Conditions: Cholestasis
Keywords: linerixibat (GSK2330672), obeticholic acid, drug interaction, primary biliary cholangitis, pharmacokinetics
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 19
Healthy volunteers: yes

Brief summary:
In participants with inadequate response/intolerance to ursodeoxycholic acid (UDCA) taking obeticholic acid (OCA) who experience pruritus (due to primary biliary cholangitis \[PBC\], OCA, or both) the addition of linerixibat to OCA therapy may be considered following marketing approval. It is therefore important to characterize any potential effect of linerixibat on the pharmacokinetics of OCA in humans at clinically relevant dosages. Accordingly, a drug-drug interaction (DDI) study with linerixibat (potential perpetrator) and OCA (potential victim) will be conducted to inform both future clinical trials with linerixibat and the potential concomitant administration of these drugs in a clinical setting. This is a single-center, one part (with optional second part) open-label, single sequence crossover, drug interaction study to investigate the effect of linerixibat on plasma concentrations of OCA and OCA conjugates in healthy participants. Approximately 19 participants will be enrolled in part A and further 19 participants in part B (if performed) in the study and will have a phone call follow-up till 7-14 days post-last linerixibat dose.

Detailed description:

Arms:
arm 1: In Part A, participants will be administered one tablet of 10 milligrams (mg) obeticholic acid once daily continuously for 37 days (study Day 1 to study Day 37). Two tablets of 45 mg linerixibat will be administered twice daily from study Day 20 to study Day 37. 1 tablet of 45 mg linerixibat will be administered on Day 38. After evaluation of Part A, if optional part B is conducted, participants will be administered linerixibat and obeticholic acid at an alternative dosing regimen.

Interventions: intervention 1: GSK2330672 (linerixibat) intervention 2: Obeticholic acid
Intervention descriptions: intervention 1: GSK2330672 is available as a tablet with unit dose strength of 45 mg. intervention 2: Obeticholic acid is available as a tablet with a unit dose strength of 10 mg (or 5 mg dependent on evaluation of Part A).

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: An open-label, single sequence crossover, drug interaction study to 
investigate the effect of linerixibat (GSK2330672) on plasma concentrations of 
obeticholic acid and conjugates in healthy participants
Protocol Number: 206224
Compound Number
or Name:
GSK2330672
Study Phase: I
Short Title: Linerixibat and obeticholic acid drug interaction study in healthy 
participants
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: will be provided separately in the 
Study Reference Manual
Regulatory Agency Identifying Number(s):
EudraCT:  2019-001581-15
Approval Date: 05-JUN-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schema ........................................................................................................9
1.3.
Schedule of Activities (SoA)........................................................................10
2.
INTRODUCTION....................................................................................................17
2.1.
Study Rationale ..........................................................................................17
2.2.
Background ................................................................................................17
2.3.
Benefit/Risk Assessment ............................................................................18
2.3.1.
Risk Assessment .........................................................................19
2.3.2.
Benefit Assessment.....................................................................21
2.3.3.
Overall Benefit: Risk Conclusion..................................................21
3.
OBJECTIVES AND ENDPOINTS...........................................................................21
4.
STUDY DESIGN ....................................................................................................22
4.1.
Overall Design ............................................................................................22
4.1.1.
Part A ..........................................................................................23
4.1.2.
Part B (Optional)..........................................................................24
4.2.
Scientific Rationale for Study Design ..........................................................25
4.3.
Justification for Dose ..................................................................................26
4.3.1.
Linerixibat ....................................................................................26
4.3.2.
OCA.............................................................................................27
4.4.
End of Study Definition ...............................................................................27
5.
STUDY POPULATION...........................................................................................27
5.1.
Inclusion Criteria.........................................................................................28
5.2.
Exclusion Criteria........................................................................................29
5.3.
Lifestyle Considerations..............................................................................32
5.3.1.
Meals and Dietary Restrictions ....................................................32
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................32
5.3.3.
Activity .........................................................................................33
5.4.
Screen Failures...........................................................................................33
6.
STUDY INTERVENTION........................................................................................34
6.1.
Study Intervention(s) Administered .............................................................34
6.1.1.
Part A ..........................................................................................34
6.1.2.
Part B (Optional)..........................................................................35
6.2.
Measures to Minimize Bias: Randomisation and Blinding ...........................35
6.3.
Preparation/Handling/Storage/Accountability..............................................35
6.4.
Study Intervention Compliance ...................................................................36
6.5.
Concomitant Therapy..................................................................................36
6.6.
Dose Modification .......................................................................................37
6.7.
Intervention after the End of the Study........................................................37
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................37
7.1.
Discontinuation of Study Intervention..........................................................37
7.1.1.
Liver Chemistry Stopping Criteria ................................................37


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7.1.2.
QTc Stopping Criteria ..................................................................38
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................39
7.3.
Lost to Follow Up........................................................................................39
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................40
8.1.
Efficacy Assessments.................................................................................41
8.2.
Safety Assessments ...................................................................................41
8.2.1.
Physical Examinations.................................................................41
8.2.2.
Vital Signs....................................................................................41
8.2.3.
Electrocardiograms......................................................................41
8.2.4.
Clinical Safety Laboratory Assessments ......................................42
8.3.
Adverse Events and Serious Adverse Events.............................................42
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................43
8.3.2.
Method of Detecting AEs and SAEs.............................................43
8.3.3.
Follow-up of AEs and SAEs.........................................................43
8.3.4.
Regulatory Reporting Requirements for SAEs .............................43
8.3.5.
Pregnancy ...................................................................................44
8.4.
Treatment of Overdose...............................................................................44
8.5.
Pharmacokinetics .......................................................................................45
8.5.1.
Part A PK Sampling Schedule .....................................................46
8.5.1.1.
PK Sampling Schedule Day 17-19 for OCA and 
Metabolites.................................................................46
8.5.1.2.
PK Sampling Schedule Day 35-38 for OCA and 
Metabolites.................................................................46
8.5.1.3.
PK Sampling Schedule Day 19-20 (Day -1 and 
1 Linerixibat) and Day 33 (Day 14 Linerixibat) 
for Linerixibat Twice Daily Dosing...............................48
8.5.2.
Part B (Optional) PK Sampling Schedule.....................................49
8.5.2.1.
PK Sampling Schedule Day 17-19 for OCA and 
Metabolites.................................................................49
8.5.2.2.
PK Sampling Schedule Day 35-38 for OCA and 
Metabolites.................................................................50
8.5.2.3.
PK Sampling Schedule Day 19-21 (Day -1, 1 
and 2 Linerixibat) for Linerixibat Once Daily
Dosing........................................................................51
8.5.2.4.
PK Sampling Schedule Days 33-34 (Days 14-
15 of Linerixibat) for Linerixibat Once Daily 
Dosing........................................................................52
8.6.
Pharmacodynamics ....................................................................................52
8.7.
Genetics .....................................................................................................52
8.8.
Biomarkers .................................................................................................53
8.9.
Immunogenicity Assessments.....................................................................53
8.10.
Medical Resource Utilization and Health Economics ..................................53
9.
STATISTICAL CONSIDERATIONS........................................................................53
9.1.
Statistical Hypotheses.................................................................................53
9.2.
Sample Size Considerations.......................................................................53
9.3.
Sample Size Sensitivity...............................................................................54
9.4.
Populations for Analyses ............................................................................54
9.5.
Interim Analysis ..........................................................................................55
9.6.
Data Monitoring Committee ........................................................................55


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9.7.
Statistical Analyses.....................................................................................55
9.7.1.
General Considerations ...............................................................56
9.7.1.1.
Treatment Assignment ...............................................56
9.7.1.2.
Missing Data...............................................................56
9.7.1.3.
Derived and Transformed Data...................................57
9.7.1.4.
Sample Size Re-estimation ........................................57
9.7.2.
Primary Comparisons of Interest..................................................57
9.7.3.
Other Analyse(s)..........................................................................57
9.7.4.
Other Safety Analyse(s)...............................................................57
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................58
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................58
10.1.1.
Regulatory and Ethical Considerations ........................................58
10.1.2.
Financial Disclosure.....................................................................58
10.1.3.
Informed Consent Process ..........................................................59
10.1.4.
Data Protection............................................................................59
10.1.5.
Dissemination of Clinical Study Data ...........................................59
10.1.6.
Data Quality Assurance ...............................................................60
10.1.7.
Source Documents ......................................................................61
10.1.8.
Study and Site Start and Closure.................................................61
10.1.9.
Publication Policy.........................................................................62
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................63
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................65
10.3.1.
Definition of AE............................................................................65
10.3.2.
Definition of SAE..........................................................................66
10.3.3.
Recording and Follow-Up of AE and SAE....................................67
10.3.4.
Reporting of SAE to GSK.............................................................69
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................70
10.4.1.
Definitions:...................................................................................70
10.4.2.
Contraception Guidance: .............................................................71
10.4.3.
Collection of Pregnancy Information: ...........................................72
10.5.
Appendix 5: Genetics..................................................................................73
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................74
10.7.
Appendix 7: Abbreviations and Trademarks................................................76
11. REFERENCES.......................................................................................................78


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: An open-label, single sequence, crossover, drug interaction study to 
investigate the effect of linerixibat (GSK2330672) on plasma concentrations of 
obeticholic acid and conjugates in healthy participants
Short Title: Linerixibat and obeticholic acid drug interaction study in healthy 
participants
Rationale: GSK2330672 (linerixibat) is a selective inhibitor of the human ileal bile acid 
transporter (IBAT) and is designed to be a non-absorbable agent restricted to the
gastrointestinal tract.  It is currently in development in Phase IIb as a novel oral treatment 
for pruritus in cholestatic liver disease. For patients with Primary Biliary Cholangitis 
(PBC), increased excretion of bile acids following IBAT inhibition is expected to reduce 
bile acid concentrations in the liver and systemic circulation, resulting in reduced 
hepatobiliary inflammation and improvement of the systemic symptom of pruritus.
Obeticholic acid (OCA), also known as Ocaliva is a farnesoid X receptor (FXR) agonist.  
FXR agonism reduces bile acid synthesis both by increasing ileal FGF19 secretion and by 
direct effects on hepatic CYP7A1 regulation. OCA is indicated for the treatment of PBC 
in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response 
to UDCA or as monotherapy in adults unable to tolerate UDCA.  
In the clinical setting there is potential for linerixibat to be used in combination with 
OCA, in patients with inadequate response/intolerance to UDCA taking OCA who
experience pruritus (due to PBC, OCA, or both). The addition of linerixibat to OCA 
therapy may be considered following marketing approval. This drug-drug interaction 
(DDI) study is being conducted to characterize any potential effect of linerixibat on the 
pharmacokinetics of OCA or it’s conjugates in healthy participants at clinically relevant 
dosages.  
Objectives and Endpoints:
Primary objectives
Endpoints
Part A: To assess the effect of oral 
linerixibat on the plasma pharmacokinetics 
of total-OCA (summation of OCA and 
taurine (tauro-OCA) and glycine (glyco-
OCA) conjugates) [Part A Regimen]
Steady state AUC (0-t), AUC (0-24), Cmax, 
and Ctrough for total-OCA plasma 
concentrations
Part B (optional):  To assess the effect of 
oral linerixibat on the plasma 
pharmacokinetics of total-OCA 
(summation of OCA and taurine (tauro-
Same as Part A


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Primary objectives
Endpoints
OCA) and glycine (glyco-OCA) 
conjugates) when linerixibat and OCA 
administration is separated by 12 hours or 
an alternative dose or dosing regimen
Secondary objectives:
Endpoints
Part A: To assess the effect of oral 
linerixibat on the additional measures of 
plasma pharmacokinetics of total-OCA
(summation of OCA and taurine (tauro-
OCA) and glycine (glyco-OCA) 
conjugates) [Part A Regimen]
Tmax for total-OCA and assessment of steady 
state using Ctrough of total-OCA, AUC(0-t), 
AUC (0-24), Cmax, Ctrough, and Tmax for 
OCA, tauro-OCA, and glyco-OCA plasma 
concentrations
Part B (optional):  To assess the effect of 
oral linerixibat on the additional measures 
of plasma pharmacokinetics of total-OCA 
(summation of OCA and taurine (tauro-
OCA) and glycine (glyco-OCA) 
conjugates) when linerixibat and OCA 
administration is separated by 12 hours or 
an alternative dose or dosing regimen
Same as Part A
Parts A & B:  To evaluate the safety and 
tolerability of linerixibat and OCA 
administered according to the dosing 
schedule in healthy participants
To assess repeat dose linerixibat plasma 
pharmacokinetics after Day 1 (Study Day 
20) and Day 14 (Study Day 33)
Adverse events, Electrocardiogram, vital signs, 
and clinical laboratory tests
AUC (0-t), AUC (0-12), Cmax, and Tmax 
(Linerixibat Day 1 (Study Day 20) and Day 14
(Study Day 33)).
Overall Design:
Study 206224 is an open-label, single sequence, crossover, drug interaction study to 
investigate the effect of linerixibat (GSK2330672) on plasma concentrations of 
obeticholic acid (OCA) and OCA conjugates in healthy participants. The study will be 
conducted in a single research centre specialized in the conduct of Phase 1 clinical trials. 
If a clinically important OCA/linerixibat drug-drug interaction (DDI) (average Ctrough of 
total-OCA <20ng/mL) is detected using this definition, the sponsor may consider the 
merit of conducting a follow-up study part (Part B) investigating an alternative 180 mg 
once daily morning dosing of linerixibat separated by 12 hours from OCA (once daily) 
dosed in the evening. The decision to conduct Part B, the dose and the dosing regimen to 
be used will require careful assessment of all PK parameters measured and analyzed in 
Part A.  Based on the analysis of preliminary PK from Part A for OCA and conjugates the 


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results and conclusion must be reached that alternative once-daily linerixibat dosing 
separated by 12 hours has the potential to reduce the DDI observed in Part A.
Importantly, the dose of linerixibat and/or OCA in the contingent Part B may be adjusted, 
prior to the initiation, should the Part A analysis suggest different doses of either study 
drug would be useful to further characterize any potential DDI.
Disclosure Statement: This is an Intervention Model (O) 
Number of Participants:
A maximum of 19 participants in Part A and a planned 19 participants in Part B 
(contingent upon analysis of Part A) will be enrolled to study intervention such that 
approximately 15 participants complete Part A and 15 participants complete Part B of the 
study (if it is conducted).
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility 
for the study, but do not participate in the study, are not considered enrolled.
Intervention Groups and Duration:
The total duration of study participation in Parts A would be up to 52 days exclusive of 
the screening visit (up to 28-35 days). If Part B is conducted, the total study participation 
would be up to 52 days.
Participants will stay in the clinical unit for an initial 2 nights (Day-1 to Day 2) before 
being discharged for 15 days of home dosing (Day 2 to Day 16). Participants will then 
return to the clinical unit for a further 21 overnight stays (Day 17 to Day 38).


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1.2.
Schema
Figure 1
Part A Study Design
Figure 2
Part B (Optional) Study Design


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1.3.
Schedule of Activities (SoA)
Table 1
Schedule of Screening, Follow Up and Early Withdrawal Activities
Procedure
Screening 
(within 
28-35
days of 
Day 1)1
Follow Up 
(7-14 days 
post last 
linerixibat 
dose)
Early 
Withdrawal
(within 7 
days of the 
last dose)
Comments
Informed 
Consent
X
Outpatient 
Visit
X
X
Early withdrawal visit to be 
performed as soon as possible after 
withdrawal date, and within 7 days 
of last dose.
Phone Call
X
Demography
X
Inclusion and 
Exclusion 
Criteria
X
Medical 
History 
X
Including drug/alcohol use and family 
history of disease
12-Lead ECG
X
X
Triplicate ECG measurements will be 
taken at screening, and in single at 
other timepoints
Vital Signs
X
X
Triplicate measurements of heart rate 
and systolic and diastolic blood 
pressure (respiratory rate and 
temperature recorded in single), at 
screening. Single measurements at 
other timepoints.
Urine drugs of 
abuse screen
X
Alcohol and 
smoking breath 
tests
X
HIV and 
hepatitis B and 
C screen
X
Not required if a test has been
performed within 3 months prior to 
first dose of study intervention
Pregnancy Test
X
Serum pregnancy test for WOCBP
only
FSH, 
Oestradiol
X
To confirm post-menopausal status in 
WONCBP only
Laboratory 
safety tests 
X
X
Haematology, Biochemistry (including 
Liver Function Tests (LFTs)) and 
urinalysis is to be performed


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Procedure
Screening 
(within 
28-35
days of 
Day 1)1
Follow Up 
(7-14 days 
post last 
linerixibat 
dose)
Early 
Withdrawal
(within 7 
days of the 
last dose)
Comments
Full physical 
exam
X
Please see Section 8.2.1 for minimum 
requirements. Weight measurement to 
be included
Brief Physical 
Exam
X
Please see Section 8.2.1 for minimum 
requirements. Weight measurement to 
be included
OCA PK 
Sample
X
OCA drug 
Accountability
X
To be performed only if participant 
withdraws between Day 3 and Day 16
AE review
X
X
AE’s will be collected from the start of 
oral dosing until the final follow up
SAE review
X
X
X
SAE’s will be collected from the 
signing of the ICF until final follow up
Concomitant 
medication 
review
X
X
X
Concomitant medications will be 
collected from the signing of the ICF 
until the final follow up
1The suggested screening is 28 days but may be increased to 35 days if necessary and in consultation with 
the medical monitor


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Table 2
Part A Schedule of Activities (Day -1 to Day 38)
Procedure
Study Day
Comments
Inpatient
OP
Inpatient
-1
1
2
3 to 
16
17
18
19
20
21 22 to 
32
33
34
35
36
37
38
Admission to 
clinical unit
X
X
Discharge from 
clinical unit
X
X
Participants will be discharged from the unit following OCA dosing 
on Day 2 with instructions to take OCA daily and return on Day 17 
(am). Participant stay may be extended for safety reasons if deemed 
necessary at the discretion of the investigator.
Inclusion/Exclusion 
Criteria
X
X
Recheck clinical status at Day -1 and Day 1 predose
Medical history 
X
Medical history updates only
12-lead ECG
X
X
X
Triplicate measurements taken Day -1. Single measurements will be 
taken at all other timepoints. If any single measurement is outside 
normal ranges, triplicate measurements to be taken and the mean of 
the triplicate measurements used.
Vital signs
X
X
X
X
Triplicate measurements of heart rate and systolic and diastolic blood 
pressure at Day -1 (respiratory rate and temperature to be taken in 
single); single measurements to be taken at all other timepoints.
Additional vital signs may be taken for safety reasons at the 
discretion of the investigator
Urine drugs of 
abuse screen
X
X
Alcohol and 
smoking breath 
tests
X
X
Pregnancy Test
X
X
Urine pregnancy test at admissions for females of child bearing 
potential only. Positive urine pregnancy test should be confirmed 
with serum pregnancy test.
Laboratory safety 
tests 
X
X
X
Haematology, Biochemistry (including liver function tests (LFTs)) 
and urinalysis is to be performed
Brief physical exam
X
X
X
Please see Section 8.2.1 for minimum requirements. Weight 
measurement to be included


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Procedure
Study Day
Comments
Inpatient
OP
Inpatient
-1
1
2
3 to 
16
17
18
19
20
21 22 to 
32
33
34
35
36
37
38
OCA 10 mg
Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
OCA will be dosed once daily (afternoon dose) at approximately 
12:00 hours (between 12:00 and 14:00). Dosing on Day 2 will occur 
prior to discharge from the clinical unit.
Dispense OCA for 
self-administration 
X
To be dispensed after dosing on Day 2
OCA
Accountability
Check
X
Clinical site to confirm OCA taken as required
Compliance Check
X
X
Participants will be required to confirm compliance with dosing 
schedule daily during this period
Linerixibat 90 mg
Administration
X
X
X
X
X
X
X
X
X
GSK2330672 will be dosed twice daily with an interval of 
approximately 12 hours.
The last linerixibat dose will be taken in the morning on Day 38.
Linerixibat PK 
Sampling
X
X
Blood samples for plasma drug assays should follow the sampling 
schedules in Section 8.5
OCA PK Sampling
X
X
X
X
X
X
X
PGx sample
X
AE Review
AE’s will be collected from the start of oral dosing until final follow 
up
SAE Review
SAE’s will be collected from the time each participant consents until 
final follow up
Concomitant 
Medication Review
Concomitant medications will be collected from the signing of 
the ICF until the final follow up

The timing and number of planned study assessments, including PK and safety assessments may be altered during the study based on newly available data 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study assessments as the result of emerging pharmacokinetic/pharmacodynamic data 
from this study 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 Competent Authority (CA) and ethics committee (EC) will be informed of any safety issues that constitute a 
substantial amendment and require alteration of the safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be 
approved by the CA and the EC before implementation. 


