodies (antinuclear dot and/or nuclear rim positive).

Liver biopsy (at any time in the past) consistent with PBC.
3.
Participants must rate their itch severity as being ≥4 on a 0 to 10-point scale for 
the majority of time (at least half the days, as recalled by the participant) during 
the 8 weeks prior to the Screening Visit.  Periods of low itch or no itch are 
acceptable as long as the worst daily itch score is ≥4 on the majority of days.
4.
Participants who are currently taking UDCA should be on stable doses of
UDCA for >8 weeks at time of screening. Participants not taking UDCA due to 
 
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intolerance may be enrolled 8 weeks after their last dose of UDCA.
Note: no changes or discontinuation is permitted until completion of the Main 
Study Period.  
Sex
5.
Male and/or female:
a.
Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 2), not 
breastfeeding, and at least one of the following conditions applies:
i.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 2
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in Appendix 2
during the treatment period and until at least 4 weeks after the last dose of 
study treatment.
Informed Consent
6.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the ICF 
and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Screening total bilirubin >2x ULN.  Total bilirubin >2x ULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%.
2.
Screening ALT or aspartate aminotransferase (AST) >6x ULN.
3.
Screening estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m²
based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation.
4.
History or presence of hepatic decompensation (e.g., variceal bleeds, 
encephalopathy or ascites).
5.
Presence of actively replicating viral hepatitis B or C (HBV, HCV) infection
and/or confirmed hepatocellular carcinoma or biliary cancer.
Note:  Other hepatic conditions (e.g., primary sclerosing cholangitis (PSC), alcoholic 
liver disease, autoimmune hepatitis, non-alcoholic steatohepatitis [NASH] are 
permitted if PBC is the dominant liver injury in the investigator’s opinion.
6.
Current diarrhea.
 
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7.
Current symptomatic cholelithiasis or inflammatory gall bladder disease.  
Participants with history of cholecystectomy ≥3 months before screening may 
be eligible for enrollment.
8.
Any current medical condition (e.g. psychiatric disorder, senility or dementia), 
which may affect the participant’s ability to comply with the protocol specified 
procedures.
Prior/Concomitant Therapy
9.
Initiation or increase in dose of colchicine, methotrexate, azathioprine, or 
systemic corticosteroids in the 2 months 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.  [Rationale:  Limited 
evidence indicates these drugs may alter disease progression in some PBC patients.]
10. Initiation or increase in dose of bezafibrate or fenofibrate at any time during the 
3 months prior to screening. Participants may join the study on stable doses of 
these medications, but no change or discontinuation is permitted until 
completion of the Main Study Period.  [Rationale:  limited evidence suggests 
fibrates may improve ALP and pruritus.]
11. Initiation or increase in dose of any of the following in the 8 weeks prior to 
screening: rifampicin, naltrexone, naloxone, nalfurafine, or sertraline. 
Participants may join the study on stable or decreased doses of these 
medications, but no change in dose is permitted until completion of the Main 
Study Period.  [Rationale:  There is limited evidence these drugs improve 
pruritus due to PBC.]
12. Bile acid binding resin use: a participant must discontinue use of 
cholestyramine, colesevelam, colestipol or colestimide prior to the start of the 
Initial Study Period (no later than Day -2).  Note: these drugs may be 
administered after completion of the Main Study Period, if clinically indicated. 
[Rationale: these resins may bind GSK2330672 and interfere with its effects.]
13. Obeticholic acid use: a participant must discontinue use of obeticholic acid at 
least 8 weeks prior to the start of the Initial Study Period and may not restart 
until after the end of the study. [Rationale: obeticholic acid use can cause 
changes in ALP and pruritus which may confound evaluation of the effects of 
GSK2330672.]
14. Administration of any other IBAT inhibitor in the 3 months prior to screening 
[Rationale:  Effects of another IBAT inhibitor may influence pruritus.]
Prior/Concurrent Clinical Study Experience
15. Current enrollment or participation within the 8 weeks before start of the Initial 
Study Period, in any other clinical study involving an investigational study 
treatment.
Diagnostic assessments
16. QTc >480 msec 
 
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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. 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
17. History of sensitivity 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. 
18. History of regular alcohol consumption within 6 months of the study defined as 
an average weekly intake of >21 units for males or >14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 
mL) of wine or 1 measure (25 mL) of spirits.
6.3.
Criteria for Randomization
Following completion of the Initial Study Period, participants will be required to meet the 
following criteria for randomization at Visit 3 [Week 4]: 

Participants with a Worst Daily Itch Score on the 0-10 numerical rating scale (NRS) 
which is ≥3 on at least 5 of the previous 7 days.

Participant has entered data into the eDiary on at least 10 of the 14 required 
occasions in the previous 7 days.
Otherwise, the participant will stop participation in the study without additional follow-
up after Visit 3 and will be considered a baseline (run-in) failure.  The Study Reference 
Manual will contain details on how to access this eligibility information.  Refer to 
Section 6.5.2 of the protocol for further information.
6.4.
Lifestyle Restrictions
6.4.1.
Meals and Dietary Restrictions
Following screening, participants will be required to attend all study visits having fasted 
for at least 6 hours (water, study treatments and other medications are permitted).  
6.4.2.
Caffeine, Alcohol, and Tobacco
There are no restrictions.
 
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6.4.3.
Activity
There are no restrictions.
6.5.
Screen and Baseline Failures
6.5.1.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the Initial Study Period of 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, and any 
serious AEs (SAEs). Additionally, the PBC-40 Scale, current and previous treatments for 
pruritus associated with PBC, observed efficacy and side effects of those treatments and 
reasons for discontinuation will also be collected.
Some individuals who do not meet the criteria for participation in Initial Study Period
may be rescreened. The only criteria for which this is acceptable are those related to the
use of PBC or anti-pruritus medications (e.g., requirements on dose stability, minimum 
time since stopping therapy), where a delay in rescreening would allow the participant to 
become eligible.  Participants should continue to meet all other eligibility criteria at the 
time of rescreening. Participants may only be rescreened once.
Additionally, participants who could become eligible as a result of a protocol amendment 
may be rescreened.  Rescreening is only permitted where the participant would have met 
all the eligibility requirements of the amended protocol at the time of the first (original) 
screening visit.  The rescreened participants must meet all the eligibility requirements at 
the time of the rescreening (subsequent screening) visit to become eligible.  Rescreening 
is only permitted once for each relevant amendment.
All rescreened participants will be reconsented and assigned a new participant number.
6.5.2.
Baseline (Run-In) Failures
Participants who do not complete the Initial Study Period or who do not meet the criteria 
for randomization at the end of the Initial Study Period (see Section 6.1) are considered 
baseline (run-in) failures and may not be rescreened without prior discussion with the 
Medical Monitor.
In the event of a confirmed baseline failure at Visit 3, the blood, urine, ECG, and 
TrialMax Slate assessments for Visit 3 are not required, and no further study treatment 
will be dispensed.  If the FOBT has been collected and returned by the participant, it 
should be sent to the laboratory for evaluation.
The Visit 3 activities in the event of a baseline failure are listed in Table 1.
 
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7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Study Treatment Name:
GSK2330672
Placebo
Dosage formulation:
White film-coated tablet
White film-coated tablet
Unit dose strength(s):
10 and 45 mg tablets
Tablets to match
Route of Administration 
Oral
Oral
Packaging and Labeling
Study Treatment will be provided in 
45 cc high density polyethylene 
bottles (HDPE) bottles.  Each bottle 
will be labelled as required per 
country requirements.
Matching bottles
Storage conditions
Store up to 30°C (86°F)
Store up to 30°C (86°F)
Manufacturer
Wuxi Apptec
Wuxi Apptec
7.1.1.
Study Treatment Administration
Study treatment will comprise:

Initial Study Period: Single-blind placebo.

Main Study Period: Double-blind randomized treatment of either placebo or one of 4 
different dose regimens of GSK2330672.

Final Study Period: Single-blind placebo.
Each study treatment will be provided to participants according to Table 3.
 
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Table 3
Study Treatments
GSK2330672
Placebo
20 mg 
Once Daily
90 mg 
Once Daily
180 mg 
Once Daily
90 mg 
Twice Daily
Bottles 
dispensed
Morning 
Dosing
2 bottles 
placebo
1 bottle 10 mg
1 bottle placebo
1 bottle 45 mg
1 bottle placebo
1 bottle 45 mg
1 bottle 45 mg
1 bottle 45 mg
1 bottle placebo
Evening 
Dosing
1 bottle 
placebo
1 bottle placebo
1 bottle placebo
1 bottle placebo
1 bottle 45mg
Dosing Instructions 
on each bottle
Take 2 tablets 
in the morning 
[evening]
Take 2 tablets in 
the morning 
[evening]
Take 2 tablets 
in the morning 
[evening]
Take 2 tablets 
in the morning 
[evening]
Take 2 tablets 
in the morning 
[evening]
Each bottle will contain 70 tablets, sufficient for 35 days treatment. Participants should 
take their study treatment twice a day approximately 12 hours apart.
Following an interim analysis the study design may be adapted to add or remove dose 
regimens of GSK2330672 up to a maximum total daily dose of 360 mg.  Blinding of 
study treatment across all study periods will be maintained.  Consequently, depending on 
the dose/regimen selected, participants enrolled into the study after the interim may be 
dispensed either up to 3 bottles of study treatment for morning dosing or up to 2 bottles 
of study treatment for evening dosing. The maximum of number bottles that will be given 
to an individual participant at each dispensing will be 4. Participants will be instructed to 
take 2 tablets from each bottle.  Further details are provided in the Study Reference 
Manual (SRM).
At the start of the Initial Study Period (Visit 2 [Day1]) participants meeting all inclusion 
criteria and no exclusion criteria will be dispensed study treatment and instructed on how 
to take their medication.  Study treatment administration will start with the evening dose 
on the day of the study visit, but may be deferred to next morning if the participant 
prefers.  Participants will continue taking study treatment twice a day as instructed and 
will return for their next study visit having fasted for at least 6 hours (water permitted) 
and having taken their morning dose of study treatment.
At the start of the Main Study Period (Visit 3 [Week 4]) participants randomized to 
double-blind study treatment will commence taking treatment that evening.  They should 
return for each study visit having taken their morning dose fasted as above. 
At the start of the Final Study Period (Visit 6 [Week 16]) participants will commence 
study treatment that evening, returning for their final clinic visit (Visit 7 [Week 20]) 
having taken their morning dose fasted as above.
At each study visit new bottles of study treatment will be dispensed in accordance with 
the SoA (see Section 2).
7.2.
Dose Modification
No modification of individual participant’s study treatment dose is permitted.
 
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7.3.
Method of Treatment Assignment
During all study periods participants will be allocated study treatment using an 
Interactive Voice/Web Response System (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. 
At the start of the Main Study Period all participants will be centrally randomized to 
double-blind study treatment using IVRS/IWRS, and randomization will be implemented 
based on a sequestered fixed randomization schedule, and will be blocked at the overall 
study level.  The randomization schedule will be computer generated by 
GlaxoSmithKline (GSK) using the randomization system Randall. Participants will be 
stratified as outlined in Section 7.3.1. Blinded study site personnel will receive a 
randomization notification indicating the unique participant identifier (randomization 
number) and the date and time of randomization.  Each randomization number will be a 
unique identifier. Once a randomization number has been assigned, the number will not 
be reused even if the participant is not administered any study treatment.  Returned study 
treatment should not be re-dispensed to the participants.
Details of the treatment assignment process are contained in the SRM.  
7.3.1.
Treatment Assignment in the Study Periods
Initial Study Period
At Visit 2 [Day1] participants who meet all inclusion and no exclusion criteria will be 
allocated single blind placebo.  
Main Study Period
At the Visit 3 [Week 4] participants meeting the randomization criteria will be allocated 
to double-blind study treatment in accordance with the randomization schedule.  
Randomization will be stratified according to region (Europe, North America, Japan) and 
the participant’s risk of PBC progression at baseline based on serum ALP and total 
bilirubin concentrations obtained at Visit 2 [Day 1] as follows: 

ALP <1.67x ULN and total bilirubin  ULN (estimated 60% of participants), or 

ALP ≥1.67x ULN and/or total bilirubin >ULN (estimated 40% of participants). 
Treatment allocation ratios will vary across these two strata (see Section 10.1). This is to 
increase the ability of the study to detect any difference in change in markers of PBC 
progression between placebo and active treatment in participants whose liver chemistry 
indicates increased risk of disease progression.
Final Study Period
At Visit 6 [Week 16] participants will be allocated single blind placebo.  
 
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7.4.
Blinding
During the Initial, Main and Final Study Periods it is important that participants remain 
blinded to changes in study treatment from single-blind placebo to randomized double-
blind treatment and subsequently to single-blind placebo.  Investigator and study site staff 
communication with participants during the informed consent procedure and all 
subsequent study procedures/visits should ensure maintenance of each participant’s 
blinding to treatment.
The IVRS/IWRS will be programmed with blind-breaking instructions. The double-blind
may be broken if, in the opinion of the investigator, it is in the participant’s best interest 
for the investigator or treating physician, to know the study treatment assignment.  GSK
must be notified before the double-blind is broken unless identification of the study 
treatment is required for a medical emergency in which the knowledge of the specific 
blinded study treatment will affect the immediate management of the participant’s 
condition.  In this case, GSK must be notified within 24 hours after breaking the blind.  
The date and reason that the blind was broken must be recorded in the source 
documentation and electronic case report form (eCRF), as applicable.
If the participant’s treatment code is unblinded by the investigator or treating physician, 
the participant must discontinue study treatment, but remain in the study and complete all 
remaining study visits (see Section 8.1).  The primary reason for the discontinuation of 
study treatment (i.e. the event or condition that led to the unblinding) will be recorded in 
the eCRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment 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 treatment assignment, may be sent to investigators in
accordance with local regulations and/or GSK policy.
7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
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 treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM. 
 
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
Under normal conditions of handling and administration, study treatment is not
expected to pose significant safety risks to site staff.  

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.
7.6.
Treatment Compliance
Blinded study treatment will be dispensed to participants at each study visit with 
sufficient tablets until the next visit based on the visit windows (see SoA [Section 2]).  At 
each visit the participants will be required to return all unused study treatment.
When participants self-administer study treatment at home, they will be required to 
document missed doses of study treatment in their eDiary.  Compliance with study 
treatment will be assessed through review of the eDiary and returned tablets, and by 
querying the participant during the study visits. Compliance will be documented in the 
source documents and eCRF.  A record of the number of study treatment tablets 
dispensed to and taken by each participant must be maintained and reconciled with study 
treatment and compliance records.  Treatment start and stop dates will also be recorded in 
the eCRF.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, topical 
agents including topical corticosteroids, vitamins, and/or herbal supplements) that the 
participant has taken in the 3 months prior to Screening, or is receiving at the time of 
enrollment 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 and frequency
Note: Anti-pruritus medications (including any topical medications and rescue therapy) 
or other interventions during the Final Study Period and reported in the Follow-up 
Telephone Contact will be recorded in the eCRF.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.1.
Prohibited Medications
Other IBAT inhibitors:  Use of any other IBAT inhibitor is not permitted at any time 
during the study.
Obeticholic acid:  Use is not permitted at any time during the study and obeticholic acid 
should be discontinued at least 8 weeks before the start of the Initial Study Period.
 
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Cholestyramine, colesevelam, colestipol or colestimide:  Use of any of these agents is 
not permitted during the Initial or Main Study Periods and will be discontinued no later 
than one full day (i.e., no later than Day -2) before the start of the Initial Study Period 
(Visit 2). During the Final Study Period and the Follow Up Period, use of these agents 
may be permitted (see Section 7.7.3).
7.7.2.
Permitted Medications
Other than the prohibited medications (see Section 7.7.1), participants may take 
medications for concomitant conditions or inter-current illness as necessary.  All use of 
any concomitant medications, including topical agents, must be recorded within the 
eCRF.  
Permitted agents for the treatment of PBC and its associated symptoms are as follows:
UDCA: Participants may be enrolled in the study on UDCA provided the dose has been 
stable during the 8 weeks prior to screening. No change or discontinuation is permitted 
until completion of the Main Study Period. Note participants not taking UDCA due to 
intolerance may be enrolled if their last dose was at least 8 weeks prior to screening (see 
Section 6.1). During the Final Study Period and the Follow Up Period UDCA may be 
permitted (see Section 7.7.3).
Participants taking UDCA will be required to not administer their morning dose of 
UDCA (if applicable) before each of the PK sampling visits and to record the time of 
their last UDCA dose (see Section 9.5).
Colchicine, methotrexate, azathioprine, or systemic corticosteroids:  Use of these 
agents is permitted during the study as long as the dose has remained stable (i.e., 
unchanged) during the 2 months prior to the screening visit and the dose does not change 
throughout the study.  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 the 
Final Study Period and the Follow Up Period UDCA may be permitted (see Section 
7.7.3).
Rifampicin, naltrexone, naloxone, nalfurafine, or sertraline:  Participants may be 
enrolled into the study on stable or decreased doses of any of these agents.  However, no 
dose increase is permitted until completion of the Main Study Period.  Note: A 
participant is not eligible for the study if he/she started or had a dose increase in any of 
these agents during the 8 weeks prior to screening (see Section 6.2). During the Final 
Study Period and the Follow Up Period, use of these agents may be permitted (see 
Section 7.7.3).
Bezafibrate or fenofibrate: Participants may be enrolled in the study on stable doses of 
these medications, but no change or discontinuation is permitted until completion of the 
Main Study Period. Note: A participant is not eligible for the study if he/she started or 
had a dose increase in either of these agents during the 3 months prior to screening (see 
Section 6.2).  During the Final Study Period and the Follow Up Period, use of these 
agents may be permitted (see Section 7.7.3).
 
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Antihistamines: Participants may be enrolled on antihistamines if taken regularly and at 
a stable dose.
Anti-diarrheals: Participants experiencing diarrhea may take anti-diarrheal treatments 
obtained over-the-counter or prescribed by the investigator or another practitioner. Use of 
these treatments and their effect will be recorded at each review of concomitant 
medications.
7.7.3.
Rescue Therapy
During the Final Study Period and Follow Up Period only, if participants’ itching recurs 
or persists and they request additional therapy, they may resume their previous anti-
pruritus medication if clinically indicated.  If the participant’s itching warrants new or 
increased doses of anti-pruritus therapy, this can be administered if clinically indicated.  
Other non-pharmacologic interventions may also be used (e.g., nasobiliary drainage) if 
clinically indicated.  Use of any rescue therapy should be recorded within the eCRF.
7.8.
Treatment after the End of the Study
The Sponsor will not provide treatment after the end of the study; participants should be 
managed according to their treating physician.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants may prematurely discontinue study treatment due to AEs or poor tolerance or 
for any other reason including withdrawal of consent. In all cases the participant should 
be encouraged to discuss any potential study treatment discontinuation with the 
investigator prior to stopping treatment. 
Premature discontinuation of study treatment due to lack of efficacy is discouraged; 
where possible participants should be encouraged to remain on study treatment until the 
end of Final Study Period. 
Participants who discontinue study treatment following randomization and before the 
scheduled end of the Final Study Period will complete Early End of Treatment 
Assessments (see SoA [Section 2]) before their last dose of study treatment, if possible. 
Participants will not be withdrawn from the study but should complete the remaining 
scheduled visits and assessments, including the eDiary, up to and including the end of the 
Final Study Period (Visit 7 [Week 20]) and undergo the End of Follow-up Telephone 
Visit (Visit 8 [Week 24]).
8.1.1.
Liver Chemistry Increased Monitoring and Stopping Criteria
Liver chemistry increased monitoring and stopping criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
 
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The study population will be recruited based on the presence of pre-existing hepatobiliary 
disease.  Study specific withdrawal criteria have been instituted in consultation with 
internal GSK advisors and external experts.
Based upon screening lab results for serum ALT and total bilirubin, participants will be 
required to return to the clinic or local specialist/collaborator within one week or 
sooner for repeat testing (including AST, ALT, total bilirubin, ALP and PT/INR) as 
indicated below if any of the following liver chemistry criteria for increased monitoring 
or for stopping study treatment are met:
Table 4
Liver Chemistry Criteria for Increased Monitoring
Post-Screening Lab Result
Actions
ALT > 2x participant’s 
screening ALT AND >3x ULN
Repeat liver chemistry testing within 1 week (AST, ALT, total bilirubin, 
ALP, and PT/INR).
Inform Medical Monitor.
Continue to monitor the above liver chemistries at least weekly until values 
stabilize or fall below the criteria for increased monitoring.
Study treatment will be stopped for a participant if any of the following liver 
chemistry stopping criteria are met:
Table 5
Liver Chemistry Criteria for Stopping Study Treatment
Post-Screening Lab Result
Actions
Total bilirubin > 2x participant’s 
screening AND >1.5x ULN 
Stop study treatment immediately.
Discuss with Medical Monitor within 24 hours.
Repeat liver chemistry testing (including AST, ALT, total bilirubin, 
ALP, and PT/INR) within 24-72 hours where possible but within 
1 week, and thereafter at least weekly until values stabilize or 
fall below the criteria for increased monitoring.
Refer to Protocol Appendix 4 for further follow-up and 
monitoring requirements.
Total bilirubin >3x ULN 
ALT > 3x participant’s screening 
ALT result AND > 5x ULN 
ALT >8x ULN of ALT
In addition, study treatment will be stopped for a participant 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 symptoms which may typically be associated with drug-induced liver 
injury (including fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia [>5%]).
 
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NOTE: Refer to Section 12.4.1 for details of the required assessments if a participant 
meets the above stopping criteria. Section 12.4 also provides diagrams to facilitate
implementation of the criteria for increased monitoring and for stopping study treatment.
8.1.2.
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 electrocardiogram (ECG) obtained 
over a brief (e.g., 5-10 minute) recording period. If an automated reading is not available 
the ECG should be manually 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 treatment:

QTc ≥530 msec AND/OR change from baseline of QTc >60 msec
8.1.3.
Renal Stopping Criteria
A serum creatinine stopping criterion has been included to support participant safety. 
A participant’s study treatment will be interrupted if there is an increase from Baseline 
(Visit 3) in serum creatinine of >0.3 mg/dL (26.52 mol/L).  The investigator should 
consult with the Medical Monitor to determine the appropriate evaluation and guidance 
on whether study treatment may be re-started.
8.1.4.
Other Stopping Criteria
Female participants who become pregnant during the study should discontinue study 
treatment immediately (see Section 9.2.6).
8.1.5.
Temporary Discontinuation
In cases where participants discontinue study treatment due to an AE the investigator 
should consult with the Medical Monitor to determine the appropriate evaluation and 
guidance on whether study treatment may be re-started.
 
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Participants who forget to take a dose of study treatment should take their next dose 
according to the dosing schedule.  
8.1.6.
Rechallenge
8.1.6.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study

Participants should be encouraged to remain on study treatment and stay in the study 
completing study assessments (see Section 8.1). Where possible, the investigator 
should consider consultation with the Medical Monitor prior to withdrawing a 
participant from the study. 

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, 
behavioural, compliance or administrative reasons.

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 withdrawing from the study after randomization should undergo Study 
Withdrawal Assessments, if possible, and be asked if they may be contacted for an 
End of Follow-up Telephone Visit (see the SoA [Section 2]).
8.3.
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.
 
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
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (see Section 2). 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA
(Table 1), 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 (Table 1).

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 
450 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Efficacy Assessments
9.1.1.
Electronic Data Collection
An eDiary will be used to collect participant’s daily symptoms and the weekly 
assessment of participant’s gastrointestinal symptoms (GI) and the Gastrointestinal 
Symptom Rating Scale (GSRS) (see Section 9.1.2).  Additionally, the eDiary will prompt 
participants to record aspects of their study treatment such as whether they have missed 
doses.
At the start of the Initial Study Period (Visit 2 [Day 1]) each participant will be provided 
with the eDiary and will be trained on its correct use, including how to complete the 
GSRS.  During the study investigators and study site staff will have on-line access to 
their individual participant’s eDiary data in order to monitor compliance with the 
completion requirements and compliance with study treatment. 
At study visits participants will complete all Patient Reported Outcomes (PROs) 
measures using an electronic device called a TrialMax Slate; all participants will be 
trained on the use of the TrialMax Slate and on completion of the PROs. 
 
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The SRM provides further details on the use of the eDiary and TrialMax Slate, and on the 
completion of the PROs.  Participants will be provided with a simple user manual to 
support correct use of the eDiary at home.
9.1.2.
Patient Reported Outcomes (PROs)
All PRO measures will be completed by the participant before any other study procedures 
are performed, the only exception to this will be the collection of fasting laboratory tests 
(Note: Participants may consume a light snack before completing the PROs). The intent 
is to minimise the interaction with the investigator and study staff prior to completion of 
the PROs. 
9.1.2.1.
Patient Reported Symptom Questionnaire
Using the eDiary participants will record details of their symptoms of itch, and its impact 
on their sleep and level of fatigue. The eDiary will be completed twice each day, in the
morning and evening approximately at the time of study treatment dosing. 

Participants will score the severity of their itching using a NRS from 0 to 10 where
represents
 and
. The NRS recorded in the 
morning will characterize the itch experienced during the night-time, whilst the NRS 
recorded in the evening will characterize the itch experienced during the day-time 
hours.  The Worst Daily Itch Score is the most severe (highest) NRS recorded on a 
given day.

Each morning participants will also score the interference of itch on their sleep using 
a NRS from 0 to 10 where
represents
 and
represents 
.  

Each evening participants will also score their level of fatigue using a NRS from 0 to 
10 where  represents 
 and
represents 
.  
Other aspects of symptoms associated with PBC and study treatment will also be 
collected, including weekly assessment of participant’s GI symptoms.
9.1.2.2.
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 was devised and 
validated with a 4 week recall period, which in this study will be modified to a recall 
period of ‘the past 7 days’.
The PBC-40 scale will be administered with a 7 day recall period at Visits 2 through 7 
[Day1 through Week 20] in the study, and if applicable at early study treatment 
discontinuation and at study withdrawal. 
In addition, the PBC-40 will be performed at Screening (Visit 1) in all enrolled 
participants in order to investigate the quality of life and previous treatment experience in 
the population being considered for inclusion in the study and to assess whether the study 
exclusion criteria preferentially include a sub-group distinct from the general patient 
population.
 
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9.1.2.3.
5-D Itch Scale
The 5-D itch scale has been developed as a brief, single page, instrument for the 
multidimensional quantification of itch that is sensitive to change over time. It has data to 
support its validity in a population of patients with pruritus and covers five dimensions of 
itch experienced by participants: duration, degree, direction, disability and distribution 
[Elman, 2010]. The distribution dimension is assessed by reference to a checklist of 
potential locations and can be summarized by counting the number of locations identified 
as itching.
The 5-D Itch scale will be administered at Visits 2, 3, 6 and 7 [Day 1 and Weeks 4, 16 
and 20] in the study, and if applicable at early study treatment discontinuation and at 
study withdrawal. 
9.1.2.4.
Gastrointestinal Symptom Rating Scale (GSRS)
The GSRS is a validated scale that will be used to assess gastrointestinal symptoms 
experienced by participants over the preceding 5 to 7 days [Svedlund, 1988].
Participants will be asked to complete the GSRS every week starting at Visit 2 through to 
Visit 7 [Day 1 through Week 20] in the study. 
9.1.2.5.
Other PRO Measures
EuroQOL 5D-5L (EQ5D-5L) will be used to assess patient health utility. Within the 
literature, there are few reported measures of health utility in the PBC patient population 
including those with pruritus. The measurements will be used to better understand change 
in participant’s symptoms, preference for treatment, and overall health utility for use in 
health economic evaluations. The EQ5D-5L will be completed at Visits 2, 3, and 6 [Day 
1 and Weeks 4 and 16] in the study, and if applicable at early study treatment 
discontinuation and at study withdrawal. 
Patient’s Global Impression of Severity (PGI-S) will be used to understand how 
participant’s daily itch score using the 0-10 NRS relates to overall participant-reported 
itch severity. The PGI-S uses a 5-level response scale and will be collected at Visit 2 
through to Visit 7 [Day 1 through Week 20] in the study, and if applicable at early study 
treatment discontinuation and at study withdrawal. 
Patient’s Global Impression of Change (PGI-C) will be used to understand how 
participant’s daily itch score using the 0-10 NRS relates to overall participant-reported 
change in itch severity.  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 Visit 3 through to Visit 7 [Week 4 through Week 20] in the study, and if 
applicable at early study treatment discontinuation and at study withdrawal. 
Beck Depression Inventory-II (BDI-II) is a 21-item questionnaire that will be used to 
assess the effect of GSK2330672 on depression associated with pruritus in PBC 
participants.  The questionnaire will be completed at Screening, Visits 3 and 6 
 
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[Screening, Weeks 4 and 16] in the study, and if applicable at early study treatment 
discontinuation and at study withdrawal.
Participant Treatment Experience Assessment is a questionnaire that will evaluate 
participants’ experience of itch and their satisfaction (benefits and disadvantages) with 
treatment, which will be performed at the end of the Final Study Period (Visit 6 [Week 
16]), or at early study treatment discontinuation.  
9.1.3.
Actigraphy Sub-Study
An Actigraphy Sub-study will be conducted and is optional for investigator sites and 
participants.  Participants who give their informed consent will wear an activity monitor 
device (similar to a wristwatch) on each wrist during the period of measurement, which 
will be used to assess the frequency and duration of scratching events.
Participating sites may offer the Sub-study to any participant considering the main study, 
providing in the investigator’s option, he/she is capable of understanding and performing 
the sub-study procedures.  Willingness to participate in the Sub-study will not influence a 
participant’s acceptance into the main study.  Participants who do not complete all the 
requested periods of measurement may continue in the main study.  Failure to complete 
the Sub-study measurements will not constitute a protocol deviation.  
Participants will be trained on how and when to use the actigraphy monitors, which will 
be given to them at Visit 2, Visit 4 and Visit 5, with activity measurements performed on 
three occasions, over at least 5 nights during a 7-day period.  In order to allow flexibility 
for participants each of the 7-day measurement periods can occur during either Week 2 or 
Week 3 (for the first measurement), Week 9 or Week 10 (for the second measurement), 
and Week 13 or Week 14 (for the third measurement), respectively.  During the 
measurement period participants may keep the monitors on all the time, or may remove 
them in the morning and put them back on before going to bed.  Participants will return 
the monitors to site staff at their next study visit when data will be downloaded and stored 
for analysis. 
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 5.
The investigator and any 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, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from time informed consent is signed until the end of the 
Final Study Period (Visit 7) at the time points specified in the SoA (Section 2).
 
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
All AEs will be collected from the start of study treatment in the Initial Study Period 
(Visit 2) until the end of the Final Study Period (Visit 7) at the time points specified 
in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the eCRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately, and 
under no circumstances should this exceed 24 hours, as indicated in Appendix 5. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. 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 treatment or study participation, the 
investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 5.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?”
9.2.3.
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 Appendix 5), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 5.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment 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 treatment under clinical 
 
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investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/ IEC, and 
investigators.

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.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAE) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular (CV) events detailed in Appendix 5 and all deaths, whether or not 
they are considered SAEs, specific CV and Death sections of the eCRF will be required 
to be completed. These sections include questions regarding CV (including sudden 
cardiac death) and non-CV 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 CV 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.
9.2.6.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until the end of the Follow-up Period.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 2.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.

Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment immediately but will remain in the study and continue to 
undergo study assessments (see Section 8.1).
9.3.
Treatment of Overdose
For this study, any dose of GSK2330672 greater than 360 mg within a 20-hour time 
period will be considered an overdose.
GSK does not recommend specific treatment for an overdose as there is no specific 
antidote for GSK2330672.  In the event of a suspected overdose, it is recommended that 
 
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the appropriate supportive clinical care should be instituted, as dictated by the 
participant’s clinical status.
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 
any associated symptoms have resolved, and for at least 5 days.
3. Obtain a plasma sample for PK analysis within 24 - 72 hours from the date of the 
last dose of study treatment, 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.
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.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (see Section 2).
All safety assessments should be performed by the investigator or a suitably qualified 
designee.
9.4.1.
Physical Examinations

A complete physical examination (Screening Visit only) will include, at a minimum, 
assessments of the skin, CV, respiratory, gastrointestinal and neurological systems. 
Height and weight will also be measured (wearing indoor clothing without shoes) 
and recorded.

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, CV system, and abdomen (liver and spleen). Weight will also be measured 
(wearing indoor clothing without shoes) and recorded.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.2.
Vital Signs

Vital signs (pulse rate and blood pressure) will be assessed as outlined in the SoA
(Table 1).

Blood pressure and pulse measurements will be assessed in the sitting position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.
 
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
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).

Vital signs (should not be performed immediately after blood collection for 
laboratory tests or PK) will consist of three readings of blood pressure and pulse. The 
first reading should be rejected. The second and third readings should be averaged to 
give the measurement to be recorded in the eCRF.
9.4.3.
Electrocardiograms

A single 12-lead ECG will be obtained as outlined in the SoA (Table 1) using 
preferably an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. If an automated reading is not available the ECG 
should be manually over-read by the investigator or an adequately trained physician. 
Refer to Section 8.1.2 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 
and any clinically significant abnormalities reported in the eCRF.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 6 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 2) for the timing and frequency. 

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition.

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 such 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 assessments, as defined in Appendix 6, must be 
conducted in accordance with the laboratory manual and the SoA (Table 1).
9.5.
Pharmacokinetics

Samples of whole blood of will be collected for measurement of plasma 
concentrations of GSK2330672 and/or UDCA as follows:
 
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
Visit 3 [Week 4] in participants on UDCA only: A 2 mL sample for analysis of 
UDCA will be collected between 1 and 3 hours following the morning dose of 
study treatment. 

Visits 4 and 5 [Weeks 8 and 12 respectively] in all participants on study 
treatment: The first sample (3 mL) will be collected between 1 and 3 hours 
following the morning dose of study treatment. The second sample (2 mL) will 
be collected between 5 and 8 hours after the morning dose of study treatment.  
The first sample will be used for analysis of both GSK2330672 and UDCA, and 
the second sample for analysis of GSK2330672.

If samples are not collected at Visit 5 [Week 12] they may alternatively be 
collected at Visit 6 [Week 16].  

The actual date and time (24-hour clock time) of each sample collection will be 
recorded.  

Participants will record the time of their morning dose of study treatment taken 
at home on a paper diary, as well as the date and time of their last dose of 
UDCA (if applicable).  Participants should bring this information with them to 
the study visit for entry into the eCRF.  

Participants taking UDCA will be required to not administer a morning dose of 
UDCA (if applicable), before each of the PK sampling visits and to record the 
time of their last UDCA dose.

If more convenient, participants may take their morning dose of study treatment 
at the clinic visit, provided they comply with other protocol requirements such 
as fasting, eDiary completion and the sampling time does not interfere with PRO 
completion (see Section 2).

Note: PK sample collection is not required for participants who have 
prematurely discontinued study treatment and have not taken study treatment on 
3 or more days prior to the Visit.

During the study, the timing of PK samples may be altered and/or PK samples may 
be obtained at additional time points.

Sample collection, processing, storage and shipping procedures are provided in the 
Laboratory Manual.

Plasma analysis for GSK2330672 and UDCA will be performed under the control of 
Bioanalytical Science and Toxicokinetics, DMPK, GlaxoSmithKline. Concentrations 
of GSK2330672 and UDCA will be determined in plasma samples using currently 
approved bioanalytical methodology.  Raw data will be archived at the bioanalytical 
site.

Samples collected for analyses of GSK2330672 and/or UDCA plasma concentrations
may also be used to evaluate safety or efficacy aspects related to concerns arising 
during or after the study.

Once the plasma has been analyzed for GSK2330672 and/or UDCA any remaining 
plasma may be analyzed for other GSK2330672-related or UDCA-related 
metabolites and the results reported under a separate protocol.
 
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
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded study personnel until the end of the study and the study 
has been unblinded. 
9.6.
Pharmacodynamics
See Section 9.8.
9.7.
Genetics
A 6 mL blood sample for DNA (deoxyribonucleic acid) 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 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 Appendix 7 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the Laboratory Manual.
9.8.
Biomarkers
The effects of GSK2330672 on markers of PBC disease progression, as well as 
biomarkers of PBC, bile acid physiology and lipids will be evaluated.  
Markers of PBC disease progression: The effects of GSK2330672 on markers of PBC 
will be evaluated among participants at high risk of PBC progression (i.e., serum ALP 
≥1.67x ULN and/or total serum bilirubin >ULN) and in all study participants. PBC 
markers to be assessed include serum ALP, ALT, AST, gamma-glutamyl transferase
(GGT), total bilirubin and albumin concentrations, and prothrombin time/international 
normalised ratio (PT/INR).
Biomarkers of PBC and bile acid physiology: The effects of IBAT inhibition by 
GSK2330672 on circulating bile acids and bile acid synthesis will be evaluated in all 
study participants.  Biomarkers include total serum bile acid and serum C4 as a marker of 
bile acid synthesis.  Additional exploratory biomarkers include serum autotaxin, 
fibroblast growth factor-19 (FGF-19), and enhanced liver fibrosis (ELF) test, and serum 
bile acid species.  Samples may be tested for other biomarkers as new data emerge.  
Lipids: The effect of GSK2330672 on fasting lipids, including direct low density 
lipoprotein (LDL) cholesterol will also be assessed. 

Fasting blood samples for biomarkers and will be collected as outlined in the SoA
(Table 1).

Full details of sample collection and processing are provided in the Laboratory 
Manual.
 
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
In addition, with the participant’s consent, serum samples will be stored and analysis 
may be performed on biomarker variants thought to play a role in PBC disease and 
circulating bile acids, to evaluate their association with observed clinical responses 
to GSK2330672.

Due to the potential for unblinding, results of biomarkers of PBC and bile acid 
physiology will not be provided to investigators or blinded study staff until the study 
has completed and has been unblinded.
9.9.
Medical Resource Utilization and Health Economics
The effect of study treatment on healthcare resource utilization parameters such as 
emergency room visits, details of hospitalisations including intensive care unit stay, will 
be evaluated.
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
Approximately 118 participants will be randomized to ensure that approximately 100 
eligible participants have an evaluable Week 16 assessment of itch.
Sample size calculations were made using simulation to assess the precision of the 
estimated difference in response between each dose of GSK2330672 and placebo from 
the Emax dose-response model (see Figure 2).
 
