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)
Phase: PHASE2
Conditions: Cholestasis
Sponsor: GlaxoSmithKline

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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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