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Table 3
Part B (Optional) Schedule of Assessments (Day -1 to Day 38)
Procedure
Study Day
Comments
Inpatient
OP1
Inpatient
-1
1
2
3 to 
16
17
18
19
20
21 22 to 
32
33
34
35
36
37
38
Admission to 
clinical unit
X
X
Discharge from 
clinical unit
X
X
Participants will be discharged from unit following OCA dosing on 
Day 2 with instructions to take OCA daily and return on Day 17 
(am). Participant stay may be extended for safety reasons if deemed 
necessary at the discretion of the investigator.
Inclusion/
Exclusion Criteria X
X
Recheck clinical status at Day -1 and Day 1 predose
Medical history
X
Medical history updates only
12-lead ECG
X
X
X
Triplicate ECG measurements will be taken Day -1. Single ECG
measurements will be taken at all other timepoints.  If any single 
measurement is outside normal ranges, triplicate measurements will be 
taken, and the mean of the triplicate measurements used.
Vital signs
X
X
X
X
Triplicate measurements of heart rate and systolic and diastolic blood 
pressure at Day -1 (respiratory rate and temperature to be taken in single); 
single measurements to be taken at all other timepoints.
Additional vital signs may be taken for safety reasons at the discretion of 
the investigator
Urine drugs of 
abuse screen
X
X
Alcohol and 
smoking breath 
tests
X
X
Pregnancy Test
X
X
Urine pregnancy test at admissions for females of child bearing potential 
only. Positive urine pregnancy test should be confirmed with serum 
pregnancy test.
Laboratory safety 
tests 
X
X
X
Haematology, Biochemistry (including LFTs) and Urinalysis is to be 
performed
Brief physical 
exam
X
X
X
Please see Section 8.2.1 for minimum requirements. Weight 
measurement to be included


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Procedure
Study Day
Comments
Inpatient
OP1
Inpatient
-1
1
2
3 to 
16
17
18
19
20
21 22 to 
32
33
34
35
36
37
38
OCA 
Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
OCA will be dosed once daily (evening dose) at approximately 20:00. 
Dosing on Day 2 will occur prior to discharge.
Dispense OCA for 
self-
administration 
X
To be dispensed after dosing on Day 2
OCA 
Accountability 
Check
X
Clinical site to confirm OCA taken as required
Compliance 
Check
X
X
Participants will be required to confirm compliance with dosing schedule 
daily during this period
Linerixibat 
Administration
X
X
X
X
X
X
X
X
X
GSK2330672 will be dosed once daily (morning dose) at approximately 
08:00.
The last linerixibat dose will be taken in the morning on Day 38.
Linerixibat PK 
Sampling
X
X
X
X
Blood samples for plasma drug assays should follow the sampling 
schedules in Section 8.5.
OCA PK 
Sampling
X
X
X
X
X
X
X
PGx sample
X
AE Review
AEs to be recorded from the start of oral dosing until final follow 
up
SAE Review
SAEs to be recorded from the time each subject consent’s to 
participate in the study until final follow up
Concomitant 
medication
Concomitant medications will be collected from the signing of the 
ICF until the final follow up

The timing and number of planned study assessments, including PK and safety assessments may be altered during 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 as the result of emerging pharmacokinetic/pharmacodynamic data 
from this study 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 Competent Authority (CA) and ethics committee (EC) will be informed of any safety issues that constitute a 
substantial amendment and require alteration of the safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be 
approved by the CA and the EC before implementation. 


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2.
INTRODUCTION
2.1.
Study Rationale
Primary biliary cholangitis (PBC), formally known as primary biliary cirrhosis is a 
chronic autoimmune liver disease characterized by chronic, progressive cholestasis 
[Metcalf, 1996], resulting in impaired flow of bile through the biliary tree and bile acid 
retention in the enterohepatic circulation (EHC). Additionally, upregulation of intestinal 
bile acid transport has been reported and is thought to contribute to the symptoms and 
progression of PBC [Hofmann, 2009] by exceeding the capacity of the canalicular bile 
acid export pump.  This failure of normal homeostasis could lead to accumulation of bile 
acids in the hepatocyte, resulting in hepatocyte necrosis or apoptosis [Woolbright, 2012],
and often end stage liver disease.  In the cholangiocyte, the accumulation of these 
potentially toxic molecules may exacerbate inflammation and necrosis of the bile 
ductules further.  The primary symptom of cholestasis is pruritus (itching), which has an 
identified mechanistic association with the accumulation of bile acids [Hegade, 2016] and 
represents a significant unmet medical need for patients.
GSK2330672 (linerixibat) is a selective inhibitor of the human ileal bile acid transporter 
(IBAT) and is designed to be a non-absorbable agent restricted to the gastrointestinal 
tract.  It is in development as a novel oral treatment for pruritus in cholestatic liver 
disease.  The IBAT is a member of the sodium-dependent bile salt transport protein 
family, SLC10A2 [Dawson, 2003].  Preferentially expressed in the distal ileum of the 
gastrointestinal tract, the IBAT actively carries bile acids from the gut lumen across the 
brush border of the ileal enterocytes for delivery to the liver via portal blood flow, 
resulting in efficient enterohepatic conservation of bile acids.  It maintains ileal negative 
feedback regulation of hepatic bile acid synthesis via FGF19 signalling to the liver, which 
leads to down-regulation of hepatic CYP7A1 and reduced plasma levels of the bile acid 
synthesis intermediate called 7α-Hydroxy-4-cholesten-3-one (C4). For patients with 
PBC, decreased absorption and increased excretion of bile acids following IBAT 
inhibition is expected to reduce bile acid concentrations in the liver and systemic 
circulation, resulting in reduced hepatobiliary inflammation and improvement of the 
systemic symptom of pruritus.  GSK2330672 is currently in development Phase 2B 
where it is being studied in a population of patients with PBC and pruritus.  
Obeticholic acid (OCA), also known as Ocaliva is a farnesoid X receptor (FXR) agonist.  
FXR agonism reduces bile acid synthesis both by increasing secretion of ileal FGF19, 
which regulates bile acid synthesis by inhibiting CYP7A1 and by direct effects on
regulation of hepatic CYP7A1.which converts cholesterol to 7-alpha-hydroxycholesterol, 
required for bile acid synthesis. OCA is indicated for the treatment of PBC in 
combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to 
UDCA or as monotherapy in adults unable to tolerate UDCA. 
2.2.
Background
In the clinical setting there is potential for linerixibat to be used in combination with 
OCA. In patients with inadequate response/intolerance to UDCA taking OCA who


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experience pruritus (due to PBC, OCA, or both) the addition of linerixibat to OCA 
therapy may be considered following marketing approval. It is therefore important to 
characterize any potential effect of linerixibat on the pharmacokinetics of OCA in 
humans at clinically relevant dosages.  OCA is a bile acid and may rely to some extent on 
the IBAT receptor in the terminal ileum for its absorption.  Additionally, OCA has 
biologically active conjugates which enter the EHC and since linerixibat inhibits the 
IBAT receptor, it is important to determine whether linerixibat inhibits the absorption of 
OCA or its conjugates to a clinically significant degree.  Accordingly, a drug interaction 
(DDI) study with linerixibat (potential perpetrator) and OCA (potential victim) is being 
conducted to inform both future clinical trials with linerixibat and the potential 
concomitant administration of these drugs in a clinical setting. Participants taking OCA 
have heretofore been ineligible for clinical trials with linerixibat, including a completed 
Phase IIa trial (BAT117213) and an ongoing Phase IIb trial (Study 201000), and data 
from this study may allow future participation of these patients.
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and potential
adverse events of linerixibat (GSK2330672) may be found in the GSK2330672 
Investigator’s Brochure (GSK Document number 2010N111289_05) and in the current 
full prescribing information for Ocaliva.


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2.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK2330672]

Diarrhoea/GI symptoms

Animal studies have shown diarrhoea and 
GI symptoms including altered bowel 
motions (see Investigator’s Brochure (IB)
GSK Document number 2010N111289_05; 
Section 4.5).

AEs for diarrhoea and GI symptoms have 
been recorded in human studies to date 
including loose stools (see IB GSK 
Document number 2010N111289_05
Section 5.3).

Exclusion criteria have been added 
excluding participants with a history of 
gastrointestinal disease, cholesystectomy 
and any current episode or recent chronic 
history of clinically significant diarrhoea
(See Section 5.2)

In this DDI study participants who may 
experience diarrhoea will not be permitted 
the use of anti-diarrheal medications of any 
kind. 

Potential gallstones due to interruption of 
enterohepatic recirculation of bile acids

Report of gallstone formation associated 
with genetic polymorphisms of the iBAT 
gene SLC10A2 in human studies (See IB, 
Version 05, GSK Document number 
2010N111289_05 Section 5.3.1). A 
nonfatal SAE of acute cholecystitis leading 
to hospitalisation for cholecystectomy and 
withdrawal from study intervention: Prior 
to dosing with metformin and linerixibat, 
the participant experienced diarrhoea, back 
pain and WBC count above the reference 
range. The SAE was considered not 
attributable to study drug by the 
investigator.

Exclusion criteria have been added to 
exclude participants with current 
symptomatic cholelithiasis or inflammatory 
gall bladder disease (See Section 5.2).

Participants will be informed that a possible 
risk of gallstones exists, but that studies in 
participants taking linerixibat have not 
shown an increase in reports of gallstones

Investigative staff will monitor participants 
for symptoms and signs of cholelithiasis in 
the informed consent form.

Increase in alanine aminotransferase 
(ALT).

Minor reversible ALT elevations have been
reported in healthy participant studies (see 
IB GSK Document number 

Clear stopping criteria have been added as 
described in Section 7.1.1.

Exclusion criteria have been added to 
exclude participants with elevated ALT (see 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
2010N111289_05 Section 5.3).
Section 5.2.
Ocaliva

Pruritus 

Risk of pruritis as described in the 
summary of product characteristics 
(SMPc) for Ocaliva

The risk of pruritus in healthy participants is 
small. Exclusion criteria have been added to 
exclude participants with a history of 
dermatologic disorders or clinically 
significant itching as described in Section 
5.2.
Other

Self-Administration of OCA by 
Participants

Participants will be self-administering 
OCA outside of the clinical unit. There is 
a risk that if participants do not 
administer the intervention during the 
required time window. This may 
introduce variability and affect data 
interpretation

During the period of self-administration, the 
clinical unit will be confirming compliance 
with the participants on a daily basis and 
ensure daily compliance from the 
participants to the extent possible. 
Participants will be given training and 
instructions prior to discharge from the 
clinical unit on Day 2 and drug 
accountability will be performed when the 
participants return to the unit.

Study participation outside of the unit

During study participation outside of the 
until participants may violate protocol 
specified procedures by taking prohibited 
medications, consuming prohibited food 
items or engaging in prohibited 
behaviours (i.e. smoking)

Participants who report non-compliance or 
demonstrate non-compliance with study 
medication or violate protocol procedures 
will be assessed on a case-by-case basis 
with the sponsor and may be asked to 
perform early withdrawal assessments and 
be withdrawn from study participation.


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2.3.2.
Benefit Assessment
There is no clinical benefit for healthy participants taking part in this study.  However, 
participants will undergo a medical evaluation during screening (including a physical 
examination, ECG, vital signs and laboratory assessments), which may provide important 
health information.
2.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures that will be implemented to minimise the risk to 
participants participating in the clinical study, the potential risks associated with the 
administration of GSK2330672 are considered to be justified by the potential benefits 
that may be afforded to patients with PBC if this and future studies with GSK2330672 
are deemed successful for the participants from the study treatment.
3.
OBJECTIVES AND ENDPOINTS
Primary objectives
Endpoints
Part A: To assess the effect of oral 
linerixibat on the plasma pharmacokinetics 
of total-OCA (summation of OCA and 
taurine (tauro-OCA) and glycine (glyco-
OCA) conjugates) [Part A Regimen]
Steady state AUC (0-t), AUC (0-24), Cmax, 
and Ctrough for total-OCA plasma 
concentrations
Part B (optional):  To assess the effect of 
oral linerixibat on the plasma 
pharmacokinetics of total-OCA
(summation of OCA and taurine (tauro-
OCA) and glycine (glyco-OCA) 
conjugates) when linerixibat and OCA 
administration is separated by 12 hours or 
an alternative dose or dosing regimen
Same as Part A
Secondary objectives:
Endpoints
Part A: To assess the effect of oral 
linerixibat on the additional measures of 
plasma pharmacokinetics of total-OCA
(summation of OCA and taurine (tauro-
OCA) and glycine (glyco-OCA) 
conjugates) [Part A Regimen]
Tmax for total-OCA and assessment of steady 
state using Ctrough of total-OCA, AUC(0-t), 
AUC (0-24), Cmax, Ctrough, and Tmax for 
OCA, tauro-OCA, and glyco-OCA plasma 
concentrations
Part B (optional):  To assess the effect of 
oral linerixibat on the additional measures 
of plasma pharmacokinetics of total-OCA
(summation of OCA and taurine (tauro-
Same as Part A


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Primary objectives
Endpoints
OCA) and glycine (glyco-OCA) 
conjugates) when linerixibat and OCA 
administration is separated by 12 hours or 
an alternative dose or dosing regimen
Parts A & B:  To evaluate the safety and 
tolerability of linerixibat and OCA 
administered according to the dosing 
schedule in healthy participants
To assess repeat dose linerixibat plasma 
pharmacokinetics after Day 1 (Study Day 
20) and Day 14 (Study Day 33)
Adverse events, Electrocardiogram, vital signs, 
and clinical laboratory tests
AUC(0-t), AUC (0-12), Cmax, and Tmax 
(Linerixibat Day 1 (Study Day 20) and Day 14 
(Study Day 33)).
4.
STUDY DESIGN
4.1.
Overall Design
This is a single-centre, one part (with optional second part) open-label, single sequence
crossover, drug interaction study to investigate the effect of linerixibat (GSK2330672) on 
plasma concentrations of obeticholic acid (OCA) and OCA conjugates in healthy 
participants. The study will be conducted in a single clinical unit specialized in the 
conduct of Phase 1 clinical trials.
Each participant will be screened up to 28-35 days before their first dose and will have a 
follow up call at 7-14 days post-last linerixibat dose. 
The study is designed to assess the effect of oral linerixibat as a potential perpetrator on 
the pharmacokinetics of OCA (victim), its taurine (tauro-OCA) and glycine (glyco-OCA) 
conjugates, and total-OCA (summation of OCA + both conjugates).  OCA, tauro-OCA 
and glyco-OCA are equipotent.
In a Phase 3 study with PBC patients, an exposure-response relationship was derived for 
% reduction of alkaline phosphatase (ALP) and Ctrough of total-OCA concentrations.  At
6 months the median total-OCA Ctrough was 45.3 ng-eq/mL. Therefore, average total-
OCA Ctrough concentrations >40ng/mL were predicted to decrease ALP by at least 30%.  
There was plateauing of ALP reduction with higher trough concentrations.  Therefore, 
total-OCA Ctrough concentrations of >40ng/mL are clinically important concentrations 
for PBC patients.
In the FDA CDER Clin Pharm review, the reviewers compared steady state plasma 
concentrations in PBC patients to steady state plasma concentrations in healthy 
participants. In general, PBC patients had higher plasma total-OCA trough concentrations 
compared to healthy participants though exact quantitation is difficult to know from the 
available data. Therefore 2-fold difference was deemed to be the best estimate. These
comparisons were made across studies and ranged from 0.76 to 3.46 with most data 


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pointing to PBC greater than healthy participants. Because this study will be conducted 
in healthy participants, the plasma target has been adjusted to reflect the study 
population.  Therefore, average total-OCA Ctrough (predose concentrations) of 40 ng-
eq/mL in PBC patients has been adjusted down to 20 ng-eq/mL for healthy participants. 
In the context of this study, a clinically important threshold of total-OCA Ctrough 
following coadministration with linerixibat 90 mg twice-daily for 18 consecutive days is 
≥20ng-eq/mL.  
If a clinically important OCA/linerixibat DDI (average Ctrough of total-OCA <20ng/mL) 
is detected using this definition the sponsor may consider the merit of conducting a 
follow-up study part (Part B) investigating a suggested alternative 180 mg once daily 
morning dose of linerixibat separated by 12 hours from OCA (once daily) dosed in the 
evening. The final doses of OCA and linerixibat used in Part B will be decided based on 
emerging PK data. The decision to conduct Part B will require careful assessment of all 
PK parameters measured and analyzed in Part A. Based on the analysis of preliminary 
PK from Part A for OCA and conjugates the results and conclusion must be reached that 
alternative once-daily linerixibat dosing separated by 12 hours has the potential to reduce 
the DDI observed in Part A.
Pharmacokinetic sampling of linerixibat is included in this protocol due to the general 
lack of plasma PK data available for linerixibat.  In the early development of linerixibat, 
the assay used to quantify linerixibat in plasma had a lower limit of quantitation (LLQ) of 
1ng/mL and most of the samples collected in clinical trials were below the LLQ.   
Recently, a new bioanalytical method was developed with a 100-fold improvement in the 
LLQ to, 10 pg/mL. The risk of OCA interfering with linerixibat PK sampling is 
considered minimal and acceptable and saves conduct of an additional cohort of 
participants.
4.1.1.
Part A
The total duration of study participation in Part A is expected to be 52 days exclusive of 
the screening visit (up to 28-35 days). Participants will stay in the clinical unit for an 
initial 2 nights (Day-1 to Day 2) before being discharged for 15 days of home dosing 
(Day 3 to Day 17). Participants will then return to the clinical unit for a further 21 
overnight stays (Day 17 to Day 38).
Approximately 19 participants will be enrolled providing 15 completers estimating an 
approximate 20% withdrawal rate. Additional participants may be enrolled to ensure 15 
completers. A participant is considered to have completed the study if he/she has 
completed all phases of the study up until discharge from the clinical unit on Day 38.
OCA will be dosed at 10 mg once-daily (once daily) for a total of 37 continuous days 
(Study Day 1 through to the afternoon of Day 37).  Linerixibat will be dosed at 90 mg 
twice-daily (BID) for total of 18.5 days (Study Day 20 to the morning of Day 38).  The 
morning dose of linerixibat and the afternoon dose of OCA should be separated by 
approximately 4 hours. 
Following informed consent and successful screening, enrolled participants will take 
OCA once-daily in the afternoon at approximately 12:00 – 14:00 while in the clinical unit


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on Study Days 1 and 2. Upon completion of all study assessments on Day 2, participants 
will be dispensed OCA for home dosing (Days 3-16), a diary card to record dosing
information (date and times) and detailed study instructions and be permitted to leave the 
clinical unit for 15 days returning on the morning of study Day 17. While participating in 
the study outside of the clinic participants will be required to report adverse events, 
contact centre personnel with questions and record the time of their daily OCA 
administration using study provided materials. 
On Study Days 3-16, participants will self-administer the OCA dose in the afternoon 
(between approximately 12:00 and14:00) with a meal or snack.  Participants will use a 
paper diary to record the date and time the dose was taken. The clinical unit will be in 
regular contact daily with the participants to remind them to take their daily dose of OCA 
within the specified period. 
Participants will return to clinic on the morning of Day 17 to prepare for their next 
scheduled OCA dose. On Study Days 17, 18 and 19 pre-dose total-OCA Ctrough samples 
will be collected. On Day 18 samples for OCA PK profiles will be collected for 24 hours
as described in Section 8.5.1. Eighteen days is considered sufficient time for OCA to 
reach steady state after continuous daily dosing. On Study Days 20 and 33, PK samples 
(0 to 12 h) for linerixibat will be collected. The last dose of OCA will be administered in 
the afternoon of Day 37 and the last dose of linerixibat will be administered in the 
morning of Study Day 38. Predose total-OCA Ctrough samples will be collected on 
Study Days 35, 36, 37 and 38. On Study Day 37 samples will be collected for OCA PK 
(0 to 24 h). Participants will be discharged from the clinical unit following the final PK 
sample on Study Day 38, once after all protocol specified lab samples are collected 
participants will be provided complete discharge instructions. These instructions will 
include details of how to contact the clinical unit with any questions, or concerns. A 
follow-up phone call will take place for all participants approximately 7 to 14 days
following final dose of linerixibat. 
4.1.2.
Part B (Optional)
Part B is optional. If required, it will be conducted as demonstrated in Section 1.2
following procedures as demonstrated in Section 1.3. In Part B, it is intended that 
linerixibat will be dosed as 180mg once daily in morning (e.g., 8:00am) and OCA will be 
dosing once daily in the evening (e.g., 8:00pm) separated by approximately 12 hours
from the morning linerixibat dose. The PK sampling schedule will also differ and will be 
taken over 24 h., as described in Section 8.5.2.
On Days 3-16 the OCA dose will be self-administered from the participant’s home. The 
OCA dose will be taken in the evening (approximately 20:00), with a snack or meal.
The doses, dose regimen (once or twice daily) and dosing window of linerixibat and/or 
OCA once daily (5mg or 10mg) in Part B may be changed as necessary based upon 
analysis of emerging PK, safety or tolerability findings.