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Figure 2
Simulated Emax Dose-Response Curve
A sample size of approximately 100 eligible participants allows sufficient precision to 
provide a minimally detectable effect of at least 2 points on the Mean Worst Daily Itch 
Score (assuming a between-participant SD of 2 points).
Participants will be stratified based on region (Europe, North America, Japan to manage 
drug supply) and participant risk of PBC progression according to serum ALP and total 
bilirubin concentrations at Visit 2 [Day 1] (see Table 6).
To optimise the dose response assessment, participants with ALP <1.67x ULN and total 
bilirubin ULN will be randomized in a 1:1:1:1:1 ratio (Placebo: 20 mg once daily: 
90 mg once daily: 180 mg once daily: 90 mg twice daily).  Participants with ALP ≥1.67x 
ULN and/or total bilirubin >ULN will be randomized in a ratio of 3:1:1:2:1, respectively
to increase the precision for the comparison of higher doses of GSK2330672 to placebo 
in participants at higher risk of disease progression.
 
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Table 6
Distribution of Participants to Treatment Arms
Strata 
Placebo
GSK2330672
Once Daily
Twice Daily
20 mg
90 mg
180 mg
90 mg
ALP <1.67x ULN and 
total bilirubin ULN 
Ratio: 
1
1
1
1
1
Participants 
14
14
14
14
14
ALP ≥1.67x ULN and/or 
total bilirubin >ULN 
Ratio: 
3
1
1
2
1
Participants: 
18
6
6
12
6
ALP = Alkaline phosphatase; ULN = Upper Limit of Normal. 
Participant numbers are approximate based on expected recruitment to rates to each strata.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICF
Randomized
All participants who were randomized to receive study treatment, 
regardless of whether they took study treatment, will be used in the 
summaries of participant disposition 
ITT (Intent to Treat) 
Population
This population will comprise all randomized participants who 
receive at least one dose of study treatment, have a baseline and at 
least one on-treatment assessment. Participants in the ITT 
Population will be classified according to the treatment as 
randomized.  The ITT population will be the primary population for 
the statistical assessment of efficacy.
Per Protocol Population
The Per Protocol (PP) Population is a subset of the ITT population 
who adhere to the major protocol requirements.  Protocol violator 
criteria will be defined in the Reporting Analysis Plan (RAP), and 
participants to be excluded from the PP population will be identified 
prior to the unblinding of the data at the end of the study.  The PP 
population will be used for analysis of the primary endpoint to 
assess the sensitivity of the ITT results. The PP population may not 
be analysed if it comprises 80% of the ITT population and is 
balanced across dose levels.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
 
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10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary objective is to estimate the relationship between doses of 
GSK2330672 and itch response.  The primary analysis will be a model-based 
dose-response analysis of the change from Baseline to Week 16 in the Mean 
Worst Daily Itch Score on the 0-10 NRS.
The primary null hypothesis (H0) assumes that there is no effect of the test drug at 
any dose level and therefore no evidence of dose response. The alternate 
hypothesis (H1) assumes that there is a monotonic Emax dose response with 
GSK2330672 on participant experience of itch. 
A four parameter Emax dose-response model, once fitted, will be used to estimate 
the minimally effective dose and 95% confidence interval of each dose level of 
GSK2330672 relative to placebo.
If problems are encountered fitting a four parameter Emax model, the model 
selection approach described by Kirby et al (Kirby, 2011) will be taken (fitting a 3-
parameter Emax model and a power model and selecting the one that best fits the 
data (i.e. smallest Akaike’s Information Criterion statistic (AIC)). If both of these 
models poorly fit, then additional models will be investigated sequentially until an 
appropriate model can be chosen (i.e. linear, quadratic, log-transformed dose).
Further details of the Emax model will be defined in the RAP.
Secondary
Analyses of the following secondary endpoints will be analyzed as the change from 
Baseline to Week 16 using similar methodology as for the primary endpoint (with 
an appropriate link-function for binary endpoints):

Mean change from Baseline in PBC-40.

Mean change from Baseline in markers of PBC disease progression 
including ALP, ALT, AST, GGT, total bilirubin, albumin and PT/INR.

Proportion of participants responding to treatment defined as ALP 
reduction to <1.67x ULN and total bilirubin ≤ULN at the end of treatment 
(in participants with ALP ≥ 1.67x ULN and /or total bilirubin >ULN at Day 
1).

Proportion of participants who are responders using 3 separate definitions 
(Mean Worst Daily Itch Score <4, 30% reduction in Mean Worst Daily 
Itch Score, 2-point reduction in Mean Worst Daily Itch Score). 

Mean number of responder days using 3 separate definitions (Worst Daily 
Itch Score <4, 30% reduction in Worst Daily Itch Score, 2-point 
reduction in Worst Daily Itch Score).

Change from Baseline in Mean Daily Sleep Score.
 
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Endpoint
Statistical Analysis Methods

Change from Baseline in Mean Daily Fatigue Score.

Change from Baseline in the 5-D Itch questionnaire.

Change from Baseline in total serum bile acids and C4.

Further details of the analysis methodology, any sensitivity analyses and 
control of the overall Type I error rate will be defined in the RAP.  
Exploratory
Will be described in the reporting and analysis plan
10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population.
Endpoint
Statistical Analysis Methods
Primary
Overall safety evaluations will be descriptive using the Safety Population (as 
described in Section 10.2). Graphical and tabular displays will be presented to 
facilitate safety data review.
AEs and SAEs will be summarised, sorted by system organ class and preferred 
term assigned by MedDRA, and presenting as number and percent by treatment 
group.  Additional summaries of AEs leading to discontinuation of study treatment 
and study treatment related AEs will also be generated.
Secondary
Change from baseline in GSRS score.
Change from baseline and percentage change from baseline for laboratory 
values will be summarised 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.  
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 
and separately, those meeting the pre-specified withdrawal criteria will be 
summarized by treatment group. 
Criteria for potential clinical importance will be specified in the RAP.
Exploratory
Will be described in the reporting and analysis plan 
10.3.3.
Other Analyses
Pharmacokinetic, PD and biomarker exploratory analyses will be described in the RAP. 
Any other population analyses (e.g., dose-response) conducted based on emerging data 
will be described in the CSR or a separate report as appropriate.
 
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10.3.4.
Interim Analyses
An interim analysis of efficacy and safety will be performed in order to determine 
whether the initial doses of GSK2330672 need to be modified.  Once a participant is 
assigned to a treatment arm, their individual treatment assignment will not change as a 
result of the outcome of the interim analysis and their data will still contribute to the final 
dose response analysis.
An interim analysis will allow for potential discontinuation for futility, elimination of less 
informative doses (e.g., those which are ineffective or poorly tolerated), and/or addition 
of lower or higher doses to more fully describe the dose-response characteristics of 
GSK2330672. 
In order to minimise bias, a firewalled analytical group will perform the interim analyses 
to maintain the integrity of the study blind within the study team.  The unblinded data 
will be reviewed by limited members of the trial leadership, who will review the results 
and may then decide to:
1.
Continue as planned.
2.
Stop for futility: Proposed futility rule to be based on a low posterior predicted 
probability that at least one dose will achieve a clinically relevant treatment 
difference to placebo (based on dose-response model). 
3.
Amend dose levels: Proposed if dose-response and/or tolerability profile 
dramatically different to pre-study assumptions. Allocation post-interim would 
be focused on most informative doses chosen from a set of possible dose levels 
that includes those used pre-interim (e.g., if larger responses are seen on the 
lower doses then the ED50 may be smaller than was assumed during design 
and hence lower dose levels could be included and higher levels dropped). 
4.
Amend sample size: Proposed if an additional dose is added, or if the observed 
variability is dramatically different to the assumptions from the initial sample 
size calculations.
The results of the interim analysis could lead to changes to the randomization ratio and/or 
a change in the total number of participants to be randomized in the study. The decision 
to adapt the study will be determined by posterior probability decision rules which will be 
pre-defined and documented prior to unblinding in the RAP. 
Based on the overall panned sample size, an interim analysis will be ideally performed 
after approximately 40 participants have reached their Visit 5 [Week 12].  However, 
should enrolment fail to occur as anticipated, the timing of the planned interim may be 
revised.  Additional interim analyses may be conducted based on the initial data. 
Details of the analyses to support the interim and the decision rules will be documented 
in a separate Interim Analysis Plan.  The final timings of the interim analyses will be 
documented in the clinical study report. 
 
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11.
REFERENCES
Elman S., Hynan L.S., Gabriel V., Mayo M.J. The 5-D itch scale: a new measure of 
pruritus. Br J Dermatol. 2010; 162:587-593.
GlaxoSmithKline Document Number 2010N111289_03: GSK2330672 Investigator's 
Brochure. 29-JUL-2016.
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.
Kirby, S., Brain, P., Jones, B. Fitting Emax models to clinical trial dose-response data.
Pharmaceut. Statist. 2011; 10: 143-149.
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.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
List of Abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BDI-II
Beck Depression Inventory-II
C4
7--hydroxy-4-cholesten-3-one
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine Phosphokinase
CSR
Clinical Study Report
CV
Cardiovascular
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDevice
Electronic Device
eDiary
Electronic Diary
eGFR
Estimated Glomerular Filtration Rate
ELF
Enhanced Liver Fibrosis
FGF-19
Fibroblast Growth Factor-19
FOBT
Fecal Occult Blood Test
 
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GCP
Good Clinical Practice
GGT
Gamma-glutamyl Transferase
GSRS
Gastrointestinal Symptoms Rating Scale
HBsAg
Hepatitis B Surface Antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDL
High-density Lipoprotein
HDPE
High Density Polyethylene Bottles 
HPLC
High Performance Liquid Chromatography
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
IBAT
Inhibitor of the Human Ileal Bile Acid Transporter
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International Normalized Ratio
IRB
Institutional Review Board
ITT
Intent to Treat
IUD
Intrauterine Device
IUS
Intrauterine Hormone-releasing System
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LDH
Lactate Dehydrogenase
 
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LDL
Low-density Lipoprotein
MSDS
Material Safety Data Sheet
NASH
Nonalcoholic Steatohepatitis
NOAEL
No Observed Adverse Effect Level
NRS
Numerical Rating Scale
PBC
Primary Biliary Cholangitis
PD
Pharmacodynamic
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PK
Pharmacokinetics
PRO
Patient Reported Outcome
PSC
Primary Sclerosing Cholangitis
PT
Prothrombin Time
RAP
Reporting Analysis Plan
SAE
Serious Adverse Event
SoA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
T2DM
Type 2 Diabetes Mellitus
UDCA
Ursodeoxycholic Acid
ULN
Upper Limit of Normal
VLDL
Very low-density Lipoprotein
WOCBP
Women of Child Bearing Potential
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None
 
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12.2.
Appendix 2: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 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, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-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 enrollment.
Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 7.
 
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Table 7
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
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 treatment. 
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.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test

Additional pregnancy testing should be performed at monthly intervals during the 
treatment period and at the end of the Final Study Period, and as required locally.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
 
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
Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed using the test 
kit provided by the central laboratory and in accordance with instructions provided in 
its package insert  
Collection of Pregnancy Information
Male participants with partners who become pregnant

Pregnancies in female partners of male participants do not need to be collected.
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 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 treatment immediately but will remain in the study and continue to 
undergo study procedures (see Section 8.1). 
 
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12.3.
Appendix 3: Study Governance Considerations
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) 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. 

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 (Code of Federal Regulations), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
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 
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.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
 
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ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study site. 

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 or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
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. 

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. 

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.
Committees Structure
The study will be conducted under the auspices of a Steering Committee comprised of 
academic and clinical experts and Sponsor representatives who will oversee the scientific 
and operational aspects of the study.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

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.
 
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Dissemination of Clinical Study Data

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 and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study subjects, as appropriate.

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 results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
eCRF 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 eCRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification 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. 

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 
Clinical Study Report (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. 
 
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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 eCRF 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.

Definition of what constitutes source data can be found in the Study Reference 
Manual.
Study and Site Closure
GSK or its 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:

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 recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.4.
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments
These figures are to assist with application of the liver chemistry increased monitoring 
and stopping criteria in Section 8.1.1.
Figure 3
Liver Chemistry Criteria for Increased Monitoring and Stopping 
Study Treatment:  ALT
 
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Figure 4
Liver Chemistry Criteria for Increased Monitoring and Stopping 
Study Treatment:  Bilirubin
12.4.1.
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 8.1.1.

Immediately withdraw the participant from study treatment.  (Note: The participant 
should remain in the study completing remaining study visits and assessments [see 
Section 8.1]).

Make every reasonable attempt to have the participant return to the clinic within 24-
72 hrs for repeat liver chemistries and additional testing.
 
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
Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to 
confirm the participant’s study treatment cessation and follow-up.

Complete the “Safety Follow-Up Procedures” listed below.

Complete the liver event CRFs.  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 until the End of Follow-up Telephone Visit; however the participant must not 
restart study treatment (see Section 8.1.6.1).

Monitor participants at least weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, total bilirubin, PT/INR) resolve, stabilize or return to within baseline 
values.
Additional Safety Follow-Up Procedures for participants who meet any of the liver 
stopping criteria:

Viral hepatitis serology including:

Hepatitis A 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 
treatment 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 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.
 
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
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 (quantifies potential acetaminophen contribution to liver injury in participants 
with definite or likely acetaminophen use 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.
 
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12.5.
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
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 treatment, whether or not considered related to the 
study treatment.

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 treatment.
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 treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment 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 fulfill the definition of an AE 
or SAE. 
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 
 
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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.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence 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 detained (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 fulfills 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 disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

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
 
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f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but 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.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Adverse events of special interest include the following:

Diarrhea reported as an AE

Elevated ALT meeting stopping criteria
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
Recording 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) 
 
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related to the event.

The investigator will then record all relevant AE/SAE information in the eCRF.

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 /AE/SAE eCRF page.

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 sufficiently 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.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment 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.

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 treatment 
administration will be considered and investigated.

The investigator will also consult the 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.
 
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
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 completed eCRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
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), in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to study treatment/study participation (causality) within 72 
hours of SAE entry into the eCRF.

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 
 
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taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the Medical Monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor.

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 CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SRM.
 
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12.6.
Appendix 6: Clinical Laboratory Tests

The tests detailed in Table 8 will be performed by the central laboratory. 
Section 9.8 provides details of biomarkers that will also be assessed.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 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.
Table 8
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology

Platelet Count

RBC Count

Hemoglobin

Hematocrit

% Reticulocytes
RBC Indices:

MCV

MCH

WBC count with 
Differential:

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils
Coagulation

Prothrombin Time (PT)/International Normalized Ratio (INR)
Clinical 
Chemistry1

BUN

Creatinine

eGFR (CKD-EPI)

Potassium

Sodium

Calcium

Glucose (fasting)2

Total cholesterol (fasting)2

Direct LDL cholesterol (fasting)2

Direct HDL cholesterol (fasting)2

Indirect LDL cholesterol (fasting)2

Indirect VLDL cholesterol (fasting)2

Triglycerides (fasting)2

Aspartate Aminotransferase (AST) 

Alanine Aminotransferase (ALT)

Alkaline Phosphatase (ALP)

Gamma Glutamyl Transferase (GGT) 

Total and direct bilirubin

Total protein

Albumin
Other

Vitamins A, D, E, K

Fecal occult blood test (FOBT) (cards to be provided for test)
Other Screening 
Tests

Follicle-stimulating hormone (FSH) (as needed in women of non-childbearing 
potential only).

Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women 
of childbearing potential).3

Serology hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV) antibody 
( HCV RNA if antibody test positive).
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 8.1.1 and Appendix 4. 
2.
Fasting (water, study treatments and other medications are permitted) samples required for all visits except 
screening.
3.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
 
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12.7.
Appendix 7: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy 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 sample will be collected for DNA analysis

DNA samples will be used for research related to GSK2330672 or PBC and related 
diseases. They may also be used to develop tests/assays including diagnostic tests) 
related to GSK2330672, or study treatments of this drug class, and PBC. 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)

DNA samples will be analyzed for understanding response to medicine, including 
any treatment regimens under investigation in this study or any concomitant 
medicines. Additional analyses 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 GSK2330672 or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report 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 GSK2330672 (or study treatments of 
this class) or PBC continues but no longer than 15 years after the last subject last 
visit or other period as per local requirements.
 
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12.8.
Appendix 8: Country-specific requirements
None
 
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12.9.
Appendix 9: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 1 15-Nov-2016
Overall Rationale for the Amendment:  To clarify requirements for liver safety 
monitoring and stopping criteria, as well as other administrative changes.
Section # and 
Name
Description of Change
Brief Rationale
8.1.1 Liver 
Chemistry 
Stopping Criteria
Repeat testing should include 
AST, ALT, total bilirubin, ALP and 
PT/INR (insertion of tests).
Clarification on which liver tests are 
required.
12.4 Appendix 4: 
Liver Safety
Inclusion of PT/INR as part of the 
liver safety follow-up tests, which 
are required at least weekly.
Following stopping of study 
treatment participants with liver 
safety findings should not be 
withdrawn but as well as liver 
safety follow-up should remain in 
the study undergoing study visits 
and assessments.
Participants who stop study 
treatment for liver safety should 
not restart study treatment.
Correction for missing test.
Correction and alignment with Section 8.1 
which states that participants who stop 
study treatment should remain in the 
study completing remaining study visits 
and assessments.
Clarification and alignment with Section 
8.1.6.1., which states that study treatment 
restart or rechallenge is not permitted.
2 Schedule of 
Activities
Update Footnote 1: Early End of 
Treatment and Study Withdrawal 
Assessments are only performed 
post-randomization. If both are 
required at the same visit only the 
Early End of Treatment 
Assessments are performed.
Clarification that the assessments are 
required only for randomized participants.
As assessments overlap, both are not 
required for the same visit.  However, 
since the Participant Treatment 
Experience Assessment is required as 
part of the Early End of Treatment 
Assessments, these should be 
conducted.
8.1 
Discontinuation 
of Study 
Treatment
Early End of Treatment 
Assessments are only performed 
post-randomization. 
8.2 Withdrawal 
from the Study
Study Withdrawal Assessments 
are only performed post-
randomization. 
Clarification that the assessments are 
required only for randomized participants.
 
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Section # and 
Name
Description of Change
Brief Rationale
2 Schedule of 
Activities
Table 1 amended to separate out 
PGI-C as this is not required at 
Visit 2.
As a measure of change PGI-C is not 
appropriate at Visit 2. 
2 Schedule of 
Activities
Sequence of PROs revised to 
move PGI-S and PGI-C before 
other PROs.
Correction of order of assessments.
2 Schedule of 
Activities
Addition of weekly gastrointestinal 
(GI) symptom collection with the 
weekly GSRS.
Alignment with eDiary data collection.
9.1.1 Electronic 
Data Collection
Addition of weekly GI symptom 
collection with the weekly GSRS.
Alignment with eDiary data collection.
9.1.2.1 Patient 
Reported 
Symptom 
Questionnaire
Addition of weekly GI symptom 
collection. 
Alignment with eDiary data collection.
9.1.2.1 Patient 
Reported 
Symptom 
Questionnaires
Update to the Itch NRS to indicate 
that a score of 
 represents the 
.
Alignment with eDiary.
9.1.2.5 Other 
PRO Measures
PGI-S is a 5-level response scale.
PGI-C comprises a 7-level 
response scale of change since 
baseline and a dichotomous (Y/N) 
question. PGI-C will not be 
collected at Visit 2.
Correction to accurately describe the 
measures and alignment with updated 
SOA.
2 Schedule of 
Activities
Update Footnote 7 to indicate if 
Visit 5 PK sample is not collected 
it may be collected at Visit 6.  
Addition of note that PK sample 
collection is not required if 
participant has prematurely 
discontinued study treatment and 
study treatment has not been 
taken on 3 or more days prior to 
the Visit.
Alignment with Section 9.5 and to clarify 
PK sample collection with respect to 
participants who discontinue treatment.
9.1.1 Electronic 
Data Collection
Deletion of text relating to 
collection of study treatment and 
UDCA dosing times in the eDiary.
Correction. To support PK evaluation 
participants will record dosing dates/times 
using a paper based diary (see Section 
 
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Section # and 
Name
Description of Change
Brief Rationale
9.5).
9.5 
Pharmacokinetics
Participants will record the study 
treatment and UDCA dosing times 
on a paper diary for visits 
requiring PK collection and will be 
entered into the eCRF.
Addition of bullet stating PK 
sample collection is not required if 
participant has prematurely 
discontinued study treatment and 
has been off treatment for greater 
than 3 days.
Clarification that dosing information will 
be collected via a paper diary and 
entered in eCRF.
Clarification on PK sample collection in 
participants who prematurely stop study 
treatment and remain in the study.
7.7 Concomitant 
Medication
Medications taken within 3 
months of Screening should be 
recorded in the eCRF.
Clarification.
12.2 Appendix 2: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
Deletion of footnote b under Table 
5.
Footnote was included in error, as 
GSK2330672 is not expected to be 
susceptible to interaction with hormonal 
contraceptives. Women of child-bearing 
potential therefore may be enrolled in the 
study using one (not two) highly effective 
methods of contraception.
12.5 Appendix 5: 
Adverse Events
Removal of AST meeting stopping 
criteria as AE of special interest. 
Cardiovascular events will be 
collected using specific CV event 
eCRF.
Evidence of Investigator or 
medically-qualified sub-
investigator review and 
verification of SAE relationship 
(causality) information is required 
in eCRF within 72 hours of SAE 
entry.
Correction as the protocol does not have 
specified stopping criteria for AST.
Update of Sponsor required protocol text 
for CV event collection.
Update of Sponsor required protocol text.
12.6 Appendix 6: 
Clinical 
Laboratory Tests
Inclusion of direct HDL 
cholesterol, indirect LDL 
cholesterol and indirect VLDL 
cholesterol in clinical chemistry 
tests.
Correction to reflect central laboratory’s 
standard lipid panel.
 
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Section # and 
Name
Description of Change
Brief Rationale
12.3 Appendix 3: 
Study 
Governance 
Considerations
Record retention time of 25 years 
is from issue of clinical study 
report/equivalent summary.
Update of Sponsor required protocol text.
12.7 Appendix 7: 
Genetics
Maximum samples retention will 
be no longer than 15 years after 
the last subject last visit or other 
period as per local requirements.
Update of Sponsor required protocol text.
12.1 Appendix 1: 
Abbreviations 
and Trademarks
Addition of abbreviations (ALT, 
CSR, HDL, INR, PT, VLDL).
Alignment with text.
 
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SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201000 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for Reporting and Analysis Plan 
for Study 201000: A randomised, double-blind, multi-dose, 
placebo-controlled study to evaluate the efficacy, safety and 
tolerability of GSK2330672 administration for the treatment 
of pruritus in participants with primary biliary cholangitis. 
Compound Number  
: GSK2330672 
Effective Date  
: Refer to Document date 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 201000 
• 
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
• 
The interim analysis was outlined in a separate Interim Analysis Plan document 
• 
This RAP will be provided to the study team members to convey the content of the 
[Reference as Required: Statistical Analysis Complete (SAC)] deliverable. 
 
RAP Author(s): 
 
Approver 
Date 
 
Principal Statistician (Future Pipelines 
Discovery, Clinical Statistics) 
7-May-2020 
 
 
 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201000 
 
2 
 
RAP Team Reviews: 
Reviewer 
Date 
RAP Team 
Review 
Confirmations 
 
Director, Clinical Development 
8-May-2020 
E-mail 
 
Medicine Development Leader, Development  
8-May-2020 
E-mail 
 
Director Discovery Medicine Scientist, PCPS 
8-May-2020 
E-mail 
  
Director, Patient Reported Outcomes 
Patient Focused Outcomes 
7-May-2020 
E-mail 
 
8-May-2020 
E-mail 
Principal Programmer, Future Pipelines Discover 
Clinical Programming 
 
 
8-May-2020 
E-mail 
Director, Clinical Pharmacology Modeling and 
Simulation, CPMS 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
 
Director, Future Pipelines Discovery, Clinical 
Statistics 
 
Programming Manager, Future Pipelines 
Discovery Clinical Programming 
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CONFIDENTIAL 
201000 
3 
TABLE OF CONTENTS 
PAGE 
1.
INTRODUCTION ...................................................................................................... 6
2.
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 6 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 6 
2.3. 
Study Design .............................................................................................. 10 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 12 
3.
PLANNED ANALYSES .......................................................................................... 13 
3.1. 
Interim Analyses ......................................................................................... 13 
3.2. 
Final Analyses ............................................................................................ 13 
4.
ANALYSIS POPULATIONS ................................................................................... 13 
4.1. 
Protocol Deviations ..................................................................................... 14 
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING
CONVENTIONS ..................................................................................................... 16 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 16 
5.2. 
Baseline Definitions .................................................................................... 16 
5.3. 
Multicentre Studies ..................................................................................... 18 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 19 
5.4.1. 
Covariates and Other Strata ........................................................ 19 
5.4.2. 
Examination of Subgroups ........................................................... 20 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 21 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 21 
6.
STUDY POPULATION ANALYSES ....................................................................... 22 
6.1. 
Overview of Planned Study Population Analyses ........................................ 22 
7.
EFFICACY ANALYSES .......................................................................................... 23 
7.1. 
Primary Efficacy Analyses .......................................................................... 23 
7.1.1. 
Endpoint / Variables ..................................................................... 23 
7.1.2. 
Summary Measure ...................................................................... 24 
7.1.3. 
Population of Interest ................................................................... 24 
7.1.4. 
Statistical Analyses / Methods ..................................................... 24 
7.1.4.1. 
Statistical Methodology Specification .......................... 24 
7.2. 
Secondary Efficacy Analyses ...................................................................... 30 
7.2.1. 
Endpoint / Variables ..................................................................... 30 
7.2.2. 
Summary Measure ...................................................................... 30 
7.2.3. 
Population of Interest ................................................................... 32 
7.2.4. 
Statistical Analyses / Methods ..................................................... 32 
7.2.4.1. 
Statistical Methodology Specification .......................... 32 
7.3. 
Exploratory Efficacy Analyses ..................................................................... 34 
7.3.1. 
Endpoint / Variables ..................................................................... 34 
7.3.2. 
Summary Measure ...................................................................... 34 
7.3.3. 
Population of Interest ................................................................... 35 
7.3.4. 
Statistical Analyses / Methods ..................................................... 35 
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8. 
SAFETY ANALYSES ............................................................................................. 37 
8.1. 
Adverse Events Analyses ........................................................................... 37 
8.2. 
Adverse Events of Special Interest Analyses .............................................. 37 
8.3. 
Clinical Laboratory Analyses ....................................................................... 37 
8.4. 
Other Safety Analyses ................................................................................ 37 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 39 
9.1. 
Primary Pharmacokinetic Analyses ............................................................. 39 
9.1.1. 
Endpoint / Variables ..................................................................... 39 
9.1.1.1. 
Drug Concentration Measures and Data 
Handling ..................................................................... 39 
9.1.1.2. 
Pharmacokinetic Concentrations for linerixibat, 
UDCA, GUDCA and TUDCA ...................................... 39 
9.1.2. 
Summary Measure ...................................................................... 40 
9.1.3. 
Population of Interest ................................................................... 40 
9.1.4. 
Statistical Analyses / Methods ..................................................... 40 
10. PHARMACODYNAMIC BIOMARKER ANALYSES ................................................ 42 
10.1. 
Primary/Secondary/Exploratory Pharmacodynamic Biomarker 
Analyses ..................................................................................................... 42 
10.1.1. 
Endpoint / Variables ..................................................................... 42 
10.1.2. 
Summary Measure ...................................................................... 42 
10.1.3. 
Population of Interest ................................................................... 43 
10.1.4. 
Statistical Analyses / Methods ..................................................... 43 
10.1.4.1. Statistical Methodology Specification .......................... 44 
11. REFERENCES ....................................................................................................... 45 
12. APPENDICES ........................................................................................................ 46 
12.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 46 
12.1.1. 
Exclusions from Per Protocol Population ..................................... 46 
12.2. 
Appendix 2: Schedule of Activities .............................................................. 48 
12.2.1. 
Protocol Defined Schedule of Events ........................................... 48 
12.3. 
Appendix 3: Assessment Windows ............................................................. 53 
12.3.1. 
Definitions of Assessment Windows for Analyses ........................ 53 
12.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 54 
12.4.1. 
Study Phases .............................................................................. 54 
12.4.1.1. Treatment Phase All Data........................................... 54 
12.4.1.2. Treatment Phase for AE Data ..................................... 54 
12.4.1.3. Study Phases for Concomitant Medication ................. 55 
12.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 56 
12.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 57 
12.5.1. 
Reporting Process ....................................................................... 57 
12.5.2. 
Reporting Standards .................................................................... 57 
12.5.3. 
Reporting Standards for Pharmacokinetic and 
Pharmacodynamic ....................................................................... 59 
12.6. 
Appendix 6: Derived and Transformed Data ............................................... 60 
12.6.1. 
General ........................................................................................ 60 
12.6.2. 
Study Population .......................................................................... 61 
12.6.3. 
Efficacy ........................................................................................ 62 
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12.6.4. 
Safety .......................................................................................... 75 
12.6.5. 
Pharmacokinetic .......................................................................... 78 
12.6.6. 
Pharmacodynamic Biomarker ...................................................... 78 
12.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 79 
12.7.1. 
Premature Withdrawals ................................................................ 79 
12.7.2. 
Handling of Missing Data ............................................................. 79 
12.7.2.1. Handling of Missing and Partial Dates ........................ 79 
12.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 82 
12.8.1. 
Laboratory Values ........................................................................ 82 
12.8.2. 
ECG ............................................................................................. 83 
12.8.3. 
Vital Signs .................................................................................... 83 
12.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 84 
12.9.1. 
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................ 84 
12.9.2. 
Population Pharmacokinetic (PopPK) Methodology ..................... 84 
12.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 85 
12.10.1. Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................ 85 
12.11. Appendix 11: Abbreviations & Trade Marks ................................................ 86 
12.11.1. Abbreviations ............................................................................... 86 
12.11.2. Trademarks ................................................................................. 88 
12.12. Appendix 12: List of Data Displays.............................................................. 89 
12.12.1. Data Display Numbering .............................................................. 89 
12.12.2. Mock Example Shell Referencing ................................................ 89 
12.12.3. Deliverables ................................................................................. 89 
12.12.4. Study Population Tables .............................................................. 90 
12.12.5. Efficacy Tables ............................................................................ 95 
12.12.6. Efficacy Figures ......................................................................... 110 
12.12.7. Safety Tables ............................................................................. 117 
12.12.8. Safety Figures ........................................................................... 127 
12.12.9. Pharmacokinetic Tables ............................................................. 129 
12.12.10. Pharmacokinetic Figures ........................................................... 132 
12.12.11. Pharmacodynamic Biomarker Tables ........................................ 137 
12.12.12. Pharmacodynamic Biomarker Figures ....................................... 141 
12.12.13. ICH Listings ............................................................................... 142 
12.12.14. Non-ICH Listings ........................................................................ 144 
12.13. Appendix 13: Example Mock Shells for Data Displays .............................. 147 
12.14. Appendix 14: Interim Analysis Results and update to the RAP ................. 148 
 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 
 
Revision Chronology: 
201000 
6-Aug-2016  
Original 
201000/ 01 
15-Nov-2016 
To clarify requirements for liver safety monitoring 
and stopping criteria, as well as other administrative 
changes. 
201000 / 02 
07-Dec-2017 
To increase access to the trial for participants who 
will more closely reflect the intended treatment 
population of PBC patients while maintaining safety, 
to clarify some existing criteria and information, to 
make administrative changes, and to correct minor 
typographical and grammatical errors 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 2 [(Dated: 07/Dec/2017)]. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary 
• To investigate the dose response of 
oral GSK2330672 on itch in PBC 
patients with moderate to severe 
pruritus at Baseline. 
• Mean change from Baseline at Week 
16 in the Mean Worst Daily Itch 
Score1. 
Key Secondary 
• To characterize the effects of 
GSK2330672 compared to placebo on 
impact of symptoms and quality of life 
in PBC patients with moderate to 
severe pruritus at Baseline. 
• 
Mean change from Baseline at Week 
16 in PBC-40 Scale.* 
• To evaluate the effects of 
In participants meeting the criteria for 
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Objectives 
Endpoints 
GSK2330672 compared to placebo on 
markers of disease among participants 
at high risk of PBC progression (i.e., 
those with serum ALP concentrations 
1.67xULN and/or total bilirubin 
concentrations >ULN at Day 1). 
high risk of PBC progression: 
• Mean change from Baseline at Week 
16 in serum ALP concentrations.  
• Proportion of participants having 
serum ALP concentrations <1.67x 
ULN and total bilirubin 
concentrations ULN at Week 16.  
• Mean change from Baseline at Week 
16 in serum ALT, AST, GGT, total 
bilirubin and albumin concentrations 
and PT/INR. 
Other Secondary 
• To determine the safety and tolerability 
of GSK2330672 compared to placebo 
in PBC patients with moderate to 
severe pruritus at Baseline. 
• AEs, clinical laboratory parameters, 
ECGs, vital signs and the GSRS. 
• To evaluate the effects of 
GSK2330672 compared to placebo on 
itch response rates in PBC patients 
with moderate to severe pruritus at 
Baseline. 
• 
Proportion of participants who are 
responders at Week 16 based on each 
of the following separate definitions: 
• 
Mean Worst Daily Itch Score1 of 
<4. 
• 
At least a 30% reduction from 
Baseline in the Mean Worst 
Daily Itch Score1. 
• 
At least a 2-point reduction from 
Baseline in the Mean Worst 
Daily Itch Score1. 
• 
Mean number of responder days 
during Weeks 5 to 16 based on each 
of the following separate responder 
day2 definitions: 
• 
Worst Daily Itch Score of <4. 
• 
Worst Daily Itch Score at least 
30% lower than the Baseline 
Mean Worst Daily Itch Score.  
• 
Worst Daily Itch Score at least 
2-points lower than the Baseline 
Mean Daily Score.+ 
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Objectives 
Endpoints 
• To further characterize the effects of 
GSK2330672 compared to placebo on 
symptoms and quality of life in PBC 
patients with moderate to severe 
pruritus at Baseline. 
Change from Baseline at Week 16 in: 
• Mean Daily Sleep Score3. 
• Mean Daily Fatigue Score4. 
• 5-D Itch Scale. 
• To evaluate the effects of 
GSK2330672 compared to placebo on 
total serum bile acid concentrations 
and on bile acid synthesis in PBC 
patients with moderate to severe 
pruritus at Baseline. 
• Mean change from Baseline at Week 
16 in serum concentrations of total 
bile acids and serum C4 as a marker 
of bile acid synthesis. 
• To investigate the PK of oral 
GSK2330672 in PBC patients with 
moderate to severe pruritus at Baseline. 
• Plasma concentrations of 
GSK2330672 after sparse sampling 
(PK parameters will be reported if 
data permit). 
Exploratory 
• 
To evaluate participant’s treatment 
experience and health status with 
GSK2330672 compared to placebo in 
PBC patients with moderate to severe 
pruritus at Baseline. 
• Treatment benefits and disadvantages 
as elicited in a Participant Treatment 
Experience Assessment at Week 16. 
• Time to worsening of itch during 
Weeks 17-20 in participants with an 
improved Worst Daily Itch Score at 
Week 16 relative to Baseline. 
• Change from Baseline at Week 16 in 
EQ-5D-5L health dimensions and 
utility index.  
• Change from Baseline at Week 16 in 
Patient Global Impression of Severity 
(PGI-S) and Patient Global 
Impression of Change (PGI-C). 
• To evaluate the effect of GSK2330672 
compared to placebo on exploratory 
biomarkers of PBC and bile acid 
physiology in PBC patients with 
moderate to severe pruritus at Baseline. 
• Change from Baseline at Week 16 in 
serum autotaxin, fibroblast growth 
factor-19 (FGF-19), enhanced liver 
fibrosis (ELF) test and individual 
serum bile acid species.  
• To evaluate the effect of GSK2330672 
compared to placebo on serum lipids 
and absorption of fat-soluble vitamins 
• Change from Baseline at Week 16 in 
fasting lipid profile, including direct 
low density lipoprotein (LDL) 
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Objectives 
Endpoints 
in PBC patients with moderate to 
severe pruritus at Baseline. 
cholesterol.  
• Change from Baseline at Week 16 in 
Vitamins A, D, E and K.  
• To evaluate the effect of GSK2330672 
compared to placebo on depressive 
symptoms associated with PBC in PBC 
patients with moderate to severe 
pruritus at Baseline. 
• Change from Baseline at Week 16 in 
the Beck Depression Inventory-II 
(BDI-II).  
• To explore the effect of GSK2330672 
on ursodeoxycholic acid (UDCA) 
concentrations in PBC patients with 
moderate to severe pruritus at Baseline. 
• Plasma concentrations of UDCA after 
sparse sampling (in participants on 
UDCA). 
• To evaluate the pharmacogenomics of 
PBC and response to GSK2330672 in 
PBC patients with moderate to severe 
pruritus at Baseline. 
• Pharmacogenomics for genes related 
to PBC, pruritus and IBAT response 
(in consenting participants). 
• To evaluate the potential of actigraphy 
to quantify scratching activity and 
sleep quality due to pruritus associated 
with PBC and to assess the effect of 
GSK2330672 on these parameters in 
PBC patients with moderate to severe 
pruritus at Baseline. 
• Mean scratching event duration, and 
frequency (events/night) of specific 
scratching movements measured by 
wrist actigraphy and derived 
parameters (in participants in the 
Actigraphy Sub-study). 
1. Mean Worst Daily Itch Score: participant’s itch severity is recorded on an electronic diary (eDiary) each 
morning and evening using a 0-10 numerical rating scale (NRS). The worst of these 2 scores is the Worst Daily 
Itch score. The Mean Worst Daily Itch Score is the worst daily itch score averaged over the 7 days preceding 
randomization at Visit 3 (Baseline) and over the 7 days preceding Visit 6 (Week 16).  
2. A responder day is based on the Worst Daily Itch Score recorded using the 0-10 NRS for that day. When the 
responder day definition is relative to Baseline, the Worst Daily Itch Score is compared to the Mean Worst Itch 
Daily Score for Baseline (see 1 above). 
3. Mean Daily Sleep Score: participant’s sleep quality is recorded on the eDiary each morning using a 0-10 NRS 
and the Daily Sleep Score is averaged over the 7 days preceding randomization at Visit 3 (Baseline) and over 
the 7 days preceding Visit 6 (Week 16). 
4. Mean Daily Fatigue Score: participants fatigue level is recorded on the eDiary each evening using a 0-10 NRS 
and the Daily Fatigue Score is averaged over the 7 days preceding randomization at Visit 3 (Baseline) and 
over the 7 days preceding Visit 6 (Week 16). 
Note:  
For all other endpoints Baseline is defined as the Visit 3 assessment and Week 16 is defined as the Visit 6 
assessment. 
In addition to Week 16, which is the primary time point of interest, other intermediate time points will also be 
assessed. 
        *Mean change from Baseline at Week 16 in all the domains of PBC-40 Scale. 
        +Mean Daily Score is a comparison to the 7 day mean worst daily itch score at baseline. 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
This is a phase IIb, multicenter, randomised, double-blind, placebo-controlled, parallel 
group, dose-finding study in adults with moderate to severe pruritus associated with PBC. 
The study has an adaptive design which aims to utilize interim data to further inform and 
potentially optimize the doses under investigation (see Section 10.3.4 of the protocol).  
 