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4.2.
Scientific Rationale for Study Design
The absorption, metabolism and excretion of linerixibat have been studied in pre-clinical 
animal models, in vitro, and in previous clinical trials. However, no dedicated clinical 
studies of drug absorption, metabolism, and excretion have been conducted for linerixibat
to date.  The dose of 90 mg (twice daily) of linerixibat is dose tested in a completed 
Phase 2a study (BAT117213) and currently being evaluated in an ongoing randomized, 
double-blind Phase IIb study (Study 201000) assessing linerixibat as a treatment for 
cholestatic pruritus in patients with PBC.  There have been no human studies assessing a 
potential DDI between linerixibat and OCA.
Several clinical pharmacology studies have been conducted in healthy participants with 
doses of OCA ranging from 5mg to 250mg (FDA CDER Clin Pharm Review, 2016) Five 
drug interaction studies have been completed with 10mg and 25mg in healthy volunteers 
for up to 28 days (Edwards, 2017). The pharmacokinetics of OCA is described below as 
referenced in product labelling [Ocaliva SMPc, 2018].  
Absorption 
Following multiple oral doses of OC 10 mg given once daily, peak plasma concentrations 
(Cmax) of OCA occurred at a median time (Tmax) of approximately 1.5 hours. The 
median Tmax for both the glyco- and tauro-conjugates of OCA was 10 hours. 
Coadministration with food did not alter the extent of absorption of OCA. 
Following multiple-dose administration of OCA 5, 10, and 25 mg given once daily (2.5 
times the highest recommend dosage) for 14 days, systemic exposures of OCA increased 
dose proportionally. Exposures to glyco-OCA and tauro-OCA, and total OCA (the sum of 
OCA and its two active conjugates) increased more than proportionally with dose. 
Distribution 
Human plasma protein binding of OCA and its conjugates is greater than 99%. The 
volume of distribution of OCA is 618 L. The volumes of distribution of glyco- and tauro-
OCA have not been determined.
Metabolism 
Obeticholic acid (OCA) is conjugated with glycine or taurine in the liver and secreted 
into bile. These glycine and taurine conjugates of OCA are absorbed in the small intestine 
leading to enterohepatic recirculation. The conjugates can be deconjugated in the ileum 
and colon by intestinal microbiota, leading to the conversion to OCA that can be 
reabsorbed or excreted in feces, the principal route of elimination. 
After daily administration of OCA, there was accumulation of the glycine and taurine 
conjugates of OCA, which have in vitro pharmacological activities similar to the parent 
drug, OCA. The metabolite-to-parent ratios of the glycine and taurine conjugates of OCA
were 13.8 and 12.3 respectively, after daily administration. An additional third OCA
metabolite, 3-glucuronide, was formed but was considered to have minimal 
pharmacologic activity. Total-OCA (OCA+OCA conjugates) t1/2 is reported as 4 days.


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Excretion 
After administration of radiolabeled OCA, about 87% of the dose was excreted in feces 
through biliary secretion. Less than 3% of the dose was excreted in the urine with no 
detection of OCA.
Specific Populations 
Age, Sex Race/Ethnicity: Based on population pharmacokinetic analysis, the 
pharmacokinetics of OCA would not be expected to be altered based on age, sex, or 
race/ethnicity, therefore there is no need to restrict age range to a younger or older 
population.  
4.3.
Justification for Dose
4.3.1.
Linerixibat
PBC patients have received linerixibat (GSK2330672) in clinical trials at a dose of 45 mg 
twice daily increased to 90 mg twice daily after 3 days and continued for 14 days in total 
(BAT117213).  The linerixibat dose chosen in Part A of this study is 90 mg twice daily.
The optional/flexible Part B dose of linerixibat is intended to be 180 mg once daily, but 
may be amended based on emerging PK, safety and tolerability data. 90mg twice daily 
and 180mg once daily doses are being evaluated in a randomized, double-blind, placebo-
controlled dose-ranging Phase 2b study with a 3-month treatment duration (201000).  The 
range doses of linerixibat being evaluated in the 201000 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)
The maximum total daily dose is 180mg as stated in the Investigator Brochure (GSK 
Document number 2010N111289_05). This 180mg dose has adequate nonclinical 
toxicology cover for local gastrointestinal tract exposure (based on administered oral 
dose, i.e., 3.6 mg/kg/day assuming 50 kg body weight): 278-fold No Observed Adverse 
Effect Level (NOAEL) in the rat and 139-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 (GSK Document number 2010N111289_05).
Participants in Part A of 206224 will receive their first 90 mg dose of linerixibat in the 
morning of Study Day 20 (corresponding to 20 days of OCA dosing). Participants will 
continue taking linerixibat 90 mg twice daily for a total of 17.5 days receiving their last 
dose in the morning of Study Day 38.  The linerixibat doses chosen for this study were 
carefully considered in the context of available pre-clinical and clinical data including 
those data describing the safety, tolerability and pharmacodynamic biomarker response to 
treatment in healthy participants and in patients with PBC.  However, the exact doses 
used may change at the discretion of the sponsor but will not exceed those which have 


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been shown to be safe and tolerable. The linerixibat Investigator Brochure (GSK 
Document number 2010N111289_05) provides further details.
4.3.2.
OCA
The recommended starting dose for OCA in patients with PBC is 5mg with guidance to 
increase to 10mg once daily if needed after assessing efficacy at 3 months.  To inform the 
drug interaction labelling for OCA, healthy participants in five separate studies received 
repeat doses of 10mg and 25mg for 19 to 24 days (Edwards, 2017). The early 
PK/tolerability studies dosed up to 250mg once daily for 12 days. Therefore, the 10mg 
dose chosen for this study will provide a more comparable Ctrough to the patient 
population than the 5mg dose providing a more meaningful result. It is anticipated that 
linerixibat will either reduce or have no effect on OCA and conjugates in plasma.
OCA and conjugates undergo enterohepatic cycling and PBPK models predict the time to 
steady state is between 14 and 21 days.  This study will dose OCA once-daily for 18 days 
prior to the first OCA PK sampling (0 to 24 h). Daily OCA dosing will continue to Study 
Day 37 at approximately 12pm.
Linerixibat is assumed to achieve gut lumen steady state exposure by 3-6 days.  This 
timeframe allows for slow and fast GI motility rates.
It is difficult to estimate when OCA will reach a new steady state with linerixibat added 
on because IBAT inhibition has the potential to alter the clearance and half-life of OCA.  
In this study linerixibat dosing begins on Study Day 20 after participants have been 
taking OCA 10 mg once-daily for a period of 20 days thereby ensuring OCA is at steady 
state.  Linerixibat (90mg twice daily and OCA 10 mg once daily) will continue 
concomitantly for a period of 18 days thereafter providing sufficient time for OCA to 
again reach steady state following the initiation of linerixibat dosing.  This robust study 
design provides confidence that OCA PK sampling on Study Day 37 (0 to24 h) is 
sufficient to assess the effects of steady state linerixibat on steady state OCA PK.
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all 
phases of the study up until discharge from the clinical unit on Day 38.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.


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5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply
AGE
1. Between 18 and 80 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF PARTICIPANT 
2. Healthy, as determined by the investigator or medically qualified designee, 
based on a medical evaluation including medical history, physical examination, 
vital signs, laboratory tests, and ECG. 
A participant with a clinical abnormality or laboratory parameter (i.e., outside 
the reference range for the population being studied), which is not specifically 
listed in the eligibility criteria, may be included only if the investigator agrees in 
consultation with the GSK Medical Monitor and documents in the source 
documentation that the finding is unlikely to introduce additional risk factors 
and will not interfere with the study procedures or outcomes.
Note: Screened participants with laboratory values outside of the normal range 
may be repeated once for inclusion into the study at the discretion of the 
Investigator.
3. Body weight >50kg and body mass index (BMI) within the range 18.5 –
32kg/m2 (inclusive)
INFORMED CONSENT
4. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.


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5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
MEDICAL CONDITIONS: 
1. Any active dermatologic disorder leading to or with the potential to cause pruritus or 
a recent history of unexplained clinically significant itching locally or generally 
within the prior 3 months.
2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones) and/or 
confirmed hepatocellular carcinoma or biliary cancer.
3. Participants with a history of cholecystectomy.
4. Current symptomatic cholelithiasis or inflammatory gall bladder disease. 
5. Significant history of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, haematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; constituting 
a risk when taking the study intervention; or interfering with the interpretation of 
data. 
6. Any clinically relevant abnormality identified at the screening medical assessment 
(physical examination/medical history) clinical laboratory tests, or 12-lead ECG.
7. Current episode, recent history (within 1 month of screening visit), or chronic history 
SEX
5. Male and female
Female participants: 
A female participant is eligible to participate if she is not pregnant not breastfeeding, 
and at least one of the following conditions applies:

Not a woman of childbearing potential as defined in Section 10.4: Appendix
4
OR

A WOCBP who agrees to follow the contraceptive guidance in Section 10.4: 
Appendix 4 during the treatment period and until at least 4 weeks after the 
last dose of study treatment.
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy


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MEDICAL CONDITIONS: 
of clinically significant diarrhoea. 
8.
Lymphoma, leukaemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years.
9. Any current medical condition (e.g. psychiatric disorder, senility, dementia, or other 
condition), clinical or laboratory abnormality, or examination finding that the 
investigator considers would put the participant at unacceptable risk, which may 
affect study compliance or prevent understanding of the aims or investigational 
procedures or possible consequences of the study.
10. Regular use of known drugs of abuse or history of drug abuse or dependence within 6 
months of the study. 
11. Regular alcohol consumption within 6 months prior to the study defined as an 
average weekly intake of >14 units for females and >21 units for males. One unit is 
equivalent to 8 g of alcohol: a glass (~240 mL) of beer, 1 small glass (~100 mL) of 
wine or 1 (~25 mL) measure of spirits.
12. History of or regular use of tobacco- or nicotine-containing products (confirmed by 
smokerlyzer test) in the 3 months prior to screening.
PRIOR/CONCOMITANT THERAPY
13. Administration of any IBAT inhibitor (including linerixibat) or OCA in the 3 months 
prior to screening.
14. Past or intended use of over-the-counter or prescription medication (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inhibitor) or 5 half-lives (whichever is longer) prior to the first dose 
of study medication, unless approved by the Investigator in conjunction with GSK.
Medical Monitor Note: 
Specific medications may be allowed as listed in Concomitant Medication section 
(Section 6.5) of the protocol. Approved medications may be considered on a case by 
case basis by the Investigator in consultation with the Medical Monitor.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
15. Current enrolment in a clinical trial; recent participation in a clinical trial and has 


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received an investigational product within 30 days (or 5 half-lives of previous trial 
intervention, whichever is longer) before the first dose in the current study.
16. Exposure to more than 4 new chemical entities within 12 months before the first dose 
in the current study.
DIAGNOSTIC ASSESSMENTS
17. Screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5x 
ULN.
18. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
19. Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C 
antibody test result at screening or within 3 months of the screening visit.
Note:  Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
20. Positive serum pregnancy test at screening or positive urine pregnancy test at 
admission in women of child bearing potential only.
21. Positive human immunodeficiency virus (HIV) antibody test.
22. QTc >450 msec on ECG performed at Screening.
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, machine-read or 
manually over-read.
The specific formula that will be used to determine eligibility and discontinuation for 
an individual subject should be determined prior to initiation of the study. In other 
words, several different formulae cannot be used to calculate the QTc for an 
individual subject and then the lowest QTc value used to include or discontinue the 
subject from the trial.
OTHER EXCLUSIONS
23. Positive pre-study drug/alcohol screen or positive drug/alcohol screen at any time 
during the study.


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24. Female participants unable or unwilling to comply with specific contraception 
restrictions as detailed in Section 10.4.
25. Where participation in the study would result in donation of blood or blood products 
in excess of 500mL within a 56-day period.
26. Unwillingness or inability to follow the procedures outlined in the protocol for the 
expected duration of study participation.
27.Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Participants will receive standard meals while in the clinical unit. Water will be 
provided ad libitum.

Participants will be provided meals or snacks at the same time as OCA dosing while 
inpatient.

Participants will be instructed to take OCA with meal or snack as outpatients 
between 12:00 and 2:00 PM.

On PK sampling days for OCA, identical meals will be provided.

Participants will be provided meals or snacks 30 minutes after linerixibat doses.

On PK sampling days for linerixibat, identical meals will be provided.

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days 
prior to the first dose of study intervention until follow up.

Participants should be fasted for at least 6 hours prior to clinical safety laboratory 
sampling at screening and admission to the clinical unit on Day -1.
5.3.2.
Caffeine, Alcohol, and Tobacco

Participants should abstain from ingesting caffeine- or xanthine-containing products 
(e.g., coffee, tea, cola drinks, and chocolate) for 24 hours prior to screening and for 
48 hours before admissions on Days -1 and 17. This restriction will be in place until 
after collection of the final pharmacokinetic (PK) and/or pharmacodynamic sample
for a given dosing session.

During the period of home dosing (from Day 3 – Day 15), participants should limit 
caffeine or xanthine-product intake to a maximum of one typical beverage (or 
chocolate bar) per day.


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
During each dosing session, participants will abstain from alcohol for 24 hours prior 
to screening and before the first dose of OCA until after collection of the final PK 
and/or pharmacodynamic sample. 

Use of tobacco or nicotine containing products will not be allowed throughout the 
study and from 3 months prior to screening until the end of study participation, as 
described in exclusion criteria #12.
5.3.3.
Activity
Participants will abstain from strenuous exercise for 72 hours before each blood 
collection and for clinical laboratory tests. Participants may take part in light recreational 
activities during stays in the clinical unit (e.g., walking, watching television, reading).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations and any 
serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened under the following conditions:

The reason for prior screen failure is deemed temporary or has been fully 
resolved.

It is a clinical abnormality or laboratory parameter which is/are not specifically 
listed in the inclusion/exclusion criteria.
In either case, the rescreening must be approved in writing by the medical monitor. 
Rescreening decisions should be documented to indicate that rescreening the participant 
will not introduce additional risk factors and will not interfere with study procedures or 
ability to interpret results. 
If the start of the study is delayed for an individual participant for any reason (but the 
participant has previously met the inclusion/exclusion criteria) and more than 28 days has 
elapsed between screening assessments and the first dosing day, all or part of the 
screening procedures may be repeated at the discretion of the investigator.
Participants may only be rescreened once and must be given a new participant number.


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6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s) or marketed 
product(s) intended to be administered to a study participant according to the study 
protocol.
6.1.
Study Intervention(s) Administered
6.1.1.
Part A
Study Treatment 
Name
GSK2330672 (linerixibat)
Ocaliva (Obeticholic acid) (OCA)
Dose Formulation
Tablet
Tablet
Unit Dose 
Strength(s)
45mg
5mg or 10mg
Dosage Level(s)
90mg Twice Daily
10mg Once Daily
Route of 
Administration
Oral
Oral
Use
Experimental, potential 
perpetrator
Experimental, Potential victim
Dosing 
Instructions
Swallowed whole with 
approximately 240mL water
Swallowed whole with 
approximately 240mL water
Sourcing
Provided centrally by 
GlaxoSmithKline
Provided centrally by 
GlaxoSmithKline
Packaging and 
Labelling
Study Intervention will be 
provided in bottles. Each 
bottle will be labelled as 
required per country 
requirement.
Study Intervention will be 
provided in bottles. Each bottle
will be labelled as required per 
country requirement.


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6.1.2.
Part B (Optional)
Study Treatment 
Name
GSK2330672 (linerixibat)
Ocaliva (Obeticholic acid) 
(OCA)
Dose Formulation
Tablet
Tablet
Unit Dose 
Strength(s)
45mg
10mg
Dosage Level(s)
180mg Once Daily
10mg Once Daily
Route of 
Administration
Oral
Oral
Use
Experimental, potential 
perpetrator
Experimental, Potential victim
Dosing Instructions
Swallowed whole with 
approximately 240mL water
Swallowed whole with 
approximately 240mL water
Sourcing
Provided centrally by 
GlaxoSmithKline
Provided centrally by 
GlaxoSmithKline
Packaging and 
Labelling
Study Intervention will be 
provided in bottles. Each
bottle will be labelled as 
required per country 
requirement.
Study Intervention will be 
provided in bottles. Each bottle
will be labelled as required per 
country requirement.
*The dosage and administration of linerixibat and/or OCA may be adjusted in the 
optional Part B if conducted. Any adjustments will be made prior to commencement of 
Part B and will be based upon the full analysis of the Part A results.
6.2.
Measures to Minimize Bias: Randomisation and Blinding
This is an open-label study with no randomization and no blinding of participants, site
personnel, or sponsor personnel.
6.3.
Preparation/Handling/Storage/Accountability

To the extent possible, the investigator or designee must confirm appropriate 
temperature conditions have been maintained during transit for all study 
intervention received and any discrepancies are reported and resolved before use of 
the study intervention.


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
Only participants enrolled in the study may receive study intervention. Only 
authorized site staff may supply or administer study intervention during inpatient 
stays, and only participants may administer study intervention during home-dosing 
period (Days 3-16). All study interventions must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual.

Under normal conditions of handling and administration, study intervention 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.
6.4.
Study Intervention Compliance

When participants are dosed at the site, they will receive study intervention directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study intervention and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person 
administering the study intervention. Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested.

When participants self-administer study intervention(s) at home, compliance with 
OCA will be assessed by the site using a daily compliance check and returned tablets 
will be counted and reconciled during the site visits. This will be documented in the 
source documents and eCRF.  
6.5.
Concomitant Therapy
Any medication (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrolment or receives during the study must be recorded along 
with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency


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The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or non-prescription drugs (including 
anti-diarrhoeal medication, vitamins and dietary or herbal supplements) within 7 days (or
14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) 
before the start of study intervention until completion of the follow-up visit, unless, in the 
opinion of the investigator and sponsor, the medication will not interfere with the study. 
Paracetamol, at doses of 2 grams/day and other concomitant medication may be
permitted for use any time during the study and must be reported to the site staff. Other 
medications may be used on a case-by-case basis as permitted by the investigator in 
consultation with the Medical Monitor (if required).
Anti-diarrhoeal medications of any kind are not permitted for use throughout the study.
6.6.
Dose Modification
Dose modification is not permitted.
6.7.
Intervention after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study as only healthy participants are eligible for study participation.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention and be withdrawn from the study. If study intervention is permanently 
discontinued, the participant should be encouraged to attend for early termination 
assessments, and these should be as per early withdrawal procedures as per Table 1. See 
the SOA for data to be collected at the time of early withdrawal.
7.1.1.
Liver Chemistry Stopping Criteria
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met:
Liver Safety Required Actions and Follow up Assessments can be found in Appendix 6.


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Liver chemistry stopping, and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. These protocol guidelines are 
in alignment with the FDA premarketing clinical liver safety guidance:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Discontinuation of study intervention for abnormal liver tests is required when:

a participant meets one of the conditions outlined or

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant. 
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious 
adverse event; ULN = upper limit of normal.
7.1.2.
QTc Stopping Criteria
A participant that meets either bulleted criterion below will be withdrawn from the study.  

QTcF > 500 msec,

Change from baseline in healthy volunteer participants: QTcF >60 msec
If an automated reading is not available, the ECG should be manually over-read by the
investigator or adequately trained physician.


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See the SoA for data to be collected at the time of early withdrawal for any further 
evaluations that need to be completed.
7.2.
Participant Discontinuation/Withdrawal 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. This is expected to be 
uncommon.

At the time of discontinuing from the study, if possible, an early withdrawal 
visit should be conducted, as soon as possible after the point of withdrawal as 
shown in Table 1. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be 
completed.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

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 who report non-compliance or demonstrate non-compliance with study 
medication or violate protocol procedures will be assessed on a case-by-case basis with 
the sponsor and may be asked to perform early withdrawal assessments and be 
withdrawn from study participation.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 


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mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

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 intervention.

Adherence to the study design requirements, including those specified in the SoA, 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.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 
mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

At timepoints where more than one procedure is to be completed at the same 
timepoint, the preferred order of assessments is as follows:

Electrocardiograms (ECGs)

Vital Signs

Pharmacokinetic (PK) blood sampling (nominal time to be recorded)
The timing of the assessments should allow the PK blood draw to occur as close as 
possible to the exact nominal time. All safety assessments will be timed and 
performed relative to the start of dosing. A table defining the allowed variance in 


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timings of assessments without being considered a protocol deviation will be 
included in the SRM.
8.1.
Efficacy Assessments
There are no efficacy assessments associated with this study.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the eyes, 
skin, joints, cardiovascular, respiratory, gastrointestinal and neurological
systems. Height and weight will also be measured and recorded in the eCRF.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen). Weight will 
also be measured.
8.2.2.
Vital Signs

Tympanic temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed.

Blood pressure and pulse measurements will be assessed in a supine position 
using a completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones).

Vitals signs will be performed in triplicate (blood pressure and heart rate only) 
will be taken at screening and Day -1, and in single at all other timepoints. At 
timepoints where triplicate values will be measured, blood pressure readings 
will be separated by at least one minute and the average of the 3 readings will be 
recorded in the eCRF. 
8.2.3.
Electrocardiograms

12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. 


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
At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed in less than 
4 minutes. The mean of these measurements will be recorded in the eCRF.

ECGs should be taken in a supine position should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones).
8.2.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) 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 CRF. 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 Medical 
Monitor consulted.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., 
SAE or AE or dose modification), then the results must be recorded in the CRF.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention (see Section 7).


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8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the informed consent form until 
completion of the follow up phone call at the time points specified in the SoA 
(Section 1.3).

All AEs will be collected from the start of dosing until completion of the follow-
up phone call at the time points specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study on Day 38, and he/she considers the event to be reasonably related to the 
study intervention or study participation, the investigator must promptly notify 
the sponsor.
8.3.2.
Method of Detecting AEs and SAEs

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 3.

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.3.3.
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 will be followed until the event is 
resolved, stabilized, otherwise explained or the participant is lost to follow-up (as defined 
in Section 7.3). Further information on follow-up procedures is given in Appendix 3.
8.3.4.
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 intervention under clinical investigation are 
met. 


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
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

For all studies except those utilizing medical devices 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 SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and
will notify the IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study intervention and until 6-8 weeks following the delivery date, providing the 
participant consents to follow-up.

If a pregnancy is reported, the investigator should inform the Medical Monitor within 
24 hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
8.4.
Treatment of Overdose
For this study, any dose of linerixibat greater than 180mg within a 24-hour period will be 
considered an overdose.
GSK does not recommend specific treatment for an overdose as there is no specific 
antidote for linerixibat. In the event of a suspected overdose, it is recommended that 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 GSK Medical Monitor immediately
2. Closely monitor the participant for AE/SAEs and laboratory abnormalities as agreed 
with the Medical Monitor on a case-by-case basis.
3. Obtain a plasma sample for PK analysis 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.


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8.5.
Pharmacokinetics
Whole blood samples will be collected for measurement of plasma concentrations of 
GSK2330672 and OCA as specified in the SoA and below in Section 8.5.1 and Section 
8.5.2.

Additional samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the Medical Monitor.

The timing of sampling may be altered during the course of the study based on 
newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.

Instructions for the collection (including the volume to be collected), handling and 
processing of biological samples will be provided in the Study Reference Manual. 
The actual date and time (24-hour clock time) of each sample will be recorded.

Samples collected for plasma concentration analyses of GSK2330672 and OCA 
may also be used to evaluate safety or efficacy aspects related to concerns arising 
during or after the study.

Genetic analyses will not be performed on these samples. 


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8.5.1.
Part A PK Sampling Schedule
8.5.1.1.
PK Sampling Schedule Day 17-19 for OCA and Metabolites
Study Day
Time relative 
to OCA dose 
(h)
Example 
Time of Day 
(24hr)
OCA Dose
PK (OCA) 
Sample 
Collection
Meals
17
-3.5
08:30
X
0
12:00
X
X1
X2
4
16:00
X
8.5
20:30
X
18
-3.5
08:30
X
0
12:00
X
X1
X2
0.25
12:15
X
0.5
12:30
X
0.75
12:45
X
1
13:00
X
1.5
13:30
X
2
14:00
X
3
15:00
X
4
16:00
X
X
5
17:00
X
6
18:00
X
7
19:00
X
8
20:00
X
8.5
20:30
X
9
21:00
X
10
22:00
X
11
23:00
X
19
12
00:00
X
14
02:00
X
20.5
08:30
X
24
12:00
X
X1
X2
28
16:00
X
32
20:00
X
1Sample taken predose, approx. 15 minutes prior to dosing
2To be given with a meal
8.5.1.2.
PK Sampling Schedule Day 35-38 for OCA and Metabolites
Study 
Day 
Time relative to 
OCA dose (h)
Example Time of 
Day (24hr)
OCA 
Dose
Linerixibat 
Dose
PK (OCA) 
Sample 
Collection
Meals
35
-4
08:00
X
-3.5
08:30
X
0
12:00
X
X1
X2


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Study 
Day 
Time relative to 
OCA dose (h)
Example Time of 
Day (24hr)
OCA 
Dose
Linerixibat 
Dose
PK (OCA) 
Sample 
Collection
Meals
4
16:00
X
8
20:00
X
8.5
20:30
X
36
-4
08:00
X
-3.5
08:30
X
0
12:00
X
X1
X2
4
16:00
X
8
20:00
X
8.5
20:30
X
37
-4
08:00
X
-3.5
08:30
X
0
12:00
X
X1
X2
0.25
12:15
X
0.5
12:30
X
0.75
12:45
X
1
13:00
X
1.5
13:30
X
2
14:00
X
3
15:00
X
4
16:00
X
X
5
17:00
X
6
18:00
X
7
19:00
X
8
20:00
X
X1
8.5
20:30
X
9
21:00
X
10
22:00
X
11
23:00
X
38
12
00:00
X
14
02:00
X
20
08:00
X
20.5
08:30
X
24
12:00
X
X
1Sample to be collected predose, approx. 15 minutes prior to dosing
2To be given with a meal


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8.5.1.3.
PK Sampling Schedule Day 19-20 (Day -1 and 1 Linerixibat) and Day 33 
(Day 14 Linerixibat) for Linerixibat Twice Daily Dosing
Study Day
Time relative 
to linerixibat 
dose (h)
Example. 
Time of 
Day 
(24hr)
OCA Dose
Linerixibat 
Dose
PK 
(Linerixibat)
Meals
19
0
08:00
X
0.5
08:30
X
4
12:00
X
X1
8
16:00
X
12
20:00
X
X
20
0
08:00
X
X2
0.25
08:15
X
0.5
08:30
X
X
0.75
08:45
X
1
09:00
X
1.5
09:30
X
2
10:00
X
3
11:00
X
4
12:00
X
X2
X1
5
13:00
X
6
14:00
X
7
15:00
X
8
16:00
X
X
9
17:00
X
10
18:00
X
11
19:00
X
12
20:00
X
X2
12.5
20:30
X
33
0
8:00
X
X2
0.25
08:15
X
0.5
08:30
X
X
0.75
08:45
X
1
09:00
X
1.5
09:30
X
2
10:00
X
3
11:00
X
4
12:00
X
X2
X1
5
13:00
X
6
14:00
X
7
15:00
X
8
16:00
X
X
9
17:00
X
10
18:00
X
11
19:00
X
12
20:00
X
X2


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Study Day
Time relative 
to linerixibat 
dose (h)
Example. 
Time of 
Day 
(24hr)
OCA Dose
Linerixibat 
Dose
PK 
(Linerixibat)
Meals
12.5
20:30
X
1To be given with a meal
2Sample taken predose, approx. 15 minutes prior to dosing
8.5.2.
Part B (Optional) PK Sampling Schedule
8.5.2.1.
PK Sampling Schedule Day 17-19 for OCA and Metabolites
Study 
Day 
Time relative to 
OCA dose (h)
Example Time of 
Day (24hr)
OCA Dose
PK (OCA) 
Sample 
Collection
Meals
17
-11.5
08:30
X
-8
12:00
X
-4
16:00
X
0
20:00
X
X1
X2
18
-11.5
08:30
X
-8
12:00
X
-4
16:00
X
0
20:00
X
X1
X2
0.25
20:15
X
0.5
20:30
X
0.75
20:45
X
1
21:00
X
1.5
21:30
X
2
22:00
X
3
23:00
X
19
4
00:00
X
5
01:00
X
6
02:00
X
7
03:00
X
8
04:00
X
9
05:00
X
10
06:00
X
11
07:00
X
12
08:00
X
12.5
08:30
X
14
10:00
X
16
12:00
X
20
16:00
X
24
20:00
X
X1
X2
1Sample to be collected predose. Approx. 15 minutes prior to dosing
2To be given with a meal


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8.5.2.2.
PK Sampling Schedule Day 35-38 for OCA and Metabolites
Study 
Day 
Time relative 
to OCA dose 
(h)
Example Time of 
Day (24hr)
OCA 
Dose
Linerixibat 
Dose
PK (OCA) 
Sample 
Collection
Meals
35
-11.5
08:30
X
-8
12:00
X
-4
16:00
X
0
20:00
X
X1
X2
36
-11.5
08:30
X
-8
12:00
X
-4
16:00
X
0
20:00
X
X1
X2
37
-12
08:00
X
-11.5
08:30
X
-8
12:00
X
-4
16:00
X
0
20:00
X
X1
X2
0.25
20:15
X
0.5
20:30
X
0.75
20:45
X
1
21:00
X
1.5
21:30
X
2
22:00
X
3
23:00
X
38
4
00:00
X
5
01:00
X
6
02:00
X
7
03:00
X
8
04:00
X
9
05:00
X
10
06:00
X
11
07:00
X
12
08:00
X
X2
12.5
08:30
X
14
10:00
X
16
12:00
X
20
16:00
X
24
20:00
X
X
1Sample to be collected predose. Approx. 15 minutes prior to dosing
2To be given with a meal


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8.5.2.3.
PK Sampling Schedule Day 19-21 (Day -1, 1 and 2 Linerixibat) for 
Linerixibat Once Daily Dosing
Study Day
Time 
relative to 
linerixibat 
dose (h)
Example
Time of 
Day (24hr)
OCA 
Dose
Linerixibat 
Dose
PK 
(Linerixibat)
Meals
19
0
08:00
X
0.5
08:30
X
4
12:00
X
8
16:00
X
12
20:00
X
X1
20
0
08:00
X
X2
0.25
08:15
X
0.5
08:30
X
X
0.75
08:45
X
1
09:00
X
1.5
09:30
X
2
10:00
X
3
11:00
X
4
12:00
X2
X1
5
13:00
X
6
14:00
X
7
15:00
X
8
16:00
X
X
9
17:00
X
10
18:00
X
11
19:00
X
12
20:00
X
X2
X1
21
14
22:00
X
16
00:00
X
18
02:00
X
24
08:00
X
X2
24.5
08:30
X
28
12:00
X
32
16:00
X
36
20:00
X
X1
1To be given with a meal
2Sample taken predose, approx. 15 minutes prior to dosing


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8.5.2.4.
PK Sampling Schedule Days 33-34 (Days 14-15 of Linerixibat) for 
Linerixibat Once Daily Dosing
Study Day
Time 
relative to 
linerixibat 
dose (h)
Example
Time of Day 
(24hr)
OCA Dose
Linerixibat 
Dose
PK 
(Linerixibat)
Meals
33
0
8:00
X
X2
0.25
08:15
X
0.5
08:30
X
X
0.75
08:45
X
1
09:00
X
1.5
09:30
X
2
10:00
X
3
11:00
X
4
12:00
X
X
5
13:00
X
6
14:00
X
7
15:00
X
8
16:00
X
X
9
17:00
X
10
18:00
X
11
19:00
X
12
20:00
X
X2
X1
34
14
22:00
X
16
00:00
X
18
02:00
X
24
08:00
X
X2
24.5
08:30
X
28
12:00
X
32
16:00
X
36
20:00
X
X1
1To be given with a meal
2Sample taken predose, approx. 15 minutes prior to dosing
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not collected in this study.
8.7.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.


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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 5 (Section 10.5) for information regarding genetic research. Details on 
processes for collection and shipment and destruction of these samples can be found in 
the Study Reference Manual.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Immunogenicity Assessments
There are no immunogenicity assessments to be performed in this study
8.10.
Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
No formal statistical hypothesis will be tested. 
This study is designed to assess the effect of linerixibat (GSK2330672) on plasma 
concentrations of OCA and conjugates. The effect will be determined by assessing the 
primary endpoints (steady state AUC (0-t), AUC(0-24), Cmax, and Ctrough on Day 38 
for total-OCA plasma concentrations) and secondary endpoints (Ctrough for assessing 
steady state of total-OCA, steady state Tmax of total-OCA and steady state AUC(0-t), 
AUC(0-24), Cmax, Ctrough, and Tmax of OCA, tauro-OCA, and glyco-OCA) during 
dosing of OCA with and without linerixibat..
9.2.
Sample Size Considerations
Approximately 19 participants will be recruited with the goal of having at least 15 
participants complete the study, to allow for up to an approximate 20% withdrawal rate. 


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If the optional Part B is conducted the same number of participants are planned to be 
recruited with the identical provision for study withdrawals. 
Reported coefficients of variance for Cmax and AUC (0-24) for total-OCA are 27.7% 
and 28.6%, respectively, while the coefficient of variance for Ctrough for total-OCA is 
20.7%. To reflect all the reported variance, a CV of 30% (on the log scale SD = 0.294) 
will be used to accommodate the variance of the primary PK parameter endpoints being 
measured. With this CV, a sample size of 15 participants will provide a precision (half-
width of the 90% confidence interval, CI) within 17% of the point estimate.
9.3.
Sample Size Sensitivity
A sensitivity analysis was conducted assuming a larger than expected CV in the study. 
Assuming a CV of 40% (on the log scale SD = 0.385), a sample size of 15 participants 
would provide a precision of the 90% CI within 21.7% of the point estimate for the 
primary PK parameters.
An additional sensitivity analysis was conducted assuming there are fewer participants 
than originally planned for in the study. Assuming the original CV of 30% and a new 
sample size of 11 participants, the precision of the 90% CI would be within 20% of the 
point estimate for the primary PK parameters.
9.4.
Populations for Analyses
The following populations are defined:
Population
Description
Screened
All participants who sign the ICF. This will be the 
population for reporting screened population data.
All Participants
All participants who take at least 1 dose of study 
intervention. Participants will be analyzed according to 
the treatment they received. This will be the population 
for reporting safety and study population data.
Pharmacokinetic 
Concentrations
All participant for whom pharmacokinetic 
concentration are reported.
Pharmacokinetic Parameters
All participants for whom pharmacokinetic parameters 
are derivable.


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9.5.
Interim Analysis
No interim analysis will be performed.
9.6.
Data Monitoring Committee
No independent data monitoring committee will be used for this study.
9.7.
Statistical Analyses
This study is intended to compare changes in steady state PK parameters AUC(0-t), AUC 
(0-24), Cmax, Ctrough for total-OCA as well as steady state PK parameters for OCA, 
tauro-OCA, and glyco-OCA before and following dosing of linerixibat 90 mg twice-daily 
for 18 consecutive days. This full assessment is important to understand the presence of a 
DDI and to fully characterize the drug interaction potential. After log transforming these 
parameters, they will be analysed by a mixed effect model by fitting a fixed effect term 
for regimen (OCA or OCA + linerixibat) and treating participant as a random effect. 
Point estimates and 90% CI for the difference between OCA + linerixibat and OCA will 
be constructed. These point estimates and CI will then be back-transformed exponentially 
to obtain point estimates and 90% CI for the ratio of OCA + linerixibat: OCA.
The underlying distributional assumptions involved in the statistical analyses will be 
assessed by visual inspection of residual plots. Normality will be examined by normal 
probability plots while homogeneity of variance will be assessed by plotting the residuals 
against the predicted values for the model. If the assumptions are seriously violated, then 
alternative statistical methods will be considered.
Estimates of within-subject variability (CVw) and between-subject variability (CVb) for 
the PK parameters will also be calculated using the following equations:
CVw (%) = SQRT (exp (MSE) – 1) x 100
where MSE is the residual mean squared error from the model, and 
CVb (%) = SQRT (exp (SD2) – 1) x 100 
where SD is the standard deviation on the log scale.
Descriptive statistics (n, arithmetic mean and associated 95% confidence interval, 
standard deviation, minimum, median, maximum) will be calculated for all PK 
parameters by OCA and OCA + linerixibat.
In addition to this assessment, the back-transformed mean and 90% CI of Ctrough for 
total-OCA following dosing of linerixibat will be compared to the clinically important 
threshold of 20 ng-eq/mL. If the lower bound of the 90% CI is < 20 ng/mL then this will 
be considered a clinically important DDI. If there is no DDI shown in the PK parameters 
in OCA or its metabolites but there is still a reduction at steady state in Ctrough for total-


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OCA so that the lower bound of the 90% CI is < 20 ng/mL this will also be considered a 
clinically important DDI.  
If there is a DDI shown among the PK parameters for OCA and its metabolites but the 
lower bound of the 90% CI of the back-transformed mean Ctrough of total-OCA ≥20 
ng/mL then it will be concluded that there is a DDI, but the findings are not clinically 
important. 
In the unexpected and unlikely event that total-OCA, in the absence of linerixibat, falls 
below 20 ng/mL, the threshold of 20 ng/mL will be re-evaluated, and the results will be 
reviewed by the study team for compliance issues and AEs.
If a clinically relevant OCA/linerixibat DDI is detected using this definition the sponsor 
may consider the merit of conducting a follow-up study (Part B) investigating an 
alternative 180 mg once daily morning dosing of linerixibat separated by 12 hours from 
OCA once daily, dosed in the evening. Importantly, the dose of linerixibat and/or OCA in 
the contingent Part B may also be adjusted, prior to the initiation, should the Part A 
analysis suggest different doses of either study drug would be useful to further 
characterize any potential DDI. The decision to conduct Part B will require careful 
assessment of PK parameters measured and analysed in Part A. Based on the full analysis 
of the results from Part A the conclusion must be reached that alternative once-daily 
linerixibat dosing separated by 12 hours and/or adjustment of study drug doses(s) in Part 
B has the potential to reduce the DDI observed or otherwise further characterize any 
potential DDI observed in Part A.
The PK parameters, including accumulation, for linerixibat will be summarized using 
descriptive statistics.
The statistical analysis plan will be finalized prior to database freeze (DBF) and it will 
include a more technical and detailed description of the statistical analyses described in 
this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints.
9.7.1.
General Considerations
9.7.1.1.
Treatment Assignment
This is a non-randomized study. All participants will receive OCA and OCA + linerixibat 
in a fixed sequence.
9.7.1.2.
Missing Data
Missing data will not be imputed.


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9.7.1.3.
Derived and Transformed Data
AUC(0-t), AUC (0-24), Cmax, and Ctrough will be log transformed prior to statistical 
analysis.
9.7.1.4.
Sample Size Re-estimation
No sample size re-estimation is planned.
9.7.2.
Primary Comparisons of Interest
The primary focus of the statistical analysis is to estimate the effect of repeat oral doses
of linerixibat on the pharmacokinetics of repeat oral doses of OCA. Thus, the primary 
comparison of interest is OCA + linerixibat relative to OCA alone for each of the 
pharmacokinetic endpoints.
9.7.3.
Other Analyse(s)
There are no other comparisons of interest.
9.7.4.
Other Safety Analyse(s)
No formal statistical analysis of safety data will be performed. Safety and tolerability
data will be descriptively summarized and presented in a tabular and/or graphical form.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, 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, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
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.


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10.1.3.
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, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study centre. 

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.
10.1.4.
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 who will be required to give 
consent for their data to be used as described in the informed consent. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.1.5.
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 


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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 participants, as appropriate.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
10.1.6.
Data Quality Assurance

All participant data relating to the study will be recorded on electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by 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. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

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. 


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
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. 
10.1.7.
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 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 Source Document 
Identification Form or equivalent form.
10.1.8.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
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 intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 


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by the applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up.
10.1.9.
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 multicentre 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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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing:

Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant's involvement in the 
study.
Table 4
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
MCV
MCH
Absolute and 
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Haemoglobin
Haematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and 
direct bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose 
(fasted2)
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 


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Laboratory 
Assessments
Parameters
leukocyte by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Alcohol breath test and urine drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)

Smoking breath test

Highly sensitive serum human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)3

Follicle stimulating hormone and oestradiol (as needed for women of 
childbearing potential).

Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody)
The results of each test must be entered into the CRF.
NOTES:
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Section 7.1 and Section 10.6 (Appendix 6)All events of ALT 
3 × upper limit of normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN 
and international normalized ratio (INR) >1.5, if INR measured, which may indicate severe liver injury 
(possible Hy’s Law), must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis).
2.
Glucose fasting at screening and admission on Day -1 only.
3.
Serum pregnancy test will be taken at screening only and urine pregnancy test will be taken at other 
timepoints. Positive urine pregnancy tests will be confirmed with serum pregnancy tests.


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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to 
the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 


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Events NOT Meeting the AE Definition 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
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:
o
Results in death
o
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.
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 fulfils any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
Results in persistent or significant 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, diarrhoea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.


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Is a congenital anomaly/birth defect
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.
10.3.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information 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 sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.


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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.


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10.3.4.
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 IP/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 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the Medical monitor or the SAE coordinator by telephone.

Contacts for SAE reporting can be found in the Study Reference Manual.
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 or the SAE coordinator. 

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 Study Reference Manual.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
10.4.1.
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview.

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, confirmation with 
more than one FSH measurement is required. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-oestrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they 
must discontinue HRT to allow confirmation of postmenopausal status before 
study enrolment.


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10.4.2.
Contraception Guidance:
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 
below

CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the absence 
of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.

Highly Effective Methodsb That Are User Dependent

Combined (oestrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc
oral
injectable

Sexual abstinence
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the participant
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.
c.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction)


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10.4.3.
Collection of Pregnancy Information:
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

The initial 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 foetal 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 for medical reasons 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 intervention by the investigator, will be reported to 
GSK as described in Appendix 3. 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 medication immediately and be withdrawn from the study. A 
follow-up appointment will be scheduled with the centre. 


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10.5.
Appendix 5: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis

DNA samples will be used for research related to PBC and/or related diseases. They 
may also be used to develop tests/assays including diagnostic tests) related to PBC
and/or related diseases. Genetic research may consist of the analysis of one or more 
candidate genes or the analysis of genetic markers throughout the genome (as 
appropriate).

Additional analyses of DNA samples may be conducted if it is hypothesized that this 
may help further understand the clinical data. 

DNA samples will be analysed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analysed as part of a multi-study assessment of genetic factors 
involved in the response to GSK2330672 or study interventions 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 PBC (or study interventions of this 
class) continues but no longer than 15 years after the last participant last visit or 
other period as per local requirements.


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10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event etiology. These guidelines are in alignment with FDA 
premarketing clinical liver safety guidance:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or 
INR >1.5, Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study 
intervention

Report the event to GSK within 24 
hours

Complete the liver event eCRF, and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE2

Perform liver event follow up 
assessments 

Monitor the participant until liver 
chemistries resolve, stabilise, or return 
to within baseline (see MONITORING
below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN 
or INR >1.5

Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 

Viral hepatitis serology3

Obtain international normalized ratio 
(INR) and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for 
pharmacokinetic (PK) analysis, 
obtained as soon as possible after liver 
event identified4

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report 


2019N406556_00
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75
Liver Chemistry Stopping Criteria 
phosphatase, bilirubin and INR) and 
perform liver event follow up 
assessments within 24 h

Monitor participants twice weekly until 
liver chemistries resolve, stabilise or 
return to within baseline

A specialist or hepatology consultation 
is recommended
If ALT≥3xULN AND bilirubin < 2xULN 
and INR ≤1.5:

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin and 
INR) and perform liver event follow up 
assessments within 24-72 h

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
form

Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, other 
over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 
2xULN or INR >1.5:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins.