Following the Screening Visit, there will be four study periods:  
• Initial Study Period: Single-blind placebo treatment for 4 weeks during which 
participants’ symptoms will be recorded in the eDiary to establish baseline symptoms and 
assess eligibility for randomization and compliance with study procedures.  
• Main Study Period: Eligible participants will be randomised to receive 12 weeks 
double-blind treatment with either placebo or one of 4 dose regimens of GSK2330672 
(20 mg, 90 mg or 180 mg taken once daily or 90 mg twice daily). Randomization will be 
stratified based on participant’s risk of PBC disease progression based on serum ALP and 
total bilirubin concentrations at Day 1 (see Section 7.3.1).  
• Final Study Period: Single-blind placebo treatment for 4 weeks to assess symptoms and 
safety post-completion of double-blind treatment.  
• Follow-up Period: to assess symptoms and use of anti-pruritus medications by 
telephone visit.  
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Overview of Study Design and Key Features 
 
Eligible participants may continue to receive some therapies for the treatment PBC 
provided these are maintained at stable doses and there is no plan to discontinue them 
during the study. Concomitant use of cholestyramine, colesevelam, colestipol or 
colestimide is not permitted until after completion of the Main Study Period. Obeticholic 
acid use is not permitted at any time during the study.  
 
All study treatment will be administered orally twice a day, using placebo tablets as 
necessary to blind dose and regimen. Participants will commence single-blinded study 
treatment at Visit 2 [Day1]. During the Initial, Main and Final Study Periods it is 
important that participants remain blind to changes in study treatment from single-blind 
placebo to randomised double-blind treatment and subsequently to single-blind placebo. 
Investigator and study site staff communication with participants should ensure 
maintenance of each participant’s blinding to treatment throughout the study.  
 
A participant’s total duration in the study will be approximately 24 weeks from Day 1 to 
completion of the Follow-up Telephone Visit.  
 
The study also includes an exploratory Actigraphy Sub-study which will be conducted at 
a limited number of study sites and in a sub-set of participants who give their consent. 
Design 
Features 
This is a Phase IIb, multicentre, randomised, double-blind, placebo-
controlled, parallel group, dose-finding study in adults with moderate to 
severe pruritus associated with PBC.    
There are 3 core study periods; Each participant will receive  
1) Single-blind placebo for 4 weeks (Initial study period - ISP), 
a. Starting at Visit 2 (Day 1) and ending on Visit 3 
2) Double-blind study treatment for 12 weeks (Main study period - MSP), 
a. Starting at Visit 3 (Baseline) and ending at Visit 6  
3) Single-blind placebo for a further 4 weeks (Final study period - FSP). 
a. Starting at Visit 6 and ending at Visit 7 
With a follow-up phone call at Visit 8 
This study has an adaptive design, which aims to utilise interim data to 
further inform and potentially optimise the doses under investigation. 
Dosing 
The study compound is GSK2330672. 
Each subject will be administered study treatment orally twice a day, using 
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Overview of Study Design and Key Features 
placebo tablets as necessary to blind dose and regimen. 
During the main study period, participants will be randomised to receive 
12 weeks double-blind treatment of one of the following dose regimens: 
• placebo 
• 20 mg once daily (QD) 
• 90 mg once daily (QD) 
• 180 mg once daily (QD) 
• 90 mg twice daily (BID) 
• In all QD dose groups in order to maintain the blind randomised 
treatment will comprise GSK2330672 taken for the morning dose 
and placebo taken for the evening dose. 
Time & 
Events 
• [Refer to Appendix 2: Schedule of Activities] 
Treatment 
Assignment 
Participants for whom exclusion/inclusion criteria are satisfied, and the 
randomisation criteria at the end of the ISP are met, will be randomised to 
double-blind treatment. 
• 
Randomisation will be stratified by region (Europe and Australia, 
North America, Japan) and participant’s risk of PBC disease 
progression (Low, High – see Table 1).  They will be randomly 
allocated to a dose group as per the ratios within each disease 
progression risk stratum.  The same randomisation ratios will be used 
within each region.  The different randomisation ratio in the high risk 
group is to allow for increased precision of comparisons between the 
high dose group and placebo in analysis of the high risk population.  It 
is believed that a subject’s itch will not differ between the Risk Group 
and Region strata. There will be a check of whether risk group affect 
the results and if so the bias associated with ignoring this effect will be 
estimated. 
Interim 
Analysis 
• Interim analyses took place after approximately 40 participants reached 
Visit 5 (Week 12).  
 
2.4. 
Statistical Hypotheses / Statistical Analyses 
The primary objective is to estimate the relationship between doses of GSK2330672 and 
Itch response.  The primary null hypothesis (H0) assumes that there is no effect of the test 
drug at any dose level and therefore no evidence of dose response.  The alternate 
hypothesis (H1) assumes that there is a dose response with GSK2330672 on participant 
experience of itch, where there is a better improvement in itch with increasing dose. 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
An interim analysis (IA) of primary efficacy and safety was performed as of the June of 
2018.  Based on the IA results the dose levels of GSK2330672 included at the 
randomisation was modified, in addition to the total sample size of the study was 
increased to a total of 140 randomised participants.   
Please refer to the IA RAP for further details.  
 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol.  The study is 
completed after all participants have completed the follow-up telephone interview 
(Visit 8, Week 24). 
2. All required database cleaning activities have been completed and final database 
release and Data Base Freeze (DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met. 
4. Randomization codes have been distributed according to RandAll NG procedures. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Enrolled  
All participants who sign the ICF 
Screening Failure 
Randomisation 
Failure 
Safety 
Randomised 
All participants who were randomised to receive 
study treatment, regardless of whether they took 
randomised study treatment. 
Study Population 
Participant 
disposition 
summaries 
ITT  
The Intent-to-Treat (ITT) Population will 
comprise all randomised participants who receive 
at least one dose of randomised study treatment, 
have a baseline and at least one on-treatment 
assessment in the Main Study Period.  Participants 
in the ITT Population will be classified according 
to the treatment as randomised.    
Efficacy 
PP 
The Per Protocol (PP) Population is a subset of 
the ITT Population who adhered to the major 
Efficacy 
(Sensitivity of 
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Population 
Definition / Criteria 
Analyses Evaluated 
protocol requirements.  The protocol deviation 
criteria are provided in Section 4.1..  Participants 
to be excluded from the PP Population will be 
identified prior to unblinding of the data at the end 
of the study.  The PP Population may not be 
analysed if each Treatment Group within the PP 
population comprises ≥ 80% of the Treatment 
Group within the ITT Population 
Primary endpoint 
analyses) 
Safety 
All randomised participants who take at least 1 
dose of randomised study treatment.  Participants 
will be analysed according to the treatment they 
actually received. 
Safety 
Initial  
All participants who were enrolled, passed 
screening and entered the placebo run-in phase, 
taking at least one dose of placebo during this 
period. 
 
High Risk 
This is a subset of the ITT population who are 
assigned to the High Risk strata for randomisation 
(based upon serum ALP concentrations 
1.67xULN and/or total bilirubin concentrations 
>ULN at Day 1 (Visit 2). 
Secondary Efficacy  
ALP, AST, ALT, 
GGT, total 
bilirubin, albumin, 
PT/INR 
Restricted 
High Risk 
This is a subset of the High Risk population. This 
population consists of all those assigned to the 
High Risk strata for randomisation who meet the 
ALP/bilirubin criteria at both Visit 2 and Visit 3 
(serum ALP concentrations 1.67xULN and/or 
total bilirubin concentrations >ULN at V2 and 
V3). 
Secondary Efficacy 
Supplementary 
Analysis 
Responders 
(>=2 point 
improvement) 
This is a subset of the ITT population. Those 
whose mean worst daily itch score improves by 2 
or more at Week 16 (as compared to Baseline). 
Time to Worsening 
Analysis 
Actigraphy  
The subset of the ITT population who gave 
additional consent for and performed 
measurements of Actigraphy  
Actigraphy 
PK 
Any randomised participant who had at least 1 PK 
sample 
PK population 
Refer to Appendix 12: List of Data Displays which details the population used for each display. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
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Important deviations which result in exclusion from the analysis population will also be 
summarised and listed. (Please refer to Appendix 1: Protocol Deviation Management and 
Definitions for Per Protocol Population). 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [April 16, 2020 Version 
3.0]. 
If a Per Protocol Population is being defined: Important deviations which result in 
exclusion from the analysis population will also be summarised and listed. (Please refer 
to Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population). 
• 
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the analysis 
are captured and categorised on the protocol deviations dataset 
• 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the study specific Protocol Deviation Management Plan, 
which is specifically developed for this study. 
• 
Important protocol deviations (which include deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed. This will be based on data recorded in the 
eCRF, particularly the protocol deviations page.  
• 
Important deviations which result in exclusion from the PP will also be summarised 
and listed.   
• 
The study endpoints will be reported using the populations detailed in this Section of 
this document. 
• 
This dataset will be the basis for the summaries and listings of protocol deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
[RandAll NG / FSO Randomization System] 
Data Displays for Reporting  
Code 
Description 
Description 
Order in TLF  
AA 
Placebo for 16 weeks 
Placebo 
1 
BB 
GSK2330672 20 mg once daily for 
12 weeks followed by placebo for 
4 weeks 
GSK2330672 20 mg QD 
2 
CC 
GSK2330672 90 mg once daily for 
12 weeks followed by placebo for 
4 weeks 
GSK2330672 90 mg QD 
3 
DD 
GSK2330672 180 mg once daily 
for 12 weeks followed by placebo 
for 4 weeks 
GSK2330672 180 mg QD 
4 
EE 
GSK2330672 90 mg twice daily 
for 12 weeks followed by placebo 
for 4 weeks 
GSK2330672 90 mg BID 
5 
Note: Refer to Appendix 14. 
 
5.2. 
Baseline Definitions 
For all endpoints (except those collected on the eDiary) the baseline will be the 
assessment performed at Visit 3 which is conducted prior to the first dosing of 
randomised medication that evening.  Where there is more than one value at any given 
time point, the mean of the replicate assessments will be used as the value for that time 
point. 
The assessment performed at Visit 3 for laboratory data, ECGs, and vital signs will be 
used as the baseline value in all data displays. 
Where the baseline (Visit 3) data are missing for laboratory results, ECGs, and vital 
signs, they will be replaced by the last measurement prior to the first randomised dose 
(Visit 2 or Visit 1, excluding unscheduled visits). 
For further information on deriving the endpoints, including rules for missing data, see 
Appendix 6 and Appendix 7. 
Weekly assessments collected on the eDiary: The baseline GSRS value will be the most 
recent GSRS assessment completed by the participant prior to randomisation, similarly 
for the baseline GI symptom questions. 
Daily data collected on the eDiary: the baseline will be as follows. 
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• Mean Worst Daily Itch will be the average of the maximum of the AM and PM 
scores in the 7 days prior to the baseline visit (Visit 3).  
• Mean Overall Daily Itch will be the average of the mean of the AM and PM 
scores in the 7 days prior to the baseline visit (Visit 3).  
• The mean sleep score, and mean fatigue score at baseline will be the average of 
the sleep scores and fatigue scores, respectively, recorded each day over the 7 
days prior to the baseline visit (Visit 3).   
Other itch symptom based eDiary assessments using a categorical response will employ a 
baseline value based on the average of the scores in the 7 days prior to the baseline visit, 
where the questions will be scored according to the process set out in Section 12.6.2. The 
categorical questions will also be summarised in terms of the mode of the responses in 
the 7 days prior to the visit, and the baseline for these summaries will be the mode of the 
responses in the 7 days prior to the baseline visit.  
 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in Data 
Display 
Visit 3 (Pre-
Main study 
dose) 
Mean of 7 
days prior 
to Visit 3 
Completed 
during Week 
preceding 
the Baseline 
Visit 
Mode of 
response in 
7 days prior 
to Visit 3 
[Efficacy] 
Mean Worst 
Daily Itch, 
Mean sleep 
score, Mean 
fatigue score 
Mean overall 
itch score 
 
X 
 
 
Baseline 
Other eDiary 
questions 
 
X 
 
X 
Baseline 
PBC-40 
5-D Itch,  
PGI-S, 
EQ-5D-5L, 
BDI-II 
X 
 
 
 
Visit 3 (V3) 
GSRS 
 
 
X 
 
Baseline 
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Parameter 
Study Assessments Considered as Baseline 
Baseline Used in Data 
Display 
Visit 3 (Pre-
Main study 
dose) 
Mean of 7 
days prior 
to Visit 3 
Completed 
during Week 
preceding 
the Baseline 
Visit 
Mode of 
response in 
7 days prior 
to Visit 3 
GI Symptoms 
Questions 
 
 
X 
 
Baseline 
[Safety] 
laboratory 
data, ECGs, 
and vital signs 
X 
 
 
 
Visit 3 (V3) 
PD/Biomarker 
samples: 
Serum 
autotaxin, 
FGF-19 
ELF 
Serum bile 
acid species 
C4 
X 
 
 
 
Visit 3 (V3) 
5.3. 
Multicentre Studies 
• 
In this multicentre global study, enrolment will be presented by Region. 
• 
Key summary tables and figures will be presented by Region, where appropriate.  
• 
Where numbers allow further key summary tables may be presented by country. 
Region 
Countries 
North America 
USA, Canada 
Japan 
Japan 
Europe and Australia 
Spain, UK, France, Australia, Italy, Germany, and Poland 
NOTES: Japan  
Key summary tables and figures will be presented for the participants from Japan only vs the 
rest of the world to determine whether the response in these participants is similar to those in 
the study as a whole. The efficacy figures for Region should display the overall results from 
the modelling, along with the data for Japan. 
 
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5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered. 
No formal statistical analysis will be produced if number of participants per cell is small 
for any of the categories listed below and only summary tables and listing will be 
produced. 
Category 
Details 
Covariates to be included in all models which consider change from baseline 
Centred Mean Worst Daily Itch at Baseline  
  
Continuous 
Covariates that will be investigated as part of supplementary analysis of the primary 
endpoint 
ALP (in units of ULN) at Day 1  
Continuous 
ALP (in units of ULN) at Baseline 
Continuous 
Total Bilirubin (in units of ULN) at Day 1 
Continuous 
Total Bilirubin (in units of ULN) at Baseline  Continuous 
Sex 
Male 
Female 
UDCA 
Patient on UDCA at Baseline 
Patient not on UDCA at Baseline 
 
serum bile acids at Baseline 
Continuous 
C4 at Baseline 
Continuous 
Time from diagnosis 
Continuous 
Note: Based on date of diagnosis and 
baseline date 
Beck Depression Inventory at Baseline 
Continuous 
Age at diagnosis 
Continuous 
Note: based on date of diagnosis and DOB 
(date of onset of symptoms/diagnosis up 
to screening)  
Baseline Itching Group 
<4                    ‘Mild’ 
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Category 
Details 
≥4 - <7 
‘Moderate’ 
≥7 - =10 
‘Severe’ 
Previous therapy  
None 
Cholestyramine 
Cholestyramine refractory 
Concomitant background therapy 
The following is a list of the concomitant 
background therapy: 
- 
Rifampicin 
- 
Oral opiate antagonists (naltrexone or 
nalmefene) 
- 
Sertraline 
- 
Gabapentin 
- 
Antihistamines 
- 
Nalfurafine 
Concomitant background therapy (Yes vs. No) 
Yes 
No 
 
Note: if a participant used any of the above 
listed concomitant background therapy then 
yes, otherwise it is no. 
 
 
5.4.2. 
Examination of Subgroups 
The list of subgroups may be used in descriptive summaries and statistical analyses. 
Additional subgroups of clinical interest may also be considered. 
• 
If the percentage of participants is small within a particular subgroup, then the 
subgroup categories may be refined prior to unblinding the trial. 
• 
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup. 
Subgroup 
Categories  
Country 
Japan only 
The rest of the world 
Strata to be investigated for impact on primary analysis 
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Subgroup 
Categories  
Risk of Disease Progression 
 
 
Low 
High 
Region  
USA 
Japan 
Europe and Australia 
 
 
5.5. 
Multiple Comparisons and Multiplicity 
Analyses of other efficacy endpoints will not be participant to any multiplicity 
adjustment. 
 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
12.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
12.2 
Appendix 2: Time & Events (Schedule of Activities) 
12.3 
Appendix 3: Assessment Windows 
12.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
12.5 
Appendix 5: Data Display Standards & Handling Conventions 
12.6 
Appendix 6: Derived and Transformed Data 
12.7 
Appendix 7: Reporting Standards for Missing Data 
12.8 
Appendix 8: Values of Potential Clinical Importance 
12.9 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
12.10 
Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses 
12.11 
Appendix 11: Abbreviations & Trade Marks 
12.12 
Appendix 12: List of Data Displays 
12.13 
Appendix 13: Example Mock Shells for Data Displays 
12.14 
Appendix 14: Interim Analysis Results and update to RAP 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the most appropriate population, unless 
otherwise specified. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 12: List of Data Displays. 
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7. 
EFFICACY ANALYSES 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Endpoint / Variables 
Mean change from baseline Week 4 (V3) at Week 16 (V6) in Mean Worst Daily Itch 
Score defined as: 
• Difference from baseline. 
 
The difference from baseline will be the primary endpoint at Visit 6 for the Mean Worst 
Daily Itch. The final chosen model will be presented in terms of the LS Mean change 
from baseline for each treatment group/total daily dose in the study along with associated 
95% CIs. The difference from placebo will also be presented with 95% CIs but as the 
study is exploratory, a p-value will not be presented.  
 
The Centred Mean Worst Daily Itch at Baseline will be included in the models as a 
covariate. It will be calculated using only the participants with change from baseline in 
Mean Worst Daily Itch data available for analysis within the population of interest. 
Comparison between each total daily dose and placebo will be provided using 2-sided t-
test with alpha level of 0.05 on the mean change from baseline at Week 16 (V6) in Mean 
Worst Daily Itch score. 
A plot of the fitted dose-response model and 95% prediction interval against total daily 
dose, with change from baseline at Week 16 overlaid as a scatter plot will be generated. 
In addition, to the above dose-response model and above plot four dose-response models 
will be generated to produced four plots for model checking and supplementary analyses 
as following: 
1.  A plot of the fitted dose-response model and 95% prediction interval against total 
daily dose, with change from baseline at Week 16 overlaid as a scatter plot using 
participants on the QD dose levels only 
2. A plot of the fitted dose-response model and 95% prediction interval against total daily 
dose, with change from baseline at Week 16 overlaid as a scatter plot using participants 
who are on the BID dose levels only 
3. A plot of the fitted dose-response model and 95% prediction interval against total daily 
dose, with change from baseline at Week 16 overlaid as a scatter plot overlay of the QD 
dose levels and BID dose levels on one plot (overlay plot 1 and 2 above) 
4. A plot of the fitted dose-response model and 95% prediction interval against total daily 
dose, with change from baseline at Week 16 overlaid as a scatter plot is converting the 
180 QD dose level to the 90 BID dose level and using the combined dose levels on one 
plot.  
See Appendix 14 for further details. 
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7.1.2. 
Summary Measure 
Summary measures are Daily Itch Scores (AM, PM and Worst Daily), Mean Worst Daily 
Itch, and Change from Baseline in Mean Worst Daily Itch at Week 16 (V6). 
7.1.3. 
Population of Interest  
The primary efficacy analyses will be based on the ITT population. A sensitivity analysis 
of the results will be performed using the PP population.   
7.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
7.1.4.1. 
Statistical Methodology Specification 
Endpoint / Variables 
Change from baseline (V3) at Week 16 (V6) in Mean Worst Daily Itch defined as: 
• Difference from baseline. 
Model Specification 
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The dose-response of the change from baseline in mean worst daily itch will be analysed 
as outlined in Figure 1. The modelling process is split into two sections:  
(A) Preliminary checks on 1) whether there is a dose-response relationship and 2) 
whether to include BID group in dose-response modelling 
(B) Dose-response modelling, identifying the most appropriate model 
 
 
Figure 1: Flow chart of the model fitting process (see Appendix 14 for more details 
related to Figure 1) 
 
 
This process, starting from the linear model in (A) and comparing models in (B) (i.e. assuming the 
same decision as to whether to exclude or include the BID group). 
 
1. Analysis of Covariance (ANCOVA) 
ANCOVA: Preliminary check of whether to include BID group in dose-response modelling 
• An ANCOVA model will be fitted using all treatment groups to test whether 90 mg BID and 
180 mg QD treatment groups are equivalent with no significant difference. 
• The model should include: 
Trtcd         -     Treatment Group – coded as: 
AA - placebo, BB – 20 mg QD, CC – 90 mg QD, DD – 180 mg QD, EE – 
90 mg BID. 
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              Cbl_itch   -     Centred Mean Worst Daily Itch at Baseline  
 
• If the confidence interval for the difference between 90 mg BID and 180 mg QD lies within (-1, 
1) and includes 0 then all dose groups will be included in the following models (where 90 mg 
BID and 180 mg QD are both total daily dose of 180 mg). Otherwise, the 90 mg BID group will 
be excluded from the dose-response analysis. 
• If ANCOVA is chosen as the final model (i.e. there is no evidence of a dose-response 
relationship) the MED will be the lowest dose at which the change from baseline in Mean 
Worst Daily Itch is < -2. If there are no treatment groups that achieve a change from baseline 
of < -2 this will be presented as NA in the appropriate table. 
 
2. Linear Model 
Linear Model: Check whether there is a dose-response relationship 
• The linear model will be fitted to the data to test whether there is evidence of a dose-response 
relationship.   
 
o 
 
 
• Whether all treatment groups are used or just placebo and 3 QD treatment groups will depend 
on the results of the ANCOVA model 
• The model should include: 
Dose         -     Total daily dose – continuous variable (e.g.  0, 20, 90 and 180 mg). 
             Cbl_itch     -     Centred Mean Worst Daily Itch at Baseline  
 
• If total daily dose is significant in the model at 10% then proceed with non-linear dose-
response modelling, otherwise the ANCOVA model should be reported as the best model. 
• The MED will be calculated for the linear model as:  
 
3. Dose-response Modelling 
• The dose-response modelling process will attempt to fit non-linear models to the data and 
using decision criteria (as outlined in Figure 1 above) a final model will be chosen. 
  
▪ Fit 4-parameter Emax model 
o If converges – 4-parameter Emax model is final chosen model 
o If doesn’t converge then fit 3-parameter Emax model and Power model  
• If there are convergence problems with both of these models 
➢ Take Linear Model as final chosen model 
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• Otherwise 
➢ Take the final chosen model to be the one with the lowest 
AIC (Akaike's Information Criterion) (linear, power or 3-
parameter Emax models) 
• All of the non-linear models will include:  
Dose      -     Total daily dose – continuous variable (e.g.  0, 20, 90 and 180 mg). 
                    Cbl_itch   -     Centred Mean Worst Daily Itch at Baseline  
 
 
• Whether all treatment groups are used or just placebo and 3 QD treatment groups will 
depend on the results of the ANCOVA model. 
4. 4-Parameter Emax Model 
Dose-response Modelling: 4-Parameter Emax Model 
The 4-parameter Emax model is given as: 
 
Where E0 is the placebo effect and Emax is the asymptotic maximum change from placebo effect.  
ED50 is the dose at which the response is mid-way point between E0 and Emax.   
Centred Mean- Mean Worst Daily Itch at Baseline  
 (Cbl_itch) will be fitted as a covariate. 
The MED will be calculated as: 
 
 
5.  3-Parameter Emax Model 
Dose-response Modelling: 3-Parameter Emax Model 
The 3-parameter Emax model is given as: 
 
This is equivalent to the 4-parameter Emax model with slope fixed and equal to 1. Mean- Centred 
Mean Worst Daily Itch at Baseline will be fit as a covariate in the model. 
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The MED is calculated as: 
 
 
6. Power Model 
Dose-response Modelling: Power Model 
As per Kirby et al (2011) the Power Model will take the form: 
 
Note that unlike the power model commonly used in PK dose proportionality, this model includes 
an intercept and will also include the Centred Mean Worst Daily Itch at Baseline  
  as a covariate. 
The MED will be calculated as: 
 
 
Model Checking & Diagnostics 
For all endpoints that uses Non-linear modelling and ANCOVA: 
Distributional assumptions underlying the model used for analysis 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 departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. 
 
For the Change from Baseline in Mean Worst Daily Itch endpoint using ANCOVA: 
 
To check whether the assumption that there is no impact of the deliberately imbalanced 
strata (i.e. that risk group does not affect the change from baseline in mean worst daily 
itch) a supplementary analysis will be undertaken to test whether there are differences 
between the strata (supplementary analysis: investigation of risk group within this section 
listed below) 
Model Results Presentation 
• For the final chosen model: 
o The LS mean change from baseline (and 95% CIs) as well as the mean 
differences in change from baseline (and 95% CIs) of each study total 
daily dose levels from placebo will be displayed along with the 95% CIs 
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in a table. 
o A figure will be presented for the LS mean difference from placebo. 
 
• Where the final chosen model is an ANCOVA, these tables and figures will be 
presented for treatment group, including the 90 mg BID group. Otherwise they 
will be presented for the total daily dose at each dose level in the study (e.g. 20, 
90 and 180 mg). 
• Similar tables will be presented for the results of the supplementary analyses. 
 
• The SAS model output, including estimated model parameters, will be provided 
in the listings  
Subgroup Analyses 
• The stratification variable Risk Group (ALP) will be fitted in the ANCOVA 
model as a covariate, as well as the interaction between Risk Group (ALP) and 
Treatment Group. 
Estimating Bias 
• If Risk Group (ALP) is found to be significant in the ANCOVA model an 
estimation of the bias in the results arising from ignoring risk group within the 
analysis will be presented. 
• A table will present the estimated change from baseline for each treatment group 
for the ANCOVA excluding risk group and the ANCOVA including risk (ALP) 
group. The table will also show the difference from placebo for each treatment 
group, and difference between 90 mg BID and 180 mg QD. 
• The bias will be estimated as: 
o  Estimate excluding risk group (ALP) – estimate including risk group 
(ALP). 
 
• A figure will also present the results.  
 
• An overall estimate of the maximum bias associated with ignoring risk group will 
be made by averaging the bias of the 20 mg QD, 90 mg QD and 90 mg BID 
groups vs. placebo. 
Supplementary Analyses 
• MMRM will be fitted using all available mean worst daily itch scores at Visit 4, 
Visit 5, Visit 6 and Visit 7 to investigate the mean change from baseline in mean 
worst daily itch at each visit and mean difference from placebo with 95% CIs.  
This will include the baseline mean worst daily itch and a treatment by visit 
interaction.  An unstructured covariance structure will be assumed; if this does not 
converge then an autoregressive [AR(1)] or compound symmetry (CS) will be 
selected based on the lowest Akaike's criterion. 
 
• The final dose-response model for the change from baseline (i.e. linear, Emax, 
power from as described above) will be fitted using only those participants in the 
PP Population. The centered mean worst daily itch, as defined for the PP 
population will be included as a covariate. 
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• An ANCOVA model for the change from baseline will be fitted including each of 
the covariates listed in Section 5.4.1, one at a time, in addition to the treatment 
group and interaction with treatment group and results will be presented in tables. 
 
7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Endpoint / Variables 
• The secondary efficacy analysis outlined in this section are listed under Section 2.2. 
and covers end-points associated with responder definitions, patient reported 
outcomes (PROs), and the analyses in the High Risk population. 
• The analysis for secondary endpoints that are defined as Pharmacokinetic (PK) or 
Pharmacodynamic (PD) biomarkers will be described in Section 9.1 and Section 10.1 
respectively. 
7.2.2. 
Summary Measure 
Responders in itch: 
Responders in itch are listed below and will be summarised accordingly:  
1. Proportion of participants who are responders in Mean Worst 
Daily Itch score at Week 16 (V6) on each of the following 
separate\ definitions: 
Improvement§≥ 2 
Score < 4 
Percentage Improvement§ ≥30% 
 
§ Mean Worst Daily Itch Score: participant’s worst itch severity is recorded on an 
electronic diary (eDiary) each morning and evening using a 0-10 numerical rating 
scale (NRS), the Worst Daily Itch Score is the average of the maximum of the AM 
and PM scores in the 7 days preceding randomization at Visit 3 (Baseline) and 
over the 7 days preceding Visit 6 (Week 16). 
 
2. Mean number of responder days during Weeks 5 to 16 based on 
each of the following separate responder day definition:  
Change from baseline at Week 16 >= 2 
Score at week 16 < 4 
Percentage change from baseline at Week 16 >30% 
 
Days Response in Worst Daily Itch score will be reported as mean number 
of days, SD, and percentage for each dose level in which responder criteria 
has been met during the main study period. 
 
 
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PRO: Other eDiary Itch questions: 
In addition to the primary endpoint further questions in the eDiary capture information on 
the itch experienced by participants. Overall itch, sleep and fatigue use the same NRS (0-
10), while the others are categorical.  
Summary measurement for Sleep, Fatigue, Overall Itch and other daily eDiary 
questions are: 
Mean Daily Fatigue Score 
Mean Daily Sleep Score 
 
PRO: Validated Questionnaires: 
In addition to the eDiary there are a number of other PROs using validated questionnaires 
which aim to capture information on the subjects’ impression of PBC (PBC-40), their itch 
(5-D itch), their quality of life (EQ-5D-5L), their mental wellbeing (BDI-II), their 
impression of severity of disease (PGI-S) and of change (PGI-C).  
The Patient Treatment Experience Assessment (PTEA) collects information at Visit 6, or 
at early end of treatment visit, on how the participant felt about the study treatment.  
The final follow-up phone-call (Visit 8) provides information on the participant’s 
experience of itch at the end of the follow-up period. 
Other PRO measurements: 
5-D Itch (For each of the 5 domain scores of the 5-D Itch and the total 5-D Itch score) 
PBC-40 domains (For each of the 6 domain scores of the PBC-40) 
 
High Risk of Disease Progression (ALP) : 
Participants are assigned to the High Risk strata at Visit 3 (baseline), for randomisation, 
based on ALP and total bilirubin measured in samples drawn at Visit 2 (ALP at V2 ≥ 
1.67*ULN and/or total bilirubin at V2 >ULN).  
As a result, the High Risk population will consist of all those assigned to the High Risk 
strata for randomisation. 
The following secondary endpoints will be examined within the High Risk population:  
• Mean change from Baseline at Week 16 in serum ALP concentrations.  
• Proportion of participants having serum ALP concentrations <1.67x ULN and total 
bilirubin concentrations ULN at Week 16.  
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• And in the Markers of Disease Measurements (Mean change from Baseline at Week 
16 in serum ALT, AST, GGT, total bilirubin and albumin concentrations and 
PT/INR). 
A sensitivity analysis of the results for the High Risk population will be carried out where 
the population is defined as all those assigned to the High Risk strata for randomisation, 
whose lab results at Visit 2 and Visit 3 confirm them as being at high risk of disease 
progression. This sensitivity analysis will only be carried out if the two populations 
differ. 
Disease Progression Risk Response Measurements: 
Disease Progression Risk Response 
7.2.3. 
Population of Interest  
The secondary efficacy analyses will be based on the ITT population, unless otherwise 
specified. 
7.2.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
7.2.4.1. 
Statistical Methodology Specification 
Endpoint / Variables 
Please see Section 2.2. for the list of the secondary endpoints. 
Model Specification 
The following is the list of the secondary endpoint and model specification: 
Endpoint 
Endpoint 
Type 
Population Models 
Covariates 
Responder 
Score < 4,  
Improvement ≥ 2 
Improvement ≥ 
30% 
A 
ITT 
Logistic 
Regression 
None 
Percentage of Responder Days 
Score < 4,  
Improvement ≥ 2 
Improvement ≥ 
30% 
A 
ITT 
ANCOVA 
None 
 
 
 
 
 
 
eDiary question and other PROs 
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Mean Overall 
Itch 
CFB 
ITT 
ANCOVA 
Mean Overall 
Itch at 
Baseline1 
Mean Sleep 
CFB 
ITT 
ANCOVA 
Mean Sleep at 
Baseline1 
Mean Fatigue 
CFB 
ITT 
ANCOVA 
Mean Fatigue 
at Baseline1 
PBC-40 
domain scores2 
CFB 
ITT 
ANCOVA 
PBC-40 
domain scores 
at Baseline1 
5-D Itch 
scores3 
CFB 
ITT 
ANCOVA 
5-D Itch scores 
at Baseline1 
Markers of Disease 
Disease 
Progression 
Risk 
A 
High Risk 
Logistic 
Regression 
None 
ALP, 
ALT 
AST 
GGT 
Total Bilirubin 
Albumin 
PT/INR 
CFB,  
 
High Risk 
ANCOVA 
Marker at 
baseline1 
A = Absolute  
CFB = Change from baseline  
 
[1] Baseline can be centred or not, it will not impact the results in the analysis 
[2] For each PBC-40 domain 
[3] For each 5-D Itch domain and the total 5-D itch score 
 
*Within the Responders (>=2 point improvement) population only treatment 
groups with at least 8 participants will be included in the analysis. 
Model Checking & Diagnostics 
See under model checking & diagnostics outlines checks that should be carried out of the 
statistical assumptions made. 
Model Results Presentation 
• An ANCOVA model will be fitted to the data to investigate the difference in response over 
the dose-groups. The response will be the endpoint of interest (i.e. percentage of days, 
change from baseline in ALT), with the treatment group as the explanatory variable. Where 
appropriate the baseline will be included as a covariate (in analyses of change from 
baseline). 
A results table will present the LS mean of the endpoint of interest for each of the 
treatment groups (and 95% CIs) as well as the LS mean differences between each 
treatment and placebo and the mean difference between 180 mg QD and 90 mg BID 
treatment groups (and 5% CIs). 
The mean differences in change from baseline from placebo will be plotted along with the 
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corresponding 95% CIs in a Figure, with a reference line at y=0. 
• For binary responder variables logistic regression models will be fitted to examine the 
relationship between treatment group and the endpoint of interest. No covariates will be 
included in these analyses. 
The LS means for the treatment groups and the LS mean differences from placebo will be 
estimated and back-transformed to provide the odds and odds ratios, respectively. 
A results table will present the odds of response for each treatment group (and 95% CIs), 
as well as the odds ratio of each active treatment group to placebo and the odds ratio of 
90 mg BID to 180  
The odds ratio will be plotted along with the corresponding 95% CIs, with a reference line 
at y=1. 
• For Time to Event data Kaplan-Meier estimates and plots will be presented for each 
treatment group. Treatment groups will only be included in this analysis if there are at least 
8 participants in the group, within the population of interest. 
Subgroup Analyses 
Please see the table above under model specification for list of covariates that are included in each 
model. 
 
7.3. 
Exploratory Efficacy Analyses 
7.3.1. 
Endpoint / Variables 
All exploratory efficacy endpoints are listed under Section 2.2.  
7.3.2. 
Summary Measure 
The exploratory efficacy endpoints will be summarised as the primary and secondary 
efficacy endpoints. 
Responders Time to Worsening: 
Responders Time to Worsening of Itch (in sub-population of Responders (>=2 point improvement 
from baseline)).  The time to worsening of itch after Week 16 (when on single-blind placebo) 
in those who have responded at Week 16 (Responders (>=2 point improvement) population).  
PRO: Other eDiary Itch questions: 
In addition to the primary endpoint further questions in the eDiary capture information on 
the itch experienced by participants. Overall itch, sleep and fatigue use the same NRS (0-
10), while the others are categorical.  
Mean Overall Itch Score 
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Other daily eDiary questions 
Other PRO measurements: 
EQ-5D-5L (For the categories of EQ-5D-5L) 
EQ-5D-5L (Separately for the derived EQ-5D-5L Utility Index Score see Section 12.6.3 
for more details and the EQ-5D-5L VAS) 
PGI-S questions 
PGI-C questions 
BDI-II (total BDI-II score) 
PTEA 
Actigraphy data: 
• Mean duration of scratching Events 
• Mean number of scratching events 
• Sleep Information 
 
 
7.3.3. 
Population of Interest  
The exploratory efficacy analyses will be based on the ITT population, unless otherwise 
specified. 
7.3.4. 
Statistical Analyses / Methods 
• Details of the planned displays are provided in Appendix 12: List of Data Displays 
and will be based on GSK data standards and statistical principles. 
• Unless otherwise specified, endpoints / variables defined in Section 7.3.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) 
and listed. 
Actigraphy: Actigraphy data will only be analysed if there is sufficient reliable data 
for the analysis to be meaningful for the subset of the participants recruited to the 
study who take part in an actigraphy study in which they will wear monitors to 
evaluate their movement. Algorithms will then transform this information into 
measures of sleep efficiency and number and duration of scratching events during 
their rest period. The monitors will be worn during at least 5 nights over a 7 day 
period, on 3 separate occasions throughout the study and for each night the mean 
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number of scratching events and mean duration of scratching events per hour, during 
the rest period, will be provided.  
Actigraphy data will be listed only. 
 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population, unless otherwise specified. 
8.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 12: List of Data Displays. 
Additional analysis will be provided for abdominal pain AEs in addition to the standard 
analyses as describe in Appendix 12.  The Kaplan-Meier curve will be provided for time 
to event analyses.  Moreover, the duration of abdominal pain will be assessed using 
swimmer plots.  The number of participants who experienced abdominal pain will be 
provided using summary statistics. 
Please refer to Section 12.6.4 to identify abdominal pain based on MedDRA terms. 
8.2. 
Adverse Events of Special Interest Analyses 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Due to the special interest in GI events, time to event analysis will be 
provided to assess both the duration and offset of GI event. The Kaplan-Meier curve will 
be provided for time to event analyses.  Moreover, the duration of diarrhoea and will be 
assessed using swimmer plots.  The number of participants who experienced diarrhoea 
will be provided; in addition, the duration of both GI events in the same participants will 
be produced using summary statistics.  
Please refer to Section 12.6.4 to identify diarrhoea based on MedDRA terms.  
8.3. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 12: List of Data 
Displays. 
 
8.4. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays. 
There are two sets of questions in the eDiary which will also be summarised within the 
safety analysis: the Gastrointestinal Symptoms Rating Scale (GSRS) questionnaire and 
specific questions pertaining to the perceived gastrointestinal (GI) side effects of the 
study treatment, namely diarrhoea and abdominal pain, these will be presented too. 
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The exploratory safety endpoints as listed under Section 2.2. will be summarised using 
descriptive statistics and will be listed as appropriate. Details of the planned displays are 
provided in Appendix 12: List of Data Displays and will be based on GSK data standards 
and statistical principles.  
Mean change from baseline at week 16 in Vitamins A, D, E, K and FOBT will be 
summarised and listed by treatment group. 
Prior to 2019 FOBT card (InsureFIT) required 2 samples of stool/fecal and were 
collected by participant at home prior to the visit. In 2018, the FOBT card (InsureFIT) 
was discontinued by the manufacturer.  In early 2019, the replacement FOBT card 
(InsureONE) was then used for the remainder of the study. 
The new FOBT InsureONE card only requires 1 stool/fecal sample to be collected at 
home, prior to the visit. 
 
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9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Primary Pharmacokinetic Analyses 
9.1.1. 
Endpoint / Variables 
9.1.1.1. 
Drug Concentration Measures and Data Handling 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3) 
Reporting Standards for Pharmacokinetic) and see below 
If a linerixibat concentration is reported as missing in the linerixibat treatment groups, 
then this will be reported as missing, if a concentration at V4, V5 or V6 is reported as 
NQ, then this will be handled as ½ LLQ (or ½ of 10pg/mL=5pg/mL) for inclusion in 
plots and PK parameter summary tables. 
If a UDCA, GUDCA or TUDCA concentration is missing or NQ, then these will be 
reported and handled as missing or NQ, respectively.  The NQ will be handled as missing 
for plots and PK parameter summary tables.  Participants on placebo are included and 
will have UDCA, GUDCA and TUDCA conjugates plasma concentrations. 
9.1.1.2. 
Pharmacokinetic Concentrations for linerixibat, UDCA, GUDCA and 
TUDCA 
Pharmacokinetic parameters are not calculable based on the sampling scheme and 
average PK concentrations will be used.   All calculations of PK concentrations will be 
based on actual sampling times that fall within the set PK windows described below 
(±0.75 hour of the PK window). Population PK and/or PD analysis may be conducted and 
will be described in a separate report. 
Use the following guide for PK concentrations handling: 
• If a Cave,V has a missing value for or both Cv,1-3h or Cv,5-8h, then don’t report Cave,V 
• For BID, the PK concentrations are associated with the first 8 hours of the first 
dosing interval of the day 
• For QD, the PK concentrations are associated with the first 8 hours of the daily 
dose 
 
PK 
Parameter 
Description 
CV3,1-3h 
Average concentration of PK analyte in time window 1-3 hr at visit 3, week 4  
CV3, 5-8h 
Average concentration of PK analyte in time window 5-8 hr at visit 3, week 4  
Cave,V3 
Average concentration in first 8 hr post-dose at visit 3, week 4 (i.e., = (CV3,1-3h + CV3, 5-8h)/2) 
CV4,1-3h 
Average concentration of PK analyte in time window 1-3 hr at visit 4, week 8 
 
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PK 
Parameter 
Description 
CV4,5-8h 
Average concentration of PK analyte in time window 5-8 hr at visit 4, week 8 
Cave,V4 
Average concentration in first 8 hr post-dose at visit 4, week 8 (i.e., = (CV4,1-3h + CV4, 5-8h)/2) 
CV5,1-3h 
Average concentration of PK analyte in time window 1-3 hr at visit 5, week 12 
CV5,5-8h 
Average concentration of PK analyte in time window 5-8 hr at visit 5, week 12 
Cave,V5 
Average concentration in first 8 hr post-dose at visit 5, week 12 (i.e., = (CV5,1-3h + CV5, 5-8h)/2) 
CV6,1-3h 
Average concentration of PK analyte in time window 1-3 hr at visit 6, week 16 
CV6,5-8h 
Average concentration of PK analyte in time window 5-8 hr at visit 6, week 16 
Cave,V6 
Average concentration in first 8 hr post-dose at visit 6, week 16 (i.e., = (CV6,1-3h + CV6, 5-8h)/2) 
Cmax 
Highest concentration reported at any time in the 16 weeks  
For BID, the PK concentrations are associated with the first 8 hours of the first dosing interval of the day 
For QD, the PK concentrations are associated with the first 8 hours of the daily dose 
If a Cave,V has a missing value for or both Cv,1-3h or Cv,5-8h, then don’t report Cave,V 
 
9.1.2. 
Summary Measure 
For each PK window listed in section above: Arithmetic mean, standard deviation, 
CV%a, 95% CI, median, range, geometric mean, CV%g, and 95% CI for geometric 
mean. 
9.1.3. 
Population of Interest  
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified. 
9.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Section 12.12.9 and Section 12.12.10, List 
of Data Displays and will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
The PK analysis will be based on appropriate sub-groups of the PK population. The 
analysis will consist of summaries of plasma concentrations, by treatment group, visit and 
time point as well as profile plots for each subject, where appropriate.  
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Linerixibat will only be summarised and presented for subjects who receive active 
treatment (20 mg QD, 90 mg QD, 180 mg QD and 90 mg BID) and from whom samples 
are available. 
UDCA will only be summarised and presented for subjects who are taking UDCA (and 
for whom UDCA samples are available). 
 
Scatter plots of concentration and actual sampling time data for linerixibat, UDCA, 
GUDCA and TUDCA will be produced.   Plots will separate groups by linerixibat 
treatment alone and linerixibat + UDCA co-treatment groups.  
Line plots of change from baseline in eGFR at V4 and V5 vs linerixibat Cave plasma 
concentrations at V4 and V5, respectively, will be produced. (renal impairment 
exploration) Box plots of linerixibat, UDCA, GUDCA and TUDCA average 
concentrations vs treatment groups will be produced (dose response and DDI exploration) 
 
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10. 
PHARMACODYNAMIC BIOMARKER ANALYSES 
10.1. 
Primary/Secondary/Exploratory Pharmacodynamic 
Biomarker Analyses 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3 
Reporting Standards for Pharmacodynamics) and see below 
If a PD biomarker concentration is missing it will be reported and handled as missing. If 
a PD biomarker is BQL it will be handled as (LLQ/2).  If a PD biomarker is above the 
quantitation limit (AQL) will be handled according to existing data conventions. 
Note: For ELF test, there is no LLQ due to nature of measurement. 
10.1.1. 
Endpoint / Variables 
List of Biomarkers of PBC and Bile Acid Physiology: 
o Total Serum Bile Acids (TSBA, available as sum of conjugated and 
unconjugated, not available separated) 
o Individual serum bile acid species (measurement provided from laboratory 
as sum of unconjugated + conjugated) for: cholic acid (CA), 
chenodeoxycholic acid (CDCA), deoxycholic acid (DCA) 
▪ (e.g., CA = CA + glycocholic acid (GCA) + taurocholic acid 
(TCA), or CDCA = CDCA + GCDCA + TCDCA, or DCA = DCA 
+ GDCA + TDCA) 
o Serum C4 (7α-hydroxy-4-cholesten-3-one) 
o Serum autotaxin enzyme protein concentrations (not autotaxin enzyme 
activity) 
o Serum Fibroblast Growth Factor –19 (FGF-19) 
o Enhanced Liver Fibrosis (ELF) Test 
o Alkaline Phosphatase (ALP)  
o Total bilirubin 
 
 
 
10.1.2. 
Summary Measure 
Summary measure will include change from baseline and absolute values for each visit 
and each dose group for biomarkers. 
The absolute values and change from baseline for all biomarkers listed in 10.1.1 will be 
summarized and tabulated and plotted by treatment and visit  
The absolute values and change from baseline for lipid biomarkers will be summarized 
and tabulated by treatment and visit. 
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10.1.3. 
Population of Interest 
The PD biomarker analyses will be based on ITT. 
10.1.4. 
Statistical Analyses / Methods 
The PD analysis will concentrate on the biomarkers of PBC and bile acid physiology as 
outlined in Section 10.1.1. Details of the planned displays are provided in Appendix 
12.12.10: List of Data Displays and will be based on GSK Data Standards and statistical 
principles. 
PD Biomarker Correlation Figures and Tables 
Details of the planned displays are provided in Section 12.12.11 and Section 12.12.12, 
List of Data Displays and will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed 
Of note, C4, FGF19, ELF are not pruritogens and not included in correlations section.   
Correlation analyses of mean changes from baseline for ALP and mean changes of 
baseline for TSBA, CA, CDCA, DCA, UDCA, GUDCA and TUDCA for V4, V5 and V6 
(Section 12.12.11) 
Absolute and change from baseline in ALP for subject taking UDCA by visit and 
treatment group. 
Correlation analyses will be produced between baseline of PD biomarkers (see list from 
10.1.1) at visit 6 with baseline NRS itch scores by treatment groups. 
Correlation analyses will be produced between change from baseline of PD biomarkers 
(as listed form 10.1.1) at visit 6 with change from baseline NRS itch scores at visit 6 by 
treatment groups. 
Pearson correlation will be produced given that the data follow the normal distribution, 
normality test such as Kologorov-Smirov will be used.  However, if the normality 
assumption failed a log transformation will be applied and if the normality assumption 
failed after the transformation a Spearman correlation will be produced. 
Unless otherwise specified, endpoints / variables defined in Section 2.2. will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
 
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10.1.4.1. 
Statistical Methodology Specification 
Endpoint / Variables 
Endpoints are listed 10.1.1 
Model Specification 
ANCOVA models for change from baseline will be fitted adjusting for baseline and 
treatment groups.  
Listings, summary statistics, and line plots to explore time course and dose response 
will be produced. 
PD biomarkers correlations as stated in 10.1.1 and as described in 12.12.11 and 
12.12.12. 
 
Model Results Presentation 
Mean difference for each treatment group from placebo, along with mean difference between 90 mg BID 
and 180 mg QD will be presented from the ANCOVA model. 
 
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11. 
REFERENCES 
GlaxoSmithKline Document Number 2010N111289_06 Investigator’s Brochure. 
Linerixibat (GSK2330672) Investigator’s Brochure. Date 29-AUG-2019 
GlaxoSmithKline Document Number 2016N280566_01 Study ID 201000. A randomised, 
double-blind, multi-dose, placebo-controlled study to evaluate the efficacy, safety and 
tolerability of GSK2330672 administration for the treatment of pruritus in patients with 
primary biliary cholangitis. (GLIMMER: GSK2330672 triaL of Ibat inhibition with 
Multidose Measurement for Evaluation of Response).Report Date 04-Nov-2017. 
GlaxoSmithKline Document Number N2015N268599_01 Clinical Pharmacology Study 
Report. A randomised, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, pharmacokinetics and pharmacodynamics of repeat doses of GSK2330672 
administration in patients with primary biliary cirrhosis (PBS) and symptoms of pruritus. 
Date 15-DEC-2016 
Hegade, VS., Kendrick SFW., 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. The Lancet, 389:1114, March 
18, 2017. 
Kirby, S., Brain, P., Jones, B. Fitting Emax models to clinical trial dose-response data. 
Pharmaceut. Statist. 2011; 10: 143-149. 
van Hout B, Janssen MF, et al. Interim scoring for the EQ-5D-5L: Mapping the EQ-5D-
5L to EQ-5D-3L value sets. Value in Health 2012 Jul-Aug;15(5):708-15. 
 
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12. 
APPENDICES 
12.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
12.1.1. 
Exclusions from Per Protocol Population 
A participant meeting any of the following criteria will be excluded from the Per Protocol 
population: 
 
Exclusion Description 
Protocol 
Deviations 
 
 
Mean Worst Daily Itch not ≥ 3 for at least 5 of the 7 days prior to the 
Baseline visit 
 
Other Important Protocol Deviations (as defined in Protocol Deviation 
Management Plan (PDMP) and discussed at blinded data review.  
Treatment 
Compliance 
 
 
Study Treatment Compliance   
Less than 80% or Greater than 120% total main treatment period (double 
blind treatment) compliance in MSP according to tablets taken (V3 to 
V6)  
 
Study Treatment Compliance   
According to the eDiary, did not take study treatment on 3 or more 
mornings in the 7 days prior to V6. 
 
Study Treatment Compliance   
According to the eDiary, did not take study treatment on 3 or more 
evenings in the 7 days prior to V6. 
Endpoint 
Compliance 
 
 
End-Point Compliance at V6 
Worst Daily Itch is missing for 3 or more of the 7 days prior to V6 
Visit Timing  
 
Missed V6  
 
V6 outside of Analysis Time Window (where Analysis Time Window is 
defined as Target day ± 7 days, i.e. Day 105 - 119) 
Medications 
 
 
Prohibited Medication use  
Other IBAT inhibitors:  Use of any other IBAT inhibitor is not permitted at any 
time during the study. 
Obeticholic acid:  Use is not permitted at any time during the study and 
obeticholic acid should be discontinued at least 8 weeks before the start 
of the Initial Study Period. 
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Exclusion Description 
Cholestyramine, colesevelam, colestipol or colestimide:  Use of any of 
these agents is not permitted during the Initial or Main Study Periods and 
will be discontinued no later than one full day (i.e., no later than Day -2) 
before the start of the Initial Study Period (Visit 2). During the Final 
Study Period and the Follow Up Period, use of these agents may be 
permitted. 
 
 
Permitted Medication use 
Please see the Protocol Section 7.7.2. for details and list of permitted 
medication use.  
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12.2. 
Appendix 2: Schedule of Activities 
12.2.1. 
Protocol Defined Schedule of Events 
Schedule of Activities Table 
 
Screening 
Initial 
Study 
Period 
Main Study Period 
Final Study 
Period 
Follow-up 
Period (FU) 
Early End of 
Treatment or 
Study 
Withdrawal 
Assessments1 
Visit Name 
Visit 1 
(Screening) 
Visit 2 
(Day 1) 
Visit 311 
(Baseline/ 
Week 4) 
Visit 4 
(Week 8) 
 
Visit 5  
(Week 12) 
 
Visit 6 
(Week 16) 
 
Visit 7 
 (Week 20) 
 
Visit 8 
(End of FU 
Phone Visit/ 
Week 24) 
Day number 
(window) 
Day -45 to -1 
Day 1 
Day 28 
(Day 28 to 35) 
Day 56 
(Day 56 to 63) 
Day 84 
(Day 84 to 91) 
Day 112 
(Day 112 to 
119) 
Day 140 
(Day 140 to 
147) 
Day 168 
(Day 168 to 
175) 
Procedure 
 
Screening procedures 
X2 
 
 
 
 
 
 
 
 
Brief physical exam 
inc. weight 
 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant 
medications 
X2 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECG 
X2 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs (HR and 
BP) 
X2 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy test (urine 
dipstick) in WOCBP 
X2 
X3 
X 
X 
X 
X 
X 
 
X 
Clinical laboratory 
tests4 
X2 
X 
X 
X 
X 
X 
X 
 
X 
AE Assessment 
 
X 
X 
X 
X 
X 
X 
 
X 
Study treatment 
dispensing 
 
X 
X 
X 
X 
X 
 
 
 
Study treatment 
administration  
 
<---------------------Participants administer morning and evening each day------------------------> 
 
 
Study treatment 
compliance 
 
 
X 
X 
X 
X 
X 
 
 
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Screening 
Initial 
Study 
Period 
Main Study Period 
Final Study 
Period 
Follow-up 
Period (FU) 
Early End of 
Treatment or 
Study 
Withdrawal 
Assessments1 
Visit Name 
Visit 1 
(Screening) 
Visit 2 
(Day 1) 
Visit 311 
(Baseline/ 
Week 4) 
Visit 4 
(Week 8) 
 
Visit 5  
(Week 12) 
 
Visit 6 
(Week 16) 
 
Visit 7 
 (Week 20) 
 
Visit 8 
(End of FU 
Phone Visit/ 
Week 24) 
Day number 
(window) 
Day -45 to -1 
Day 1 
Day 28 
(Day 28 to 35) 
Day 56 
(Day 56 to 63) 
Day 84 
(Day 84 to 91) 
Day 112 
(Day 112 to 
119) 
Day 140 
(Day 140 to 
147) 
Day 168 
(Day 168 to 
175) 
Final eligibility and 
Randomization 
 
 
X12 
 
 
 
 
 
 
PD/Biomarker blood 
samples4 
 
 
X 
X 
X 
X 
X 
 
X 
FOBT5 
 
 
X 
 
 
X 
 
 
 
Genetics sample6 
 
 
X 
 
 
 
 
 
 
PK samples7 
 
 
X 
X 
X 
 
 
 
 
Symptom eDiary 
 
<-----------------------------------------------Morning and evening each day----------------------------------> 
 
 
GSRS and GI 
symptoms on eDiary 
 
<--------------------------------------------------------Once weekly-------------------------------------------------> 
 
 
PBC-40 Scale 
X2 
X 
X 
X 
X 
X 
X 
 
X 
5D-Itch Scale 
 
X 
X 
 
 
X 
X 
 
X 
EuroQOL 5D-5L 
 
X 
X 
 
 
X 
 
 
X 
PGI-S 
 
X 
X 
X 
X 
X 
X 
 
X 
PGI-C 
 
 
X 
X 
X 
X 
X 
 
X 
BDI-II 
X2 
 
X 
 
 
X 
 
 
X 
Actigraphy8 
 
X 
 
X 
X 
 
 
 
 
Participant Treatment 
Experience 
Assessment 
 
 
 
 
 
X 
 
 
X9 
Telephone review10 
 
 
 
 
 
 
 
X 
 
 
 
 
 
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Footnotes: 
1. Early End of Treatment Assessments to be completed for participants who prematurely discontinue study treatment following randomization (see Section 8.1 of the protocol).  
Study Withdrawal Assessments to be completed for participants who withdraw consent for any further participation in the study following randomization (see Section 8.2 of the 
protocol). Note: If a participant discontinues study treatment at the same time they withdraw from the study, only the End of Treatment Assessments are required. 
2. See the table below for detailed description of Screening Procedures. 
3. Urine dipstick pregnancy test will be standard unless serum testing is required by local regulation or IRB/IEC.  Urine dipstick test at Visit 2 not required if the screening test was 
performed <1 week of Visit 2. 
4. For clinical laboratory tests see Section 9.4.4. of the protocol and biomarkers see Section 9.8 of the protocol. All laboratory and biomarker assessments will be fasting (water, 
study treatment and other medications are permitted) except for Screening Visit. 
5. FOBT (card test on 2 different stool/fecal samples) will be performed by participant at home prior to the visit.  
6. Genetics sample in randomised participants only, to be collected preferably at Visit 3, but may be collected at Visit 4. 
7. PK sample at Visit 3 for participants on UDCA only. At other visits, two plasma samples will be collected on each PK occasion in all participants (see Section 9.5 of the protocol).  
If PK sample collection is not collected at Visit 5 it may alternatively be collected at Visit 6. Note: PK sample collection is not required for participants who have prematurely 
discontinued study treatment and have not taken study treatment on the 3 or more days prior to the Visit. 
8. Participants who give consent for the Actigraphy Sub-study will be given actigraphy monitors at Visit 2, Visit 4 and Visit 5 with activity measurements performed over at least 5 
nights during Weeks 2 or 3, 9 or 10, and 13 or 14 respectively (see Section 9.1.3 of the protocol). 
9. Participant Treatment Experience Assessment only required for Early End of Treatment Assessments. 
10. End of Follow Up Telephone Visit to review participant’s itch and anti-pruritus medications. 
11. In the event of a confirmed baseline (run-in) failure at Visit 3, blood, urine, ECG, and TrialMax Slate assessments are not required, and no further study treatment will be 
dispensed.  If the FOBT has been collected and returned by the participant, it should be sent to the laboratory for evaluation.  Refer to Section 6.5.2 of the protocol for more 
information. 
12. Randomization criteria must be met at this visit for a participant to be randomised.  Refer to Section 6.3 of the protocol. 
 
Abbreviations: 
AE= Adverse Event; BDI-II= Beck Depression Inventory-II; BP= Blood Pressure; ECG= Electrocardiogram; EQ-5D= EuroQOL 5D-5L; FOBT= Fecal Occult Blood Test; GI= 
gastrointestinal; GSRS= Gastrointestinal Symptoms Rating Scale; HR= Heart Rate; IEC= Independent Ethics Committee; IRB= Institutional Review Board; NRS= Numerical Rating 
Scale; PD= Pharmacodynamic; PGI-S= Patient Global Impression of Severity; PGI-C= Patient Global Impression of Change; PK= Pharmacokinetics; UDCA= Ursodeoxycholic acid; 
WOCBP= Women of Child Bearing Potential 
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• 
For assessments scheduled at the same visit, where possible they should be 
performed in the following order: fasting blood tests and pharmacokinetic (PK) 
sample (1-3 hour post-dose and 5-8 hours), patient reported outcomes (PROs) [i.e., 
PGI-S, PGI-C, PBC-40, 5D-Itch, EQ-5D, BDI-II, Participant Treatment Experience 
Assessment], ECGs, vital signs, physical exam, other assessments, PK sample (5-8 
hours post-dose). See Section 9 of the protocol for further details. 
• 
All reasonable attempts should be made to ensure compliance with the visit schedule, 
however participants will not be considered out of compliance if visit windows 
extend because of extraordinary events that make it impossible for participants to 
complete a visit within the required window. Determination of the maximum visit 
window deviation is at the discretion of the Medical Monitor. 
• 
The timing and number of planned study assessments specifically PK or 
pharmacodynamic (PD)/biomarkers assessments 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.  
• 
Any changes in the timing or addition of time points for any planned study 
assessments specified above must be documented and approved by the relevant study 
team member and then archived in the sponsor and site study files, but will not 
constitute a protocol amendment. The Institutional Review Boards (IRB)/ 
Independent Ethics Committees (IEC) will be informed of any safety issues that 
require alteration of the safety monitoring scheme or amendment of the informed 
consent form (ICF). 
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Screening Procedures Table 
 
Screening 
Notes 
 
Visit 1 
Window 
Day -45 to -1 
Procedure 
 
 
Informed Consent 
X 
 
Inclusion/Exclusion Criteria 
X 
 
Demography 
X 
 
Full physical examination including height 
and weight 
X 
 
Medical history (includes substance usage, 
family history of liver disease, cancer and 
cardiovascular disease) 
X 
Substances: alcohol and tobacco  
Past and current medical conditions, 
including PBC and pruritus history, and 
associated medications 
X 
Includes use and response to 
UDCA, cholestyramine, 
colesevalem and other anti-pruritus 
medications 
PBC-40 Scale 
X 
 
BDI-II 
X 
 
12-lead ECG 
X 
 
Vital signs 
X 
 
Laboratory assessments (non-fasting), 
including liver chemistries 
X 
 
Urine dipstick pregnancy test (WOCBP 
only)1 
X 
 
Hepatitis B and C screening 
X 
 
1. 
Footnotes: 
1. Urine testing will be standard unless serum testing is required by local regulation or IRB/IEC. 
 
Abbreviations 
BDI-II= Beck Depression Inventory-II 
ECG= electrocardiogram 
PBC= Primary Biliary Cholangitis 
WOCBP = Women Of Child Bearing Potential 
UDCA = Ursodeoxycholic acid 
 
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12.3. 
Appendix 3: Assessment Windows 
12.3.1. 
Definitions of Assessment Windows for Analyses 
Analysis Time 
point 
End of 
Week 
Target  
Protocol Window 
Analysis Window 
 
 
Beginning 
Time point 
Ending 
Time point 
Beginning 
Time point 
Ending 
Time point 
Visit 1 
NA 
Screening 
Day -45 
Day -1 
Day -45 
Day -1 
Visit 2 
NA 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Visit 3 (Baseline) 
Week 4 
Day 28 
Day 28 
Day 35 
Day 21 
Day 35 
Visit 4 
Week 8 
Day 56 
Day 56 
Day 63 
Day 49 
Day 63 
Visit 5 
Week 12 
Day 84 
Day 84 
Day 91 
Day 77 
Day 91 
Visit 6 
Week 16 
Day 112 
Day 112 
Day 119 
Day 105 
Day 119 
Visit 7 
Week 20 
Day 140 
Day 140 
Day 147 
Day 133 
Day 147 
Visit 8 
Week 24 
Day 168 
Day 168 
Day 175 
Day 161 
Day 175 
NA=Not Applicable. 
Note: Visits outside the protocol windows will be recorded as protocol deviations. For the 
purposes of the analysis visits will only be excluded from the PP figures, summaries, and 
statistical analyses if they fall outside the analysis windows. 
Definitions of Days for Diary Assessments 
Analysis Time 
point 
Day of 
Analysis 
Time point 
Labels for 
Summaries 
Diary Data Days used 
in Summaries 
Visit 1 
V1 
Screening (V1) 
NA 
Visit 2 
V2 
Day 1 (V2) 
NA 
Visit 3 (Baseline) 
V3 
Week 4 (V3) 
V3-7 to V3-1 
Visit 4 
V4 
Week 8 (V4) 
V4-7 to V4-1 
Visit 5 
V5 
Week 12 (V5) 
V5-7 to V5-1 
Visit 6 
V6 
Week 16 (V6) 
V6-7 to V6-1 
Visit 7 
V7 
Week 20 (V7) 
V7-7 to V7-1 
Visit 8 
V8 
Week 24 (V8) 
NA 
Vx = Day of Visit x. 
FU = Follow-up. 
NA=Not Applicable. 
 
 
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12.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
12.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
the ISP, MSP, FSP and FU 
Treatment 
Period 
Abbreviation 
 
Treatment 
Details 
Definition 
 
Notes 
Screening  
 
None 
Date < V2 
 
Initial Study 
ISP 
placebo only 
V2 ≤ Date < V3 
 
Main Study 
MSP 
Randomised 
V3 ≤ Date ≤ V6 
Responder Days will use data 
from V3+1 to V6-1 
 
Final Study 
FSP 
placebo only 
V6 < Date < V7 
Time to Worsening will use data 
from V6+1 to V7-1 
Follow-up 
FU 
None 
V7 ≤ Date ≤ V8 
 
Vx = day of Visit x (Section 14.3.1.) 
 
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the main study period. 
12.4.1.1. 
 Treatment Phase All Data 
Study Phase 
Definition 
Pre-Treatment 
Date < Date of first Randomised Treatment 
On-Treatment 
Date of first Randomised Treatment ≤ Date ≤ Date of last Randomised Treatment 
Post-Treatment 
Date of last Randomised Treatment < Date  
• Date = Assessment/Start Date 
12.4.1.2. 
Treatment Phase for AE Data 
Treatment State 
Definition  
Pre-Treatment 
AE Start Date < Date of first Randomised Treatment 
On-Treatment 
Date of first Randomised Treatment  ≤ AE Start Date ≤ Date of last 
Randomised Treatment + 2 
Post-Treatment 
Date of last Randomised Treatment + 2 < AE Starts Date  
Onset Time  Since 1st 
Dose (MSP Day) 
If Date of first Randomised Treatment  ˃  AE Onset Date = AE Onset Date – 
Date of first Randomised Treatment   
If Date of first Randomised Treatment    ≤ AE Onset Date = AE Onset Date – 
Date of first Randomised Treatment    +1 
Missing otherwise. 
Duration (Days)  
AE Resolution Date – AE Onset Date + 1 
Drug-related 
If relationship is marked ‘YES’ on eCRF 
 
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12.4.1.3. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
Any medication or vaccine (including over-the-counter or prescription 
medicines, topical agents including topical corticosteroids, vitamins, 
and/or herbal supplements) that the participant has taken in the 3 
months prior to Screening. 
Concomitant 
Any medication receiving at the time of enrolment or receives during 
the study period (Initial Study Period, Main Study Period, and Final 
Study Period) A medication could potentially be both prior and 
concomitant. 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial 
dates for concomitant medication. Use the rules in this table if concomitant medication date is 
completely missing. 
 
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12.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• If AE onset date is on or after treatment (Main study period or Final 
study period) start date & on or before treatment stop date. (plus 
Final study period or protocol-specified time limit (e.g. half-life of 
drug, certain number of days, etc.). 
• Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop 
Date [+ 2 days]. 
• For studies with greater than one treatment period (e.g., crossover 
study), if AE onset is during one period and worsens during a later 
period it would be counted in both periods. For the initial period the 
logic would be as above. For the later period the logic would use the 
treatment dates associated with the later period: 
• Treatment Period Start Date ≤ AE Worsening Date ≤ Study 
Treatment Stop Date [+ 2 days]. 
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
• 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 
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12.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
12.5.1. 
Reporting Process 
Software 
•
The currently supported versions of SAS software will be used.
Reporting Area 
HARP Server 
: us1salx00259 
HARP 
Compound 
: \ARPROD\ GSK2330672\mid201000 
Analysis Datasets 
•
Analysis datasets will be created according to CDISC standards (SDTM IG
Version 3.2 & ADaM IG Version 2.0).
•
For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary
datasets will be implemented for conversion from SI to SDTM.
Generation of RTF Files 
•
RTF files will be generated for all the tables described in the RAP.
12.5.2. 
Reporting Standards 
General 
•
The current GSK Integrated Data Standards Library (IDSL) will be applied for 
reporting, unless otherwise stated (IDSL Standards Location:
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):
•
4.03 to 4.23: General Principles
•
5.01 to 5.08: Principles Related to Data Listings
•
6.01 to 6.11: Principles Related to Summary Tables
•
7.01 to 7.13: Principles Related to Graphics
•
Do not include participant level listings in the main body of the GSK Clinical Study 
Report. All participant level listings should be located in the modular appendices as 
ICH or non-ICH listings 
Formats 
•
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be
adopted for reporting of data based on the raw data collected, unless otherwise stated.
•
Numeric data will be reported at the precision collected on the eCRF.
•
The reported precision from non eCRF sources will follow the IDSL statistical
principles but may be adjusted to a clinically interpretable number of DP’s.
•
For [Insert Endpoint / Parameter] the following DP’s places will be applied:
•
Summary Statistics:
•
Listings:
Planned and Actual Time 
•
Reporting for tables, figures and formal statistical analyses:
•
Planned time relative to dosing will be used in figures, summaries, statistical
analyses and calculation of any derived parameters, unless otherwise stated.
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• The impact of any major deviation from the planned assessment times and/or 
scheduled visit days on the analyses and interpretation of the results will be 
assessed as appropriate. 
• Reporting for Data Listings:  
• Planned and actual time relative to study drug dosing will be shown in listings 
(Refer to IDSL Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the participant’s 
listings.  
Unscheduled Visits 
• Unscheduled visits will not be included in summary tables except where 
specifically justified and flagged at the blind data review meeting.  Such data 
(decided on an individual case basis) will replace the respective nominal visit in 
summary statistics. 
• In most cases, unscheduled visits will not contribute to summary statistics or plots 
of summary statistics or box plots.   
 
• Unscheduled visits will be included in figures of individual data where profile 
plots are presented over time and will be presented within any relevant listings, 
and in tables of values of potential clinical importance. 
 
• All unscheduled visits will be included in listings in chronological order with 
respect to the scheduled visits. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
 
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12.5.3. 
Reporting Standards for Pharmacokinetic and Pharmacodynamic 
Refer to 9.1.1.1 for PK concentration and 9.1.1.2 for PK concentration data handling and 
reporting. 
Refer to 10.1 for PD concentration data handling and reporting 
Pharmacokinetic Concentration Data 
 
Refer to 9.1.1.1 for PK concentration 
Note: Concentration values for BQL will be imputed using LLQ/2 as 
per GUI_51487 
Descriptive 
Summary 
Statistics, 
Graphical 
Displays and 
Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values for BQL will be imputed using LLQ/2 as 
per GUI_51487 for descriptive summary statistics/analysis and 
summarized graphical displays only.  
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived by 
Programmer 
NA 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
NA 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
and Section 9.1.1.1 and Section 9.1.1.2 
 
 
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12.6. 
Appendix 6: Derived and Transformed Data 
12.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
If there is more than one measurement at any given nominal time point, the mean of all 
the measurements will be calculated and used in any derivation of summary statistics, but 
if listed, all measurements will be presented.  
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. 
If there is more than one entry in the e-diary data for either ‘Worst Itch’ or ‘Sleep’ on any 
given day and timepoint (AM or PM) then it will use the worst score for that day or 
timepoint. The derivation of mean worst daily itch and mean sleep score will continue as 
in Sections 12.6.3, respectively, if there are enough non-missing data to satisfy the 
conditions of the derivation. 
If there is more than one entry for the questionnaires (GSRS and GI symptoms) on any 
given date or timepoint the worst score will be used for that date or timepoint as 
conservative approach. 
If data were missing from one or more item in a GSRS questionnaire, the mean of the 
completed items in the same dimension will be used provided that more than half of the 
items in that dimension had been completed. 
If data are missing from a PBC-40 domain (typically missed or duplicated answers) the 
whole domain should be discarded if <50% of items are completed. If >50% of responses 
are present, then the median value for the completed items in the domain will be ascribed 
to the missing item. 
Study Day 
Calculated as the number of days from start of initial study period date (Day 1) with no 
Day 0 defined: 
Ref Date = Missing                       → Study Day = Missing  
Ref Date < Date of Day 1             → Study Day = Ref Date – Date of Day 1        
Ref Date ≥ Date of Day 1             → Study Day = Ref Date – date of Day 1 + 1     
 
Demographics 
Age 
GSK standard IDSL algorithms will be used for calculating age where date of birth 
(DOB) will be imputed as follows: 
Any participant with a missing day will have this imputed as day ‘15’.   
Any participant with a missing day and month will have this imputed as ‘30th June’. 
Birth date will be presented in listings as ‘YYYY’. 
The Date of Birth will be assumed to be 30 June YYYY and age will be calculated at 
screening visit (Visit 1) using this assumed date of birth. 
Body Mass Index (BMI) 
Calculated as Weight (kg) / [Height (m)]2 
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Demographics 
Country 
A number of tables will be displayed by the subgroup Country (Japan only and The rest 
of the world). 
General Displays note: 
Use Planned Treatment (TRT01P or TRTP) for all outputs except for Safety and PK which will 
use Actual Treatment (TRT01A or TRTA). 
 
 
12.6.2. 
Study Population 
Treatment Compliance Number of Tablets 
Compliance will be calculated based on the number of tablets dispensed and returned 
within the MSP (dispensed at V3, V4 and V5 and returned at V4, V5 and V6). 
 
MSP Compliance =100 * (total number of tablets dispensed from V3 to V6 – total 
number of tablets returned from V3 to V6) / (expected number of tablets to be taken) 
Where expected number of tablets to be taken = 6 tablets per day * (V6 –V3). 
 
If a participant is lost to follow-up, compliance will be calculated up to last Visit 
attended, assuming no tablets were taken from any bottles dispensed at this visit. These 
participants should 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 MSP. 
 
For example, if a participant does not return for V5 their compliance will be calculated 
as: 
 
100 * (total number of tablets dispensed from V3 to V4 – total number of tablets returned 
from V3 to V4) / (expected number of tablets to be taken) 
Where expected number of tablets to be taken = 6 tablets per day * (V4 –V3). 
 
With a flag added to say that the participant dropped out after Visit 4. 
 
Compliance based on number of tablets will also be calculated for the containers marked 
as AM (2 containers, 4 tablets a day) and PM bottles (1 container, 2 tablets a day) over 
the duration of the main study period (Exposure start date at V3 to Exposure end date at 
V6). 
 
Compliance will be calculated similarly for the initial study period (V2 to V3) and final 
study period (V6 to V7). 
 
Refer to Appendix 14 for further details. 
 
Compliance E-diary 
The compliance will be calculated for the period that participants are taking randomised 
study treatment during the Main Study period (MSP) from baseline (Visit 3) until the 
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primary timepoint for the analysis (Visit 6). 
 
For each day during this period, from the evening of Visit 3 until the morning of Visit 6, 
the following will be calculated:  
  
CEQ1am = 1 if ‘Have you taken your study medication for the morning’ is Yes; 
                = 0 if No 
CEQ2am = 1 if ‘I will take my study treatment after I completed the diary’ is 
chosen; 
                = 0 otherwise 
 
CEQam = maximum(CEQ1am, CEQ2am) so = 1 if CEQ1am or CEQ2am = 1 
 
Total CEQam = Number of days that CEQam = 1 between V3 + 1 and V6. 
 
Total CEQpm will be calculated similarly (between V3 and V6-1) for the same questions 
in the PM diary entries. 
 
MSP AM Compliance = 100 * (Total CEQam)/(V6-V3) 
MSP PM Compliance = 100 * (Total CEQpm)/(V6-V3) 
MSP Compliance =mean (MSP AM compliance, MSP PM Compliance) 
 
Extent of Exposure 
Number of days of exposure to study drug during MSP (V3 to V6) will be calculated 
based on the formula:   
Duration of Exposure in Days = Treatment Stop Date –Treatment Start Date + 1 
Participants who were randomised but did not report a treatment start date will be 
categorised as having zero days of exposure.   
 
The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Duration of Exposure x Total Daily Dose) 
 
If there are any treatment breaks during the study, exposure data will be adjusted 
accordingly.  If the treatment break is greater than one day then the duration of exposure 
in days will be adjusted by excluding the treatment break. 
 
If length of break>1 day then:  
Duration of Exposure in Days = Treatment Stop Date – Treatment Start Date + 1 – Duration 
of Breaks. 
 
12.6.3. 
Efficacy 
 Mean Worst Daily Itch 
The primary analysis will be based on the Worst Itch NRS; this is completed twice per 
day (morning and evening) and the Worst Daily Itch Score is the maximum of the AM 
and PM responses. 
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Worst Daily Itch = Maximum (AM Worst Itch, PM Worst Itch). (possible scores 0-10) 
Missing Data within day (where day is AM and PM on the same day): 
Missing AM Worst Itch score then                   Worst Daily Itch = PM Worst Itch score 
Missing PM Worst Itch score then                    Worst Daily Itch = AM Worst Itch score 
Missing AM and PM Worst Itch score then      Worst Daily Itch = Missing 
 
Mean Worst Daily Itch at each visit is the mean of the Worst Daily Itch on the 7 days 
prior to the relevant visit 
Mean Worst Daily Itch at: 
Baseline (Visit 3) = average of worst daily itch V3 -1 to V3 -7. 
Visit 4 = average of worst daily itch on V4 -1 to V4 -7 
Visit 5 = average of worst daily itch on V5 -1 to V5 -7 
Visit 6 = average of worst daily itch on V6 -1 to V6 -7 
Visit 7 = average of worst daily itch on V7 -1 to V7 -7 
 
If more than 3 of the 7 worst daily itch scores are missing in any one week then the mean 
worst daily itch will be set to missing. 
 