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study intervention for that participant if ALT 
3xULN and bilirubin 2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury. 
2.
All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3xULN and 
INR>1.5, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); the threshold value stated will not apply 
participants receiving anticoagulants
3.
Includes: Hepatitis A immunoglobulin (gM) antibody; HBsAg and HBcAb; Hepatitis C RNA; 
Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing) and Hepatitis E IgM antibody 
4.
PK sample may not be required for participants known to be receiving placebo or non-GSK 
comparator interventions.  Record the date/time of the PK blood sample draw and the date/time of the 
last dose of study intervention prior to PK blood sample draw on the CRF. 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 in the SRM. Not required for single-dose 
parts of this study


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10.7.
Appendix 7: Abbreviations and Trademarks
Abbreviation
Explanation
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC (0-12)
Area under the Concentration curve from time 
0 to 12 hour
AUC (0-24)
Area under the Concentration curve from time
0 to 24 hour
AUC (0-t)
Area under the Concentration curve from time 
0 to t
BID
Twice Daily
BMI
Body Mass Index
BP
Blood Pressure
Cmax
Maximum Observed Plasma Concentration
CRF
Case Report Form
Ctrough
Trough Concentration
DBF
Database Freeze
DDI
Drug-drug Interaction
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EHC
Enterohepatic Circulation
FDA
Food and Drug Administration
FGF
Fibroblast Growth Factor
FSH
Follicle Stimulating Hormone
FXR
Farnesoid X Receptor
GI
Gastrointestinal
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface antigen
HIV
Human Immunodeficiency Virus
HR
Heart Rate
H
Hour
IBAT
Ileal bile acid Transport
ICF
Informed Consent Form
IDSL
Independent Data Standards Library
IEC
Independent Ethics Committee
IRB
Institutional Review Board
Kg
Kilogram
LFT
Liver Function Tests
LLQ
Lower Limit of Quantitation
mg
Milligram
mmHg
Millimetres of Mercury
ng
Nanogram
NOAEL
No-Observed Adverse Effect Level
OCA
Obeticholic Acid
PBC
Primary Biliary Cholangitis
PD
Pharmacodynamics
PGx
Pharmacogenetics


2019N406556_00
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Abbreviation
Explanation
PK 
Pharmacokinetics
QD
Once Daily
RAP
Reporting and Analysis Plan
SAE 
Serious Adverse Event
SD
Standard Deviation
SMPc
Summary of Product Characteristics
SoA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse 
Reaction
Tlast
Time to last observation
Tmax
Time to maximum concentration
UDCA
Ursodeoxycholic Acid
ULN
Upper Limit of Normal
WOCBP
Women of Child Bearing Potential
WONCBP
Women of non-child bearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
Linerixibat
Ocaliva


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11.
REFERENCES
Dawson PA; Haywood J; Craddock AL; Wilson M; Tietjen M; Kluckman K; Maeda N; 
Parks J.S. Targeted Deletion of the Ileal Bile Acid Transporter Eliminates Enterohepatic 
Cycling of Bile Acids in Mice; Journal of Biological Chemistry 2003; 278; 33920-33927.
Edwards JE; Eliot L; Parkinson A; Karan S; MacConell L. Assessment of 
Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, 
Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin and Digoxin in Phase 1 Studies 
in Healthy Subjects. Adv Ther (2017) 34:2120-2138.
Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) 
Clinical Pharmacology and Biopharmaceutics Review(s) for Obeticholic Acid for the 
treatment of primary biliary cirrhosis (PBC) in combination with ursodeoxycholic acid 
(UDCA) in adults with an inadequate response to UDCA or as a monotherapy in adults 
unable to tolerate UDCA. Last Updated 2016. Website Link: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/207999Orig1s000ClinPharm
R.pdf
GSK2330672 Investigator's Brochure, Version 05, 03-Sep-2018.GSK Document Number
2010N111289_05.
Hegade VS; Boier R, Oude Eferink R, Beuers U, Kendrick S, Jones D. A systematic 
approach to the management of cholestatic pruritus in primary biliary cirrhosis. Frontline 
Gastroenterology 2016; 7(3): 158-166.
Hofmann AF. Bile Acids: Trying to Understand Their Chemistry and Biology with the 
Hope of Helping Patients. Hepatology 2009; 49:1402-1418 
Metcalf, JV; Mitchison HC; Palmer JM; Jones DE; Primary Biliary Cirrhosis: 
Epidemiology Helping the Clinician. British Medical Journal 1996; 312:1181
Ocaliva® EMA prescribing information (Summary of Product Characteristics) 2018.
Woolbright BL; Jaeschke H. Novel Insight into Mechanisms of Cholestatic Liver Injury. 
World Journal of Gastroenterology; 2012; 18 (36): 4985-4993.

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
206224 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for 206224: An open-label, 
single sequence crossover, drug interaction study to 
investigate the effect of linerixibat (GSK2330672) on 
plasma concentrations of obeticholic acid and conjugates in 
healthy participants 
Compound Number  : GSK2330672 
Effective Date  
: 07-FEB-2020 
 
Description: 
 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for original protocol of 206224 (GSK 
Document Number 2019N406556_00). 
 
This RAP is intended to describe the analyses required for the study.  
 
This RAP will be provided to the study team members to convey the content of 
the Statistical Analysis Complete (SAC) deliverable. 
 
Author’s Name and Functional Area:  
 
 
Principal Statistician (FPD, Biostatistics) 
 
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
206224 
 
2 
 
RAP Team Approvals: 
Approver 
Date 
Approval 
Method 
 
 
 
Clinical Development Director, Clinical 
Science (Respiratory & Speciality) 
 
 
 
Discovery Medicine Scientist Director 
(Discovery Medicine, R&D) 
 
 
 
Quantitative Clinical Development 
(Pharmacokinetics, Clinical Pharmacology) 
 
 
 
Principal Data Manager (Global Clinical & 
Data Operations, RD Projects Clinical 
Platforms & Sciences) 
 
 
 
Senior Programmer (FPD, Biostatistics) 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Date 
Approval 
Method 
 
 
 
Statistics Director (FPD, Biostatistics) 
 
 
 
Programming Manager (FPD, Biostatistics) 
 
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PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
 
206224 
 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 7 
2.3. 
Study Design ................................................................................................ 9 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 11 
3. 
PLANNED ANALYSES .......................................................................................... 12 
3.1. 
Interim Analyses ......................................................................................... 12 
3.2. 
Final Analyses ............................................................................................ 12 
4. 
ANALYSIS POPULATIONS ................................................................................... 12 
4.1. 
Protocol Deviations ..................................................................................... 12 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 14 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 14 
5.2. 
Baseline Definitions .................................................................................... 14 
5.3. 
Multicentre Studies ..................................................................................... 14 
5.3.1. 
Covariates and Other Strata ........................................................ 14 
5.3.2. 
Examination of Subgroups ........................................................... 15 
5.4. 
Multiple Comparisons and Multiplicity ......................................................... 15 
5.5. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 15 
6. 
STUDY POPULATION ANALYSES ....................................................................... 16 
6.1. 
Overview of Planned Study Population Analyses ........................................ 16 
7. 
EFFICACY ANALYSES .......................................................................................... 17 
7.1. 
Primary Efficacy Analyses .......................................................................... 17 
7.1.1. 
Endpoint / Variables ..................................................................... 17 
7.1.2. 
Summary Measure ...................................................................... 17 
7.1.3. 
Population of Interest ................................................................... 17 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 17 
7.1.5. 
Statistical Analyses / Methods ..................................................... 17 
7.1.5.1. 
Statistical Methodology Specification .......................... 17 
7.2. 
Secondary Efficacy Analyses ...................................................................... 17 
7.2.1. 
Endpoint / Variables ..................................................................... 17 
7.2.2. 
Summary Measure ...................................................................... 17 
7.2.3. 
Population of Interest ................................................................... 17 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 17 
7.2.5. 
Statistical Analyses / Methods ..................................................... 17 
7.2.5.1. 
Statistical Methodology Specification .......................... 17 
7.3. 
Exploratory Efficacy Analyses ..................................................................... 19 
8. 
SAFETY ANALYSES ............................................................................................. 20 
8.1. 
Adverse Events Analyses ........................................................................... 20 
8.2. 
Adverse Events of Special Interest Analyses .............................................. 20 
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8.3. 
Clinical Laboratory Analyses ....................................................................... 20 
8.4. 
Other Safety Analyses ................................................................................ 20 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 21 
9.1. 
Primary Pharmacokinetic Analyses ............................................................. 21 
9.1.1. 
Endpoint / Variables ..................................................................... 21 
9.1.1.1. 
Drug Concentration Measures .................................... 21 
9.1.1.2. 
Derived Pharmacokinetic Parameters......................... 21 
9.1.2. 
Summary Measure ...................................................................... 22 
9.1.3. 
Population of Interest ................................................................... 22 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 22 
9.1.5. 
Statistical Analyses / Methods ..................................................... 22 
9.1.5.1. 
Statistical Methodology Specification .......................... 23 
9.2. 
Secondary Pharmacokinetic Analyses ........................................................ 25 
9.2.1. 
Endpoint / Variables ..................................................................... 25 
9.2.1.1. 
Drug Concentration Measures .................................... 25 
9.2.1.2. 
Derived Pharmacokinetic Parameters......................... 25 
9.2.2. 
Summary Measure ...................................................................... 26 
9.2.3. 
Population of Interest ................................................................... 26 
9.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 26 
9.2.5. 
Statistical Analyses / Methods ..................................................... 26 
9.2.5.1. 
Statistical Methodology Specification .......................... 27 
9.3. 
Exploratory Pharmacokinetic Analyses ....................................................... 28 
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 29 
10.1. 
Statistical Analyses / Methods .................................................................... 29 
11. PHARMACODYNAMIC AND BIOMARKER ANALYSES ........................................ 30 
11.1. 
Primary Pharmacodynamic and Biomarker Analyses .................................. 30 
11.1.1. 
Endpoint / Variables ..................................................................... 30 
11.1.2. 
Summary Measure ...................................................................... 30 
11.1.3. 
Population of Interest ................................................................... 30 
11.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 30 
11.1.5. 
Statistical Analyses / Methods ..................................................... 30 
11.1.5.1. Statistical Methodology Specification .......................... 30 
11.2. 
Secondary Pharmacodynamic and Biomarker Analyses ............................. 30 
11.2.1. 
Endpoint / Variables ..................................................................... 30 
11.2.2. 
Summary Measure ...................................................................... 30 
11.2.3. 
Population of Interest ................................................................... 30 
11.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 30 
11.2.5. 
Statistical Analyses / Methods ..................................................... 30 
11.2.5.1. Statistical Methodology Specification .......................... 31 
11.3. 
Exploratory Pharmacodynamic and Biomarker Analyses ............................ 31 
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 32 
12.1. 
Statistical Analyses / Methods .................................................................... 32 
13. REFERENCES ....................................................................................................... 33 
14. APPENDICES ........................................................................................................ 34 
14.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 34 
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14.1.1. 
Exclusions from Per Protocol Population ..................................... 34 
14.2. 
Appendix 2: Schedule of Activities .............................................................. 37 
14.2.1. 
Protocol Defined Schedule of Events ........................................... 37 
14.3. 
Appendix 3: Assessment Windows ............................................................. 43 
14.3.1. 
Definitions of Assessment Windows for Analyses ........................ 43 
14.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 44 
14.4.1. 
Study Phases .............................................................................. 44 
14.4.1.1. Study Phases for Concomitant Medication ................. 44 
14.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 45 
14.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 46 
14.5.1. 
Reporting Process ....................................................................... 46 
14.5.2. 
Reporting Standards .................................................................... 46 
14.5.3. 
Reporting Standards for Pharmacokinetic .................................... 47 
14.6. 
Appendix 6: Derived and Transformed Data ............................................... 48 
14.6.1. 
General ........................................................................................ 48 
14.6.2. 
Study Population .......................................................................... 48 
14.6.3. 
Efficacy ........................................................................................ 48 
14.6.4. 
Safety .......................................................................................... 49 
14.6.5. 
Pharmacokinetic .......................................................................... 50 
14.6.6. 
Population Pharmacokinetic (PopPK) .......................................... 50 
14.6.7. 
Pharmacodynamic and Biomarker ............................................... 50 
14.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 51 
14.7.1. 
Premature Withdrawals ................................................................ 51 
14.7.2. 
Handling of Missing Data ............................................................. 51 
14.7.2.1. Handling of Missing and Partial Dates ........................ 51 
14.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 53 
14.8.1. 
Laboratory Values ........................................................................ 53 
14.8.2. 
ECG ............................................................................................. 53 
14.8.3. 
Vital Signs .................................................................................... 54 
14.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 55 
14.9.1. 
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................ 55 
14.9.2. 
Population Pharmacokinetic (PopPK) Methodology ..................... 55 
14.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 56 
14.10.1. Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................ 56 
14.10.2. Pharmacokinetic / Pharmacodynamic Methodology ..................... 56 
14.11. Appendix 11: Abbreviations & Trade Marks ................................................ 57 
14.11.1. Abbreviations ............................................................................... 57 
14.11.2. Trademarks ................................................................................. 58 
14.12. Appendix 12: List of Data Displays.............................................................. 59 
14.12.1. Data Display Numbering .............................................................. 59 
14.12.2. Mock Example Shell Referencing ................................................ 59 
14.12.3. Deliverables ................................................................................. 59 
14.12.4. Study Population Tables .............................................................. 60 
14.12.5. Efficacy Tables ............................................................................ 61 
14.12.6. Efficacy Figures ........................................................................... 61 
14.12.7. Safety Tables ............................................................................... 62 
14.12.8. Safety Figures ............................................................................. 65 
14.12.9. Pharmacokinetic Tables ............................................................... 66 
14.12.10. Pharmacokinetic Figures ............................................................. 69 
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14.12.11. Pharmacokinetic Population (PopPK) Tables ............................... 72 
14.12.12. Pharmacokinetic Population (PopPK) Figures ............................. 73 
14.12.13. Pharmacodynamic and Biomarker Tables .................................... 73 
14.12.14. Pharmacodynamic and Biomarker Figures .................................. 73 
14.12.15. Pharmacokinetic / Pharmacodynamic and Biomarker 
Tables .......................................................................................... 73 
14.12.16. Pharmacokinetic / Pharmacodynamic and Biomarker 
Figures ........................................................................................ 73 
14.12.17. ICH Listings ................................................................................. 74 
14.12.18. Non-ICH Listings .......................................................................... 77 
14.13. Appendix 13: Example Mock Shells for Data Displays ................................ 78 
 
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206224 
 
7 
 
1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 
Revision Chronology: 
2019N406556_00 05-JUN-2019 
Original 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There have been no changes or deviations to the originally planned statistical analysis 
specified in the protocol. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
Part A: To assess the effect of oral 
Linerixibat on the plasma 
pharmacokinetics of total-OCA 
(summation of OCA and taurine 
(tauro-OCA) and glycine (glyco-
OCA) conjugates) [Part A 
Regimen] 
 
 
Steady state AUC(0-t), AUC(0-24), Cmax, and 
Ctrough for total-OCA plasma concentrations 
Part B (optional): To assess the 
effect of oral Linerixibat on the 
plasma pharmacokinetics of total-
OCA (summation of OCA and 
taurine (tauro-OCA) and glycine 
(glyco-OCA) conjugates) when 
Linerixibat and OCA 
administration is separated by 12 
hours or an alternative dose or 
dosing regimen 
 
 
Same as Part A 
Secondary Objectives 
Secondary Endpoints 
Part A: To assess the effect of oral 
Linerixibat on the additional 
measures of plasma 
pharmacokinetics of total-OCA 
(summation of OCA and taurine 
(tauro-OCA) and glycine (glyco-
OCA) conjugates) [Part A 
Regimen] 
 
Tmax for total-OCA and assessment of steady 
state using Ctrough of total-OCA, AUC(0-t), 
AUC(0-24), Cmax, Ctrough, and Tmax for 
OCA, tauro-OCA, and glyco-OCA plasma 
concentrations 
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206224 
 
8 
 
Objectives 
Endpoints 
 
Part B (optional): To assess the 
effect of oral Linerixibat on the 
additional measures of plasma 
pharmacokinetics of total-OCA 
(summation of OCA and taurine 
(tauro-OCA) and glycine (glyco-
OCA) conjugates) when 
Linerixibat and OCA 
administration is separated by 12 
hours or an alternative dose or 
dosing regimen 
 
 
Same as Part A 
Part A & Part B (optional): To 
evaluate the safety and tolerability 
of Linerixibat and OCA 
administered according to the 
dosing schedule in healthy 
participants  
 
To assess repeat dose Linerixibat 
plasma pharmacokinetics after Day 
1 (Study Day 20) and Day 14 
(Study Day 33) 
 
 
Adverse events, Electrocardiogram, vital signs, 
and clinical laboratory tests 
 
 
 
 
 
AUC(0-t), AUC(0-12), Cmax, Tmax, and 
accumulation (Linerixibat Day 1 (Study Day 
20) and Day 14 (Study Day 33)) 
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9 
 
2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Part A Study Design 
 
Part B (Optional) Study Design 
 
Design 
Features 
 This will be a one part (with optional second part) open-label, single 
sequence, crossover, drug interaction study to investigate the effect 
of Linerixibat (GSK2330672) on plasma concentrations of 
Obeticholic acid (OCA) and OCA conjugates in healthy participants. 
 
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Overview of Study Design and Key Features 
 The study will be conducted in a single research centre specialized in 
the conduct of Phase 1 clinical trials. 
 
 
No washout period is required between dosing in each session. 
 
 A maximum of 19 participants in Part A and a planned 19 
participants in Part B (contingent upon analysis of Part A) will be 
enrolled to study intervention such that approximately 15 participants 
complete Part A and approximately 15 participants complete Part B 
of the study (if it is conducted).  
 
 The total duration of study participation in Part A would be up to 52 
days exclusive of the screening visit (up to 28-35 days). If Part B is 
conducted, the total study participation would be up to 52 days. 
  
 Participants will stay in the clinical unit for 2 nights (Day -1 to Day 
2) before being discharged for 15 days of home dosing (Day 2 to Day 
16). Participants will then return to the clinical unit for a further 21 
overnight stays (Day 17 to Day 38). 
 
 If a clinically important OCA/Linerixibat drug-drug interaction 
(DDI) (average Ctrough of total-OCA < 20 ng/mL) is detected using 
this definition, the sponsor may consider the merit of conducting a 
follow-up study (Part B) investigating an alternative 180 mg once 
daily morning dosing of Linerixibat separated by 12 hours from OCA 
(once daily) dosed in the evening. 
 
 The dose of Linerixibat and/or OCA in the contingent Part B may be 
adjusted, prior to the initiation, should the Part A analysis suggest 
different doses of either study drug would be useful to further 
characterize any potential DDI. 
 
Dosing 
Part A: 
 
OCA will be dosed at 10 mg once-daily (QD) for a total of 37 
continuous days (Study Day 1 through to the afternoon of Day 37). 
 
 
Linerixibat will be dosed at 90 mg twice-daily (BID) for total of 
18.5 days (Study Day 20 to the morning of Day 38).  
 
 
The morning dose of Linerixibat and the afternoon dose of OCA 
should be separated by approximately 4 hours. 
 
Part B: 
 
OCA will be dosed at 10 mg once-daily (QD) for a total of 37 
continuous days (Study Day 1 through to the afternoon of Day 37). 
 
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Overview of Study Design and Key Features 
 
Linerixibat will be dosed at 180 mg once-daily (QD) for total of 18.5 
days (Study Day 20 to the morning of Day 38). 
 
 
Separation of OCA and Linerixibat dosing to be determined. 
 
Treatment 
Assignment 
 
This is an open label, single sequence study. All participants will 
receive the same treatment assignment in Part A and all participants 
will receive the same treatment assignment in Part B (depending on 
the analysis of Part A). 
 
Interim 
Analysis 
 
No interim analysis is planned for this study. 
 
2.4. 
Statistical Hypotheses / Statistical Analyses 
No formal statistical hypothesis will be tested. 
 
This study is designed to assess the effect of Linerixibat (GSK2330672) on plasma 
concentrations of OCA and conjugates. The effect will be determined by assessing the 
primary endpoints (steady state AUC (0-t), AUC(0-24), Cmax, and Ctrough on Day 38 
for total-OCA plasma concentrations) and secondary endpoints (Ctrough for assessing 
steady state of total-OCA, steady state Tmax of total-OCA and steady state AUC(0-t), 
AUC(0-24), Cmax, Ctrough, and Tmax of OCA, tauro-OCA, and glyco-OCA) during 
dosing of OCA with and without Linerixibat. 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
No interim analysis is planned for this study. 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol.  
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
Analyses outlined in this RAP are for Part A only and may be updated if Part B is 
performed. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
 
All participants who sign the ICF. This will 
be the population for reporting screened 
population data. 
 
Study 
Population 
All Participants 
 
 
All participants who take at least 1 dose of 
study intervention. Participants will be 
analyzed according to the treatment they 
received. This will be the population for 
reporting safety and study population data. 
 
Safety and 
Study 
Population 
Pharmacokinetic 
Concentrations 
 
All participants for whom pharmacokinetic 
concentrations are reported. 
 
PK 
Concentration 
Pharmacokinetic 
Parameters 
 
All participants for whom pharmacokinetic 
parameters are derivable. 
 