If there is more than one entry in the e-diary data for ‘Worst Itch’ on any given day and 
timepoint (AM or PM) then the worst (the highest) score will be used from each duplicate 
record for that day and timepoint and it will be used in the derivation of mean worst daily 
itch.  
Change from Baseline in Mean Worst Daily Itch from Baseline at Visit x 
= Mean Worst Daily Itch at Visit x – Mean Worst Daily Itch at Visit 3 
 
Centred Mean Worst Daily Itch at Baseline  
 
 
This will be used as a covariate in the analyses of Mean Worst Daily Itch Score. It will be 
calculated using only the participants with change from baseline in Mean Worst Daily 
Itch data available for analysis within the population of interest. 
 
Rolling Average Worst Daily Itch 
This is calculated for all participants in the ITT population.  The analysis considers a 
rolling average of mean worst daily itch. This allows the daily fluctuation of the worst 
daily itch to be taken into account as well as ensuring that a clear picture of the mean 
worst daily itch can be seen throughout the study period. 
 
For each patient the rolling average is calculated from day of V2+1 until day of V7. 
  
For each day the rolling average of the worst daily itch from the 7 days prior to each day 
will be calculated. This will be calculated using only data available within the relevant 
study period. 
 
Initial Study Period (Day 2 to V3 inclusive): 
Day 2 = average worst daily itch from Day 1, 
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Day3 = average of worst daily itch form Day 1 and Day 2 
Day8 = average of worst daily itch from Day 1 to Day 7 
Day 9 = average of worst daily itch from Day 2 to Day 8 
….. 
Day of V3 = average of worst daily itch from day of V3-1 to day of V3-7. 
 
Main Study Period (V3+1 to V6 inclusive): 
Day of V3 + 1 = average of worst daily itch from Day of V3 
Day of V3 + 2 = average of worst daily itch from Day V3 to Day of V3 + 1 
Day of V3 + 8 = average of worst daily itch from Day V3 to Day of V3 + 7 
Day of V3 + 9 = average of worst daily itch from Day V3 + 1 to Day of V3 + 8 
……. 
Day of V6 = average of worst daily itch from day of V6-1 to day of V6-7. 
 
 
Final Study Period: 
Day of V6 + 1 = average of worst daily itch from Day of V6 
Day of V6 + 2 = average of worst daily itch from Day V6 to Day of V6 + 1 
Day of V6 + 8 = average of worst daily itch from Day V6 to Day of V6 + 7 
Day of V6 + 9 = average of worst daily itch from Day V6 + 1 to Day of V6 + 8 
……. 
Day of V7 = average of worst daily itch from day of V7-1 to day of V7-7. 
 
Responder in Mean Worst Daily Itch 
Improvement in Mean Worst Daily Itch is a reduction in the score (10 is the highest and 
worst severity, 0 lowest and least severe). 
 
Mean Worst Daily Itch Responders at Visit x: 
 
Mean Worst Daily Itch Visit x Responder: 
= 1,     If Mean Worst Daily Itch Score at Vx is < 4 
= 0,     Otherwise 
 
Mean Worst Daily Itch Percentage Improvement Responder 
= 1,     If ratio of baseline at Vx< 0.7 (i.e. at least a 30% reduction from baseline in worst 
daily itch score)  
= 0,     Otherwise 
 
Mean Worst Daily Itch Improvement Responder 
= 1,     If change from V3 in mean worst daily itch at Vx ≤ - 2. 
= 0,     Otherwise 
 
Responder Days in Worst Daily Itch (Responder Days) 
Number of responder days between V3+1 and V6-1 where response is defined, according 
to the following 3 definitions, for each day as: 
 
Worst Daily Itch Responder: 
= 1,     If Worst Daily Itch Score < 4 
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= 0,     Otherwise 
= missing if worst daily itch score is missing 
 
Worst Daily Itch Percentage Improvement Responder 
= 1,     If ratio of baseline < 0.7 (i.e. at least a 30% reduction from baseline in worst daily itch score) 
= 0,     Otherwise 
= missing if worst daily itch score is missing 
 
Worst Daily Itch Improvement Response 
= 1,     If change from baseline in mean worst daily itch ≤ - 2. 
= 0,     Otherwise 
= missing if worst daily itch score is missing 
 
For each of these the baseline is taken as the Mean Worst Daily Itch at V3 (see above). 
The number of responder days is the total number of days where response is 1 between 
V3+1 and V6-1 inclusive. 
 
The percentage of responder days during the MSP is then calculated, for each responder 
definition, as: 
(Number of responder days / total number days from V3+1 to V6-1 for which a 
worst daily itch score was available) * 100 
 
Note: days for which no worst daily itch score is available will not contribute to either the 
numerator or the denominator. 
 
Time to Worsening of Itch 
The improver population with improvement in Mean Worst Daily Itch at V6 i.e. those 
with:  
Change in Mean Worst Daily Itch from Baseline ≤ -2 at Week 16 (i.e. Improved by at 
least 2 points between baseline and Week 16). 
 
This is calculated in the subset of the ITT population with improved Mean Worst Daily 
Itch.  The analysis considers a rolling average of mean worst daily itch. This allows the 
daily fluctuation of the worst daily itch to be taken into account as well as ensuring that 
the comparisons being made are equivalent. This is similar to the Rolling Average Worst 
Daily Itch form above, although there are different rules on what data are included in this 
calculation. 
 
Data are restricted to use only the worst daily itch scores available in the Final Study 
Period (FSP) from V6+1 to V7-1.  
 
In order for data to be comparable to mean worst daily itch score at Week 16 (the 
comparator used to determine if a participant has worsened), a 7 day moving average 
(MAV) of worst daily itch is calculated where at least 4 values must be non-missing.  
 
MAVx  = average of worst daily itch on Day x-3  to Day x+3 around the mid-point Day x 
from V6+1 to V7-1. 
 
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Note that for MAV at x=V6+1, there are no contributing values for the 3 days prior to 
Day x as these are not considered in the MSP.  Similarly, for MAV at x=V7-1, there are 
no contributing values for the 3 days after Day x as these are not considered in the FSP.  
 
Example:  
Define FSP Day relative to V6 so that x days after V6 is FSP Day x. 
So for example, MAV5 is calculated as the average worst daily itch scores over FSP Day 
2 to 8. 
 
For each MAVx, the median of the corresponding FSP Days is calculated (DMAVx).   
So DMAX5 = median (2, 3, 4, 5, 6, 7, 8) = 5. 
 
So, in the case of 7 contributing values and no missing data, DMAVx = x. 
 
However, if for example, data on FSP Day 2 was missing then DMAX5 = median (3, 4, 
5, 6, 7, 8) = 5.5. 
 
 
Time of worsening is calculated as the first day (DMAVx) where the participants moving 
average around this point is higher than their Week 16 mean worst daily itch by 2 or 
more points: 
MAVx  - Mean Worst Daily Itch at V6 (Week 16) ≥ 2  
 
If the participant’s MAV does not increase by 2 points (or more) by the end of the FSP 
then the time of worsening will be censored at the last DMAVx based on at least 4 
evaluable days in FSP.   
 
Example: 
Consider a participant who does not worsen and attends for Visit 6 and Visit 7 on Days 
82 and 112, respectively.  The last MAV was calculated based on non-missing data on 
Days 108, 109 ,110, and 111 (which relative to V6 at Day 82 equates to FSP Day 26 to 
29), the censored time of worsening value will be median (26, 27, 28, 29) = 27.5.    
 
PRO: Other eDiary Itch Questions: Mean Sleep and Fatigue Score 
Mean Sleep Score at each visit is the mean of the sleep scores (0-10 NRS) from the 7 
days prior to the relevant visit. The Daily Sleep Score is obtained from the morning 
eDiary entries. 
 
Mean Fatigue Score at each visit is the mean of the fatigue scores from the 7 days prior to 
the relevant visit. The Daily Fatigue Score is obtained from the evening eDiary entries. 
 
Each of these are derived as for Mean Worst Daily Itch from Vx-1 to Vx-7 for Visit x. 
 
If more than 3 of the 7 fatigue scores are missing in any one week then the Mean Fatigue 
Score is missing; a similar approach is taken for the Mean Sleep Score. 
 
If there is more than one entry in the e-diary data for the sleep score on any given day 
then the worst score will be used for that day and it will be used in the derivation of mean 
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daily sleep score. 
 
PRO: Other eDiary Itch Questions: Mean Overall Itch 
Another question in the eDiary asks about ‘overall or average itch’ using a 0-10 NRS.  
This question is asked in both the morning and evening diaries and will be summarised 
by taking the average of the morning and evening scores each day and averaging this 
over the 7 days prior to each visit. 
 
Average Overall Itch = Average (AM Overall itch, PM Overall itch).  (possible scores 0-
10) 
 
Missing Data within day (where day is the AM and PM on the same date): 
Missing AM Overall Itch score then                    Average Overall Itch = PM Overall Itch 
score 
Missing PM Overall Itch score then                    Average Overall Itch = AM Overall Itch 
score 
Missing AM and PM Overall Itch score then       Average Overall Itch = Missing 
 
The Mean Overall Itch is then derived as for the Mean Worst Daily Itch, using the 
Average Overall Itch from Vx-1 to Vx-7 for Visit x. 
 
PRO: Other eDiary Itch Questions: Other eDiary Questions 
There are a number of other eDiary questions, listed below. They will be summarised 
over the 7 days prior to each visit in 2 ways; summarising the categorical answers and by 
deriving a numerical score.  
 
Average Response 
 
Table A below shows the scores that should be assigned to the answers for these 
questions. 
Morning diary 
Evening Diary  
 
Table A of Scoring for the Other eDiary questions 
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For each participant and question the average score over the 7 days prior to each visit will 
be calculated as per see Mean Sleep and Fatigue Score above.  
As with all questions in the eDiary if the score for more than 3 of the 7 days is missing 
the Mean score will be missing. 
 
Most Frequent response 
 
For each participant/question 
 
Most Frequent Response = Mode (response to question on Vx-1 to Vx-7) 
If there is more than one mode the worst case will be taken as the response with the 
highest score (in the table above), with the exception of question A4 where the worst 
response is No (the response with the lowest score).  
For example, if a participant answers to question A1 are as follows: 
A little bit, Quite a bit, Quite a bit, A little bit, Not at all, Quite a bit, Quite a bit – the 
Most Frequent Response will be ‘Quite a bit’ 
If a participant answers are: 
A little bit, Quite a bit, Quite a bit, A little bit, Not at all, Quite a bit, A little bit – the 
Most Frequent Response will still be ‘Quite a bit’. There will be 2 modes, ‘A little bit’ 
and ‘Quite a bit’, but ‘Quite a bit’ is the worst case for that question and so will be taken 
as the Most Frequent Response. 
 
PTEA 
The responses to the PTEA (closed questions) will be displayed as categories and will not 
be converted to scores. 
Follow-Up Phone Call 
The follow-up phone call will ask about the participant’s worst itch, worst fatigue and 
how much itching interferes with sleep on the 0-10 NRS. This will be presented as 
summary of the scores. 
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The remaining questions have categorical responses which will be summarised using 
contingency tables. 
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 (summarised 
below). 
Question 1 is scored as: 
 
 
 
Question 2 to 27 (inclusive) are scored as: 
 
 
 
Questions 28 to 33 (inclusive) are scored as: 
 
 
 
 
Questions 34-39 (inclusive) are scored as: 
 
 
 
Question 40 is scored as: 
 
 
 
For all Questions, an answer of 
 will be scored . 
For each visit the PBC-40 questionnaire should provide scores for 6 domains: 
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 should be marked as missing.  If 50% or 
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more of the corresponding question scores are complete the median of these responses 
should be imputed for the missing values within the domain before calculating the 
domain score. 
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 
PBC-Emotional = sum of scores of questions 28 30 33 
PBC-Social = sum of scores of questions 29 31 32 and 34 to 40 
 
If data are missing from a PBC-40 domain (typically missed or duplicated answers) the 
whole domain should be discarded if <50% of items are completed. If >50% of responses 
are present, then the median value for the completed items in the domain will be ascribed 
to the missing item. 
5-D Itch 
For each visit the 5-D itch score is broken down into 5 domains 
Duration Score    = Score for question on duration (on scale of 1 to 5) 
Degree Score      = Score for question on degree (on scale of 1 to 5) 
Direction Score    = Score for question direction (on scale of 1 to 5) 
Disability Score    = Maximum score given for all four questions under the Disability 
heading (sleep, leisure/social, housework/errands, work/school) 
Distribution Score = Total number of areas of the body affected is obtained, which is then 
used to determine a Distribution score:  
Total number of areas affected = 0-2 then Distribution Score = 1 
Total number of areas affected = 3-5 then Distribution Score = 2 
Total number of areas affected = 6-10 then Distribution Score = 3 
Total number of areas affected = 11-13 then Distribution Score = 4 
Total number of areas affected = 14-16 then Distribution Score = 5 
Total 5-D itch score can then be taken as the total of the scores from each domain: 
5-D Itch Score = Duration Score + Degree Score + Direction Score + Disability Score + 
Distribution Score. 
If any domain score is missing then the Total 5-D Itch score will also be missing. 
 
EQ-5D-5L and EQ-VAS 
The EQ-5D is a standardised instrument used to measure health utility.  It is a two-part 
self-assessment questionnaire, the first part being a descriptive system comprising five 
dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/ depression, 
the second part requires the participant to indicate their perceived health on a visual 
analogue scale (EQ-VAS). 
In the descriptive system for each of the five dimensions there are five levels of response 
ranging from ‘no problems’ to ‘extreme problems’ and reflecting the participant’s current 
health status. The responses are scored 1-5 as shown in Table B.  
 
Table B: EQ-5D scores 
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Dimension 
Response  
Score 
Mobility 
 
Self-care 
 
Usual activities (e.g. work, 
study, housework, family or 
leisure activities) 
Pain/discomfort 
 
Anxiety/depression 
 
 
Ambiguous values (i.e. 2 boxes ticked for a single question) should be treated as missing.   
A participant is classified into one of 3125 distinct health states (each being referred to by 
a 5-digit code based on the responses to each dimension in the descriptive system, e.g. 
11111 or 55555).  
This health state is then converted to a utility index score. EQ-5D-5L health state utility 
index scores summarize how good or bad health problems are on a scale anchored at 
(
) and
(
). Health states considered worse than dead are 
given utility index scores <0.  
The responses to each of the dimensions will be summarized at each assessment time for 
which there are adequate data.  
The utility index score will be derived and summarized by pruritus severity and overall 
with summary statistics at each assessment time for which there are adequate data. 
Summary statistics on change from baseline will also be provided; overall and by 
baseline severity.   
 
Due to concerns raised by independent quality assurance of the analytical methods used 
to create the 5L valuation set for England, NICE currently does not recommend using the 
5L valuation set and that companies, academic groups and others preparing evidence 
submissions for NICE should use the 3L valuation set for reference-case analyses. 
Utility values should be calculated by mapping the 5L descriptive system data onto the 
3L valuation set. The nonparametric model mapping function developed by van Hout et 
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al. (2012) should be used. A more detailed description of the crosswalk model and 
methodology, the actual index values and an Excel based calculator can be downloaded 
from the EuroQol site: (https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/valuation-
standard-value-sets/crosswalk-index-value-calculator/) the UK value set should be used. 
The Excel calculator for MS Windows is below (also available for Mac via the link 
above. 
 
Other country specific value-sets are available (Denmark, France, Germany, Japan, the 
Netherlands, Spain, Thailand, UK, US and Zimbabwe) and future analyses may explore 
these.  
EQ-VAS 
The EQ-VAS requires the participant to indicate their perceived health on a visual 
analogue scale (EQ-VAS), where the endpoints are labelled ‘
’ 
anchored at 
 and ‘
’ anchored at . 
The EQ-5D Thermometer will be summarized with summary statistics at each assessment 
time for which there are adequate data. Summary statistics on change from baseline will 
also be provided.  
 
PGI-S 
PGI-S: Score will be on a scale of 1-5 from the PGI-S question: 
 
 
 
 
 
PGI-S Response 
 
The response to the PGI-S question will also be summarised in terms of frequency and 
percentage at each Visit. 
PGI-C 
PGI-C: Score will be on a scale of 1-7 from the PGI-C question. 
 
 
 
 
 
 
 
 
 
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PGI-C Response 
 
The response to the PGI-C question will also be summarised in terms of frequency and 
percentage at each Visit. 
 
BDI-II 
The Beck Depression Inventory –II consists of 21 questions, with possible responses 
being scored from  (
) to  (
). 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 
 
Question 18: 
Collection  
Code 
Label 
Item  
Score 
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Actigraphy 
For each participant participating in the actigraphy sub-study, data will be provided for 
up to 5 records (nights) over 7 days in each of the 3 time-periods in which they 
participate. (Week 2 or Week 3, Week 9 or Week 10, Week 13 or Week 14).  
If in a time period there are 3 or fewer records, then the data for that time period should 
be disregarded. 
Otherwise all figures and analysis should use all of the data as provided. 
 
For each of the 3 time periods for which data are available the average number of 
scratching events per hour will be calculated for the time period, for each participant, as: 
 
Total number of scratching events for night j (NSj)  
           = Average number of scratching events per hour on night j * duration of rest 
period on night j 
DRj = Duration of rest period on night j. 
 
Average number of scratching events per hour over the time period  
= (sum of NSj in the time period) / (sum of DRj in the time period). 
 
The average duration of scratching events over each time period will be calculated 
similarly. 
 
Risk Group 
The risk group strata is assigned for all participants at baseline visit (V3) for 
randomisation and is based on the lab results of the samples taken at visit 2 (ALP).  
 
High Risk Population 
The High Risk Population will be defined as those that were assigned to the High Risk 
strata for randomisation at V3. This population will be used to look at the change in 
disease progression markers in those at High Risk of disease progression. 
 
Restricted High Risk Population 
As part of a sensitivity analysis the High Risk population will be restricted to those 
confirmed to be still at High Risk of disease progression at V3, based on lab results and 
will additionally exclude anyone who was mis-stratified to the High Risk strata for 
randomisation. 
 
Restricted High risk Population will be defined as: 
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Those assigned to High Risk strata for randomisation (V3) AND whose lab values at 
BOTH V2 and V3 meet the criteria below: 
 
 
ALP at VX ≥ 1.67*ULN   AND/OR   total bilirubin at VX >ULN 
 
The sensitivity analysis will only be undertaken if the Restricted High Risk population 
differs from the High Risk population. 
 
Disease Progression Risk Responders at each Visit 
For all of those in the High Risk Population. 
 
= 1,      If ALP at VX < 1.67 * ULN  AND  total bilirubin at VX  ≤ ULN 
= 0,     Otherwise 
 
12.6.4. 
Safety 
GSRS Domain Score 
GSRS Responses 
The responses to the individual GSRS questions asked at each visit will be displayed in 
terms of frequency and percentage at each Visit. 
 
GSRS Domain Score 
The responses to each question in the GSRS range from 
 ( ) to 
 
 ( ). 
 
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 should be marked as missing.  If 50% or 
more of the corresponding question scores are complete the mean of these responses 
should be imputed for the missing values within the domain before calculating the 
domain score.   
For each Visit the GSRS scores will be the weekly questionnaire completed within 7 days 
prior to the visit. 
 
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. 
 
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GI symptoms 
            Symptoms – Diarrhoea 
There are 3 diarrhoea questions within the weekly eDiary, with categorical 5-point 
responses.  
 
Response will be provided to the weekly eDiary diarrhoea questions each week after start 
of ISP. The weekly eDiary diarrhoea responses for a visit will be those provided within 7 
days prior to the visit. 
 
If there are multiple entries for that same question for the questionnaires (GI symptoms) 
on the same date the worst score will be used for that date as conservative approach. 
            Symptoms – Abdominal Pain 
There are 2 abdominal pain questions within the weekly eDiary, one with categorical 5-
point response and one with 0-10 NRS. 
 
Response will be provided to the weekly eDiary abdominal pain questions each week 
after start of ISP. The weekly eDiary abdominal pain responses for a visit will be those 
provided within 7 days prior to the visit. 
 
If there is more than one entry for the questionnaires (GI symptoms) on any given date or 
timepoint the worst score will be used for that date or timepoint as conservative 
approach. 
ECG Parameters: 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 : 
 
Otherwise if QTcF is machine read, then:  
 
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. 
ECG Parameters: 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:  
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Adverse Events (AEs and AEs of Special Interest) 
Elevated ALT meeting stopping criteria, as per Section 8.1.1 of the protocol table 5. 
Post-Screening Lab Result 
Actions 
 
Total bilirubin > 2x participant’s 
screening AND >1.5x ULN  
 
 
Stop study treatment immediately. 
 
Discuss with Medical Monitor within 24 hours. 
 
Repeat liver chemistry testing (including AST, ALT, total 
bilirubin, ALP, and PT/INR) within 24-72 hours where possible 
but within 1 week, and thereafter at least weekly until values 
stabilize or fall below the criteria for increased monitoring. 
 
Refer to Protocol Appendix 4 for further follow-up and 
monitoring requirements. 
 
 
Total bilirubin >3x ULN  
 
ALT > 3x participant’s screening 
ALT result AND > 5x ULN  
 
 
ALT >8x ULN of ALT 
In addition, study treatment will be stopped for a participant 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 symptoms which may typically be associated with drug-induced liver 
injury (including fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia [>5%]). 
As the ALT would naturally fluctuate in these subjects, the AESIs are the ALTs that have 
met the stopping criteria above. If the stopping criteria has been met then the liver event 
form should be completed.  
 
Diarrhoea and Abdominal Pain  
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 Abdominal Pain AEs and diarrhoea 
AEs of special interest 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 provided in a separate 
document ‘TOI Diarrhoea_MedDRA.xlsx’ 
 
Other Adverse Events 
At blinded data review other adverse events may be identified for further investigation. 
 
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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 
 
 
12.6.5. 
Pharmacokinetic 
Endpoints detailed in Ssection in 9.1.1.1 
 
 
12.6.6. 
Pharmacodynamic Biomarker 
Endpoints and variables are detailed in Section 10.1.1 
 
 
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12.7. 
Appendix 7: Reporting Standards for Missing Data 
12.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Participant study completion was defined as in the Protocol Section 5.3.  
• Withdrawn participants will not be replaced in the study. 
• All available data from participants who were withdrawn from the study 
will be listed and all available planned data will be included in summary 
tables and figures, unless otherwise specified.  
• 
Withdrawal visits will be slotted as per Appendix 3: Assessment 
Windows or will be summarised as withdrawal visits. 
12.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, 
leading to blank fields on the collection instrument: 
• These data will be indicated by the use of a “blank” in participant 
listing displays. Unless all data for a specific visit are missing in 
which case the data is excluded from the table.  
• Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such. 
 
Outliers 
• Any participants excluded from the summaries and/or statistical 
analyses will be documented along with the reason for exclusion in the 
clinical study report. Footnotes should be added to the outputs, where 
appropriate. 
12.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in participant listing displays. 
Adverse 
Events 
The eCRF allows for the possibility of partial dates (i.e., only month and 
year) to be recorded for AE start and end dates; that is, the day of the month 
may be missing.  In such a case, the following conventions will be applied 
for calculating the time to onset and the duration of the event: 
Missing Start Day: First of the month will be used unless this is before the 
start date of randomised study treatment; in this case the study treatment 
start date will be used and hence the event is considered On-treatment. 
Missing Stop Day: Last day of the month will be used, unless this is after 
the stop date of randomised study treatment; in this case the study treatment 
stop date will be used. 
Completely missing start or end dates will remain missing, with no 
imputation applied.  Consequently, time to onset and duration of such 
events will be missing. 
 
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Element 
Reporting Detail 
Concomita
nt 
Medicatio
ns/Medica
l History 
Partial dates for any concomitant medications and medical history recorded 
in the CRF will be imputed using the following convention: 
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month 
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
Unless after the study completion the end date will used. For example, if a 
participant ended study on 21 May 2019 then stop date will end of study 
date. 
The recorded partial date will be displayed in listings. 
Handling 
of values 
outside 
limit of 
quantificat
ion 
Data marked as below a value (e.g. < X) will be replaced with 0.5*X for any 
summaries and analysis of this data. A footnote should be included in any 
tables to indicate the imputation that has been made. 
 
Handling 
of Missing 
Data for 
Statistical 
Analysis 
Randomised participants that withdraw from treatment early will be 
followed-up at each Visit as per the protocol with the aim of reducing the 
level of dropouts.  Only those who withdraw from the study entirely or are 
lost to follow-up will not complete the Study Visits. 
 
There are four possible ways that data can be missing: 
• Withdrawn/lost to follow-up  
• Missed Visit 
• Missing data within a Visit 
• Missing data within an instrument/measure 
 
The critical time points for the majority of primary and secondary endpoints 
are the baseline measurement (Visit 3) and the Week 16 measurement (Visit 
6), and for eDiary data the 7 days prior to these visits. 
 
It is expected that the level of missing data will be less than 10%.  Prior to 
breaking the blind, the data will be reviewed, examining the pattern and 
percentage of missing data.  If the level of missing data is greater than 10%, 
different methods of dealing with this missing data will be investigated, 
including: 
• Use all available data to derive the endpoints 
In general, Mean Worst Daily Itch is missing if the worst daily itch 
is missing for more than 3 days out of 7.  If this option were to be 
chosen the Mean Worst Daily Itch would be using all data available 
within the relevant 7 days. 
• Fit Mixed Model Repeated Measures (MMRM) using all data 
available at Visits 3, 4 and 5 to investigate the change from baseline. 
• Use Multiple Imputation Techniques to replace the missing data 
 
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Element 
Reporting Detail 
For some of the derived endpoints, if the level of missing raw data reaches a 
certain level then the endpoint is forced to be missing.  In these instances it 
may be possible to make use of the unused raw data, depending on the 
method that is chosen to deal with the missing data.   
 
Last Observation Carried Forward (LOCF) will not be used to replace 
missing data. 
 
 
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12.8. 
Appendix 8: Values of Potential Clinical Importance 
12.8.1. 
Laboratory Values 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Haematocrit  
Ratio of 
1 
Male 
 
0.54 
Female 
 
0.54 
∆ from BL 
↓0.075 
 
Haemoglobin  
g/L 
 
Male 
 
180 
Female 
 
180 
∆ from BL 
↓25 
 
Lymphocytes  
x109/ L 
 
0.8 
 
Neutrophil Count  
x109/ L 
 
1.5 
 
Platelet Count  
x109/ L 
 
100 
550 
While Blood Cell Count (WBC) 
x109/ L 
 
3 
20 
Red Blood Cell Count (RBC) 
 
 
NA 
NA 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
g/L 
 
30 
 
Albumin 
 
CFB 
20% decrease 
 
Calcium 
mmol/L 
 
2 
2.75 
Creatinine 
 
umol/L 
∆ from BL 
 
↑ 26.5 
Glucose (fasting) 
mmol/L 
 
3 
9 
Magnesium 
mmol/L 
 
0.5 
1.23 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
eGFR (CKD-EPI) 
mL/min/ 
1.73m2 
 
<45 
- 
BUN 
 
 
NA 
NA 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT  
U/L 
% ∆ from 
BL 
↑ 50% 
AST  
U/L 
% ∆ from 
BL 
↑ 50% 
ALP 
U/L 
% ∆ from 
BL 
↑ 50% 
T Bilirubin  
µmol/L 
% ∆ from 
BL 
↑ 50% 
T.  Bilirubin + ALT 
µmol/L 
High 
2xULN T.  Bilirubin 
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Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
 
+ 
U/L 
 5x ULN ALT 
GGT 
U/L 
 
NA 
 
12.8.2. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
 
> 450 [1] 
Absolute PR Interval 
msec 
< 110 [1] 
> 220 [1] 
Absolute QRS Interval 
msec 
< 75 [1] 
> 110 [1] 
Change from Baseline 
Increase from Baseline QTc 
msec 
> 60 [1] 
 
12.8.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 
 
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12.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
12.9.1. 
Population Pharmacokinetic (PopPK) Dataset Specification 
[NA] 
12.9.2. 
Population Pharmacokinetic (PopPK) Methodology 
[NA] 
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12.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
12.10.1. 
Pharmacokinetic / Pharmacodynamic Dataset Specification 
[NA] 
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12.11. 
Appendix 11: Abbreviations & Trade Marks 
12.11.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
ADCM 
Data Structure for Adverse Event Analysis 
ADAE 
Data Structure for Adverse Event Analysis 
AE 
Adverse Event 
AIC 
Akaike’s Information Criterion 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AR(1) 
Autoregressive 
AST 
Aspartate Aminotransferase 
BDI-II 
Beck Depression Inventory-II 
BID 
Twice a Day 
BL 
Baseline 
BLC 
Baseline Change 
BP 
Blood Pressure  
bpm 
beats per minute 
BUN 
Blood Urea Nitrogen 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CS 
Compound Symmetry  
C4 
7--hydroxy-4-cholesten-3-one 
DBF 
Database Freeze 
Cmax 
Maximum concentration 
Cave 
Average concentration 
DOB 
Date of Birth 
DP 
Decimal Places 
ECG 
Electrocardiogram 
eCRF 
Annotated Case Record Form 
eDiary 
Electronic Diary 
ELF 
Enhanced Liver Fibrosis 
eGFR  
Estimated glomerular filtration rate using (CKD-EPI equation) 
EQ-5D-5L 
EuroQOL 5D-5L 
FGF-19 
Fibroblast Growth Factor -19 
FOBT 
Fecal Occult Blood Test 
FSP 
Final Study Period 
FU 
Follow-Up 
GGT 
Gamma-Glutamyl Transpeptidase 
GI 
Gastrointestinal 
GSRS 
Gastrointestinal Symptoms Rating Scale 
H0 
Primary Null Hypothesis 
H1 
Alternate Hypothesis 
HDL 
High Density Lipoprotein 
HR 
Heart Rate 
IA 
Interim Analysis 
IAP 
Interim Analysis Plan 
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Abbreviation 
Description 
IBAT 
Ileal Bile Acid Transporter 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDSL 
Integrated Data Standards Library 
IP 
Investigational Product 
ISP 
Initial Study Period 
ITT 
Intent-To-Treat 
GSK 
GlaxoSmithKline 
GUI 
Guidance 
L 
Litres 
LDL 
Low-Density Lipoprotein 
LOCF 
Last Observation Carries Forward 
LS 
Least Squares 
MAV 
Moving Average 
Max 
Maximum 
MCV 
Mean Corpuscular Volume 
MCH 
Mean Corpuscular Hemoglobin 
mg 
milligram 
Min 
Minimum 
MMRM 
Mixed Model Repeated Measures 
msec 
milliseconds 
MSP 
Main Study Period 
NRS 
Numerical Rating Scale 
PBC 
Primary Biliary Cholangitis 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PGI-C 
Patient Global Impression of Change 
PGI-S  
Patient Global Impression of Severity 
PP 
Per Protocol 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
PT/INR 
Prothrombin Time/International Normalised Ratio 
QC 
Quality Control 
QD 
Once a Day 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomisation & Medication Ordering System  
RBC 
Red Blood Cells 
RTF 
Rich Text File 
SAC 
Statistical Analysis Complete 
SDTM 
Study Data Tabulation Model 
SD 
Standard Deviation 
SI 
Standard  
SOA 
Schedule of Activities 
SOC 
System Organ Class 
TFL 
Tables, Figures & Listings  
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Abbreviation 
Description 
U 
Universal Unit 
UDCA 
Ursodeoxycholic acid 
UK 
United Kingdom 
ULN 
Upper Limit of Normal 
USA 
United States of America 
VAS 
Visual Analogue Scale 
WASO 
Wake After Sleep Onset 
WBC 
White Blood Cells 
µg 
Micrograms 
µmol 
Micromoles 
V 
Visit 
12.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
[Phoenix WinNonlin] 
 
 
[SAS] 
 
 
 
 
 
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12.12. 
Appendix 12: List of Data Displays 
12.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.39 
 
Efficacy 
2.1 to 2.110 
2.1 to 2.53 
Safety 
3.1 to 3.87 
3.1 to 3.15 
Pharmacokinetic 
4.1 to 4.12 
4.1 to 4.18 
Pharmacodynamic and / or Biomarker 
5.1 to 5.30 
5.1 to 5.3 
Section 
Listings 
ICH Listings 
1 to 31 
Other Listings 
32 to 61 
 
 
12.12.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays. 
 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Pharmacodynamic and / or Biomarker 
PD_Fn 
PD_Tn 
PD_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
 
12.12.3. 
Deliverables 
Delivery [Priority] [1] 
Description 
HLR 
Headline Results 
SAC 
Final Statistical Analysis Complete 
Country 
By Japan only and by The rest of the world 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 
 
 
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12.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Populatio
n 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
1.1.  
Randomise
d 
ES1 
Summary of Participant 
Disposition  
 As per shell 
SAC 
1.2.  
Initial 
ES4 
Summary of Participant 
Disposition at Each Study Phase 
 
Where study phases are:  
Screening (V1, prior to V2).  
ISP If the Participant is 
assigned single-blind placebo 
at V2 they have started the 
ISP. 
MSP: If the Participant is 
assigned to the double-blind 
treatment at V3 they have 
entered the MSP. 
FSP: If the Participant is 
assigned the placebo at V6 
they have entered the FSP. 
Follow-up Participant 
completes V7 they have 
entered follow-up (which 
ends at time of V8 – follow-up 
phone call). 
Footnote: 
The Initial Study period starts 
on Visit 2 and ends on Visit 3. 
The Main Study Period starts 
on Visit 3 and ends on Visit 6. 
The Final Study Period starts 
on Visit 6 and ends on Visit 7. 
Follow-up runs to V8. 
HLR 
1.3.  
Enrolled 
ES6 
Screening Status and Summary 
of Reasons for Screen Failure 
To produce a table 
describing, for all those that 
were enrolled into the study, 
the reasons for screen failure 
Add a footnote to table: 
Participants are classed as 
screening failures if they do 
not pass into the ISP. 
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Study Population Tables 
No. 
Populatio
n 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
1.4.  
Initial 
ES6 
Summary of Reasons for Baseline 
Failure 
To produce a table 
describing, for all those that 
were entered into the ISP, 
the reasons for 
randomisation failure. 
As per ES6 but with: 
‘Randomisation Status’ rather 
than ‘Screening Status’ 
‘Entered Initial Study Period’ 
rather than ‘Enrolled’ 
 
Add a footnote to table: 
Participants are classed as 
randomisation failures if they 
do not pass into the MSP. 
SAC 
1.5.  
Safety 
SD1 
Treatment Status and Summary 
of Reasons for Discontinuation of 
Study Treatment During the Main 
Study Period 
 
SAC 
1.6.  
Initial 
ES10 
Treatment Status and Summary 
of Reasons for Discontinuation of 
Placebo Run-in During the Initial 
Study Period  
This will be shown separately 
for the initial study period and 
will show anyone who has 
stopped taking placebo 
during either of these periods 
 
SAC 
1.7.  
Safety 
SD1 
Treatment Status and Summary 
of Reasons for Discontinuation of 
Placebo Treatments During the 
Final Study Period  
This will be shown separately 
for the final study period and 
will show anyone who has 
stopped taking placebo 
during either of these periods 
Programming notes: only the 
placebo during the final study 
period column should be 
showed for this table  
SAC 
1.8.  
Initial 
SD1 
Summary of Reasons for 
Withdrawal from the Study  
Please add footnote: Note: 
During the entire study period 
 
Programming note: during 
the entire study period 
 
SAC 
1.9.  
Enrolled 
NS1 
Summary of Number of 
Participants by Centre 
As per shell NS1 with the 
addition of column ‘not 
entered into ISP’ as well as 
‘not randomised’, where not 
entered into ISP is a 
screening failure and not 
randomised is a 
randomisation failure 
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Study Population Tables 
No. 
Populatio
n 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
1.10. 
 
Randomise
d 
DV1 
Summary of Important Protocol 
Deviations 
 
SAC 
1.11. 
 
Enrolled 
Pop_T1 
Summary of Populations 
Summary of N in each of the 
populations.  
Calculate the percentages for 
the Restricted High Risk 
population based on the ITT 
population. 
Programming notes: remove 
the actigraphy pop from the 
table and add the PK pop. 
Please see Shell for update. 
HLR 
1.12. 
 
ITT 
Pop_T4 
Summary of Risk Group Miss-
stratification 
 
SAC 
1.13. 
 
ITT 
Pop_T5 
Summary of Changes in Risk 
Group Prior to Main Study Period 
 
SAC 
1.14. 
 
Safety 
DM1 
Summary of Demographic 
Characteristics  
 
HLR 
1.15. 
 
Safety 
DM11 
Summary of Age Ranges 
 
SAC 
1.16. 
 
Safety 
DM5 
Summary of Race and Racial 
Combinations 
 
SAC 
1.17. 
 
Safety 
DM6 
Summary of Race and Racial 
Combinations Details 
 
SAC 
1.18. 
 
Safety 
SU1 
Summary of Substance Use 
 
SAC 
1.19. 
 
Safety 
CM1 
Summary of Concomitant 
Medication ATC Categories by 
Ingredient 
 
SAC 
1.20. 
 
Safety 
CM1 
Summary of Previous Treatment 
for PBC 
 
SAC 
1.21. 
 
Safety 
MH1 
Summary of Past Medical 
Conditions 
 
SAC 
1.22. 
 
Safety 
MH1 
Summary of Current Medical 
Conditions 
 
SAC 
1.23. 
 
Safety 
Pop_T6 
Summary of PBC History  
All information on 
MEDHX_PBC eCRF page, 
including Duration of PBC, 
Duration of Pruritus, PBC 
Diagnostic Criteria and Liver 
Transplant History. 
To calculate duration please 
use the date of onset of 
symptoms/diagnosis up to 
Screening, impute missing 
dates per the RAP rules for 
Medical History. Liver 
Transplant History will be 
reported as Yes/No. 
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Study Population Tables 
No. 
Populatio
n 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
1.24. 
 
Safety 
LB1 
Summary of Liver Chemistry at 
Screening 
It would be a LB summary 
which you would subset to 
the liver chemistry tests. 
SAC 
1.25. 
 
Safety 
EX1 
Summary of Exposure  
For the Main Study Period – 
time on active treatment – 
from V3 to V6 (inclusive) 
SAC 
1.26. 
 
Safety 
Pop_T3 
Summary of Treatment 
Compliance (defined by e-diary) 
in Main Study Period (AM, PM 
and Total) 
For the Main Study Period – 
compliance in terms of e-
diary for morning (AM), 
evening (PM) and Total – 
from V3 to V6 (inclusive). 
 
SAC 
1.27. 
 