PK Analysis 
Refer to Appendix 12: List of Data Displays which details the population used for each display. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan (05-AUG-2019, V1). 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.  
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o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
The primary focus of the statistical analysis is to estimate the effect of repeat oral doses 
of Linerixibat on the pharmacokinetics of repeat oral doses of OCA.  Thus, the primary 
comparison of interest is OCA 10 mg QD + Linerixibat 90 mg BID relative to OCA 10 
mg QD for each of the pharmacokinetic endpoints summarized on day 38. 
Treatment Description 
Code [Use for 
treatment in 
displays] 
Description 
OCA 
Ocaliva 10 mg QD 
OCA+Linerixibat 
Ocaliva 10 mg QD + Linerixibat 90 mg BID 
Note: Period 1 is defined as dosing of OCA alone. 
          Period 2 is defined as dosing of OCA and Linerixibat together. 
          This note will be used in displays where applicable. 
 
5.2. 
Baseline Definitions 
Parameter 
Study Assessments 
Considered as Baseline 
Baseline Used in 
Data Display 
Screening 
Day -1 
 
Safety 
Vital Signs 
X [1] 
X [1] 
Day -1 [2] 
Laboratory safety tests 
X 
X 
Day -1 [2] 
12-lead ECG 
X[1] 
X[1] 
Day -1 [2] 
[1] Taken in triplicate. 
[2] If Day-1 is missing then Screening will be used as baseline. 
If Day-1 and Screening are both missing, then Baseline will be considered missing. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
5.3. 
Multicentre Studies 
This is a single centre study. 
5.3.1. 
Covariates and Other Strata 
 There are no other strata planned. 
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5.3.2. 
Examination of Subgroups 
There are no subgroups planned for analysis. 
5.4. 
Multiple Comparisons and Multiplicity 
No adjustment for pre-planned multiple comparisons are planned. 
5.5. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
14.3 
Appendix 3: Assessment Windows 
14.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
14.5 
Appendix 5: Data Display Standards & Handling Conventions 
14.5 
Appendix 6: Derived and Transformed Data 
14.7 
Appendix 7: Reporting Standards for Missing Data 
14.8 
Appendix 8: Values of Potential Clinical Importance 
 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the “Screened” and “All Participants” 
population, unless otherwise specified. 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
pharmacokinetics, and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 12: List of Data Displays. 
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7. 
EFFICACY ANALYSES 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Endpoint / Variables 
Not applicable. 
7.1.2. 
Summary Measure 
Not applicable. 
7.1.3. 
Population of Interest  
Not applicable. 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Not applicable. 
7.1.5. 
Statistical Analyses / Methods 
Not applicable. 
7.1.5.1. 
Statistical Methodology Specification 
Not applicable. 
7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Endpoint / Variables 
Not applicable. 
7.2.2. 
Summary Measure 
Not applicable. 
7.2.3. 
Population of Interest  
Not applicable. 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Not applicable. 
7.2.5. 
Statistical Analyses / Methods 
Not applicable. 
7.2.5.1. 
Statistical Methodology Specification 
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Not applicable. 
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7.3. 
Exploratory Efficacy Analyses 
Not applicable. 
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8. 
SAFETY ANALYSES 
No formal statistical analysis of safety data is planned. 
8.1. 
Adverse Events Analyses 
Adverse events including adverse events (AEs), Serious (SAEs) and other significant 
AEs will be listed and summarized by study phase (Pre-study/screening, OCA alone, 
OCA+Linerixibat, and follow up) based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 12: List of Data Displays. 
8.2. 
Adverse Events of Special Interest Analyses 
No adverse events of special interest specified in the protocol. Not applicable. 
8.3. 
Clinical Laboratory Analyses 
Clinical laboratory evaluations will be summarized, and any values of potential clinical 
concern will be listed. The details of the planned displays are in Appendix 12: List of 
Data Displays. 
8.4. 
Other Safety Analyses 
Other safety measures will be listed and summarized. The details of the planned displays 
are presented in Appendix 12: List of Data Displays. 
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9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Primary Pharmacokinetic Analyses 
9.1.1. 
Endpoint / Variables 
Steady state AUC (0-t), AUC (0-24), Cmax, and average Ctrough for total-OCA plasma 
concentrations. 
 
Total-OCA is calculated by summing OCA and the adjusted concentrations of its two 
metabolites using the following formula: 
 
Total-OCA = OCA + (0.8805 x glyco-OCA) + (0.7969  x tauro-OCA) 
 
9.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 14.5.3 
Reporting Standards for Pharmacokinetic) 
9.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
Phoenix® WinNonlin®. All calculations of non-compartmental parameters will be based 
on actual sampling times. Pharmacokinetic parameters listed will be determined from the 
plasma concentration-time data, as data permits. 
Parameter 
Parameter Description 
AUC(0-t) 
Area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration (C(t)) will be calculated using the linear 
trapezoidal rule for each incremental trapezoid and the log trapezoidal rule 
for each decremental trapezoid. Will be calculated for total-OCA. 
AUC(0-24) Area under the concentration-time curve from time zero to the end of the 
dosing interval (24 hours), using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid. Will be calculated for total-OCA. 
Cmax 
Maximum observed concentration, determined directly from the 
concentration-time data. Will be calculated for total-OCA. 
Average 
Ctrough 
Average concentration at the end of a dosing interval (i.e., average for Days 
16, 17, and 18, and average for 34, 35, 36, and 37). Will be determined by 
the average of Ctrough of total-OCA from Days 17, 18 and 19 for dosing of 
OCA alone and by the average Ctrough of total-OCA from Days 35, 36, 37, 
and 38 for dosing of OCA+Linerixibat.  
NOTES: 
 
Additional parameters may be included as required. 
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9.1.2. 
Summary Measure 
See section 9.1.5 for summary measures. 
9.1.3. 
Population of Interest  
The primary pharmacokinetic analyses will be based on the Pharmacokinetic Parameters 
population, unless otherwise specified. 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
PK parameters will not be imputed if data is missing. 
9.1.5. 
Statistical Analyses / Methods 
After log transforming PK parameters AUC(0-t), AUC(0-24), and Cmax for total-OCA, 
they will be analyzed by a mixed effect model by fitting a fixed effect term for treatment 
regimen (OCA or OCA+Linerixibat) and treating participant as a random effect. Point 
estimates for each treatment regimen, the difference between the treatment regimens, and 
90% confidence interval (CI) for the difference between the treatment regimens will be 
constructed. These point estimates, difference, and CI will then be back-transformed 
exponentially to obtain point estimates, a ratio, and 90% CI for the ratio of 
OCA+Linerixibat: OCA. 
 
The underlying distributional assumptions involved in the statistical analyses will be 
assessed by visual inspection of residual plots. Normality will be examined by normal 
probability plots while homogeneity of variance will be assessed by plotting the residuals 
against the predicted values for the model. If the assumptions are seriously violated, then 
alternative statistical methods will be considered. 
 
Estimates of within-subject variability (CVw) for the PK parameters will also be 
calculated using the following equation: 
 
CVw(%) = SQRT (exp (MSE) – 1) x 100 
 
where MSE is the residual mean squared error from the model. 
 
Descriptive statistics (n, arithmetic mean, associated 95% CI, standard deviation, 
minimum, median, maximum) will be calculated for all PK parameters by OCA and 
OCA+Linerixibat. Geometric means, associated 95% CI, and between-subject variability 
(CVb) for AUC(0-t), AUC(0-24), Cmax, and average Ctrough will be calculated for each 
treatment regimen where: 
 
Geometric mean = exp(mean on loge scale)  
and 
CVb(%) = SQRT (exp (SD2) – 1) x 100 
 
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where SD is the standard deviation on the log scale. 
 
In addition to this assessment, the average Ctrough parameter for total-OCA of the 
OCA+Linerixibat treatment regimen will be log transformed and the mean and 90% CI 
will be calculated. This mean and 90% CI will then be back-transformed and will be 
compared to the clinically important threshold of 20 ng/mL. If the lower bound of the 
90% CI is < 20 ng/mL then this will be considered a clinically important DDI. If there is 
no DDI shown in the PK parameters in OCA or its metabolites but there is still a 
reduction at steady state in the mean of average Ctrough for total-OCA so that the lower 
bound of the 90% CI is < 20 ng/mL this will also be considered a clinically important 
DDI. 
 
If there is a DDI shown among the PK parameters for OCA and its metabolites but the 
lower bound of the 90% CI of the mean of average Ctrough of total-OCA ≥ 20 ng/mL 
then it will be concluded that there is a DDI, but the findings are not clinically important. 
 
In the unexpected and unlikely event that total-OCA, in the absence of Linerixibat, falls 
below 20 ng/mL, the threshold of 20 ng/mL will be re-evaluated, and the results will be 
reviewed by the study team for compliance issues and AEs. 
 
If a clinically important OCA/Linerixibat DDI is detected using this definition the 
sponsor may consider the merit of conducting a follow-up study (Part B) investigating an 
alternative 180 mg once daily morning dosing of Linerixibat separated by 12 hours from 
OCA once daily, dosed in the evening. Importantly, the dose of Linerixibat and/or OCA 
in the contingent Part B may also be adjusted, prior to the initiation, should the Part A 
analysis suggest different doses of either study drug would be useful to further 
characterize any potential DDI. The decision to conduct Part B will require careful 
assessment of PK parameters measured and analyzed in Part A. Based on the full analysis 
of the results from Part A the conclusion must be reached that alternative once-daily 
Linerixibat dosing separated by 12 hours and/or adjustment of study drug doses(s) in Part 
B has the potential to reduce the DDI observed or otherwise further characterize any 
potential DDI observed in Part A. 
 
9.1.5.1. 
Statistical Methodology Specification 
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles). 
Endpoint / Variables 
 Log transformed AUC(0-t), AUC(0-24), and Cmax for total-OCA plasma 
concentrations.  
 
 Log transformed average Ctrough for total-OCA plasma concentration. 
 
Model Specification 
 PK parameters will be analyzed for the Pharmacokinetic Parameters Population 
using a mixed effect model. 
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 The following covariates will be in the model: treatment regimen (OCA or 
OCA+Linerixibat) as a fixed effect and subject as a random effect. 
 
 Models will be fitted for log(AUC(0-t)), log(AUC(0-24)), and log(Cmax). 
 
 The variance-covariance matrix will be assumed unstructured. 
 
 Kenward Roger (KR) method will be used for calculating degrees of freedom. If 
the analysis cannot converge using the KR method, then the residual method will 
be used instead. 
 
 90% CI will be calculated for the difference between OCA+Linerixibat and OCA. 
 
 The point estimates, the difference, and associated 90% CI will then be back-
transformed to provide point estimates, a ratio, and 90% CI for the ratio on the 
original scale. 
 
 Model will not include log(average Ctrough) as a dependent variable. Rather, a 
90% CI will be calculated for mean log(average Ctrough) for OCA+Linerixibat, 
which will then be back-transformed and compared to the threshold of 20 ng/mL. 
 
Model Checking & Diagnostics 
 Distributional assumptions underlying the model used for analysis will be 
examined by obtaining a normal probability plot of the residuals and a plot of the 
residuals versus the fitted values (i.e. checking the normality assumption and 
constant variance assumption of the model respectively) to gain confidence that the 
model assumptions are reasonable. 
 
Model Results Presentation 
 The N, the mean of each treatment regimen, the estimate of the ratio between 
treatment regimens, the 90% CI, and the CVw(%) will be presented for AUC(0-t), 
AUC(0-24), and Cmax.  
 
 The mean of average Ctrough and the associated 90% CI will be presented for the 
OCA+Linerixibat treatment regimen to compare to 20 ng/mL. 
 
Subgroup Analyses 
 Not applicable. 
Sensitivity and Supportive Analyses 
 Not applicable. 
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9.2. 
Secondary Pharmacokinetic Analyses 
9.2.1. 
Endpoint / Variables 
Tmax, Tlast, Ctrough, and average Ctrough of total-OCA; AUC(0-t), Tlast, AUC(0-24), 
Cmax, average Ctrough, and Tmax for OCA, tauro-OCA, and glyco-OCA plasma 
concentrations; AUC(0-t), Tlast, AUC(0-12), Cmax, Tmax, and accumulation ratios 
RAUC and RCmax for Linerixibat. 
 
9.2.1.1. 
Drug Concentration Measures  
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 14.5.3 
Reporting Standards for Pharmacokinetic) 
9.2.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
Phoenix® WinNonlin®. All calculations of non-compartmental parameters will be based 
on actual sampling times. Pharmacokinetic parameters listed will be determined from the 
plasma concentration-time data, as data permits. 
 
Parameter 
Parameter Description 
AUC(0-t) 
Area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration (C(t)) will be calculated using the linear 
trapezoidal rule for each incremental trapezoid and the log trapezoidal rule 
for each decremental trapezoid. Will be calculated for OCA, tauro-OCA, 
glyco-OCA, and Linerixibat. 
AUC(0-24) Area under the concentration-time curve from time zero to the end of the 
dosing interval (24 hours), using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid. Will be calculated for OCA, tauro-OCA, and glyco-OCA. 
AUC(0-12) Area under the concentration-time curve from time zero to the end of the 
dosing interval (12 hours), using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid. Will be calculated for Linerixibat. 
Cmax 
Maximum observed concentration, determined directly from the 
concentration-time data. Will be calculated for OCA, tauro-OCA, glyco-
OCA, and Linerixibat. 
Ctrough 
Concentration at the end of a dosing interval. Will be calculated for total-
OCA. 
Average 
Ctrough 
Average concentration at the end of a dosing interval (i.e., average for Days 
16, 17, and 18, and average for 34, 35, 36, and 37). Will be determined by 
the average Ctrough from Days 17, 18 and 19 for dosing of OCA alone and 
by the average Ctrough from Days 35, 36, 37, and 38 for dosing of 
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Parameter 
Parameter Description 
OCA+Linerixibat. Will be calculated for total-OCA, OCA, tauro-OCA, and 
glyco-OCA. 
Tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
Will be calculated for total-OCA, OCA, tauro-OCA, glyco-OCA, and 
Linerixibat. 
Tlast 
Time of the last measurable concentration in the dosing interval. Will be 
calculated for total-OCA, OCA, tauro-OCA, glyco-OCA, and Linerixibat. 
RAUC 
The area under the curve AUC(0-12) on Day 14 of Linerixibat dosing 
divided by the area under the curve over the initial dosing interval on Day 1 
of Linerixibat dosing. Will be calculated for Linerixibat. 
RCmax 
The maximum concentration in the dosing on Day 14 of Linerixibat dosing 
divided by the maximum concentration during the initial dosing interval on 
Day 1 of Linerixibat dosing. Will be calculated for Linerixibat. 
NOTES: 
 
Additional parameters may be included as required. 
9.2.2. 
Summary Measure 
See section 9.2.5 for summary measures. 
9.2.3. 
Population of Interest  
The secondary pharmacokinetic analyses will be based on the Pharmacokinetic 
Parameters population, unless otherwise specified. 
9.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
PK parameters will not be imputed if data is missing. 
9.2.5. 
Statistical Analyses / Methods 
After log transforming PK parameters average Ctrough for total-OCA, and AUC(0-t), 
AUC(0-24), Cmax, and average Ctrough for OCA, tauro-OCA, and glyco-OCA, they will 
be analyzed by a mixed effect model by fitting a fixed effect term for treatment regimen 
(OCA or OCA+Linerixibat) and treating participant as a random effect. Point estimates 
for each treatment regimen, the difference between the treatment regimens, and 90% CI 
for the difference between the regimens will be constructed. These point estimates, 
differences, and CI will then be back-transformed exponentially to obtain point estimates, 
a ratio, and 90% CI for the ratio of OCA+Linerixibat: OCA for OCA, tauro-OCA, and 
glyco-OCA. 
 
The underlying distributional assumptions involved in the statistical analyses will be 
assessed by visual inspection of residual plots. Normality will be examined by normal 
probability plots while homogeneity of variance will be assessed by plotting the residuals 
against the predicted values for the model. If the assumptions are seriously violated, then 
alternative statistical methods will be considered. 
 
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Estimates of CVw(%) for the PK parameters will also be calculated. 
 
Steady state of the OCA and OCA+Linerixibat treatment regimens will be summarized 
and assessed graphically using pre-dose Ctrough from Days 17, 18, and 19 and Days 35, 
36, 37, and 38 for total-OCA, OCA, glyco-OCA, and tauro-OCA. 
 
Descriptive statistics (n, arithmetic mean and associated 95% CI, standard deviation, 
minimum, median, maximum) will be calculated for all PK parameters by OCA, tauro-
OCA, and glyco-OCA for each treatment regimen. Geometric means, associated 95% CI, 
and CVb(%) for AUC(0-t), AUC(0-24), Cmax, and average Ctrough of OCA and its 
metabolites will be calculated for each treatment regimen. 
 
Tmax and Tlast will be summarized using descriptive statistics by total-OCA, OCA, 
glyco-OCA, and tauro-OCA for each treatment regimen. 
 
The PK parameters, including AUC(0-t), Tlast, AUC(0-12), Cmax, and Tmax for 
Linerixibat will be summarized using descriptive statistics for Day 20 and Day 33. The 
PK parameters RAUC and RCmax for Linerixibat will be summarized using descriptive 
statistics. 
 
9.2.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
 Tmax and Tlast for total-OCA plasma concentrations. 
 
 Ctrough of total-OCA plasma concentrations for assessment of steady state and log 
transformed average Ctrough of total-OCA for analysis. 
 
 Tmax, Tlast, and log transformed AUC(0-t), AUC(0-24), Cmax, and average 
Ctrough for OCA, tauro-OCA, and glyco-OCA plasma concentrations. 
 
Model Specification 
 PK parameters will be analyzed for the Pharmacokinetic Parameters Population 
using a mixed effect model. 
 
 The following covariates will be in the model: regimen (OCA or OCA+Linerixibat) 
as a fixed effect and subject as a random effect. 
 
 Models will be fitted for log(average Ctrough) for total-OCA and log(AUC(0-t)), 
log(AUC(0-24)), log(Cmax), and log(average Ctrough) for OCA and its 
metabolites by treatment regimen. 
 
 The variance-covariance matrix will be assumed unstructured. 
 
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 Kenward Roger (KR) method will be used for calculating degrees of freedom. If 
the analysis cannot converge using the KR method, then the residual method will 
be used instead. 
 
 90% CI will be calculated for the difference between OCA+Linerixibat and OCA. 
 
 The point estimates, the difference, and associated 90% CI will then be back-
transformed to provide point estimates, a ratio, and 90% CI for the ratio on the 
original scale. 
 
Model Checking & Diagnostics 
 Distributional assumptions underlying the model used for analysis will be 
examined by obtaining a normal probability plot of the residuals and a plot of the 
residuals versus the fitted values (i.e. checking the normality assumption and 
constant variance assumption of the model respectively) to gain confidence that the 
model assumptions are reasonable. 
 
Model Results Presentation 
 The N, the mean of each treatment regimen, the estimate of the ratio between 
treatment regimens, the 90% CI, and the CVw(%) will be presented for average 
Ctrough of total-OCA. 
 
 Ctrough of total-OCA for each time point will be presented by each treatment 
regimen by visual display. 
 
 The N, the mean of each treatment regimen, the estimate of the ratio between 
treatment regimens, the 90% CI, and the CVw(%) will be presented for AUC(0-t), 
AUC(0-24), Cmax, and average Ctrough by OCA, tauro-OCA, and glyco-OCA.  
 
Subgroup Analyses 
 Not applicable. 
Sensitivity and Supportive Analyses 
 Not applicable. 
 
9.3. 
Exploratory Pharmacokinetic Analyses 
Not applicable. 
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10. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
Linerixibat concentration time data may be used and reported in a separate analysis under 
a separate POPPK RAP and report. 
10.1. 
Statistical Analyses / Methods 
Not applicable. 
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11. 
PHARMACODYNAMIC AND BIOMARKER ANALYSES 
11.1. 
Primary Pharmacodynamic and Biomarker Analyses 
11.1.1. 
Endpoint / Variables 
Not applicable. 
11.1.2. 
Summary Measure 
Not applicable. 
11.1.3. 
Population of Interest 
Not applicable. 
11.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Not applicable. 
11.1.5. 
Statistical Analyses / Methods 
Not applicable. 
11.1.5.1. 
Statistical Methodology Specification 
Not applicable. 
11.2. 
Secondary Pharmacodynamic and Biomarker Analyses 
11.2.1. 
Endpoint / Variables 
Not applicable. 
11.2.2. 
Summary Measure 
Not applicable. 
11.2.3. 
Population of Interest  
Not applicable. 
11.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Not applicable. 
11.2.5. 
Statistical Analyses / Methods 
Not applicable. 
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11.2.5.1. 
Statistical Methodology Specification 
Not applicable. 
11.3. 
Exploratory Pharmacodynamic and Biomarker Analyses 
Not applicable. 
 
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12. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
Not applicable. 
 
12.1. 
Statistical Analyses / Methods 
Not applicable. 
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13. 
REFERENCES 
Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) 
Clinical Pharmacology and Biopharmaceutics Review(s) for Obeticholic Acid for the 
treatment of primary biliary cirrhosis (PBC) in combination with ursodeoxycholic acid 
(UDCA) in adults with an inadequate response to UDCA or as a monotherapy in adults 
unable to tolerate UDCA. Last Updated 2016. Website Link: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/207999Orig1s000ClinPharm
R.pdf 
GlaxoSmithKline Document Number 2019N406556_00. An open-label, single sequence 
crossover, drug interaction study to investigate the effect of linerixibat (GSK2330672) on 
plasma concentrations of obeticholic acid and conjugates in healthy participants, 05-JUN-
2019. 
 
GUI_51487 (5.0) Non-Compartmental Analysis of Pharmacokinetic Data, CPMS Global. 
 
SOP_54838: Development, Review & Approval of Reporting & Analysis Plan, Global; 
GSK. 
 
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14. 
APPENDICES 
14.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for All Participants Population 
14.1.1. 
Exclusions from All Participants Population 
A participant meeting any of the following criteria will be excluded from the All 
Participants population: 
Number 
Exclusion Description 
01 
Any active dermatologic disorder leading to or with the potential to cause 
pruritus or a recent history of unexplained clinically significant itching 
locally or generally within the prior 3 months. 
02 
Current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones) and/or confirmed hepatocellular carcinoma or biliary cancer.  
03 
Participants with a history of cholecystectomy.  
04 
Current symptomatic cholelithiasis or inflammatory gall bladder disease  
05 
Significant history of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, haematological, or neurological disorders 
capable of significantly altering the absorption, metabolism, or elimination 
of drugs; constituting a risk when taking the study intervention; or 
interfering with the interpretation of data. 
06 
Any clinically relevant abnormality identified at the screening medical 
assessment (physical examination/medical history) clinical laboratory tests, 
or 12-lead ECG. 
07 
Current episode, recent history (within 1 month of screening visit), or 
chronic history of clinically significant diarrhea. 
08 
Lymphoma, leukaemia, or any malignancy within the past 5 years except 
for basal cell or squamous epithelial carcinomas of the skin that have been 
resected with no evidence of metastatic disease for 3 years. 
09 
Any current medical condition (e.g. psychiatric disorder, senility, dementia, 
or other condition), clinical or laboratory abnormality, or examination 
finding that the investigator considers would put the participant at 
unacceptable risk, which may affect study compliance or prevent 
understanding of the aims or investigational procedures or possible 
consequences of the study. 
10 
Regular use of known drugs of abuse or history of drug abuse or 
dependence within 6 months of the study. 
11 
Regular alcohol consumption within 6 months prior to the study defined as 
an average weekly intake of >14 units for females and >21 units for males. 
One unit is equivalent to 8 g of alcohol: a glass (~240 mL) of beer, 1 small 
glass (~100 mL) of wine or 1 (~25 mL) measure of spirits. 
12 
History of or regular use of tobacco- or nicotine-containing products 
(confirmed by smokerlyzer test) in the 3 months prior to screening. 
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Number 
Exclusion Description 
13 
Administration of any IBAT inhibitor (including linerixibat) or OCA in the 
3 months prior to screening. 
14 
Past or intended use of over-the-counter or prescription medication 
(including vitamins and dietary or herbal supplements) within 7 days (or 14 
days if the drug is a potential enzyme inhibitor) or 5 half-lives (whichever is 
longer) prior to the first dose of study medication, unless approved by the 
Investigator in conjunction with GSK. 
15 
Current enrolment in a clinical trial; recent participation in a clinical trial 
and has received an investigational product within 30 days (or 5 half-lives 
of previous trial intervention, whichever is longer) before the first dose in 
the current study. 
16 
Exposure to more than 4 new chemical entities within 12 months before the 
first dose in the current study. 
17 
Screening alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >1.5x ULN. 
18 
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%). 
19 
Presence of Hepatitis B surface antigen (HBsAg) at screening or positive 
Hepatitis C antibody test result at screening or within 3 months of the 
screening visit. 
20 
Positive serum pregnancy test at screening or positive urine pregnancy test 
at admission in women of child bearing potential only. 
21 
Positive human immunodeficiency virus (HIV) antibody test. 
22 
QTc >450 msec on ECG performed at Screening. 
23 
Positive pre-study drug/alcohol screen or positive drug/alcohol screen at any 
time during the study. 
24 
Female participants unable or unwilling to comply with specific 
contraception restrictions as detailed in Section 10.4 of the protocol. 
25 
Where participation in the study would result in donation of blood or blood 
products in excess of 500mL within a 56-day period. 
26 
Unwillingness or inability to follow the procedures outlined in the protocol 
for the expected duration of study participation. 
27 
Sensitivity to any of the study interventions, or components thereof, or drug 
or other allergy that, in the opinion of the investigator or medical monitor, 
contraindicates participation in the study. 
NOTES: 
    Medical Monitor Note: Specific medications may be allowed as listed in 
Concomitant Medication section (Section 6.5) of the protocol. Approved 
medications may be considered on a case by case basis by the Investigator in 
consultation with the Medical Monitor. 
 Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. 
 The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or 
manually over-read.  
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The specific formula that will be used to determine eligibility and discontinuation 
for an individual subject should be determined prior to initiation of the study. In 
other words, several different formulae cannot be used to calculate the QTc for an 
individual subject and then the lowest QTc value used to include or discontinue 
the subject from the trial. 
 
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14.2. 
Appendix 2: Schedule of Activities 
14.2.1. 
Protocol Defined Schedule of Events 
Schedule of Screening, Follow Up and Early Withdrawal Activities 
Procedure 
Screening 
(within 
28-35 
days of 
Day 1)1 
Follow Up 
(7-14 days 
post last 
linerixibat 
dose) 
Early 
Withdrawal 
(within 7 
days of the 
last dose) 
Comments 
Informed 
Consent 
X 
 
 
 
Outpatient 
Visit 
X 
 
X 
Early withdrawal visit to be 
performed as soon as possible 
after withdrawal date, and within 
7 days of last dose. 
Phone Call 
 
X 
 
 
Demography 
X 
 
 
 
Inclusion and 
Exclusion 
Criteria 
X 
 
 
 
Medical 
History  
X 
 
 
Including drug/alcohol use and family 
history of disease 
12-Lead ECG 
X 
 
X 
Triplicate ECG measurements will be 
taken at screening, and in single at 
other timepoints 
Vital Signs 
X 
 
X 
Triplicate measurements of heart rate 
and systolic and diastolic blood 
pressure (respiratory rate and 
temperature recorded in single), at 
screening. Single measurements at 
other timepoints. 
Urine drugs of 
abuse screen 
X 
 
 
 
Alcohol and 
smoking 
breath tests 
X 
 
 
 
HIV and 
hepatitis B and 
C screen 
X 
 
 
Not required if a test has been 
performed within 3 months prior to 
first dose of study intervention 
Pregnancy 
Test 
X 
 
 
Serum pregnancy test for WOCBP 
only 
FSH, 
Oestradiol 
X 
 
 
To confirm post-menopausal status in 
WONCBP only 
Laboratory 
safety tests  
X 
 
X 
Haematology, Biochemistry 
(including Liver Function Tests 
(LFTs)) and urinalysis is to be 
performed 
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Procedure 
Screening 
(within 
28-35 
days of 
Day 1)1 
Follow Up 
(7-14 days 
post last 
linerixibat 
dose) 
Early 
Withdrawal 
(within 7 
days of the 
last dose) 
Comments 
Full physical 
exam 
X 
 
 
Please see Section Error! Reference 
source not found. of protocol for 
minimum requirements. Weight 
measurement to be included 
Brief Physical 
Exam 
 
 
X 
Please see Section Error! Reference 
source not found. of protocol for 
minimum requirements. Weight 
measurement to be included 
OCA PK 
Sample 
 
 
X 
 
OCA drug 
Accountability 
 
 
X 
To be performed only if participant 
withdraws between Day 3 and Day 16 
AE review 
 
X 
X 
AE’s will be collected from the start 
of oral dosing until the final follow up 
SAE review 
X 
X 
X 
SAE’s will be collected from the 
signing of the ICF until final follow 
up 
Concomitant 
medication 
review 
X 
X 
X 
Concomitant medications will be 
collected from the signing of the ICF 
until the final follow up 
1The suggested screening is 28 days but may be increased to 35 days if necessary and in consultation 
with the medical monitor 
 
Part A Schedule of Activities (Day -1 to Day 38) 
Procedure 
Study Day 
Comments 
InpatientOP
Inpatient 
-1 1 2 
3 
to 
16 
17 1819 20 21
22 
to 
32 
33 34 353637 38 
Admission to 
clinical unit 
X  
 
 X   
 
 
 
 
 
 
 
 
 
 
Discharge from 
clinical unit 
 
 X  
 
  
 
 
 
 
 
 
 
 X 
Participants will be discharged from the 
unit following OCA dosing on Day 2 with 
instructions to take OCA daily and return 
on Day 17 (am). Participant stay may be 
extended for safety reasons if deemed 
necessary at the discretion of the 
investigator. 
Inclusion/Exclusion 
Criteria 
X X  
 
 
  
 
 
 
 
 
 
 
 
 Recheck clinical status at Day -1 and Day 1 
predose 
Medical history  
X  
 
 
 
  
 
 
 
 
 
 
 
 
 
Medical history updates only 
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Procedure 
Study Day 
Comments 
InpatientOP
Inpatient 
-1 1 2 
3 
to 
16 
17 1819 20 21
22 
to 
32 
33 34 353637 38 
12-lead ECG 
X  
 
 X   
 
 
 
 
 
 
 
 X 
Triplicate measurements taken Day -1. 
Single measurements will be taken at all 
other timepoints. If any single 
measurement is outside normal ranges, 
triplicate measurements to be taken and the 
mean of the triplicate measurements used. 
Vital signs 
X X  
 X   
 
 
 
 
 
 
 
 X 
Triplicate measurements of heart rate and 
systolic and diastolic blood pressure at Day 
-1 (respiratory rate and temperature to be 
taken in single); single measurements to be 
taken at all other timepoints. 
Additional vital signs may be taken for 
safety reasons at the discretion of the 
investigator 
Urine drugs of 
abuse screen 
X  
 
 X   
 
 
 
 
 
 
 
 
 
 
Alcohol and 
smoking breath 
tests 
X  
 
 X   
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X  
 
 X   
 
 
 
 
 
 
 
 
 
Urine pregnancy test at admissions for 
females of child bearing potential only. 
Positive urine pregnancy test should be 
confirmed with serum pregnancy test. 
Laboratory safety 
tests  
X  
 
 X   
 
 
 
 
 
 
 
 X 
Haematology, Biochemistry (including 
liver function tests (LFTs)) and urinalysis 
is to be performed 
Brief physical 
exam 
X  
 
 X   
 
 
 
 
 
 
 
 X 
Please see Section Error! Reference 
source not found. for minimum 
requirements. Weight measurement to be 
included 
OCA 10 mg 
Administration 
 X X X X X X X X X X X X X X  
OCA will be dosed once daily (afternoon 
dose) at approximately 12:00 hours 
(between 12:00 and 14:00). Dosing on Day 
2 will occur prior to discharge from the 
clinical unit. 
Dispense OCA for 
self-administration  
 
 X  
 
  
 
 
 
 
 
 
 
 
 
To be dispensed after dosing on Day 2 
OCA 
Accountability 
Check 
 
 
 
 X   
 
 
 
 
 
 
 
 
 
Clinical site to confirm OCA taken as 
required 
Compliance Check 
 
 
 X X   
 
 
 
 
 
 
 
 
 
Participants will be required to confirm 
compliance with dosing schedule daily 
during this period 
Linerixibat 90 mg 
Administration 
 
 
 
 
 
  X X X X X X X X X 
GSK2330672 will be dosed twice daily 
with an interval of approximately 12 hours. 
The last linerixibat dose will be taken in 
the morning on Day 38. 
 
Linerixibat PK 
Sampling 
 
 
 
 
 
  X  
 X  
 
 
 
 
Blood samples for plasma drug assays 
should follow the sampling schedules in 
Section Error! Reference source not 
found. 
 
OCA PK Sampling 
 
 
 
 X X X  
 
 
 
 X X X X 
 
PGx sample 
 X  
 
 
  
 
 
 
 
 
 
 
 
 
 
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Procedure 
Study Day 
Comments 
InpatientOP
Inpatient 
-1 1 2 
3 
to 
16 
17 1819 20 21
22 
to 
32 
33 34 353637 38 
AE Review 
 
 
AE’s will be collected from the start of oral 
dosing until final follow up 
SAE Review 
 
SAE’s will be collected from the time each 
participant consents until final follow up 
Concomitant 
Medication Review 
 
Concomitant medications will be 
collected from the signing of the ICF 
until the final follow up 
 
The timing and number of planned study assessments, including PK and safety assessments may be 
altered during the study based on newly available data (e.g., to obtain data closer to the time of peak 
plasma concentrations) to ensure appropriate monitoring.  
 
Any changes in the timing or addition of time points for any planned study assessments as the result 
of emerging pharmacokinetic/pharmacodynamic data from this study 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 Competent Authority (CA) and ethics committee (EC) 
will be informed of any safety issues that constitute a substantial amendment and require alteration of 
the safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be 
approved by the CA and the EC before implementation.  
 
Part B (Optional) Schedule of Assessments (Day -1 to Day 38) 
Procedure 
Study Day 
Comments 
Inpatient OP1
Inpatient 
-1 1 2 3 to 
16 17 18 19 20 21 
22 
to 
32 
33 34 35 36 37 38 
Admission to 
clinical unit 
X  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
Discharge 
from clinical 
unit 
 
 X 
 
 
 
 
 
 
 
 
 
 
 
 X 
Participants will be discharged from unit 
following OCA dosing on Day 2 with 
instructions to take OCA daily and return 
on Day 17 (am). Participant stay may be 
extended for safety reasons if deemed 
necessary at the discretion of the 
investigator. 
Inclusion/ 
Exclusion 
Criteria 
X X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Recheck clinical status at Day -1 and Day 1 
predose 
Medical 
history 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history updates only 
12-lead ECG 
X  
 
 
X  
 
 
 
 
 
 
 
 
 X 
Triplicate ECG measurements will be taken Day 
-1. Single ECG measurements will be taken at 
all other timepoints.  If any single measurement 
is outside normal ranges, triplicate 
measurements will be taken, and the mean of 
the triplicate measurements used. 
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Procedure 
Study Day 
Comments 
Inpatient OP1
Inpatient 
-1 1 2 3 to 
16 17 18 19 20 21 
22 
to 
32 
33 34 35 36 37 38 
Vital signs 
X X  
 
X  
 
 
 
 
 
 
 
 
 X 
Triplicate measurements of heart rate and 
systolic and diastolic blood pressure at Day -1 
(respiratory rate and temperature to be taken in 
single); single measurements to be taken at all 
other timepoints. 
Additional vital signs may be taken for safety 
reasons at the discretion of the investigator 
Urine drugs of 
abuse screen 
X  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
Alcohol and 
smoking 
breath tests  
X  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Test 
X  
 
 
X  
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test at admissions for females 
of child bearing potential only. Positive urine 
pregnancy test should be confirmed with serum 
pregnancy test. 
Laboratory 
safety tests  
X  
 
 
X  
 
 
 
 
 
 
 
 
 X Haematology, Biochemistry (including LFTs) 
and Urinalysis is to be performed 
Brief physical 
exam 
X  
 
 
X  
 
 
 
 
 
 
 
 
 X 
Please see Section Error! Reference source 
not found. for minimum requirements. Weight 
measurement to be included 
OCA 
Administration  X X X X X X X X X X X X X X  
OCA will be dosed once daily (evening dose) at 
approximately 20:00. Dosing on Day 2 will 
occur prior to discharge. 
Dispense OCA 
for self-
administration  
 
 X 
 
 
 
 
 
 
 
 
 
 
 
 
 
To be dispensed after dosing on Day 2 
OCA 
Accountability 
Check 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 Clinical site to confirm OCA taken as required 
Compliance 
Check 
 
 
 
X X  
 
 
 
 
 
 
 
 
 
 
Participants will be required to confirm 
compliance with dosing schedule daily during 
this period 
Linerixibat 
Administration  
 
 
 
 
 
 X X X X X X X X X 
GSK2330672 will be dosed once daily 
(morning dose) at approximately 08:00. 
The last linerixibat dose will be taken in the 
morning on Day 38. 
 
Linerixibat PK 
Sampling 
 
 
 
 
 
 
 X X  X X  
 
Blood samples for plasma drug assays 
should follow the sampling schedules in 
Section Error! Reference source not 
found.. 
 
OCA PK 
Sampling 
 
 
 
 
X X X  
 
 
 
 X X X X 
 
PGx sample 
 X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Review 
 
 
AEs to be recorded from the start of oral 
dosing until final follow up 
SAE Review 
 
SAEs to be recorded from the time each 
subject consent’s to participate in the study 
until final follow up 
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Procedure 
Study Day 
Comments 
Inpatient OP1
Inpatient 
-1 1 2 3 to 
16 17 18 19 20 21 
22 
to 
32 
33 34 35 36 37 38 
Concomitant 
medication 
 
Concomitant medications will be collected 
from the signing of the ICF until the final 
follow up 
 
The timing and number of planned study assessments, including PK and safety assessments may be 
altered during the study based on newly available data (e.g., to obtain data closer to the time of peak 
plasma concentrations) to ensure appropriate monitoring.  
 
Any changes in the timing or addition of time points for any planned study assessments as the result 
of emerging pharmacokinetic/pharmacodynamic data from this study 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 Competent Authority (CA) and ethics committee (EC) 
will be informed of any safety issues that constitute a substantial amendment and require alteration of 
the safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be 
approved by the CA and the EC before implementation.  
 
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14.3. 
Appendix 3: Assessment Windows 
Nominal time will be used for all analysis except PK analysis where planned and actual 
time will be used. 
14.3.1. 
Definitions of Assessment Windows for Analyses 
Not applicable. 
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14.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
14.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
the first dose of OCA. 
Study Phase 
Definition 
Pre-Treatment  
Screening ≤ Date ≤ Day -1 
OCA 
Day 1 ≤ Date ≤ Day19 
OCA+Linerixibat 
Day 20 ≤ Date ≤ Day 38 
Follow up 
Day 39 ≤ Date ≤ Day 52 
NOTES:  
 
Screening can occur within 28-35 days of Day 1. 
 
14.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before 28 days prior to screening visit 
Concomitant 
Any medication that is not a prior 
NOTES:  
 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
 
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14.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
 
If AE onset date is on or after treatment start date & on or before treatment stop 
date. (plus washout or protocol-specified time limit (e.g. half-life of drug, certain 
number of days, etc.). 
 
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date 
 
For studies with greater than one treatment period (e.g., crossover study), if AE 
onset is during one period and worsens during a later period it would be 
counted in both periods. For the initial period the logic would be as above. For 
the later period the logic would use the treatment dates associated with the 
later period: 
 
Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop 
Date 
NOTES:  
 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 
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14.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
14.5.1. 
Reporting Process 
Software 
 
The currently supported version of SAS software will be used. 
Reporting Area 
HARP Server 
us1salx00259.corpnet.com 
HARP Compound 
/arenv/arprod/gsk2330672/mid206224 
Analysis Datasets  
 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1) 
Generation of RTF Files 
 
RTF files will be generated for SAC.  
14.5.2. 
Reporting Standards 
General 
 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
 
4.03 to 4.23: General Principles 
 
5.01 to 5.08: Principles Related to Data Listings 
 
6.01 to 6.11: Principles Related to Summary Tables 
 
7.01 to 7.13: Principles Related to Graphics  
 
Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject 
level listings should be located in the modular appendices as ICH or non-ICH listings 
Formats 
 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated. 
 
Numeric data will be reported at the precision collected on the eCRF. 
 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
 
Reporting for tables, figures and formal statistical analyses: 
 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
 
The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate. 
 
Reporting for Data Listings:  
 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
 
Unscheduled or unplanned readings will be presented within the subject’s listings.  
Unscheduled Visits 
 
Unscheduled visits will not be included in summary tables and/or figures. 
 
All unscheduled visits will be included in listings. 
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 
Unscheduled visits will be used for calculating worst case QTcB and QTcF. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
14.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (CSV format) for the Non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
current working practices with WinNonLin 5.2 or higher 
Note: Concentration values will be imputed as per Non-Compartmental Analysis of 
Pharmacokinetic Data, CPMS Global (GUI_51487 v5.0) 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 v5.0 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
NONMEM/Pop PK 
File 
Not applicable. 
NONMEM/PK/PD 
File 
Not applicable. 
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived by 
Programmer 
The following PK parameters will be derived by the Programmer: 
RAUC for Linerixibat, RCmax for Linerixibat, Average Ctrough of OCA, glyco-OCA, 
tauro-OCA, and total-OCA from days 17, 18, and 19, and days 35, 36, 37, and 38. 
Formulas for these derivations are given in section 14.6.5. 
PK Parameter to be 
Derived by CPMS 
The following PK parameters will be derived by CPMS: 
AUC(0-t) for OCA, glyco-OCA, tauro-OCA, total-OCA, and Linerixibat 
AUC(0-12) for Linerixibat 
AUC(0-24) for OCA, glyco-OCA, tauro-OCA, and total-OCA 
CMax for OCA, glyco-OCA, tauro-OCA, total-OCA, and Linerixibat 
Ctrough for OCA, glyco-OCA, tauro-OCA, and total-OCA 
Tmax for OCA, glyco-OCA, tauro-OCA, total-OCA, and Linerixibat 
Tlast for OCA, glyco-OCA, tauro-OCA, total-OCA, and Linerixibat 
Accumulation Ratios (RAUC and RCmax) for Linerixibat. 
Note: PK Parameters are derived as per Non-Compartmental Analysis of 
Pharmacokinetic Data, CPMS Global (GUI_51487 v5.0) 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
No  
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards or refer to Appendix shell wherever applicable.  
 