Safety 
Pop_T3 
Summary of Treatment 
Compliance (defined by tablets 
taken) in Main Study Period (AM, 
PM and Total) 
 
For the Main Study Period – 
compliance in terms of 
tablets taken for morning 
(AM), evening (PM) and Total 
– from V3 to V6 (inclusive) 
 
Footnote should read:  
Note: compliance 
calculations are based on the 
number of tablets dispensed 
and returned. 
SAC 
1.28. 
 
ITT 
Pop_T2 
Summary of Participants 
Attendance at Clinic Visits and 
Participants with Evaluable Diary 
Itch Data Evaluable Mean Worst 
Daily Itch 
 
SAC 
1.29. 
 
ITT 
COV1 
Summary of Covariates for 
Analysis of Mean Worst Itch 
Score 
Summarise the following 
covariates, strata, and 
subgroups. 
Footnote “Risk of Disease 
Progression was used as 
assigned for randomisation   
See Section 5.4 for the full 
list 
HLR 
Country 
1.30.  
Randomise
d 
ES1 
Summary of Participant 
Disposition by Country 
 As per shell 
SAC 
1.31.  
ITT 
DV1 
Summary of Protocol Deviations 
by Country 
 
SAC 
1.32.  
Enrolled 
Pop_T1 
Summary of Populations by 
Country 
Summary of N in each of the 
populations.  
SAC 
1.33.  
Safety 
DM1 
Summary of Demographic 
Characteristics by Country 
 
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Study Population Tables 
No. 
Populatio
n 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
1.34.  
Safety 
Pop_T6 
Summary of PBC History by 
Country 
All information on 
MEDHX_PBC eCRF page, 
including Duration of PBC, 
Duration of Pruritus, PBC 
Diagnostic Criteria and Liver 
Transplant History. 
To calculate duration please 
use the date of onset of 
symptoms/diagnosis up to 
Screening, impute missing 
dates per the RAP rules for 
Medical History. Liver 
Transplant History will be 
reported as Yes/No. 
SAC 
1.35.  
Safety 
LB1 
Summary of Liver Chemistry at 
Screening by Country 
 
SAC 
1.36.  
Safety 
EX1 
Summary of Exposure by 
Treatment Group by Country 
For the Main Study Period – 
time on active treatment – 
from V3 to V6 (inclusive) 
SAC 
1.37.  
Safety 
Pop_T3 
Summary of Treatment 
Compliance (defined by e-diary) 
in Main Study Period (AM, PM 
and Total) by Country 
For the Main Study Period – 
compliance in terms of e-
diary for morning (AM), 
evening (PM) and Total – 
from V3 to V6 (inclusive). 
 
SAC 
1.38.  
Safety 
Pop_T3 
Summary of Treatment 
Compliance (defined by tablets 
taken) in Main Study Period (AM, 
PM and Total) by Country 
 
For the Main Study Period – 
compliance in terms of 
tablets taken for morning 
(AM), evening (PM) and Total 
– from V3 to V6 (inclusive) 
 
Footnote should read:  
Note: compliance 
calculations are based on the 
number of tablets dispensed 
and returned. 
SAC 
1.39.  
ITT 
COV1 
Summary of Covariates for 
Analysis of Mean Worst Itch 
Score by Country 
Summarise the following 
covariates, strata, and 
subgroups. 
Footnote “Risk of Disease 
Progression was used as 
assigned for randomisation   
See Section 5.4 for the full 
list 
SAC 
 
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12.12.5. 
Efficacy Tables 
 
Efficacy: Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Mean Worst Daily Itch Score 
2.1.  ITT 
Eff_T1 
Summary of Mean Worst Daily Itch Score. 
For V3 to V7 (inclusive) 
Note: N, n, Mean, SD, Min, Max, 
Median by Treatment Group and 
Visit 
SAC 
2.2.  ITT 
Eff_T1 
Summary of Change from Baseline in Mean 
Worst Daily Itch Score 
For V3 to V7 (inclusive) 
HLR 
2.3.  ITT 
Eff_T1 
Summary of Percent Change from Baseline in 
Mean Worst Daily Itch Score 
For V3 to V7 (inclusive) 
SAC 
2.4.  ITT 
Eff_T2 
Preliminary ANCOVA Analysis of Change from 
Baseline in Mean Worst Daily Itch Score at 
Week 16 (V6). 
Mean difference for each treatment 
group from placebo, along with 
mean difference between 90 mg 
BID and 180 mg QD. 
See Appendix 14 for updated shell 
Eff_T2 
HLR 
2.5.  ITT 
Eff_T3 
Preliminary Linear Model of Change from 
Baseline in Mean Worst Daily Itch Score at 
Week 16 (V6). 
Mean difference for each total daily 
dose level from placebo. Note 
inclusion of the 90 mg BID group 
(at total daily dose of 180 mg) 
depends on 2.4. 
SAC 
2.6.  ITT 
Eff_T3a 
See Appendix 14 
 
SAC 
2.7.  ITT 
Eff_T4a 
(for 
ANCOVA) 
or Eff_T4b 
Primary Analysis of Change from Baseline in 
Mean Worst Daily Itch Score at Week 16 (V6). 
This will only be displayed for the 
final chosen model (e.g. Emax 4-
parameter, Emax 3-parameter, 
ANCOVA, Linear Model, Power 
Model). 
If the ANCOVA model is the best 
model then this will be done for 
each treatment group in the study, 
otherwise it will be for total daily 
doses in the study.  
 
Programming Note: Please see 
updated shell Eff_T4c under 
Appendix 14. 
HLR 
2.8.  ITT 
EFF_T18 
T-test analysis Change from Baseline in Mean 
Worst Daily Itch Score at Week 16 (V6) 
T-test analysis comparison 
between placebo and each dose 
level 
SAC 
2.9.  PP 
Eff_T1 
Summary of Mean Worst Daily Itch Score. 
For V3 to V7 (inclusive) 
SAC 
2.10. PP 
Eff_T1 
Summary of Change from Baseline in Mean 
Worst Daily Itch Score. 
For V3 to V7 (inclusive) 
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2.11. PP 
Eff_T4a 
(ANCOVA) 
or Eff_T4b 
Analysis of Change from Baseline in Mean 
Worst Daily Itch Score at Week 16 (V6). 
The final model chosen as part of 
the model selection process for the 
ITT population will be fitted using 
the PP population. 
 
This will only be displayed for the 
final chosen model (e.g. Emax 4-
parameter, Emax 3-parameter, 
ANCOVA, Linear Model, Power 
Model). 
If the ANCOVA model is the best 
model then this will be done for 
each treatment group in the study.  
SAC  
2.12. ITT 
Eff_T7 
MMRM Analysis of Change from Baseline in 
Mean Worst Daily Itch Score for each 
Treatment Group. 
This will be done using data Visits 
4 -7. This will be done for each 
treatment group. 
Mean difference for each treatment 
group from placebo at each visit as 
well as mean difference between 
90 mg BID and 180 mg QD 
treatment groups. 
SAC 
2.13. ITT 
Eff_T8 
Analysis of Change from Baseline in Mean 
Worst Daily Itch Score at Week 16 (V6). 
ANCOVA Investigation of Risk Group. 
The model fitted here will include 
Risk Group, Treatment Group and 
Risk Group-Treatment Group 
interaction 
SAC 
2.14. ITT 
Eff_T14 
Analysis of Change from Baseline in Mean 
Worst Daily Itch Score at Week 16 (V6). 
Estimated Bias Associated with Ignoring 
Impact of Risk Group 
ONLY if Risk Group is significant in 
ANCOVA 
SAC 
2.15. ITT 
Eff_T15 
Analysis of Change from Baseline in Mean 
Worst Daily Itch Score at Week 16 (V6). 
ANCOVA Results: Impact of covariates 
Results for ANCOVA models fitting 
each covariate in Section 5.4 one 
at a time will be displayed. 
SAC 
Itch Responders  
2.16. ITT 
Eff_T9 
Summary of Mean Worst Daily Itch 
Responders 
Frequency and Percentage of 
responders. 
The three definitions should be 
shown in the one table. 
For V4 to V7 (inclusive) 
HLR 
2.17. ITT 
Eff_T10 
Logistic Regression Analysis of Mean Worst 
Daily Itch Responders at Week 16 (V6) 
Odds of response at Week 16, and 
odds ratio of reaching responder 
criteria for each treatment group 
vs. placebo, for each placebo 
definition. 
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Responder Days 
2.18. ITT 
Eff_T1 
Summary of Responder Days in Worst Daily 
Itch During the Main Study Period 
By treatment group.  
Include all 3 responder definitions 
in one table with column added to 
left of table to identify the response 
definition 
1) Worst Daily Itch < 4 
2) Improvement in Mean 
Worst Daily Itch from 
Baseline ≥ 2 
3) Improvement in Worst 
Daily Itch from Baseline 
≥30% 
Note: Percentage and number of 
Days of Responder Days in Mean 
Worst Daily Itch: number of days 
response V3+1 and V6-1/ number 
of days mean worst daily itch 
scores available 
SAC 
2.19. ITT 
Eff_T4a 
ANCOVA Analysis of Responder Days in 
Mean Worst Daily Itch at Week 16 (V6) 
Include all 3 responder definitions 
in one table with column added to 
left of table to identify the response 
definition 
1) Mean Worst Daily Itch < 
4 
2) Improvement in Mean 
Worst Daily Itch from 
Baseline ≥ 2 
3) Improvement in Mean 
Worst Daily Itch from 
Baseline ≥30% 
Note: Percentage of Responder 
Days in Mean Worst Daily Itch: 
number of days response V3+1 
and V6-1/ number of days mean 
worst daily itch scores available 
Programming notes: please 
remove number of days 
parameter and keep %of days 
only for this table. 
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Time to Worsening of Mean Worst Daily Itch 
2.20. Responders 
(>=2 point 
improvement) 
Eff_T1 
Summary of Time to Worsening of Mean Worst 
Daily Itch following Visit 6 in those that have 
improved between Baseline and Visit 6. 
Footnotes as below:  
Note: Improvement is defined as 
those that have a change from 
baseline in mean worst daily itch of 
at least -2. 
Note: A participant is defined as 
worsened at the time their rolling 
average Mean Worst Daily Itch is 
at least 2 higher than their Mean 
Worst Daily Itch at Visit 6. 
 
Note: Treatment groups are only 
included in this analysis if they 
consist of at least 8 participants. 
SAC 
2.21. Responders 
(>=2 point 
improvement)  
TTE7 
Time to Event Analysis for Time to Worsening 
of Mean Worst Daily Itch following Visit 6. 
Instructions on how to derive the 
time to worsening is provided in the 
RAP. 
SAC 
Other eDiary itch questions 
2.22. ITT 
Eff_T1 
Summary of Mean Daily Sleep Score 
Footnote: 
Note: Mean Daily Sleep Score is 
defined as the average of the daily 
sleep scores provided in the 7 days 
prior to the relevant visit. 
SAC 
2.23. ITT 
Eff_T1 
Summary of Change from Baseline in Mean 
Daily Sleep Score 
Note: Mean Daily Sleep Score is 
defined as the average of the daily 
sleep scores provided in the 7 days 
prior to the relevant visit. 
SAC 
2.24. ITT 
Eff_T1 
Summary of Mean Daily Fatigue Score 
Note: Mean Daily Fatigue Score is 
defined as the average of the daily 
fatigue scores provided in the 7 
days prior to the relevant visit. 
SAC 
2.25. ITT 
Eff_T1 
Summary of Change from Baseline in Mean 
Daily Fatigue Score 
Note: Mean Daily Fatigue Score is 
defined as the average of the daily 
fatigue scores provided in the 7 
days prior to the relevant visit. 
SAC 
2.26. ITT 
Eff_T1 
Summary of Mean Overall Itch Score. 
Footnote: Note: Mean Overall 
Itching Score is defined as the 
average of the mean of the 
morning and evening overall itching 
scores provided in the 7 days prior 
to the relevant visit. 
SAC 
2.27. ITT 
Eff_T1 
Summary of Change from Baseline in Mean 
Overall Itch Score 
Note: Mean Overall Itch Score is 
defined as the average of the mean 
of the morning and evening overall 
itch scores provided in the 7 days 
prior to the relevant visit. 
SAC 
2.28. ITT 
Eff_T4a 
ANCOVA Analysis of Change from Baseline in 
Mean Overall Itch, Mean Sleep and Mean 
Fatigue Scores at Week 16 (V6). 
This will be displayed for both the 
mean daily sleep and mean daily 
fatigue and mean overall itching 
(on 0-10 NRS) scores in one table, 
paginated by endpoint. 
SAC 
2.29. ITT 
Eff_T1 
Summary of Average Response to Categorical 
Itch Questions in eDiary (AM) 
 
 
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2.30. ITT 
Eff_T1 
Summary of Change from Baseline in Average 
Response to Categorical Itch Questions in 
eDiary (AM) 
Between Baseline (V3) and Week 
16 (V6) 
SAC 
2.31. ITT 
Eff_T13 
Summary of Most Frequent Response for 
Categorical Itch Questions in eDiary (AM) 
Repeat, paginated by question with 
full question in sub-title, for all 
questions in e-diary (AM) that are 
not on 0-10 NRS. 
Footnote: Most Frequent Response 
is taken as the mode of responses 
for each participant in the 7 days 
prior to each Visit. 
Footnote: If there is more than one 
mode the Most Frequent Response 
is taken to be the worst of the 
modes. 
SAC 
2.32. ITT 
Eff_T17 
Shift Table of Most Frequent Response to 
Categorical Itch Questions in eDiary (AM) 
Between Baseline (V3) and Week 
16 (V6) 
Footnote: Most Frequent Response 
is taken as the mode of responses 
for each participant in the 7 days 
prior to each Visit. 
Footnote: If there is more than one 
mode the Most Frequent Response 
is taken to be the worst of the 
modes. 
SAC 
2.33. ITT 
Eff_T1 
Summary of Average Response to Categorical 
Itch Questions in eDiary (PM) 
Repeat, paginated by question with 
full question in sub-title, for all 
questions in e-diary (PM) that are 
not on 0-10 NRS. 
SAC 
2.34. ITT 
Eff_T1 
Summary of Change from Baseline in Average 
Response to Categorical Itch Questions in 
eDiary (PM) 
Between Baseline (V3) and Week 
16 (V6) 
SAC 
2.35. ITT 
Eff_T13 
Summary of Most Frequent Response to 
Categorical Itch Questions in eDiary (PM) 
Repeat, paginated by question with 
full question in sub-title, for all 
questions in e-diary (PM) that are 
not on 0-10 NRS. 
Footnote: Most Frequent Response 
is taken as the mode of responses 
for each participant in the 7 days 
prior to each Visit. 
Footnote: If there is more than one 
mode the Most Frequent Response 
is taken to be the worst of the 
modes. 
SAC 
2.36. ITT 
Eff_T17 
Shift Table of Most Frequent Response to 
Categorical Itch Questions in eDiary (PM) 
Between Baseline (V3) and Week 
16 (V6) 
Footnote: Most Frequent Response 
is taken as the mode of responses 
for each participant in the 7 days 
prior to each Visit. 
Footnote: If there is more than one 
mode the Most Frequent Response 
is taken to be the worst of the 
modes. 
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2.37. ITT 
Eff_T1 
Summary of Itch, Fatigue and Sleep at Follow-
up (Visit 8) 
Table should include a summary of 
the scores give to worst itching, 
itching interfere with sleep and 
worst fatigue at the follow-up 
telephone call. 
SAC 
2.38. ITT 
Eff_T13 
Summary of Response to Categorical Itch 
Questions at Follow-up (Visit 8) 
Table should include counts and 
percentages of the responses to 
the categorical questions asked 
during the follow-up phone call 
SAC 
Validated Questionnaires 
5-D Itch 
2.39. ITT 
Eff_T1 
Summary of 5-D Itch Scores. 
By treatment group and visit 
Note: N, n, Mean, SD, Min, Max, 
Median 
Paginated by domain, with domain 
(as below) in subtitle. Only for V2, 
V3, V6 and V7. 
Duration, Degree, Direction, 
Disability, Distribution, Total 5-D 
Itch Score 
SAC 
2.40. ITT 
Eff_T1 
Summary of Change from Baseline in 5-D Itch 
Scores. 
Paginated by domain, with domain 
(as below) in subtitle. Only for, V6 
and V7. 
Duration, Degree, Direction, 
Disability, Distribution, Total 5-D 
Itch Score 
SAC 
2.41. ITT 
Eff_T4a 
ANCOVA Analysis of Change from Baseline in 
5-D Itch at Week 16 (V6). 
This will be displayed for each of 
the 5-D Itch domains as well as the 
overall score (with 95% CI). 
SAC 
PBC-40 
2.42. ITT 
Eff_T1 
Summary of PBC-40 Scores 
Paginated by domain, with domain 
(as below) in subtitle.  
Itch, Fatigue, Symptoms, 
Cognitive, Social, Emotional 
For V1 to V7 (inclusive) 
 
Note: Summary (N, n, Mean, SD, 
Min, Max, Median) by Treatment 
Group 
SAC 
2.43. ITT 
Eff_T1 
Summary of Change from Baseline in PBC-40 
Scores 
Paginated by domain, with domain 
(as below) in subtitle.  
Itch, Fatigue, Symptoms, 
Cognitive, Social, Emotional 
For V4 to V7 (inclusive) 
Note: Summary (N, n, Mean, SD, 
Min, Max, Median) by Treatment 
Group 
SAC 
2.44. ITT 
Eff_T4a 
ANCOVA Analysis of Change from Baseline in 
PBC-40 at Week 16 (V6). 
This will be displayed for each of 
the 6 PBC-40 domains.  
SAC 
Other PROs 
2.45. ITT 
Eff_T16 
Summary of Responses to EQ-5D-5L 
Questions. 
By Treatment Group and Visit 
5 questions, 5 responses (no, 
slight, moderate, severe, unable 
to).  
For V2, V3 and V6 
Note: N, n, Mean, SD, Min, Max, 
Median 
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2.46. ITT 
Eff_T1 
Summary of Derived EQ-5D-5L Utility Index 
Score by severity of Itch score at Baseline. 
By Treatment Group and Visit 
For V2, V3 and V6  
Note: N, n, Mean, SD, Min, Max, 
Median 
SAC 
2.47. ITT 
Eff_T1 
Summary of Change from Baseline in Derived 
EQ-5D-5L Utility Index Score by Severity Itch 
score at Baseline. 
By Treatment Group and Visit 
For V6 
Note: N, n, Mean, SD, Min, Max, 
Median 
SAC 
2.48. ITT 
Eff_T1 
Summary of EQ-5D-5L VAS. 
By Treatment Group and Visit 
For V2, V3 and V6 
Note: N, n, Mean, SD, Min, Max, 
Median 
SAC 
2.49. ITT 
Eff_T1 
Summary of Change from Baseline in EQ-5D-
5L VAS. 
For V6 
Note: N, n, Mean, SD, Min, Max, 
Median 
SAC 
2.50. ITT 
Eff_T4a 
ANCOVA Analysis of Change from Baseline in 
Derived EQ-5D-5L Utility Index Score and EQ-
5D-5L VAS at Week 16 (V6). 
LS Mean Change from Baseline 
with 95% CI for both EQ-5D-5L 
utility index score and VAS 
SAC 
2.51. ITT 
Eff_T16 
Summary of PGI-S. 
PGI-S should be shown from V2 to 
V7 (inclusive). Show counts and 
percentages for each response. 
 
SAC 
2.52. ITT 
Eff_T17 
Shift Table of Change from Baseline in PGI-S. 
Show counts and percentages in 
each response pair (i.e. Severe at 
baseline, slight at Visit 4) 
From V4 to V7 
SAC 
2.53. ITT 
Eff_T1 
Summary of Derived PGI-S score. 
PGI-S should be shown from V2 to 
V7 (inclusive). 
 
SAC 
2.54. ITT 
Eff_T1 
Summary of Change from Baseline in Derived 
PGI-S Score. 
From V4 to V7 
SAC 
2.55. ITT 
Eff_T4a 
ANCOVA Analysis of LS Mean Change from 
Baseline in PGI-S at Week 16 (V6) with 95% 
Confidence Intervals. 
 
SAC 
2.56. ITT 
Eff_T16 
Summary of PGI-C 
PGI-C should be shown from V3 to 
V7 (inclusive). 
 
SAC 
2.57. ITT 
Eff_T1 
Summary of Derived PGI-C Score. 
PGI-C should be shown from V3 to 
V7 (inclusive). 
 
SAC 
2.58. ITT 
Eff_T4a 
ANCOVA Analysis of PGI-C at Week 16 (V6). 
LS Mean PGI-C score (with 95% 
CI), Mean difference for each 
treatment group from Placebo, 
along with mean difference 
between 90 mg BID and 180 mg 
QD, for the derived PGI-C score 
(with 95% CI) 
SAC 
2.59. ITT 
Eff_T1 
Summary of BDI-II Score.  
For V1, V3 and V6 
Note: N, n, Mean, SD, Min, Max, 
Median 
SAC 
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2.60. ITT 
Eff_T1 
Summary of Change from Baseline in BDI-II 
Score. 
For V6 
SAC 
2.61. ITT 
Eff_T4a 
ANCOVA Analysis of Change from Baseline in 
BDI-II Score at Week 16 (V6). 
 
SAC 
2.62. ITT 
Eff_T12 
Summary of Participant Treatment Experience 
Assessment (PTEA) on Treatment Benefits 
and Disadvantages at Week 16 (V6) 
 
HLR 
High Risk Population – Risk Responders 
2.63. High Risk 
Eff_T9 
Summary of Disease Progression Risk 
Responders. 
For V2 to V7 (inclusive). 
Footnotes: 
Note: Participants were assigned to 
the High Risk Group at 
randomisation based on lab results 
at Visit 2. 
Note: Risk Responder criteria is 
ALP < 1.67 * ULN  AND  total 
bilirubin ≤ ULN at the relevant Visit. 
 
SAC 
2.64. High Risk 
Eff_T10 
Logistic Regression Analysis of Disease 
Progression Risk at Week 16 (V6). 
Add footnotes: 
Note: Participants were assigned to 
the High Risk Group at 
randomisation based on lab results 
at Visit 2. 
Note: Disease Progression Risk 
Responder criteria is  ALP at Week 
16 (V6) < 1.67 * ULN  AND  total 
bilirubin at Week 16 (V6)  ≤ ULN.  
 
SAC 
2.65. High Risk 
Eff_T20 
ANCOVA Analysis of Percentage Change from 
Baseline in Serum ALP Concentrations at 
Week 16 (V6) 
Include only placebo,180QD, and 
90BID. 
Use BMI as covariate in the Model 
to adjust for. 
 
HLR 
High Risk Population - Markers of Disease  
2.66. High Risk 
LB1 
Summary of Markers of Disease  
Markers of Disease are:  
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR 
SAC 
2.67. High Risk 
LB1 
Summary of Change from Baseline (V3) at 
Week 16 (V6) in Markers of Disease. 
Markers of Disease are:  
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR 
HLR 
2.68. High Risk 
Eff_T4a 
ANCOVA Analysis of Change from Baseline in 
Markers of Disease at Week 16 (V6). 
This will include the difference of all 
treatment groups to placebo and 
the difference between 90 mg BID 
and 180 mg QD dose groups. 
Markers of Disease are:  
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR 
SAC 
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Restricted High Risk Population – Risk Responders 
2.69. Restricted 
High Risk 
Eff_T9 
Summary of Disease Progression Risk 
Responders. 
For V2 to V7 (inclusive). 
Footnotes: 
Note: Those assigned to High Risk 
strata for randomisation who were 
still at High Risk at Baseline 
(confirmed as at High Risk at V2 
and V3 based on lab results). 
Note: Risk Responder criteria is 
ALP < 1.67 * ULN  AND  total 
bilirubin ≤ ULN at the relevant Visit. 
 
SAC 
2.70. Restricted 
High Risk 
Eff_T10 
Logistic Regression Analysis of Disease 
Progression Risk at Week 16 (V6). 
Add footnotes: 
Note: Those assigned to High Risk 
strata for randomisation who were 
still at High Risk at Baseline (High 
Risk at V2 and V3 based on lab 
results). 
Note: Disease Progression Risk 
Responder criteria is ALP at Week 
16 (V6) < 1.67 * ULN AND total 
bilirubin at Week 16 (V6) ≤ ULN.  
 
SAC 
Restricted High Risk Population - Markers of Disease 
2.71. Restricted 
High Risk 
LB1 
Summary of Change from Baseline (V3) at 
Week 16 (V6) in Markers of Disease 
Note: Those assigned to High Risk 
strata for randomisation who were 
still at High Risk at Baseline (High 
Risk at V2 and V3 based on lab 
results). 
Markers of Disease are:  
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR 
SAC 
2.72. Restricted 
High Risk 
Eff_T4a 
ANCOVA Analysis of Change from Baseline in 
Markers of Disease at Week 16 (V6). 
Note: Those assigned to High Risk 
strata for randomisation who were 
still at High Risk at Baseline (High 
Risk at V2 and V3 based on lab 
results). 
This will include the difference of all 
treatment groups to placebo and 
the difference between 90 mg BID 
and 180 mg QD dose groups. 
Markers of Disease are:  
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR 
SAC 
 
 
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Country 
Mean Worst Daily Itch 
2.73. 
ITT 
Eff_T1 
Summary of Mean Worst Daily Itch by Country 
For V3 to V7 (inclusive) 
 
SAC 
2.74. 
ITT 
Eff_T1 
Summary of Change from Baseline in Mean 
Worst Daily Itch by Country 
For V3 to V7 (inclusive) 
SAC 
Itch Responders  
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2.75. 
ITT 
Eff_T9 
Summary of Mean Worst Daily Itch Responders 
by Country 
The three definitions should be 
shown in the one table. 
For V4 to V7 (inclusive) 
SAC 
Responder Days 
2.76. 
ITT 
Eff_T1 
Summary of Responder Days in Mean Worst 
Daily Itch During the Main Study Period by 
Country 
By treatment group and visit 
Include all 3 responder definitions in 
one table with column added to left 
of table to identify the response 
definition 
Note: Percentage of Responder 
Days in Mean Worst Daily Itch: 
number of days response V3+1 and 
V6-1/ number of days mean worst 
daily itch scores available 
SAC 
Time to Worsening of Mean Worst Daily Itch 
2.77. 
Responders 
(>=2 point 
improveme
nt) 
Eff_T1 
Summary of Time to Worsening of Itch 
following Visit 6 in those that have improved 
between Baseline and Visit 6 by Country 
Footnotes as below:  
Note: Improvement is defined as 
those that have a change from 
baseline in mean worst daily itch of 
at least -2. 
Note: A participant is defined as 
worsened at the time their rolling 
average Mean Worst Daily Itch is at 
least 2 higher than their Mean Worst 
Daily Itch at Visit 6. 
 
Note: Treatment groups are only 
included in this analysis if they 
consist of at least 8 participants. 
SAC 
Other eDiary itch questions 
2.78. 
ITT 
Eff_T1 
Summary of Mean Daily Sleep Score by 
Country 
Footnote: 
Note: Mean Daily Sleep Score is 
defined as the average of the daily 
sleep scores provided in the 7 days 
prior to the relevant visit. 
SAC 
2.79. 
ITT 
Eff_T1 
Summary of Change from Baseline in Mean 
Daily Sleep Score by Country 
Note: Mean Daily Sleep Score is 
defined as the average of the daily 
sleep scores provided in the 7 days 
prior to the relevant visit. 
SAC 
2.80. 
ITT 
Eff_T1 
Summary of Mean Daily Fatigue Score by 
Country 
Note: Mean Daily Fatigue Score is 
defined as the average of the daily 
fatigue scores provided in the 7 
days prior to the relevant visit. 
SAC 
2.81. 
ITT 
Eff_T1 
Summary of Change from Baseline in Mean 
Daily Fatigue Score by Country 
Note: Mean Daily Fatigue Score is 
defined as the average of the daily 
fatigue scores provided in the 7 
days prior to the relevant visit. 
SAC 
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2.82. 
ITT 
Eff_T1 
Summary of Mean Overall Itch Score by 
Country 
Footnote: Note: Mean Overall 
Itching Score is defined as the 
average of the mean of the morning 
and evening overall itching scores 
provided in the 7 days prior to the 
relevant visit. 
SAC 
2.83. 
ITT 
Eff_T1 
Summary of Change from Baseline in Mean 
Overall Itch Score by Country 
Note: Mean Overall Itch Score is 
defined as the average of the mean 
of the morning and evening overall 
itch scores provided in the 7 days 
prior to the relevant visit. 
SAC 
2.84. 
ITT 
Eff_T13 
Summary of Average Response to Categorical 
Itch Questions in eDiary (AM) by Country 
 
 
SAC 
2.85. 
ITT 
Eff_T13 
Summary of Most Frequent Response for 
Categorical Itch Questions in eDiary (AM) by 
Country 
Repeat, paginated by question with 
full question in sub-title, for all 
questions in e-diary (AM) that are 
not on 0-10 NRS. 
Footnote: Most Frequent Response 
is taken as the mode of responses 
for each participant in the 7 days 
prior to each Visit. 
Footnote: If there is more than one 
mode the Most Frequent Response 
is taken to be the worst of the 
modes. 
SAC 
2.86. 
ITT 
Eff_T13 
Summary of Average Response to Categorical 
Itch Questions in eDiary (PM) by Country 
Repeat, paginated by question with 
full question in sub-title, for all 
questions in e-diary (PM) that are 
not on 0-10 NRS. 
SAC 
2.87. 
ITT 
Eff_T13 
Summary of Most Frequent Response to 
Categorical Itch Questions in eDiary (PM) by 
Country 
Repeat, paginated by question with 
full question in sub-title, for all 
questions in e-diary (PM) that are 
not on 0-10 NRS. 
Footnote: Most Frequent Response 
is taken as the mode of responses 
for each participant in the 7 days 
prior to each Visit. 
Footnote: If there is more than one 
mode the Most Frequent Response 
is taken to be the worst of the 
modes. 
SAC 
2.88. 
ITT 
Eff_T1 
Summary of Itch, Fatigue and Sleep at Follow-
up (Visit 8) by Country 
Table should include a summary of 
the scores give to worst itching, 
itching interfere with sleep and 
worst fatigue at the follow-up 
telephone call. 
SAC 
2.89. 
ITT 
Eff_T13 
Summary of Response to Categorical Itch 
Questions at Follow-up (Visit 8) by Country 
Table should include counts and 
percentages of the responses to the 
categorical questions asked during 
the follow-up phone call 
SAC 
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Validated Questionnaires 
5-D Itch 
2.90. 
ITT 
Eff_T1 
Summary of 5-D Itch Scores. by Country 
By treatment group and visit 
Note: N, n, Mean, SD, Min, Max, 
Median 
Paginated by domain, with domain 
(as below) in subtitle. Only for V2, 
V3, V6 and V7. 
Duration, Degree, Direction, 
Disability, Distribution, Total 5-D Itch 
Score 
SAC 
2.91. 
ITT 
Eff_T1 
Summary of Change from Baseline in 5-D Itch 
Scores by Country 
Paginated by domain, with domain 
(as below) in subtitle. Only for, V6 
and V7. 
Duration, Degree, Direction, 
Disability, Distribution, Total 5-D Itch 
Score 
SAC 
PBC-40 
2.92. 
ITT 
Eff_T1 
Summary of PBC-40 Scores by Country 
Paginated by domain, with domain 
(as below) in subtitle.  
Itch, Fatigue, Symptoms, Cognitive, 
Social, Emotional 
For V1 to V7 (inclusive) 
 
Note: Summary (N, n, Mean, SD, 
Min, Max, Median) by Treatment 
Group 
SAC 
2.93. 
ITT 
Eff_T1 
Summary of Change from Baseline in PBC-40 
Scores by Country 
Paginated by domain, with domain 
(as below) in subtitle.  
Itch, Fatigue, Symptoms, Cognitive, 
Social, Emotional 
For V4 to V7 (inclusive) 
Note: Summary (N, n, Mean, SD, 
Min, Max, Median) by Treatment 
Group 
SAC 
Other PROs 
2.94. 
ITT 
Eff_T16 
Summary of Responses to EQ-5D-5L 
Questions by Country 
By Treatment Group and Visit 
5 questions, 5 responses (no, slight, 
moderate, severe, unable to).  
For V2, V3 and V6 
Note: N, n, Mean ,SD, Min, Max, 
Median 
SAC 
2.95. 
ITT 
Eff_T1 
Summary of Derived EQ-5D-5L Utility Index 
Score by severity of Itch score at Baseline by 
Country 
By Treatment Group and Visit 
For V2, V3 and V6 
Note: N, n, Mean ,SD, Min, Max, 
Median 
SAC 
2.96. 
ITT 
Eff_T1 
Summary of Change from Baseline in Derived 
EQ-5D-5L Utility Index Score by severity of Itch 
score at Baseline by Country 
By Treatment Group and Visit 
For V6 
Note: N, n, Mean ,SD, Min, Max, 
Median 
SAC 
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2.97. 
ITT 
Eff_T1 
Summary of EQ-5D-5L VAS by Country 
By Treatment Group and Visit 
For V2, V3 and V6 
Note: N, n, Mean ,SD, Min, Max, 
Median 
SAC 
2.98. 
ITT 
Eff_T1 
Summary of Change from Baseline in EQ-5D-
5L VAS by Country 
For V6 
Note: N, n, Mean ,SD, Min, Max, 
Median 
SAC 
2.99. 
ITT 
Eff_T16 
Summary of PGI-S by Country 
PGI-S should be shown from V2 to 
V7 (inclusive). Show counts and 
percentages for each response. 
 
SAC 
2.100. ITT 
Eff_T17 
Shift Table of Change from Baseline in PGI-S 
by Country 
Show counts and percentages in 
each response pair (i.e. Severe at 
baseline, slight at Visit 4) 
From V4 to V7 
SAC 
2.101. ITT 
Eff_T1 
Summary of Derived PGI-S score by Country 
PGI-S should be shown from V2 to 
V7 (inclusive). 
 
SAC 
2.102. ITT 
Eff_T1 
Summary of Change from Baseline in Derived 
PGI-S Score by Country 
From V4 to V7 
SAC 
2.103. ITT 
Eff_T16 
Summary of PGI-C by Country 
PGI-C should be shown from V3 to 
V7 (inclusive). 
 
SAC 
2.104. ITT 
Eff_T1 
Summary of Derived PGI-C Score by Country 
PGI-C should be shown from V3 to 
V7 (inclusive). 
 
SAC 
2.105. ITT 
Eff_T1 
Summary of BDI-II Score by Country 
For V1, V3 and V6 
Note: N, n, Mean, SD, Min, Max, 
Median 
SAC 
2.106. ITT 
Eff_T1 
Summary of Change from Baseline in BDI-II 
Score by Country 
For V6 
SAC 
2.107. ITT 
Eff_T12 
Summary of Participant Treatment Experience 
Assessment (PTEA) on Treatment Benefits and 
Disadvantages at Week 16 (V6) by Country 
 
SAC 
High Risk Population – Risk Responders 
2.108. High Risk 
Eff_T9 
Summary of Disease Progression Risk 
Responders by Country 
For V2 to V7 (inclusive). 
Footnotes: 
Note: Participants were assigned to 
the High Risk Group at 
randomisation based on lab results 
at Visit 2. 
Note: Risk Responder criteria is 
ALP < 1.67 * ULN  AND  total 
bilirubin ≤ ULN at the relevant Visit. 
 
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High Risk Population - Markers of Disease 
2.109. High Risk 
LB1 
Summary of Markers of Disease by Country 
Markers of Disease are:  
ALP, ALT, AST, GGT, Total bilirubin 
and albumin concentrations and 
PT/INR 
SAC 
2.110. High Risk 
LB1 
Summary of Change from Baseline (V3) at 
Week 16 (V6) in Markers of Disease by Country 
Markers of Disease are:  
ALP, ALT, AST, GGT, Total bilirubin 
and albumin concentrations and 
PT/INR 
SAC 
 
 
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12.12.6. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Mean Worst Daily Itch 
2.1.  
ITT 
Eff_F18 
Plot of Rolling Average Worst Daily Itch 
Score against Study Day by Treatment 
Group 
From Visit 2 (Day 1) to Visit 7 
(end of final study period). 
 
Note: 
The rolling average is calculated 
as the average worst daily itch 
during the 7 days prior to each 
study day, within each study 
period.  
SAC 
2.2.  
ITT 
Eff_F1 
Individual Mean Worst Daily Itch against Day: 
with AM and PM Itch for 7 Days Prior to Each 
Visit (V3 to V7) by Treatment Group 
with Participant ID in plot subtitle 
not in the title. 
Scatterplot of 7 days scores (AM 
and PM) prior to visit, with 
different symbols/colours for AM 
and PM.  
Overlay the mean worst daily 
itch for each Visit, spanning the 
7 days that contribute to it on the 
plot. 
Add ref line at the day of each 
Visit and label it with appropriate 
visit number 
This should include Visits 3 to 7 
inclusive. 
  
SAC 
2.3.  
ITT 
Eff_F2 
Spaghetti Plot of Change from Baseline in 
Mean Worst Daily Itch against Visit: Panelled 
by Treatment Group and Risk Group.  
Do not include legend 
SAC 
2.4.  
ITT 
Eff_F3 
Boxplot of Change from Baseline in Mean 
Worst Daily Itch grouped by Treatment 
Group: Panelled by Visit 
Visits 4-7 inclusive. Include ref 
line at y=0 
SAC 
2.5.  
ITT 
Eff_F4 
Line Plot of Mean Treatment Group Change 
from Baseline in Mean Worst Daily Itch 
against Visit 
Line for each treatment group. 
Include markers to differentiate 
BID and QD dosing. Visits 4-7 
inclusive. Include ref line at y=0 
SAC 
2.6.  
ITT 
Eff_F4 
Line Plot of Mean Treatment Group Percent 
Change from Baseline Mean Worst Daily Itch 
against Visit 
Line for each treatment group. 
Include markers to differentiate 
BID and QD dosing. Visits 4-7 
inclusive. Include ref line at y=0 
SAC 
2.7.  
ITT 
Eff_F5 
Preliminary Checks: ANCOVA: Estimated 
Mean Difference from Placebo in Change 
from Baseline in Mean Worst Daily Itch at 
Week 16 (V6) with 95% Confidence Intervals. 
Include ref line at y=0 
SAC 
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Efficacy: Figures 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.8.  
ITT 
Eff_F6 
Preliminary Checks: Linear Model: Estimated 
Mean Difference from Placebo in Change 
from Baseline in Mean Worst Daily Itch at 
Week 16 (V6) with 95% Confidence Intervals 
Against Total Daily Dose. 
Include ref line at y=0 
SAC 
2.9.  
ITT 
Eff_F6 
See Appendix 14 
 
SAC 
2.10. 
ITT 
Eff_F7a or 
Eff_F7b 
 
Estimated Mean Difference from Placebo in 
Change from Baseline in Mean Worst Daily 
Itch at Week 16 (V6) with 95% Confidence 
Intervals Against Total Daily Dose. 
If the final chosen model is 
ANCOVA then the x-axis will be 
categorical and will include the 
treatment groups (as per 
Eff_F7a) 
Alternatively the x-axis will be 
continuous and will include the 
total daily dose levels used in 
the study (as per Eff_F7b). 
Include ref line at y=0 
SAC 
2.11. 
ITT 
Eff_F8 
Fitted Dose-Response Model for Change 
from Baseline in Mean Worst Daily Itch with 
95% Prediction Intervals Against Total Daily 
Dose. 
Include ref line at y=0 
Change from baseline at Week 
16 will be overlaid as a scatter 
plot. 
SAC 
2.12. 
ITT 
Eff_F8 
Fitted Dose-Response Model for Change 
from Baseline in Mean Worst Daily Itch with 
95% Prediction Intervals Against Total Daily 
Dose (QD Dose levels only). 
Include ref line at y=0 
Change from baseline at Week 
16 will be overlaid as a scatter 
plot QD Dose Levels only) 
SAC 
2.13. 
ITT 
Eff_F8 
Fitted Dose-Response Model for Change 
from Baseline in Mean Worst Daily Itch with 
95% Prediction Intervals Against Total Daily 
Dose (BID Dose Levels only).  
Include ref line at y=0 
Change from baseline at Week 
16 will be overlaid as a scatter 
plot BID Dose Levels only. 
SAC 
2.14. 
ITT 
Eff_F8 
Fitted Dose-Response Model for Change 
from Baseline in Mean Worst Daily Itch with 
95% Prediction Intervals Against Total Daily 
Dose (overlay of QD and BID Dose). 
Include ref line at y=0 
Change from baseline at Week 
16 will be overlaid as a scatter 
plot Overlay of QD and BID 
Dose levels on one figure (2 
curves overlay). 
HLR 
2.15. 
ITT 
Eff_F8 
Fitted Dose-Response Model for Change 
from Baseline in Mean Worst Daily Itch with 
95% Prediction Intervals Against Total Daily 
Dose (Convert 180 QD Dose level to 90 BID 
Dose level). 
Include ref line at y=0 
Change from baseline at Week 
16 will be overlaid as a scatter 
plot convert 180 QD dose level 
to 90 BID does level. 
SAC 
2.16. 
ITT 
Eff_F12 
MMRM: Mean Difference from Placebo in 
Change from Baseline in Mean Worst Daily 
Itch at Week 16 (V6) with 95% Confidence 
Intervals 
Include ref line at y=0 
SAC 
2.17. 
ITT 
Eff_F17 
Estimated bias associated with ignoring the 
impact of Risk Group 
ONLY if Risk Group is significant 
in ANCOVA 
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Efficacy: Figures 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.18. 
ITT 
Eff_F20 
Pie Chart of Baseline Itch category and at 
Week 16 (V6) by Treatment Group 
. 
Use itch category as by 
variables Repeat figure by 
treatment group 
Programming notes: please add 
n (%), see shell for more details 
HLR 
2.19. 
ITT 
Eff_F22 
Line Plot of Mean ALP over the Main Study 
Period by Treatment Group 
Add a reference line at 125 and 
(N=) in addition to the treatment 
group in the legend 
x-axis is visit in weeks. 
 
SAC 
Itch Responders 
2.20. 
ITT 
Eff_F14 
Odds Ratio of Responder in Mean Worst 
Daily Itch at Week 16 (V6), vs. Placebo, with 
95% Confidence Intervals. 
Panelled by response definition 
SAC 
Itch Responder Days 
2.21. 
ITT 
Eff_F15 
Boxplot of Percentage of Responder Days in 
Mean Worst Daily Itch over Main Study 
Period. 
Include each of the 3 response 
definitions on one figure. 
Panelled by responder definition 
SAC 
2.22. 
ITT 
Eff_F7a 
Mean Difference from placebo in Percentage 
of Responder Days in Mean Worst Daily Itch 
over Main Study Period with 95% Confidence 
Intervals. 
Panelled by Responder 
definition 
SAC 
Time to Worsening of Mean Worst Daily Itch 
2.23. 
Responders 
(>=2 point 
improveme
nt)s 
TTE10 
Kaplan-Meier Plot of Time to Worsening of 
Mean Worst Daily Itch following Visit 6. 
 
SAC 
Other eDiary itch questions 
2.24. 
ITT 
Eff_F4 
Line Plot of Mean Sleep, Fatigue and Overall 
Itch Scores (NRS) against Visit for each 
Treatment Group 
Line for each treatment group. 
Include markers. 
Visits 3-7 inclusive 
Panelled by endpoint – one plot 
each for Mean Sleep, mean 
fatigue and mean overall itch 
within one page. 
SAC 
2.25. 
ITT 
Eff_F7a 
Mean Difference from placebo in Change 
from Baseline in Sleep, Fatigue and Overall 
Itch Scores (NRS) at Week 16 (V6) with 95% 
Confidence Intervals. 
Change from baseline. 
Include Mean Sleep Score, 
Mean Fatigue Score and Mean 
Overall Itch on one page – 
panelled by endpoint 
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113 
 
Efficacy: Figures 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Validated Questionnaires 
5-D Itch 
2.26. 
ITT 
Eff_F16 
Boxplot of Change from Baseline in 5-D Itch 
Scores against Visit: Panelled by Domain 
Panelled by 5 5-D Itch domains 
and total score in a 2*3 grid (plot 
each Domain per page, since 
the scale differ per domain) 
SAC 
2.27. 
ITT 
Eff_7a 
Mean Difference from placebo in Change 
from Baseline in 5-D Itch at Week 16 (V6), 
with 95% Confidence Intervals. 
Change from baseline. 
Panelled by 5-D Itch domain and 
Total score in a 3*2 grid 
 
SAC 
PBC-40 
2.28. 
ITT 
Eff_F16 
Boxplot of PBC-40 Scores against Visit: 
Panelled by Domain 
Panelled by PBC-40 domain  
SAC 
2.29. 
ITT 
Eff_F7a 
Mean Difference from Placebo in Change 
from Baseline in PBC-40 Score at Week 16 
(V6), with 95% Confidence Intervals. 
Change from baseline. 
Panelled by PBC-40 domain 
SAC 
Other PROs 
2.30. 
ITT 
EFF_F4 
Line Plot of Derived EQ-5D-5L Utility Index 
Score against Visit. 
Different line for each treatment 
group 
SAC 
2.31. 
ITT 
Eff_F4 
Line Plot of EQ-5D-VAS against Visit. 
Different line for each treatment 
group 
SAC 
2.32. 
ITT 
Eff_F7a 
Mean Difference from Placebo in Change 
from Baseline in Derived EQ-5D-5L Utility 
Index Score and EQ-5D-5L VAS at Week 16 
(V6), with 95% Confidence Intervals. 
Change from baseline. 
Panel for each of the two scores 
SAC 
2.33. 
ITT 
Eff_F16 
Boxplot of PGI-S Scores by Visit and 
Treatment Group 
 
SAC 
2.34. 
ITT 
Eff_F13 
Bar Chart of PGI-C Response against Visit 
Percentage of Participants in 
each treatment group with each 
response – with a panel for each 
visit the score is available  
SAC 
2.35. 
ITT 
Eff_F16 
Boxplot of PGI-C Scores by Visit and 
Treatment Group 
 
SAC 
2.36. 
ITT 
Eff_F16 
Boxplot of BDI-II Scores against Visit 
 
SAC 
2.37. 
ITT 
Eff_F7a 
Mean Difference from Placebo in Change 
from Baseline in BDI-II at Week 16 (V6), with 
95% Confidence Intervals. 
Change from baseline. 
SAC 
High Risk Population – Risk Response 
2.38. 
High Risk 
Eff_F13 
Bar chart of Percentage of Responders in 
Disease Progression Risk at each Visit). 
Percentage of Responders.  
Y-axis range from 0-100%. 
SAC 
2.39. 
High Risk 
Eff_F14 
Odds Ratio of Response in Disease 
Progression Risk at Week 16 (V6), vs. 
Placebo, with 95% Confidence Intervals. 
 
SAC 
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Efficacy: Figures 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.40. 
High Risk 
LB11 
Line Plot of Markers of Disease against Visit. 
One page per patient – panelled 
plot with 3 plots 
1) ALP, AST, ALT, 
2)  GGT, Albumin, Total 
Bilirubin–  
3) PT/INR  
 
Plot 1 and 2 should use a 
different colour for each marker 
(should be set up in attribute 
map so colours are consistent 
across all Participants) 
The y-axis for plot 1 and 2 
should be marker/ULN, may be 
more appropriate for this axis to 
be displayed on the log-scale if it 
makes the data display clearer. 
The levels of clinical concern for 
each marker should be shown 
on the plot 
SAC 
2.41. 
High Risk 
LB9 
Boxplots of Markers of Disease against Visit. 
Boxplot of each marker of 
disease for each visit. 
Panel by Treatment Group 
One page per Marker  
Different colour for treatment 
group (set up an attribute map 
so colours are consistent) 
The y-axis will be the 
marker/ULN, may be more 
appropriate for this axis to be 
displayed on the log-scale if it 
makes the data display clearer. 
The levels of clinical concern 
should be shown as a line on the 
plot 
SAC 
2.42. 
High Risk 
Eff_F7a 
Mean Difference from Placebo in Change 
from Baseline in Markers of Disease at Week 
16 (V6) with 95% Confidence Intervals. 
Change from baseline. 
Panelled by marker 
SAC 
 
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Country 
2.43. ITT 
Eff_F19a 
or 
Eff_F19b 
 
Estimated Mean Difference from Placebo in 
Change from Baseline in Mean Worst Daily 
Itch at Week 16 (V6) with 95% Confidence 
Intervals Against Total Daily Dose by 
Country. 
If the final chosen model 
is ANCOVA then the x-
axis will be categorical 
and will include the 
treatment groups (as per 
Eff_F19a) 
Alternatively the x-axis 
will be continuous and 
will include the total daily 
dose levels used in the 
study (as per Eff_F19b). 
Include ref line at y=0. 
Programming notes: 
Change symbols to 
different shapes 
SAC 
Itch Responders 
2.44. ITT 
Eff_F19a 
Odds Ratio of Responder in Mean Worst 
Daily Itch at Week 16 (V6), vs. Placebo, with 
95% Confidence Intervals by Country. 
Panelled by response 
definition. Eff_F19a but 
for odds ratio 
Programming notes: 
Change symbols to 
different shapes 
SAC 
Itch Responder Days 
2.45. ITT 
Eff_F19a 
Mean Difference from placebo in Percentage 
of Responder Days in Mean Worst Daily Itch 
over Main Study Period with 95% Confidence 
Intervals by Country. 
Panelled by Responder 
definition 
Programming notes: 
Change symbols to 
different shapes 
SAC 
Other eDiary itch questions 
2.46. ITT 
Eff_F19a 
Mean Difference from placebo in Change 
from Baseline in Sleep, Fatigue and Overall 
Itch at Week 16 (V6) with 95% Confidence 
Intervals by Country. 
Change from baseline. 
Include Mean Sleep 
Score, Mean Fatigue 
Score and Mean Overall 
Itch on one page – 
panelled by endpoint 
Programming notes: 
Change symbols to 
different shapes 
SAC 
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Validated Questionnaires 
5-D Itch 
2.47. ITT 
Eff_19a 
Mean Difference from placebo in Change 
from Baseline in 5-D Itch at Week 16 (V6), 
with 95% Confidence Intervals by Country. 
Change from baseline. 
Panelled by 5-D Itch 
domain and Total score 
in a 3*2 grid 
Programming notes: 
Change symbols to 
different shapes 
SAC 
PBC-40 
2.48. ITT 
Eff_F19a 
Mean Difference from Placebo in Change 
from Baseline in PBC-40 Score at Week 16 
(V6), with 95% Confidence Intervals by 
Country. 
Change from baseline. 
Panelled by PBC-40 
domain 
Programming notes: 
Change symbols to 
different shapes 
SAC 
Other PROs 
2.49. ITT 
Eff_F19a 
Mean Difference from Placebo in Change 
from Baseline in Derived EQ-5D-5L Utility 
Index Score and EQ-5D-5L VAS at Week 16 
(V6), with 95% Confidence Intervals by 
Country. 
Change from baseline. 
Panel for each of the two 
scores 
Programming notes: 
Change symbols to 
different shapes 
SAC 
2.50. ITT 
Eff_F19a 
Mean Difference from Placebo in Change 
from Baseline in PGI-S at Week 16 (V6), with 
95% Confidence Intervals by Country. 
Programming notes: 
Change symbols to 
different shapes 
SAC 
2.51. ITT 
Eff_F19a 
Mean difference from Placebo in Change 
from Baseline in PGI-C at Week 16 (V6), with 
95% Confidence Intervals by Country. 
Not change from 
baseline. 
Programming notes: 
Change symbols to 
different shapes 
SAC 
2.52. ITT 
Eff_F19a 
Mean Difference from Placebo in Change 
from Baseline in BDI-II at Week 16 (V6), with 
95% Confidence Intervals by Country. 
Change from baseline.  
Programming notes: 
Change symbols to 
different shapes 
SAC 
High Risk Population – Risk Response 
2.53. 
High 
Risk 
Eff_F19a 
Mean Difference from Placebo in Change 
from Baseline in Markers of Disease at Week 
16 (V6) with 95% Confidence Intervals by 
Country. 
Change from baseline. 
Panelled by marker 
Programming notes: 
Change symbols to 
different shapes 
SAC 
 
 
 
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12.12.7. 
Safety Tables 
Safety : Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
3.1.  Safety 
AE1 
Summary of All Adverse Events 
Number of adverse events by 
SOC and PT 
HLR 
3.2.  Initial 
AE1 
Summary of Pre-Treatment Adverse Events 
Footnote: Pre-Treatment is 
defined as the period from start 
of Initial Study Period (V2) until 
early withdrawal of study 
treatment or V3, whichever is 
earliest. 
SAC 
3.3.  Safety 
AE1 
Summary of On-Treatment Adverse Events 
Footnote: On-Treatment is 
defined as from the date if first 
randomised study treatment until 
the date of last randomised study 
treatment + 2 days 
SAC 
3.4.  Safety 
AE1 
Summary of Post-Treatment Adverse Events 
Footnote: Note: Post-
Treatment is defined as 
within 30 days of date of 
last randomised study 
treatment 
Programming note:Post-
treatment is defined as date of 
last randomised study treatment 
+ 30 days. 
SAC 
3.5.  Safety 
AE1 
Summary of On-Treatment Drug-Related 
Adverse Events 
 
SAC 
3.6.  Safety 
AE3 
Summary of Common (>=5%) Adverse Events 
by Overall Frequency 
 
SAC 
3.7.  Safety 
AE3 
Summary of the 10 Most Frequent On-treatment 
Adverse Events in Each Treatment Group  
Count most frequent number of 
events, not Participants and %. 
Sort by descending total 
incidence (sum of number of 
Participants with event). 
SAC 
3.8.  Initial 
AE1 
Summary of Pre-Treatment Fatal Serious 
Adverse Events 
 
SAC 
3.9.  Safety 
AE1 
Summary of On-Treatment Fatal Serious 
Adverse Events 
 
SAC 
3.10. Safety 
AE1 
Summary of Post-Treatment Fatal Serious 
Adverse Events 
 
SAC 
3.11. Safety 
AE1 
Summary of On-Treatment Drug-Related Fatal 
Serious Adverse Events 
 
SAC 
3.12. Initial 
AE1 
Summary of Pre-Treatment Non-Fatal Serious 
Adverse Events 
 
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Safety : Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.13. Safety 
AE1 
Summary of On-Treatment Non-Fatal Serious 
Adverse Events 
 
SAC 
3.14. Safety 
AE1 
Summary of Post-Treatment Non-Fatal Serious 
Adverse Events 
 
SAC 
3.15. Safety 
AE1 
Summary of On-Treatment Drug-Related Non-
Fatal Serious Adverse Events 
 
SAC 
3.16. Safety 
AE1 
Summary of Adverse Events Leading to 
Permanent Discontinuation of Study Drug 
Note: use the main study period 
part of this table for HLR for 
presentation purpose only (no 
change to the standard table). 
HLR 
3.17. Safety 
AE1 
Summary of Adverse Events Leading to 
Permanent Discontinuation of Study Drug (during 
placebo run-in) 
 
SAC 
3.18. Safety 
AE1 
Summary of Adverse Events Leading to 
Withdrawal from Study 
 
SAC 
3.19. Safety 
AE1 
Summary of Adverse Events Leading to 
Withdrawal from Study (during placebo run-in) 
 
SAC 
3.20. Initial 
AE1 
Summary of Pre-Treatment Diarrhoea Adverse 
Events of Special Interest  
Diarrhoea adverse event as 
defined in RAP 
SAC 
3.21. Safety 
AE1 
Summary of On-Treatment Diarrhoea Adverse 
Events of Special Interest 
Diarrhoea adverse event as 
defined in RAP 
HLR 
3.22. Safety 
AE1 
Summary of Post-Treatment Diarrhoea Adverse 
Events of Special Interest  
Diarrhoea adverse event as 
defined in RAP 
SAC 
3.23. Safety  
TTE7 
Time to Event Analysis for Time to Diarrhoea. 
Diarrhoea adverse event as 
defined in RAP 
SAC 
3.24. Safety 
AE1 
Summary of On-Treatment Abdominal Pain 
Adverse Events 
Abdominal pain adverse event as 
defined in RAP 
SAC 
3.25. Safety 
AE1 
Summary of Post-Treatment Abdominal Pain 
Adverse Events 
Abdominal pain adverse event as 
defined in RAP 
SAC 
3.26. Safety  
TTE7 
Time to Event Analysis for Time to Abdominal 
Pain. 
Abdominal Pain adverse event as 
defined in RAP 
SAC 
3.27. Safety 
AE1 
Number and Percent of Participants with 
Diarrhoea and Abdominal Pain during the Main 
Study Phase 
 
SAC 
3.28. Initial 
AE1 
Summary of Pre-Treatment Liver Adverse Events 
of Special Interest 
Liver AESI Met the Stopping Criteria 
ALT AESI as defined in RAP 
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No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.29. Safety 
AE1 
Summary of On-Treatment Liver Adverse Events 
of Special Interest 
Liver AESI Met the Stopping Criteria 
ALT AESI as defined in RAP 
SAC 
3.30. Safety 
AE1 
Summary of Post-Treatment Liver Adverse 
Events of Special Interest 
Liver AESI Met the Stopping Criteria 
ALT AESI as defined in RAP 
SAC 
Clinical Laboratory Parameters 
Chemistry Data 
3.31. Safety 
LB1 
Summary of Change from Baseline in Chemistry 
Data  
Include absolute values for V1, 
V2, and V3 (Baseline) as well as 
change from baseline for all other 
visits  
Chemistry Data includes: 
BUN, creatinine, eGRF (CKD-
EPI), Potassium, Sodium, 
Calcium. The liver function tests 
will be presented separately 
 
SAC 
3.32. Safety 
LB17 
Summary of Chemistry Data of Potential Clinical 
Importance  
Chemistry Data includes: 
BUN, creatinine, eGRF (CKD-
EPI), Potassium, Sodium, 
Calcium.  The liver function tests 
will be presented separately 
 
SAC 
Liver Function Tests 
3.33. Safety 
LB1 
Summary of Change from Baseline in Liver 
Function Tests  
Include absolute values for V1, 
V2, and V3 (Baseline) as well as 
change from baseline for all other 
visits  
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR. This 
will include central lab data only 
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No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.34. Safety 
LB1 
Summary of Change from Baseline in Liver 
Function Tests by Visit by Risk of Disease 
Progression 
Include absolute values for V1, 
V2, and V3 (Baseline) as well as 
change from baseline at all other 
visits  
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR. This 
will include central lab data only 
(Note to GSK: For HLR slides 
presentation Pull out ALT, ALP, 
and Bilirubin only from this table) 
HLR 
3.35. Safety 
LB1 
Summary of Ratio of Upper Limit of Normal in 
Liver Function Tests (Scheduled) 
Include V1 – V7  
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR This 
will include central lab data only 
SAC 
3.36. Safety 
LB1 
Summary of Ratio of Upper Limit of Normal in 
Liver Function Tests (Unscheduled) 
Include V1 – V7  
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR This 
will include local lab data only 
and will present the data from 
unscheduled liver monitoring 
visits. 
SAC 
3.37. Safety 
LB15 
Summary of Liver Function Tests: Normal Range 
Categories 
This will include central lab data 
only 
SAC 
3.38. Safety 
LB4 
Shift Table of Change from Baseline in Normal 
Range Categories for Liver Function Tests  
Show proportion moving between 
the categories from baseline 
category. This will include central 
lab data only 
SAC 
3.39. Safety 
LB17 
Summary of Change from Baseline in Liver 
Function Tests of Potential Clinical Importance  
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR. This 
will include central lab data only 
SAC 
3.40. Safety 
Eff_T2 
ANCOVA Analysis of Change from Baseline in 
Liver Function Tests at Week 16 (V6). 
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR. This 
will include central lab data only 
SAC 
3.41. Safety 
LB17 
Summary of Change from Baseline in Laboratory 
Data of Potential Clinical Importance  
This will include all lab data with 
a change from baseline PCI flag 
– albumin, creatinine, 
haematocrit, haemoglobin,  
 
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No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Fasting Lipid Profile 
Vitamin Absorption 
3.42. Safety 
LB1 
Summary of Change from Baseline in Vitamin 
Absorption  
Include absolute values for both 
V2 and V3 (Baseline) as well as 
change from baseline for all other 
visits  
Vitamin Absorption includes: 
Vitamin A, D, E and K 
SAC 
3.43. Safety 
Eff_T2 
ANCOVA Analysis of Change from Baseline in 
Vitamin Absorption at Week 16 (V6). 
This will include the difference of 
all treatment groups to placebo 
and the difference between 90 
mg BID and 180 mg QD dose 
groups. 
Vitamin Absorption includes: 
Vitamin A, D, E and K 
SAC 
Haematology 
3.44. Safety 
LB1 
Summary of Change from Baseline in 
Haematology Data  
Include absolute values for both 
V2 and V3 (Baseline) as well as 
change from baseline for all other 
visits 
SAC 
3.45. Safety 
LB17 
Summary of Haematology Data of Potential 
Clinical Importance  
 
SAC 
FOBT 
3.46. Safety 
LB1 
Summary of Faecal Occult Blood Data 
 
SAC 
Urinalysis 
3.47. Safety 
UR1 
Summary of Urinalysis Results by Visit 
 
SAC 
Hepatobiliary (Liver) 
3.48. Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event 
Reporting During Main Study Period 
During MSP 
HLR 
3.49. Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event 
Reporting During Initial Study Period 
During ISP 
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No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Vital Signs and ECGs 
3.50. Safety 
VS1 
Summary of Change from Baseline in Vital Signs 
by Visit 
Include absolute values for V1, 
V2, and V3 (Baseline) as well as 
change from baseline for all other 
visits. 
SAC 
3.51. Safety 
EG1 
Summary of ECG Findings  
Summary (freq and %) of 
Participants with normal and 
abnormal ECG results at each 
visit 
SAC 
3.52. Safety 
EG2 
Summary of Change from Baseline in ECG 
Values by Visit 
Include absolute values for V1, 
V2, and V3 (Baseline) as well as 
change from baseline for all other 
visits. 
SAC 
GSRS 
3.53. Safety 
Eff_T16 
Summary of responses to GSRS questions  
 
SAC 
3.54. Safety 
Eff_T1 
Summary of GSRS Scores  
As per Eff_T1, paginated by 
domain.  
For V3 to V7 (inclusive) 
SAC 
3.55. Safety 
Eff_T1 
Summary of Change from Baseline in GSRS 
Scores  
As per Eff_T1, paginated by 
domain.  
For V4 to V7 (inclusive) 
SAC 
3.56. Safety 
EFF_T16 
Summary of Weekly e-diary GI symptoms 
questions (categorical)  
The number and proportion of 
people choosing each of the 
categories for each of the 
symptoms questions.  
As per Eff_T9 with a sub-table 
per question. 
SAC 
3.57. Safety 
Eff_T1 
Summary of Weekly e-diary GI symptoms 
questions (0-10 NRS)  
 
SAC 
3.58. Safety 
Eff_T1 
Summary of Change from Baseline in Weekly e-
diary GI symptoms questions (0-10 NRS)  
 
SAC 
3 Safety 
AE1 
Summary of all Adverse Events by Country 
Number of adverse events by 
SOC and PT 
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Safety : Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.60. Safety 
AE1 
Summary of On-Treatment Drug-Related 
Adverse Events by Country 
 
SAC 
3.61. Safety 
AE1 
Summary of Adverse Events Leading to 
Permanent Discontinuation of Study Drug by 
Country 
 
SAC 
3.62. Safety 
AE1 
Summary of Adverse Events Leading to 
Permanent Discontinuation of Study Drug (by 
Country, during placebo run-in) 
 
SAC 
3.63. Safety 
AE1 
Summary of Adverse Events Leading to 
Withdrawal from Study by Country 
 
SAC 
3.64. Safety 
AE1 
Summary of Adverse Events Leading to 
Withdrawal from Study (by Country, during 
placebo run-in) 
 
SAC 
3.65. Safety 
AE1 
Summary of On-Treatment Diarrhoea Adverse 
Events of Special Interest, by Country 
Diarrhoea adverse event as 
defined in RAP 
SAC 
3.66. Safety 
AE1 
Summary of On-Treatment Abdominal Pain 
Adverse Events by Country 
Abdominal Pain adverse event as 
defined in RAP 
SAC 
3.67. Safety 
AE1 
Summary of On-Treatment Liver Adverse Events 
of Special Interest by Country 
ALT AESI as defined in RAP 
SAC 
Clinical Laboratory Parameters 
Chemistry Data 
3.68. Safety 
LB1 
Summary of Change from Baseline in Chemistry 
Data by Country 
Include absolute values for  V1, 
V2, and V3 (Baseline) as well as 
change from baseline for all other 
visits  
Chemistry Data includes: 
BUN, creatinine, eGRF (CKD-
EPI), Potassium, Sodium, 
Calcium. The liver function tests 
will be presented seperately 
 
SAC 
3.69. Safety 
LB17 
Summary of Chemistry Data of Potential Clinical 
Importance by Country 
Chemistry Data includes: 
BUN, creatinine, eGRF (CKD-
EPI), Potassium, Sodium, 
Calcium.  The liver function tests 
will be presented seperately 
 
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No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Liver Function Tests 
3.70. Safety 
LB1 
Summary of Change from Baseline in Liver 
Function Tests by Country 
Include absolute values for V1, 
V2 and V3 (Baseline) as well as 
change from baseline for all other 
visits  
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR. This 
will include central lab data only 
SAC 
3.71. Safety 
LB15 
Summary of Liver Function Tests: Normal Range 
Categories by Country 
This will include central lab data 
only 
SAC 
3.72. Safety 
LB17 
Summary of Change from Baseline in Liver 
Function Tests of Potential Clinical Importance 
by Country 
ALP, ALT, AST, GGT, Total 
bilirubin and albumin 
concentrations and PT/INR. This 
will include central lab data only 
SAC 
3.73. Safety 
LB17 
Summary of Change from Baseline in Laboratory 
Data of Potential Clinical Importance by 
Country 
This will include all lab data with a 
change from baseline PCI flag – 
albumin, creatinine, haematocrit, 
haemoglobin,  
 
SAC 
Fasting Lipid Profile 
3.74. Safety 
LB1 
Summary of Change from Baseline in Fasting 
Lipid Profile by Country 
Include absolute values for both 
V2 and V3 (Baseline) as well as 
change from baseline for all other 
visits  
Fasting Lipid Profile include: 
LDL Cholesterol, HDL 
Cholesterol,  Total Cholesterol, 
Triglycerides 
SAC 
Vitamin Absorption 
3.75. Safety 
LB1 
Summary of Change from Baseline in Vitamin 
Absorption by Country 
Include absolute values for both 
V2 and V3 (Baseline) as well as 
change from baseline for all other 
visits  
Vitamin Absorption includes: 
Vitamin A, D, E and K 
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Safety : Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Haematology 
3.76. Safety 
LB1 
Summary of Change from Baseline in 
Haematology Data by Country 
Include absolute values for both 
V2 and V3 (Baseline) as well as 
change from baseline for all other 
visits 
SAC 
3.77. Safety 
LB17 
Summary of Haematology Data of Potential 
Clinical Importance by Country 
 
SAC 
Urinalysis 
3.78. Safety 
UR1 
Summary of Urinalysis Results by Visit by 
Country 
 
SAC 
Vital Signs and ECGs 
3.79. Safety 
VS1 
Summary of Change from Baseline in Vital Signs 
by Visit by Country 
Include absolute values for V1, 
V2 and V3 (Baseline) as well as 
change from baseline for all other 
visits. 
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Safety : Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.80. Safety 
EG1 
Summary of ECG Findings by Country 
Summary (freq and %) of 
Participants with normal and 
abnormal ECG results at each 
visit 
SAC 
3.81. Safety 
EG2 
Summary of Change from Baseline in ECG 
Values by Visit by Country 
Include absolute values for V1, 
V2 and V3 (Baseline) as well as 
change from baseline for all other 
visits. 
SAC 
GSRS 
3.82. Safety 
Eff_T1 
Summary of GSRS Scores by Country 
As per Eff_T1, paginated by 
domain.  
For V3 to V7 (inclusive) 
SAC 
3.83. Safety 
Eff_T1 
Summary of Change from Baseline in GSRS 
Scores by Country 
As per Eff_T1, paginated by 
domain.  
For V4 to V7 (inclusive) 
SAC 
3.84. Safety 
EFF_T16 
Summary of Weekly e-diary GI symptoms 
questions (categorical) by Country 
The number and proportion of 
people choosing each of the 
categories for each of the 
symptoms questions.  
As per Eff_T9 with a sub-table 
per question. 
SAC 
3.85. Safety 
Eff_T1 
Summary of Weekly e-diary GI symptoms 
questions (0-10 NRS) by Country 
 
SAC 
3.86. Safety 
Eff_T1 
Summary of Change from Baseline in Weekly e-
diary GI symptoms questions (0-10 NRS) by 
Country 
 
SAC 
Country 
3.87. Safety 
AE1 
Summary of All Adverse Events by Country 
Number of adverse events by 
SOC and PT 
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12.12.8. 
Safety Figures 
Safety : Figures 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
Laboratory Data 
3.1.  Safety 
EG9 
Line Plot of Change from Baseline in 
Chemistry Data against Visit  
 
SAC 
3.2.  Safety 
EG9 
Line Plot of Change from Baseline in Liver 
Function Test Data against Visit  
 
SAC 
3.3.  Safety 
EG9 
Line Plot of Change from Baseline in Liver 
Function Test Data against Visit by Risk of 
Disease Progression 
 
SAC 
3.4.  Safety 
EG9 
Line Plot of Change from Baseline in Fasting 
Lipid Profile against Visit  
 
SAC 
3.5.  Safety 
EG9 
Line Plot of Change from Baseline in Vitamin 
Absorption against Visit  
 
SAC 
3.6.  Safety 
EG9 
Line Plot of Change from Baseline in 
Haematology against Visit  
 
SAC 
ECGs and Vital Signs 
3.7.  Safety 
EG9 
Line Plot of Change from Baseline in QTc 
against Visit. 
 
SAC 
3.8.  Safety 
EG9 
Line Plot of Change from Baseline in Vital 
Signs against Visit  
One plot for each vital 
signs element  
 
SAC 
GSRS 
3.9.  Safety 
Eff_F16 
Boxplot of GSRS Scores against Visit: 
Panelled by Domain 
Category = visit 
Group = trtcd 
Use a different colour for 
each treatment group. 
Programming notes: plot 
each domain on a page 
with the appropriate 
scale (these are not all 
on the same scale as the 
range for the domains 
differs). 
SAC 
3.10. Safety 
Eff_F7a 
Mean Difference from Placebo in Change 
from Baseline in GSRS Score at Week 16 
(V6), with 95% Confidence Intervals 
Panelled by GSRS 
domain 
 
SAC 
3.11. Safety 
Eff_F19a 
Mean Difference from Placebo in Change 
from Baseline in GSRS Score at Week 16 
(V6), with 95% Confidence Intervals by 
Country 
Panelled by GSRS 
domain 
Programming notes: 
Change symbols to 
different shapes 
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Safety : Figures 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
Special Interest AEs Diarrhoea 
3.12. Safety 
TTE10 
Kaplan-Meier Plot of Time to Diarrhoea 
 y-axis title should be 
"Probability without 
Diarrhoea" 
SAC 
3.13. Safety 
Eff_F21 
Swimmer Plot of start of Diarrhoea and End 
of Diarrhoea by Treatment Group 
Refer to mock ups. Each 
dose has one swimmer 
plot. Each lane is for 
each individual 
participant. Legend will 
be AE in question 
(during the ISP, MSP, 
and final study period). 
x-axis should be visit in 
weeks  
 
 
HLR 
3.14. Safety 
TTE10 
Kaplan-Meier Plot of Time to Abdominal Pain 
 y-axis title to be 
"Probability without 
abdominal pain" 
SAC 
3.15. Safety 
Eff_F21 
Swimmer Plot of start of Abdominal Pain and 
End of Abdominal Pain by Treatment Group 
Refer to mock ups. Each 
dose has one swimmer 
plot. Each lane is for 
each individual 
participant. Legend will 
be AE in question 
(during the ISP, MSP, 
and final study period). 
x-axis should be visit in 
weeks. 
 
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12.12.9. 
Pharmacokinetic Tables 
Pharmacokinetic : Tables 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
 
 
 
 
 
 
4.1.  PK 
PKCT1 
Summary of Linerixibat (GSK2330672) 
Plasma Pharmacokinetic Concentration-
Actual Time Data (pg/mL)  
 
Include all samples 
where linerixibat was 
measured (V3, V4, V5, 
and V6). 
Record NQ and nearest 
Visit 
See data specification 
section 
By treatment group 
SAC 
4.2.  PK 
PKCT1 
Summary of UDCA Plasma Pharmacokinetic 
Concentration-Actual Time Data by (UDCA 
dose is same for all participants) 
Include all samples for 
which UDCA was 
measured (V3, V4, V5 
and V6). 
Record NQ and nearest 
Visit 
Need the unites for 
UDCA for PK 
By treatment group 
SAC 
4.3.  PK 
PKCT1 
Summary of GUDCA Plasma 
Pharmacokinetic Concentration-Actual Time 
Data by (UDCA dose is same for all 
participants) 
Include all samples for 
which GUDCA was 
measured (V3, V4, V5, 
and V6. 
Record NQ and nearest 
Visit 
Need the unites for 
GUDCA for PK 
By treatment group 
SAC 
4.4.  PK 
PKCT1 
Summary of TUDCA Plasma 
Pharmacokinetic Concentration-Actual Time 
Data by (UDCA dose is same for all 
participants) 
Include all samples for 
which TUDCA was 
measured (V3, V4, V5, 
and V6. 
Record NQ and nearest 
Visit 
Need the unites for 
TUDCA for PK 
By treatment group 
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Pharmacokinetic : Tables 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
 
 
 
 
 
 
4.5. PK 
PKCT1 
Summary of Linerixibat (GSK2330672) 
Plasma Pharmacokinetic Concentration-
Actual Time Data (pg/mL) by Country 
Include all samples 
where linerixibat was 
measured (V3, V4, V5, 
and V6). 
Record NQ and nearest 
Visit 
See data specification 
section 
By treatment group 
SAC 
4.6.  PK 
PKCT1 
Summary of UDCA Plasma Pharmacokinetic 
Concentration-Actual Time Data by (UDCA 
dose is same for all participants) by Country 
Include all samples for 
which UDCA was 
measured (V3, V4, V5, 
and V6. 
Record NQ and nearest 
Visit 
By treatment group 
SAC 
4.7.  PK 
PKCT1 
Summary of GUDCA Plasma 
Pharmacokinetic Concentration-Actual Time 
Data by (UDCA dose is same for all 
participants) by Country 
Include all samples for 
which GUDCA was 
measured (V3, V4, V5, 
and V6. 
Record NQ and nearest 
Visit 
By treatment group 
SAC 
4.8.  PK 
PKCT1 
Summary of TUDCA Plasma 
Pharmacokinetic Concentration-Actual Time 
Data by (UDCA dose is same for all 
participants) by Country 
Include all samples for 
which TUDCA was 
measured (V3, V4, V5, 
and V6. 
Record NQ and nearest 
Visit 
By treatment group 
SAC 
4.9.  PK 
pkpt1 
and 
pkpt3 
Summary of Derived PK Concentrations for 
Linerixibat  
Separate linerixibat and 
linerixibat +UDCA 
cotreatment groups 
(programming notes that 
is applied to all pkpt1 
and pkpt3: pkpt1 is linear 
(un transformed data) 
and pkpt3 log 
transformed) 
By treatment group 
SAC   
  
4.10. PK  
pkpt1 
and 
pkpt3 
Summary of Derived PK Concentrations for 
UDCA  
Separate UDCA and 
UDCA +linerixibat 
cotreatment groups 
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Pharmacokinetic : Tables 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
 
 
 
 
 
 
4.11. PK 
pkpt1 
and 
pkpt3 
Summary of Derived PK Concentrations for 
GUDCA  
Separate UDCA and 
UDCA +linerixibat 
cotreatment groups 
SAC  
4.12. PK 
pkpt1 
and 
pkpt3 
Summary of Derived PK Concentrations for 
TUDCA  
Separate UDCA and 
UDCA +linerixibat 
cotreatment groups 
SAC  
 
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12.12.10. Pharmacokinetic Figures 
Pharmacokinetic : Figures 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
4.1.  PK 
PKCF1X 
Line Plots of Individual Participant Linerixibat 
(GSK2330672) Plasma Pharmacokinetic 
Concentration-Actual Time Data (pg/mL) by 
Treatment Group 
1 plot per treatment 
group.  Profile plot 1 line 
per participant 
Header of plot should 
include in the legend a 
that there is a separate 
line for linerixibat alone 
and a separate line for 
linerixibat + UDCA. 
 
Separate out Linerixibat 
Treatment only group 
from Linerixibat + UDCA 
co-treatment groups. 
Linear and log plots 
 
SAC 
4.2.  PK 
PKCF1X 
Line Plots of Individual Participant UDCA 
Plasma Pharmacokinetic Concentration-
Actual Time Data by Treatment Group 
(UDCA dose is same for all participants) 
1 plot per treatment 
group.  Profile plot 1 line 
per participant 
Header of plot should 
include in the legend a 
that there is a separate 
line for linerixibat alone 
and a separate line for 
linerixibat + UDCA. 
 
Separate out Linerixibat 
Treatment only group 
from  Linerixibat + UDCA 
co-treatment groups 
Linear and log plots 
 
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Pharmacokinetic : Figures 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
4.3.  PK 
PKCF1X 
Line Plots of Individual Participant GUDCA 
Plasma Pharmacokinetic Concentration-
Actual Time Data by Treatment Group 
(UDCA dose is same for all participants) 
1 plot per treatment 
group.  Profile plot 1 line 
per participant 
Header of plot should 
include in the legend a 
that there is a separate 
line for linerixibat alone 
and a separate line for 
linerixibat + UDCA. 
 
Separate out Linerixibat 
Treatment only group 
from Linerixibat + UDCA 
co-treatment groups 
Linear and log plots 
 
SAC 
4.4.  PK 
PKCF1X 
Line Plots of Individual Participant TUDCA 
Plasma Pharmacokinetic Concentration-
Actual Time Data by Treatment Group 
(UDCA dose is same for all participants) 
1 plot per treatment 
group.  Profile plot 1 line 
per participant 
Header of plot should 
include in the legend a 
that there is a separate 
line for linerixibat alone 
and a separate line for 
linerixibat + UDCA. 
 
Separate out Linerixibat 
Treatment only group 
from Linerixibat + UDCA 
co-treatment groups 
Linear and log plots 
 
SAC 
4.5.  PK 
PKCF1X 
Line Plots of Individual Participant Linerixibat 
(GSK2330672) Plasma Pharmacokinetic 
Concentratin-Actual Time Data (pg/mL) by 
Treatment Group and by Country 
1 plot per treatment 
group.  Profile plot 1 line 
per participant 
Header of plot should 
include in the legend a 
that there is a separate 
line for linerixibat alone 
and a separate line for 
linerixibat + UDCA. 
 
Separate out Linerixibat 
Treatment only group 
from Linerixibat + UDCA 
co-treatment groups. 
Linear and log plots 
 
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Pharmacokinetic : Figures 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
4.6.  PK 
PKCF1X 
Line Plots of Individual Participant UDCA 
Plasma Pharmacokinetic Concentration-
Actual Time Data by Treatment Group 
(UDCA dose is same for all participants) and 
by Country 
1 plot per treatment 
group.  Profile plot 1 line 
per participant 
Header of plot should 
include in the legend a 
that there is a separate 
line for linerixibat alone 
and a separate line for 
linerixibat + UDCA. 
 
Separate out Linerixibat 
Treatment only group 
from Linerixibat + UDCA 
co-treatment groups. 
Linear and log plots 
 
SAC 
4.7.  PK 
PKCF1X 
Line Plots of Individual Participant GUDCA 
Plasma Pharmacokinetic Concentration-
Actual Time Data by Treatment Group 
(UDCA dose is same for all participants) and 
by Country 
1 plot per treatment 
group.  Profile plot 1 line 
per participant 
Header of plot should 
include in the legend a 
that there is a separate 
line for linerixibat alone 
and a separate line for 
linerixibat + UDCA. 
 
Separate out Linerixibat 
Treatment only group 
from Linerixibat + UDCA 
co-treatment groups. 
Linear and log plots 
 
SAC 
4.8.  PK 
PKCF1X 
Line Plots of Individual Participant TUDCA 
Plasma Pharmacokinetic Concentration-
Actual Time Data by Treatment Group 
(UDCA dose is same for all participants) and 
by Country 
1 plot per treatment 
group.  Profile plot 1 line 
per participant 
Header of plot should 
include in the legend a 
that there is a separate 
line for linerixibat alone 
and a separate line for 
linerixibat + UDCA. 
 
Separate out Linerixibat 
Treatment only group 
from Linerixibat + UDCA 
co-treatment groups. 
Linear and log plots 
 
SAC 
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Pharmacokinetic : Figures 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
4.9.  PK 
Eff_F23 
Box Plots of Linerixibat Cave by Treatment 
Group and by Visit 4 and Visit 5 
X axis is treatment group 
Y axis is C average 
QD (low to high dose) 
then BID (low to high) 
doses left to right. 
Legend is Visit 4 and 
Visit 5 
SAC 
4.10. PK 
Eff_F23 
Box Plots of UDCA Cave by Treatment  
Group and by Visit 4 and Visit 5 
X axis is treatment group 
Y axis is C average 
QD (low to high dose) 
then BID (low to high) 
doses left to right 
DDI investigation 
Legend is Visit 4 and 
Visit 5 
SAC 
4.11. PK 
Eff_F23 
Box Plots of GUDCA Cave by Treatment 
Group and by Visit 4 and Visit 5 
X axis is treatment group 
Y axis is C average 
QD (low to high dose) 
then BID (low to high) 
doses left to right 
DDI investigation 
Legend is Visit 4 and 
Visit 5 
SAC 
4.12. PK 
Eff_F23 
Box Plots of TUDCA Cave by Treatment 
Group and by Visit 4 and Visit 5 
X axis is treatment group 
Y axis is C average 
QD (low to high dose) 
then BID (low to high) 
doses left to right 
DDI investigation 
Legend is Visit 4 and 
Visit 5 
SAC 
4.13. PK 
Eff_F23 
Box Plots of Linerixibat Cave by Treatment 
Group by Visit 4 and Visit 5 and by Country 
X axis is treatment group 
Y axis is C average 
QD (low to high dose) 
then BID (low to high) 
doses left to right 
DDI investigation 
Legend is Visit 4 and 
Visit 5 
SAC 
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Pharmacokinetic : Figures 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
4.14. PK 
Eff_F23 
Box Plots of UDCA Cave by Treatment 
Group by Visit 4 and Visit 5 and by Country 
X axis is treatment group 
Y axis is C average 
QD (low to high dose) 
then BID (low to high) 
doses left to right 
DDI investigation 
Legend is Visit 4 and 
Visit 5 
SAC 
4.15. PK 
Eff_F23 
Box Plots of GUDCA Cave by Treatment 
Group by Visit 4 and Visit 5 and by Country 
X axis is treatment group 
Y axis is C average 
QD (low to high dose) 
then BID (low to high) 
doses left to right 
DDI investigation 
Legend is Visit 4 and 
Visit 5 
SAC 
4.16. PK 
Eff_F23 
Box Plots of TUDCA Cave by Treatment 
Group by Visit 4 and Visit 5 and by Country 
X axis is treatment group 
Y axis is C average 
QD (low to high dose) 
then BID (low to high) 
doses left to right 
DDI investigation 
Legend is Visit 4 and 
Visit 5 
SAC 
4.17. PK 
PKCF1X 
Line plot of change from baseline eGFR at 
V4 vs linerixibat Cave at V4. 
(renal impairment exploration) 
eGFR on y axis 
C average on x axis 
Participant must have a 
value for eGFR near V4 
and linerixibat Cave near 
V4 to be included in plot 
Linear and log plots 
SAC 
4.18. PK 
PKCF1X 
Line plot of change from baseline eGFR at 
V5 y-axis vs linerixibat Cave at V5. 
(renal impairment exploration) 
eGFR on y axis 
C average on x axis 
Participant must have a 
value for eGFR near V5 
and linerixibat Cave near 
V5 to be included in plot 
Linear and log plots 
SAC 
 
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12.12.11. Pharmacodynamic Biomarker Tables 
Pharmacodynamic Biomarker: Tables 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
Markers of Disease 
Biomarkers of PBC and Bile Acid Physiology 
5.1. 
ITT 
LB1 
Summary of change from baseline for PD 
biomarkers 
Include absolute values 
for V3 (baseline), V4, 
V5, V6 and V7 as well as 
change from baseline 
and % change from 
baseline for all other 
visits.  
PD biomarker data 
includes list in 10.1.1 
and plasma lipid 
biomarkers. 
SAC 
5.2. 
ITT 
LB1 
Summary of change from baseline for ALP 
for Subjects Taking UDCA  
Include absolute values 
for V3 (baseline), V4, 
V5, V6 and V7 as well as 
change from baseline 
and % change from 
baseline for all other 
visits.  
SAC 
5.3. 
ITT 
LB1 
Summary of change from baseline for PD 
biomarkers by Country 
Include absolute values 
for V3 (baseline), V4, 
V5, V6 and V7 as well as 
change from baseline 
and % change from 
baseline for all other 
visits.  
PD biomarker data 
includes list in 10.1.1 
and plasma lipid 
biomarkers. 
SAC 
5.4. 
ITT 
LB2 
Summary of change from V6 to V7 for PD 
biomarkers  
Treat Visit 6 as baseline. 
PD biomarker data 
includes list in 10.1.1 
and plasma lipid 
biomarkers. 
(off treatment washout 
observations) 
SAC 
5.5. 
ITT 
LB2 
Summary of change from V6 to V7 for PD 
biomarkers by Country 
Treat Visit 6 as baseline. 
PD biomarker data 
includes list in 10.1.1 
and plasma lipid 
biomarkers. 
(off treatment washout 
observations) 
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Pharmacodynamic Biomarker: Tables 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
5.6. 
ITT 
Eff_T2 
ANCOVA of mean change from baseline in 
TSBA at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo and the 
difference between 90 
mg BID and 180 mg QD 
dose groups. 
SAC 
5.7. 
ITT 
Eff_T2 
ANCOVA of mean change from baseline in 
cholic acid (CA) at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo and the 
difference between 90 
mg BID and 180 mg QD 
dose groups. 
SAC 
5.8. 
ITT 
Eff_T2 
ANCOVA of Mean Change from Baseline in 
Chenodeoycholic Acid (CDCA) at V6 (Week 
16) 
 
This will include the 
difference of all 
treatment groups to 
placebo and the 
difference between 90 
mg BID and 180 mg QD 
dose groups. 
SAC 
5.9. 
ITT 
Eff_T2 
ANCOVA of Mean Change from Baseline in 
Deoxycholic Acid (DCA) at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo and the 
difference between 90 
mg BID and 180 mg QD 
dose groups. 
SAC 
5.10. ITT 
Eff_T2 
ANCOVA of Mean Change from Baseline in 
Serum C4 at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo and the 
difference between 90 
mg BID and 180 mg QD 
dose groups. 
SAC 
5.11. ITT 
Eff_T2 
ANCOVA of Mean Change from Baseline in 
Autotaxin Concentrations at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo and the 
difference between 90 
mg BID and 180 mg QD 
dose groups. 
SAC 
5.12. ITT 
Eff_T2 
ANCOVA of Mean Change from Baseline in 
FGF-19 at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo and the 
difference between 90 
mg BID and 180 mg QD 
dose groups. 
SAC 
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Pharmacodynamic Biomarker: Tables 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
5.13. ITT 
Eff_T2 
ANCOVA of Mean Change from Baseline in 
ELF Test at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo and the 
difference between 90 
mg BID and 180 mg QD 
dose groups. 
SAC 
5.14. ITT 
Eff_T2 
ANCOVA of Mean Change from Baseline in 
Alkaline Phosphatase (ALP) at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo and the 
difference between 90 
mg BID and 180 mg QD 
dose groups. 
SAC 
5.15. ITT 
Eff_T2 
ANCOVA of Mean Change from Baseline in 
Total Cholesterol at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo 
SAC 
5.16. ITT 
Eff_T2 
ANCOVA of Mean Change from Baseline in 
HDL Cholesterol at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo 
SAC 
5.17. ITT 
Eff_T2 
ANCOVA of Mean Change from Baseline in 
Direct LDL Cholesterol at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo 
SAC 
5.18. ITT 
Eff_T2 
ANCOVA of mean Mean Change from 
Baseline in Triglycerides at V6 (Week 16) 
 
This will include the 
difference of all 
treatment groups to 
placebo 
SAC 
5.19. ITT 
Eff_19 
Correlation Analysis of Baseline Biomarkers 
and Baseline Mean Worst Daily Itch Score by 
Treatment Group 
List of PD biomarkers 
10.1.1 and total bilirubin 
SAC 
5.20. ITT 
Eff_19 
Correlation analysis of Mean Change from 
Baseline at V6 for PD Biomarkers and Mean 
Change from Baseline at V6 for Mean Worst 
Daily Itch Score by Treatment Group 
List of PD biomarkers 
10.1.1 and total bilirubin 
SAC 
5.21. ITT 
Eff_19 
Correlation Analysis of change from baseline 
for ALP (V4-V3) and change from baseline 
for TSBA, CA, CDCA, DCA by Treatment 
Group for Visit 4 (Week 8)  
V3 is baseline,  
 
SAC 
5.22. 
ITT 
Eff_19 
Correlation Analysis of change from baseline 
for ALP (V5-V3) and change from baseline 
for TSBA, CA, CDCA, DCA by Treatment 
Group for Visit 5 (Week 12) 
V3 is baseline,  
 
SAC 
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Pharmacodynamic Biomarker: Tables 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
5.23. 
ITT 
Eff_19 
Correlation Analysis of change from baseline 
for ALP(V6-V3) and change from baseline for 
TSBA, CA, CDCA, DCA by Treatment Group 
Visit 6 (Week 16) 
V3 is baseline,  
 
SAC 
5.24. 
ITT 
Eff_19 
Correlation Analysis change from baseline 
for ALP (V7-V6) and change from baseline 
for TSBA, CA, CDCA, DCA by Treatment 
Group for Visit 7 (Week 20) 
V6 is baseline, 
Off treatment washout 
view 
From V6 to V7 
SAC 
5.25. 
ITT 
Eff_19 
Correlation analysis of change from baseline 
for ALP (V4-V3) and UDCA Cave, V4 
concentration by Treatment Group (for 
placebo use concentrations zero for UDCA) 
for Visit 4 (Week 8) 
V3 is baseline, 
 
SAC 
5.26. 
ITT 
Eff_19 
Correlation Aanalysis of change from 
baseline for ALP (V5-V3) and UDCA Cave, 
V5 concentration by Treatment Group (for 
placebo use concentrations zero for UDCA) 
for Visit 5 (Week 12) 
V3 is baseline, 
 
SAC 
5.27. 
ITT 
Eff_19 
Correlation Analysis of change from baseline 
for ALP (V4-V3) and GUDCA Cave, V4 
concentration by Treatment Group (for 
placebo use concentrations zero for GUDCA) 
for Visit 4 (Week 8) 
V3 is baseline, 
 
SAC 
5.28. 
ITT 
Eff_19 
Correlation Analysis of change from baseline 
for ALP (V5-V3) and GUDCA Cave, V5 
concentration by Treatment Group (for 
placebo use concentrations zero for GUDCA) 
for Visit 5 (Week 12)  
V3 is baseline, 
 
SAC 
5.29. 
ITT 
Eff_19 
Correlation Analysis of change from baseline 
for ALP (V4-V3) and TUDCA Cave, V4 
concentration by Treatment Group (for 
placebo use concentrations zero for TUDCA) 
for Visit 4 (Week 8)  
V3 is baseline, 
 
SAC 
5.30. 
ITT 
Eff_19 
Correlation Analysis of change from baseline 
for ALP (V5-V3) and TUDCA Cave, V5 
concentration by Treatment Group (for 
placebo use concentration zero for TUDCA) 
for Visit 5 (Week 12)  
V3 is baseline, 
 
SAC 
 
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12.12.12. Pharmacodynamic Biomarker Figures 
Pharmacodynamic Biomarker: Figures 
No. 
Populati
on 
IDSL / 
TST ID / 
Exampl
e Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
Markers of Disease 
Biomarkers of PBC and Bile Acid Physiology 
5.1.  
ITT 
Eff_F4 
Line Plots of Mean PD Biomarkers Over 
Time by Treatment Group 
 
Absolute values for V3, 
V4, V5 and V6. (mean 
+/- SD), PD biomarkers 
listed in 10.1.1 
 
Programming notes: use 
the same shell but add 
+/- SD 
SAC 
5.2.  
ITT 
Eff_F4 
Line Plots of Mean Change from Baseline for 
PD Biomarkers vs Visit  by Treatment Group 
 
V3 is baseline 
(allows for view of PD 
response over time, PD 
biomarkers listed in 
10.1.1) 
Visit 4, Visit 5, and Visit 
6 on one plot for each 
PD biomarker for 
Treatment Group (mean 
+/- SD) 
(For example, PD CFB 
V4-V3 vs V4, V5-V3 vs 
V5, V6-V3 vs V6) 
SAC 
5.3.  
ITT 
Eff_F24 
Bar Chart of mean change from baseline for 
PD biomarkers per Visit.  
V3 is baseline 
(dose response plots, 
PD biomarkers listed in 
10.1.1) 
One Bar chart with SD 
per visit for V4 
V5, and V6; 
with treatment 
group on x-
axis 
Programming note: use 
the Eff_F24 
shell and add 
SD 
Treatment group colours 
should be 
consistent 
across all 
figures 
SAC 
 
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12.12.13. ICH Listings 
ICH : Listings 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1. 
 
Enrolled 
ES7 
Listing of Reasons for Screen Failure 
 
SAC 
2. 
 
Initial 
ES7 
Listing of Reasons for Baseline Failure 
 
SAC 
3. 
 
Initial 
ES2 
Listing of Reasons for Premature Withdrawal 
from the study 
Add a column with study 
period in which Participant 
was withdrawn (ISP, MSP, 
FSP) 
SAC 
4. 
 
Initial 
SD2 
Listing of Reasons for Discontinuation of Study 
Treatment 
Add a column with study 
period in which Participant 
was withdrawn (ISP, MSP, 
FSP) 
SAC 
5. 
 
Randomise
d 
BL1 
Listing of Participants for Whom the Treatment 
Blind was Broken During the Study 
 
SAC 
6. 
 
Randomise
d 
TA1 
Listing of Planned and Actual Treatments 
 
SAC 
7. 
 
Randomise
d 
DV2 
Listing of Important Protocol Deviations 
Add a column with study 
period in which protocol 
deviation occurred (ISP, 
MSP, FSP) 
Please add a flag for ITT in 
this listing 
SAC 
8. 
 Randomise
d 
IE3 
Listing of Participants with Inclusion\Exclusion 
Criteria Deviations 
 
SAC 
9. 
 
Enrolled 
SP3 
Listing of Participants Excluded from any 
Population 
 
SAC 
10.  
Safety 
DM2 
Listing of Demographic Characteristics 
 
SAC 
11.  
Safety 
DM9 
Listing of Race 
 
SAC 
12.  
Safety 
CM3 
Listing of Concomitant Medications 
 
SAC 
13.  
Safety 
CM3 
Listing of Previous Treatments for PBC 
 
SAC 
14.  
Safety 
EX3 
Listing of Exposure  
 
SAC 
15.  
Safety 
EX3 
Listing of Compliance  
Column for each of AM/PM 
and total compliance based 
on tablets and e-diary for 
each Visit in the Main Study 
Period (V3 to V6) 
SAC 
16.  
Safety 
AE8 
Listing of all Adverse Events 
 
SAC 
17.  
Safety 
AE7 
Listing of Participant Numbers for Individual 
Adverse Events 
 
SAC 
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ICH : Listings 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
18.  
Safety 
AE2 
Listing of Relationship Between Adverse Event 
System Organ Classes, Preferred Terms, and 
Verbatim Text 
 
SAC 
19.  
Safety 
AE9 
Listing of Serious Adverse events 
 
SAC 
20.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious 
Adverse Event 
 
SAC 
21.  
Safety 
AE9 
Listing of Adverse Events Leading to 
Discontinuation of Study Drug or Withdrawal 
from the Study 
 
SAC 
22.  
Safety 
AE9 
Listing of Adverse Events of Special Interest 
 
SAC 
23.  
Safety 
AE9 
Listing of Other Significant Adverse Events 
 
SAC 
24.  
Safety 
MH2 
Listing of Medical Conditions for Participants 
with Liver Stopping Events 
 
SAC 
25.  
Safety 
SU2 
Listing of Substance Use for Participants with 
Liver Stopping Events 
 
SAC 
26.  
Safety 
LB6 
Listing of All Chemistry Data for Participants 
With at Least One Value of Potential Clinical 
Importance 
 
SAC 
27.  
Safety 
LB6 
Listing of All Haematology Data for Participants 
With at Least One Value of Potential Clinical 
Importance 
 
SAC 
28.  
Safety 
LB6 
Listing of All Urinalysis Data for Participants 
With at Least One Value of Potential Clinical 
Importance 
 
SAC 
29.  
Safety 
VS5 
Listing of All Vital Signs Data for Participants 
with at least one value of Potential Clinical 
Importance 
 
SAC 
30.  
Safety 
EG4 
Listing of All ECG Values for Participants With 
at Least One Value of Potential Clinical 
Importance 
 
SAC 
31.  
Safety 
EG6 
Listing of Abnormal ECG Findings 
 
SAC 
 
 
 
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12.12.14. Non-ICH Listings 
Non-ICH : Listings 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
Analysis 
32.  
ITT 
 
Listing of Risk Group Miss-stratification 
List the risk group strata, 
ALP and total bilirubin 
values (both in terms of 
ratio of ULN) for Visit 2 
and Visit 3 – for all those 
who were mis-stratified 
and/or changed risk 
group between V2 and 
V3 
SAC 
Safety 
33.  Safety 
LB6 
Listing of Liver Chemistry at Screening and 
at each Visit during the study 
 
SAC 
34.  Safety 
LB6 
Listing of All Faecal Occult Blood Data 
 
SAC 
35.  Safety 
UR2a 
Listing of All Urinalysis Data 
 
SAC 
36.  Safety 
  
Listing of GSRS Responses and Scores at 
each Week 
Column for each domain 
SAC 
37.  Safety 
  
Listing of Response to Symptoms Questions 
at each Week 
Column for each 
question, categorical and 
NRS 
SAC 
38.  Safety 
  
SAS output of Time to Diarrhoea 
Include output of SAS 
statistical procedure 
SAC 
39.  Safety 
  
SAS output of Time to Abdominal Pain 
Include output of SAS 
statistical procedure 
SAC 
eDiary Data 
40.  
ITT 
  
Listing of Daily Worst Itch, Fatigue, Sleep 
and Overall Itch Scores 
Column for each of AM, 
PM worst itch, AM, PM 
overall itch, , fatigue and 
sleep per Participant per 
day  - for 7 days prior to 
each visit only 
SAC 
41.  
ITT 
  
Listing of mean worst daily itch, mean 
fatigue, mean sleep and mean overall itch 
scores per visit 
Column for mean worst 
daily itch, mean sleep, 
mean fatigue and mean 
overall itch per 
Participant per visit 
SAC 
42.  
ITT 
  
SAS output for modelling of change from 
baseline in mean worst daily itch 
Include output of SAS 
statistical procedure 
SAC 
43.  
PP 
 
SAS output for modelling of change from 
baseline in mean worst daily itch 
Include output of SAS 
statistical procedure 
SAC 
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Non-ICH : Listings 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
Responders in Itch 
44.  
ITT 
 
Listing of Participants meeting any of the 
Responder in Itch criteria at Week 16 (V6) 
and Number of Responder Days 
A column for each 
responder criteria with 
Yes/No if met criteria at 
Week 16, a column for 
each responder 
definition with number of 
days criteria met 
between V3 and V6. 
SAC 
Time to Worsening of Itch 
45.  
ITT 
 
Listing of Time to Worsening of Itch 
Column for time to 
worsening and indicator 
of whether censored or 
not 
SAC 
Other eDiary itch questions 
46.  
ITT 
 
Listing of Other e-diary questions (AM) 
Column for response to 
each AM question in 7 
days prior to each visit 
SAC 
47.  
ITT 
 
Listing of Other e-diary questions (PM) 
Column for response to 
each AM question in 7 
days prior to each visit 
SAC 
48.  
ITT 
 
Listing of Response to Follow-up telephone 
interview 
 
SAC 
Validated Questionnaires 
5-D Itch 
49.  
ITT 
 
Listing of 5-D Itch Scores 
Column for 5-D Itch 
domains and total score 
at each visit 
SAC 
PBC-40 
50.  
ITT 
 
Listing of PBC-40 Responses 
Column for each 
question in the PBC-40, 
grouped by domain at 
each visit 
SAC 
EQ-5D-5L 
51.  
ITT 
 
Listing of EQ-5D-5L Responses 
Column for each of the 5 
questions in addition to a 
column for the VAS 
score and the derived 
Utility Index Score at 
each visit 
SAC 
PGI 
52.  
ITT 
 
Listing of PGI-C and PGI-S 
Column for PGI-S and 
PGI-C responses at 
each visit 
SAC 
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Non-ICH : Listings 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
BDI-II 
53.  
ITT 
 
Listing of BDI-II Responses 
Column for BDI-II score 
at each visit 
SAC 
PTEA 
54.  
ITT 
 
Listing of PTEA Responses 
Column for each PTEA 
question 
SAC 
Actigraphy 
55.  Actigrap
hy 
 
Listing of Actigraphy Data 
Column for Rest Period 
Duration, WASO, Sleep 
Efficiency, Mean 
Duration of Scratching 
events per hour and 
Mean Number of 
scratching events per 
hour for each night there 
is data available. 
SAC 
High Risk Population 
56.  
High 
Risk 
 
Listing of Responders in Disease 
Progression Risk 
Column for those in the 
high risk population – 
whether met disease 
progression risk 
responder criteria at 
each visit 
SAC 
57.  
High 
Risk 
 
Listing of Markers of Disease  
Column for each marker 
of disease at each visit 
for all Participants in the 
high risk population 
SAC 
Pharmacodynamic and Biomarkers of Disease 
58.  
ITT 
 
Listing of PBC and Bile Acid Physiology 
This will include:  
Total serum bile acid, 
serum C4, serum 
autotaxin, FGF-19, ELF 
test, Serum Bile Acid 
Species 
SAC 
PK 
59.  
PK 
  
Listing of Plasma Pharmacokinetic 
Concentration-Time Data 
Column for each of 
UDCA and GSK2330672 
plasma concentration at 
each time point and visit. 
SAC 
60.  
PK 
 
Listing of PK Concentrations 
Linerixibat, UDCA, 
GUDCA and TUDCA 
SAC 
Medical Resource Utilization and Health Economics 
61.  Safety 
Listing 32 
Listing of Medical Resource Utilization 
and Health Economics 
This listing based on the 
hospital form 
SAC 
 
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12.13. 
Appendix 13: Example Mock Shells for Data Displays 
Data Display Specification will be made available on request. 
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12.14. 
Appendix 14: Interim Analysis Results and update to the 
RAP 
This appendix will be a separate document due to the sensitivity of interim analysis 
results.  Please refer to Appendix 14 for additional details. 
 
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Signature Page for  201000 TMF-1771570 v1.0
Signature Page for TMF-1771570 v1.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 14-May-2020 15:12:01 GMT+0000
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 14-May-2020 16:23:40 GMT+0000
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PPD
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201000 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) Appendix 14  
 
Title 
: Reporting and Analysis Plan for Reporting and Analysis Plan 
for Study 201000: A randomised, double-blind, multi-dose, 
placebo-controlled study to evaluate the efficacy, safety and 
tolerability of GSK2330672 administration for the treatment 
of pruritus in participants with primary biliary cholangitis. 
Compound Number  
: GSK2330672 
Effective Date  
: 11-May-2020 
 
Description: 
• 
This RAP Appendix 14 contains sensitive information based on the Interim Analysis 
(IA) of the study.  The Appendix will be reviewed and approved by the study team 
members who were unblinded to the aggregated IA results.  
 
RAP Author(s): 
Approver 
Date 
Approval Method 
Principal Statistician (Future Pipelines 
Discovery, Clinical Statistics) 
7-May-2020 
 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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2 
 
RAP Team Approvals: 
Approver 
Date 
Approval 
Method 
 
Medicine Development Leader  
8-May-2020 
email 
 
Principal Programmer, Future Pipelines Discover 
Clinical Programming 
11-May-2020 
email 
 
8-May-2020 
email 
Director, Clinical Pharmacology Modeling and 
Simulation, CPMS 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Date 
Approval 
Method 
 
Director, Future Pipelines Discovery, Clinical 
Statistics 
8-May-2020 
email 
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201000 
3 
 
12.14. 
Appendix 14: Interim Analysis Results and update to RAP 
This appendix contains an update to RAP (Reporting and Analysis Plan_Study201000) 
which is based on interim analysis (IA) results. This document reflects the IA decision 
based on the IA results; the outcome of instream decisions on future treatment groups, 
and this information is not revealed to the entire study team. To maintain concealment of 
the sensitive information that the interim analysis decision documents contain, this 
document will be stored in a restricted area outside the Pharma TMF until data base 
freeze. 
The IA results are in “GSK2330672-201000 Interim Analysis (IA) Details decision July 
2018” document.  
• The pre-specified decision criteria are listed in the protocol under Section 10.3.4 and 
based on the IA results the team agreed to select decision criteria #3 and #4 and 
proceed with the trial accordingly. 
• To better characterize the dose-response model for BID dosing and maximize 
information the following it was decided: 
o Drop 20 mg QD 
o Add 40 mg BID 
o Increase sample size to 140 subjects randomized 
▪ Ensure n = 20 for 40 mg BID 
▪ Increase n for 90 mg BID doses 
As result, randomization schedule #7 (Drop 20mg QD and add 40mg BID, complete 
study with: 90mg QD, 180mg QD, 40mg BID and 90mg BID + placebo (increase N to 
140)) was implemented.   
This appendix will be reviewed and approved by the study team who were unblinded to 
the aggregated IA results.  
All tables, figures and listings under the current RAP document will be updated for study 
population, safety, efficacy, PK, and biomarkers to include the new dose level 40 mg BID 
in addition to the 5 dose levels.   
 
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2.6 
Considerations for Data analyses and Data Handling 
Conventions 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
[RandAll NG / FSO Randomization System] 
Data Displays for Reporting  
Code 
Description 
Description 
Order in TLF  
AA 
Placebo for 16 weeks 
Placebo 
1 
BB 
GSK2330672 20 mg once daily for 
12 weeks followed by placebo for 
4 weeks 
GSK2330672 20 mg QD 
2 
CC 
GSK2330672 90 mg once daily for 
12 weeks followed by placebo for 
4 weeks 
GSK2330672 90 mg QD 
3 
DD 
GSK2330672 180 mg once daily 
for 12 weeks followed by placebo 
for 4 weeks 
GSK2330672 180 mg QD 
4 
II 
GSK2330672 40 mg twice daily 
for 12 weeks followed by placebo 
for 4 weeks 
GSK2330672 40 mg BID 
5 
EE 
GSK2330672 90 mg twice daily 
for 12 weeks followed by placebo 
for 4 weeks 
GSK2330672 90 mg BID 
6 
 
 
12.6.2 
 Study Population 
Treatment Compliance Number of Tablets 
Treatment compliance calculations for study participant who were randomized using 
randomization schedule 2 up to IA should follow Section 12.6.2. under treatment 
compliance of the RAP. Randomization schedule 2 used 4 digits randomization number. 
  
Post IA participant who were randomized using randomization schedule 7 (used 5 digits 
randomization number), treatment compliance will be calculated as following: 
Compliance will be calculated based on the number of tablets dispensed and returned 
within the MSP (dispensed at V3, V4 and V5 and returned at V4, V5 and V6). 
 
MSP Compliance =100 * (total number of tablets dispensed from V3 to V6 – total 
number of tablets returned from V3 to V6) / (expected number of tablets to be taken) 
Where expected number of tablets to be taken = 8 tablets per day * (V6 –V3). 
 
If a participant is lost to follow-up, compliance will be calculated up to last Visit 
attended, assuming no tablets were taken from any bottles dispensed at this visit. These 
participants should be flagged, and a footnote added to any summaries of compliance to 
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5 
 
provide information on the number of participants where compliance has not been 
calculated over the entirety of the MSP. 
 
 
For example, if a participant does not return for V5 their compliance will be calculated 
as: 
 
100 * (total number of tablets dispensed from V3 to V4 – total number of tablets returned 
from V3 to V4) / (expected number of tablets to be taken) 
Where expected number of tablets to be taken = 8 tablets per day * (V4 –V3). 
 
With a flag added to say that the participant dropped out after Visit 4. 
 
However, compliance based on number of tablets will also be calculated for the 
containers marked as AM (2 containers, 4 tablets a day) and PM bottles (2 container, 4 
tablets a day) over the duration of the main study period (Exposure start date at V3 to 
Exposure end date at V6). 
 
Compliance will be calculated similarly for the initial study period (V2 to V3) and final 
study period (V6 to V7). 
 
 
 
7.1.4.1.  Statistical Methodology Specification 
Primary efficacy analysis: 
All primary efficacy analysis outputs will include the 40mg BID dose.  Figure 1 under 
Section 7.1.4.1 is updated to include 40mg BID as below.  Note the 4 parameter Emax 
model in part B of the figure will include 40mg BID. 
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6 
 
Figure 1 
Flow chart of the model fitting process 
 
 
The primary efficacy analysis is updated as below (Please see example shells). In 
addition to the tables and figure that are listed under Section 12.12.5 and Section 12.12.6. 
in the RAP Table (2.6) and Figure (2.8) are added to the current primary efficacy outputs 
both outputs are to examine the BID doses only. 
 
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Efficacy Tables 
Efficacy: Tables 
No. 
Popul
ation 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
Mean Worst Daily Itch Score 
2.6 
ITT 
Eff_T3a 
ANCOVA Analysis of Change from Baseline 
in Mean Worst Daily Itch Score at Week 16 
(V6). 
Placebo and BID Doses 
 Mean difference for 
each total daily dose 
level from placebo. Note 
Include Placebo, 40mg 
BID, and 90 mg BID 
group. 
SAC 
 
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Efficacy Figures 
Efficacy: Figures 
No. 
Populat
ion 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverab
le 
[Priority] 
Mean Worst Daily Itch 
2.8. 
ITT 
Eff_F6 
ANCOVA Model: Estimated Mean Difference 
from Placebo in Change from Baseline in 
Mean Worst Daily Itch at Week 16 (V6) with 
95% Confidence Intervals  
 
Include ref line at y=0 
Programming note:   BID 
doses only, 
refer to the shell in the 
RAP.  Label X-axis 
“BID Treatment 
Group”. 
SAC 
 
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Example  
: Eff_T2 
 
 
 
 
 
 
 
 
 
 
 Page 1 of n 
Protocol 
: 201000 
Population: [ITT] 
Table X.X: Preliminary ANCOVA Analysis of Change from Baseline in Mean Worst Daily Itch at Week 16 (V6) 
 
 
 
Change from Baseline 
Difference vs.  
Placebo 
Difference vs.  
GSK2330672 90 mg BID 
 
Treatment 
Group 
N 
n 
LS Mean 
95% CI 
LS Mean 95% CI [1] 
LS Mean
95% CI [2]
Placebo
X 
X 
x.x (x.x, x.x) 
NA
 
NA
20 mg QD
X 
X 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
NA
90 mg QD 
X 
X 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
NA
180 mg QD 
X 
X 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
x.x
(x.x, x.x)
40 mg BID 
X 
X 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
x.x
(x.x, x.x)
90 mg BID 
X 
X 
x.x (x.x, x.x) 
x.x (x.x, x.x) 
NA
 
[1] Mean difference < 0 favours active treatment, while mean difference > 0 favours placebo.  
[2] If 95% CI is within (-1, 1) and includes zero, then the 90 mg BID and 180 mg QD can be thought of as 
equivalent (90 mg BID included in dose-response modelling at total daily dose of 180 mg). 
Note: Mean Worst Daily Itch is the average of the worst daily scores provided in the 7 days prior to visit. 
Note: The ANCOVA model includes Treatment Group and centred Mean Worst Daily Itch at Baseline. 
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Example  
: Eff_T3a 
 
 
 
 
 
 
 
 
 
 
 Page 1 of n 
Protocol 
: 201000 
Population : [ITT] 
Table X.X: ANCOVA Analysis of Change from Baseline in Mean Worst Daily Itch at Week 16 (V6) 
Placebo and BID Dose 
 
 
 
Change from Baseline 
Difference vs. Placebo 
Treatment Group 
N
n 
LS Mean 
95% CI 
LS Mean
95% CI[1]
Placebo 
X
X 
x.x 
(x.x, x.x) 
NA
40 mg BID 
X
X 
x.x 
(x.x, x.x) 
x.x
(x.x, x.x)
90 mg BID 
X
X 
x.x 
(x.x, x.x) 
x.x
(x.x, x.x)
 
 
 
 
 
[1] Mean difference < 0 favours active treatment, while mean difference > 0 favours placebo.  
Note: Mean Worst Daily Itch is the average of the worst daily scores provided in the 7 days prior to visit. 
Note: The ANCOVA model includes Treatment Group and centred Mean Worst Daily Itch at Baseline. 
N is the number in the population for each treatment group and n is the number of Participants with non-
missing data available for analysis.  
 
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Example  
: Eff_T4c 
 
 
 
 
 
 
 
 
 
 
 Page 1 of n 
Protocol 
: 201000 
Population : [ITT] 
Table X.X: Primary Analysis of Change from Baseline in Mean Worst Daily Itch at Week 16 (V6) 
 
 
 
Change from Baseline 
Difference vs. 
Placebo [1] 
Probability 
Treatment 
Difference 
>= 2 
Mininally
Effective
Dose mg [2}
Treatment 
Group 
N 
n 
LS Mean 
95% CI 
LS Mean 
95% CI
P-value 
Placebo
X 
X 
x.x (x.x, x.x) 
NA 
 
20 mg QD
X 
X 
x.x (x.x, x.x) 
x.x 
(x.x, x.x)
 
90 mg QD
X 
X 
x.x (x.x, x.x) 
x.x 
(x.x, x.x)
 
180 mg QD
X 
X 
x.x (x.x, x.x) 
x.x 
(x.x, x.x)
 
40 mg BID
X 
X 
x.x (x.x, x.x) 
x.x 
(x.x, x.x)
 
90 mg BID
X 
X 
x.x (x.x, x.x) 
x.x 
(x.x, x.x)
 
 
[1] Mean difference < 0 favours active treatment, while mean difference > 0 favours placebo.  
[2] Minimally Effective Dose is the lowest dose treatment group at which the change from baseline in Mean 
Worst Daily Itch is at least 2. 
Note: Mean Worst Daily Itch is the average of the worst daily scores provided in the 7 days prior to visit. 
Note: The ANCOVA model includes Treatment Group and centred Mean Worst Daily Itch at Baseline. 
Programming Note: The final column ‘probability treatment difference >=2’ should only be included for the mean 
worst daily itch analysis. See RAP for details on how to calculate these columns. 
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Programming Note: This table will only be displayed if the ANCOVA is chosen as the best model (i.e. the dose-
response modelling fails). 
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