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14.6. 
Appendix 6: Derived and Transformed Data 
14.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables. 
Study Day 
 
Calculated as the number of days from First Dose Date: 
 
Ref Date = Missing              → Study Day = Missing  
 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
 
Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
 
14.6.2. 
Study Population 
Treatment Compliance 
 
Treatment compliance will be calculated based on the formula:   
Treatment Compliance = Number of Actual Doses / (Planned Treatment Duration in Days * 
Frequency) 
 
Frequency is 2 for BID and 1 for QD. Treatment compliance could be greater than 100% if there are 
events of overdose. Cumulative compliance (since Day 1) at each visit will be calculated. 
 
Planned Treatment Duration is defined as Day 1 to Day 37 for OCA and Day 20 to Day 38 for 
Linerixibat. 
Extent of Exposure 
 
Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1 
 
Exposure should be calculated for both OCA and OCA+Linerixibat. 
 
Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure.  
 
The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Number of Days x Total Daily Dose) 
 
If there are any treatment breaks during the study, exposure data will be adjusted accordingly. 
14.6.3. 
Efficacy 
Not applicable. 
 
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14.6.4. 
Safety 
Laboratory Parameters 
 
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a 
character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment 
field) is present, the number of significant digits in the observed values will be used to determine how 
much to add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01 
o Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
 
ECG Parameters 
RR Interval 
 
If RR interval (msec) is not provided directly, then RR can be derived as: 
[1] If QTcF is machine read, then:  
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐹)
3
] ∗1000 
 
If ECGs are manually read, the RR value preceding the measurement QT interval should be a collected 
value. THEN do not derive. 
Corrected QT Intervals 
 
When not entered directly in the ClinBase, corrected QT intervals by Fredericia’s (QTcF) formula will be 
calculated in msec, depending on the availability of other measurements. 
 
IF RR interval (msec) is provided then missing QTcF will be derived as:  
 
𝑄𝑇𝑐𝐹= 
𝑄𝑇
3√𝑅𝑅
1000
 
 
 
No adverse events of special interest have been defined for this analysis.  
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14.6.5. 
Pharmacokinetic 
PK Derivations and Conversions 
Analytes 
 
Total-OCA = OCA + (0.8805 x glyco-OCA) + (0.7969 x tauro-OCA) 
Note: If OCA, glyco-OCA, or tauro-OCA are non-quantifiable, then let that analyte be equal to 0 
in the above equation. 
See CDER document for reference. 
PK Parameters 
 
AUC(0-t), AUC(0-12), AUC(0-24), Cmax, Ctrough, Tmax, and Tlast will be calculated using 
Phoenix WinNonlin 
 
 
RAUC = (AUC(0-12) on Day 33) / (AUC(0-12) on Day 20) 
 
 
RCmax = (Cmax on Day 33) / (Cmax on Day 20) 
 
 
Average Ctrough when dosed on OCA alone = (Ctrough Day 17 + Ctrough Day 18 + Ctrough 
Day 19) / (Number of non-missing Ctrough measurements from Days 17, 18, and 19) 
 
 
Average Ctrough when dosed on OCA+Linerixibat = Ctrough Day 35 + Ctrough Day 36 + 
Ctrough Day 37 + Ctrough Day 38 / (Number of non-missing Ctrough measurements from Days 
35, 36, 37, and 38) 
Log Scale Conversions 
 
Geometric mean = exp(mean on loge scale)  
 
 
CVb(%) = SQRT (exp (SD2) – 1) x 100 
where SD is the standard deviation on the loge scale 
 
 
CVw(%) = SQRT (exp (MSE) – 1) x 100 
where MSE is the residual mean squared error from the model 
 
 
Lower bound of 90% CI = exp(lw) 
where lw is the lower bound of the 90% CI on the loge scale 
 
 
Upper bound of 90% CI = exp(up) 
where up is the upper bound of the 90% CI on the loge scale  
NOTE: PK Derivations and Conversions will be performed by clinical programming. 
 
14.6.6. 
Population Pharmacokinetic (PopPK) 
Not applicable. 
 
14.6.7. 
Pharmacodynamic and Biomarker 
Not applicable. 
 
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14.7. 
Appendix 7: Reporting Standards for Missing Data 
14.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
 
Subject study completion is defined as completion of all phases of the study including 
the follow up phone call.  
 
Withdrawn subjects will be replaced in the study if there are less than 15 completers. 
 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
14.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
 
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
 
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
PK 
 
Missing PK parameters will not be imputed. 
 
For missing and NQ values in PK concentration data, refer GUI_51487 v5.0 
14.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
 
Partial dates will be displayed as captured in subject listing displays. 
Adverse 
Events 
 
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event: 
 
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events. 
 
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used. 
 
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. 
Concomitant 
Medications/
Medical 
History 
 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
 
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
 
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month. 
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Element 
Reporting Detail 
 
The recorded partial date will be displayed in listings. 
 
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14.8. 
Appendix 8: Values of Potential Clinical Importance 
14.8.1. 
Laboratory Values 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit 
Ratio of 
1 
∆ from BL 
>0.075 
 
Ratio of 
1 
 
 
0.54 
Haemoglobin 
g/L 
∆ from BL 
>25 
 
g/L 
 
 
180 
Lymphocytes  
x109/ L 
 
<0.8 
 
Neutrophil Count  
x109/ L 
 
<1.5 
 
Platelet Count  
x109/ L 
 
<100 
>550 
While Blood Cell Count (WBC) 
x109/ L 
 
<3 
>20 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Calcium 
mmol/L 
 
<2.0 
>2.75 
Creatinine 
umol/L 
∆ from BL 
 
>44.2 
Glucose 
mmol/L 
 
<3.0 
>9.0 
Potassium 
mmol/L 
 
<3.0 
>5.5 
Sodium 
mmol/L 
 
<130 
>150 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT/SGPT  
U/L 
High 
>=2xULN 
AST/SGOT  
U/L 
High 
>=2xULN 
AlkPhos  
U/L 
High 
>=2xULN 
T Bilirubin  
µmol/L 
High 
>=1.5xULN 
T. Bilirubin + ALT 
µmol/L 
High 
1.5xULN T. Bilirubin 
 
+ 
U/L 
 2x ULN ALT 
 
14.8.2. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
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ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute QTc Interval 
msec 
 
>450 
Absolute PR Interval 
msec 
<110 
>220 
Absolute QRS Interval 
msec 
<75 
>110 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
>60 
14.8.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
<85 
>160 
Diastolic Blood Pressure 
mmHg 
<45 
>100 
Pulse Rate 
bpm 
<40 
>110 
 
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14.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
14.9.1. 
Population Pharmacokinetic (PopPK) Dataset Specification 
Not applicable. 
14.9.2. 
Population Pharmacokinetic (PopPK) Methodology 
Not applicable. 
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14.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
14.10.1. 
Pharmacokinetic / Pharmacodynamic Dataset Specification 
Not applicable. 
14.10.2. 
Pharmacokinetic / Pharmacodynamic Methodology 
Not applicable. 
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14.11. 
Appendix 11: Abbreviations & Trade Marks 
14.11.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
A&R 
Analysis and Reporting  
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
MMRM 
Mixed Model Repeated Measures 
MSE 
Mean Squared Error 
OCA 
Obeticholic Acid, Ocaliva® 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
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Abbreviation 
Description 
SAC 
Statistical Analysis Complete 
SDSP 
Study Data Standardization Plan 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
SQRT 
Square Root 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
14.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
HARP 
 
Phoenix WinNonlin (6.3 or greater) 
 
 
SAS 9.4 
 
 
Ocaliva® 
 
 
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14.12. 
Appendix 12: List of Data Displays 
14.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.12 
 
Safety 
2.1 to 2.15 
2.1 to 2.3 
Pharmacokinetic 
3.1 to 3.10 
3.1 to 3.9 
Section 
Listings 
ICH Listings 
1 to 30 
Other Listings 
31 to 34 
 
14.12.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
NOTES:  
 
Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
14.12.3. 
Deliverables 
Delivery [Priority] [1] 
Description 
HLR [1] 
Headline Results 
SAC [2] 
Final Statistical Analysis Complete 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 
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14.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
All 
Participants 
ES1A 
Summary of Participant Disposition for the Participant 
Conclusion Record 
ICH E3, FDAAA, EudraCT 
SAC [2] 
1.2. 
All 
Participants 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment 
ICH E3 
 
SAC [2] 
1.3. 
All 
Participants 
ES4 
Summary of Participant Disposition at Each Study Phase 
ICH E3 
 
HLR [1] 
1.4. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
SAC [2] 
1.5. 
All 
Participants 
 
NS1 
Summary of Number of Participant by Country and Site ID 
EudraCT/Clinical Operations 
SAC [2] 
Protocol Deviation 
1.6. 
All 
Participants 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
SAC [2] 
Population Analysed 
1.7. 
Screened 
SP1 
Summary of Study Populations  
IDSL 
HLR [1] 
Demographic and Baseline Characteristics 
1.8. 
All 
Participants 
DM3 
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
HLR [1] 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.9. 
All 
Participants 
DM11 
Summary of Age Ranges 
EudraCT 
Only have Total. 
We can use All Participants flag, for this 
study it is the same as Enrolled 
population flag. 
HLR [1] 
1.10. 
All 
Participants 
DM5 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
HLR [1] 
Prior and Concomitant Medications 
1.11. 
All 
Participants 
CM1 
Summary of Concomitant Medications 
ICH E3 
HLR [1] 
Exposure and Treatment Compliance 
1.12. 
All 
Participants 
EX1 
Summary of Exposure to Study Treatment 
ICH E3 
Use OCA and OCA+Linerixibat 
treatment regimens. 
HLR [1] 
 
14.12.5. 
Efficacy Tables 
Not applicable. 
 
 
14.12.6. 
Efficacy Figures 
Not applicable. 
 
 
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14.12.7. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
2.1.  
All 
Participants 
AE1 
Summary of All Adverse Events by System Organ Class and 
Preferred Term 
ICH E3 
 
SAC [2] 
2.2.  
All 
Participants 
AE1          
 
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term 
 
ICH E3 
HLR [1] 
Serious and Other Significant Adverse Events 
2.3.  
All 
Participants 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) 
FDAAA, EudraCT 
 
HLR [1] 
Laboratory: Chemistry  
2.4.  
All 
Participants 
LB1 
Summary of Chemistry Changes from Baseline  
ICH E3 
 
SAC [2] 
2.5.  
All 
Participants 
LB15 
Summary of Worst Case Chemistry Results Relative to Normal 
Range 
ICH E3 
 
SAC [2] 
Laboratory: Hematology 
2.6.  
 All 
Participants 
LB1 
Summary of Hematology Changes from Baseline 
ICH E3 
 
SAC [2] 
2.7.  
All 
Participants 
LB15 
Summary of Worst Case Hematology Results Relative to Normal 
Range 
ICH E3 
 
SAC [2] 
Laboratory: Urinalysis 
2.8.  
All 
Participants 
UR1 
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline 
ICH E3 
 
SAC [2] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Hepatobiliary (Liver) 
2.9.  
 All 
Participants 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
IDSL 
Keep:  
ALT >3xULN and BIL >2xULN 
ALT >3xULN and INR >1.5 
ALT >3xULN 
ALT >5xULN 
BIL >2xULN 
ALP >2xULN and Baseline ALP 
<2xULN or Baseline ALP missing 
Time from First Dose to First ALT 
Elevation >3xULN (days) 
HLR [1] 
ECG 
2.10. 
 All 
Participants 
EG1 
Summary of ECG Findings  
IDSL 
 
SAC [2] 
2.11. 
All 
Participants 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category 
IDSL 
 
SAC [2] 
2.12. 
All 
Participants 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
IDSL 
 
SAC [2] 
2.13. 
All 
Participants 
EG11 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category 
IDSL 
SAC [2] 
Vital Signs 
2.14. 
All 
Participants 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
SAC [2] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.15. 
All 
Participants 
VS3 
Summary of Worst Case Vital Signs Results Relative to 
Potential Clinical Importance Range 
IDSL 
SAC [2] 
 
 
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14.12.8. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory 
2.1.  
All 
Participants 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT 
IDSL 
SAC [2] 
2.2.  
All 
Participants 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin 
IDSL 
SAC [2] 
2.3.  
All 
Participants 
SAF_F1 
Individual Plots of ALT at Day -1, 17, and 38 
 
HLR [1] 
 
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14.12.9. 
Pharmacokinetic Tables 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
OCA 
3.1.  Pharmacokinetic 
Concentrations 
PK01 
Summary of Plasma Total-OCA, OCA, Glyco-OCA, and 
Tauro-OCA Pharmacokinetic Concentration-Time Data 
Treatment will be OCA and 
OCA+Linerixibat. 
Separated by analytes of Total-OCA, 
OCA, Glyco-OCA, and Tauro-OCA. 
SAC [2] 
3.2.  Pharmacokinetic 
Parameters 
PK06 
Summary of Derived Plasma Total-OCA, OCA, Glyco-OCA, 
and Tauro-OCA Pharmacokinetic Parameters by Treatment 
Regimen 
Use AUC(0-t), AUC(0-24), Cmax, 
and average Ctrough.  
Generate for OCA, OCA+Linerixibat, 
and the difference between the two 
periods (OCA+Linerixibat) – (OCA). 
Separated by analytes of Total-OCA, 
OCA, Glyco-OCA, and Tauro-OCA. 
HLR [1] 
3.3.  Pharmacokinetic 
Parameters 
PK04 
Summary of Derived Plasma Total-OCA, OCA, Glyco-OCA, 
and Tauro-OCA Pharmacokinetic Time Parameters by 
Treatment Regimen 
Use Tmax and Tlast. 
Generate for OCA, OCA+Linerixibat, 
and the difference between the two 
periods (OCA+Linerixibat) – (OCA). 
Separated by analytes of Total-OCA, 
OCA, Glyco-OCA, and Tauro-OCA 
SAC [2] 
3.4.  Pharmacokinetic 
Parameters 
PK03 
Summary of Derived Ctrough of Total-OCA by Days 17, 18, 
and 19 and Days 35, 36, 37, and 38 
Treatment will be OCA and 
OCA+Linerixibat 
SAC [2] 
3.5.  Pharmacokinetic 
Parameters 
PK_T1 
Analysis of Derived Plasma Total-OCA, OCA, Glyco-OCA, 
and Tauro-OCA Pharmacokinetic Parameters 
Use AUC(0-t), AUC(0-24), Cmax, 
and average Ctrough. 
Separated by analytes of Total-OCA, 
OCA, Glyco-OCA, and Tauro-OCA 
HLR [1] 
3.6.  Pharmacokinetic 
Parameters 
PK_T2 
Analysis of Ctrough of total-OCA Compared to 20 ng/mL 
Threshold. 
Use average Ctrough from 
OCA+Linerixibat treatment regimen. 
HLR [1] 
Linerixibat 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.7.  Pharmacokinetic 
Concentrations 
PK01 
Summary of Plasma Linerixibat Pharmacokinetic 
Concentration-Time Data 
The two treatment time points are 
Day 20 and Day 33. 
SAC [2] 
3.8.  Pharmacokinetic 
Parameters 
PK06 
Summary of Derived Plasma Linerixibat Pharmacokinetic 
Parameters by Day 20 and Day 33 
The two treatment time points are 
Day 20 and Day 33. 
Use AUC(0-t), AUC(0-12), and 
Cmax. 
SAC [2] 
3.9.  Pharmacokinetic 
Parameters 
PK04 
Summary of Derived Plasma Linerixibat Pharmacokinetic 
Time Parameters by Day 20 and Day 33 
Use Tmax and Tlast. 
The two treatment time points are 
Day 20 and Day 33. 
Generate for Day 20, Day 33, and 
the difference between the two time 
points (Day 33 – Day 20). 
SAC [2] 
3.10. Pharmacokinetic 
Parameters 
PK_T3 
Summary of Derived Plasma Linerixibat Pharmacokinetic 
Accumulation Parameters by Day 20 and Day 33 
Use RAUC and RCmax. 
SAC [2] 
 
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14.12.10. Pharmacokinetic Figures 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
OCA 
3.1.  Pharmacokinetic 
Concentration 
PK24 
Individual Concentration-Time Plots of Total-OCA, OCA, 
Glyco-OCA, and Tauro-OCA by Treatment Regimen 
All OCA analytes represented, 
separated by OCA and OCA+IBAT 
regiments. 
SAC [2] 
3.2.  Pharmacokinetic 
Concentration 
PK24 
Individual Concentration-Time Plots of Treatment Regimen by 
Total-OCA, OCA, Glyco-OCA, and Tauro-OCA 
Represent OCA and OCA+IBAT 
regiment on z-axis, separated by all 
OCA analytes. 
SAC [2] 
3.3.  Pharmacokinetic 
Concentration 
PK17 
Mean Concentration-Time Plot of Total-OCA, OCA, Glyco-
OCA, and Tauro-OCA by Treatment Regimen 
All OCA analytes represented, 
separated by OCA and OCA+IBAT 
regiments. 
SAC [2] 
3.4.  Pharmacokinetic 
Concentration 
PK17 
Mean Concentration-Time Plot of Treatment Regimen by 
Total-OCA, OCA, Glyco-OCA, and Tauro-OCA 
Represent OCA and OCA+IBAT 
regiment on z-axis, separated by all 
OCA analytes. 
SAC [2] 
3.5.  Pharmacokinetic 
Parameters 
PK17 
Mean Ctrough of Total-OCA, OCA, Glyco-OCA, and Tauro-
OCA by Days 17, 18, and 19, and Days 35, 36, 37, and 38 
X-axis is study day rather than 
Planned Relative Time. 
One plot for Days 17, 18, and 19, 
and another plot for Days 35, 36, 37, 
and 38, for each analyte. 
HLR [1] 
3.6.  Pharmacokinetic 
Parameters 
PK30 
Linear Plot of Individual PK Parameters by Total-OCA, OCA, 
Glyco-OCA, and Tauro-OCA 
X-axis is the study day rather than 
log(dose). 
Days when OCA and 
OCA+Linerixibat PK draw occurred 
labelled on the x-axis study day. 
SAC [2] 
Linerixibat 
3.7.  Pharmacokinetic 
Concentration 
PK24 
Individual Concentration-Time Plots of Linerixibat by Day 20 
and Day 33 
 
SAC [2] 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.8.  Pharmacokinetic 
Parameters 
PK17 
Mean Concentration-Time Plot of Linerixibat by Day 20 and 
Day 33 
 
SAC [2] 
3.9.  Pharmacokinetic 
Parameters 
PK30 
Linear Plot of Individual PK Parameters for Day 20 and Day 
33 
X-axis is the study day rather than 
log(dose).  
Days when Linerixibat PK draw 
occurred labelled on the x-axis study 
day. 
SAC [2] 
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14.12.11. Pharmacokinetic Population (PopPK) Tables 
Not applicable. 
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14.12.12. Pharmacokinetic Population (PopPK) Figures 
Not applicable. 
14.12.13. Pharmacodynamic and Biomarker Tables 
Not applicable. 
 
14.12.14. Pharmacodynamic and Biomarker Figures 
Not applicable. 
 
14.12.15. Pharmacokinetic / Pharmacodynamic Biomarker Tables 
Not applicable. 
 
14.12.16. Pharmacokinetic / Pharmacodynamic Biomarker Figures 
Not applicable. 
 
 
 
 
 
 
 
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14.12.17. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
Journal Guidelines 
SAC [2] 
2.  
All 
Participants 
ES2xo 
Listing of Reasons for Study Withdrawal 
ICH E3 
SAC [2] 
3.  
All 
Participants 
SD2xo 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
SAC [2] 
4.  
All 
Participants 
CP_RD1x 
Listing of Planned and Actual Treatments 
IDSL 
SAC [2] 
Protocol Deviations 
5.  
All 
Participants 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
SAC [2] 
6.  
All 
Participants 
IE3 
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
SAC [2] 
Populations Analysed 
7.  
Screened 
SP3xo 
Listing of Participants Excluded from Any Population 
ICH E3 
SAC [2] 
Demographic and Baseline Characteristics 
8.  
All 
Participants 
DM2 
Listing of Demographic Characteristics 
ICH E3 
SAC [2] 
9.  
All 
Participants 
DM9xo 
Listing of Race 
ICH E3 
SAC [2] 
Prior and Concomitant Medications 
10.  
All 
Participants 
CM10xo 
Listing of Concomitant Medications 
IDSL 
SAC [2] 
Exposure and Treatment Compliance 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
11.  
All 
Participants 
EX3xo 
Listing of Exposure Data 
ICH E3 
For OCA and for Linerixibat 
SAC [2] 
12.  
All 
Participants 
COMP2 
Listing of Overall Compliance 
ICH E3 
For OCA and for Linerixibat 
SAC [2] 
Adverse Events 
13.  
All 
Participants 
AE8xo 
Listing of All Adverse Events 
ICH E3 
SAC [2] 
14.  
All 
Participants 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
SAC [2] 
15.  
All 
Participants 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text 
IDSL 
SAC [2] 
Serious and Other Significant Adverse Events 
16.  
All 
Participants 
AE8CPaxo 
Listing of Serious Adverse Events 
ICH E3 
SAC [2] 
17.  
All 
Participants 
E14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
SAC [2] 
18.  
All 
Participants 
AE8CPxo 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
ICH E3 
SAC [2] 
Hepatobiliary (Liver) 
19.  
All 
Participants 
LIVER6 
Listing of Liver Stopping Event Information 
IDSL 
 
SAC [2] 
20.  
All 
Participants 
SU2 
Listing of Substance Use for Participants with Liver Stopping 
Events 
IDSL 
SAC [2] 
All Laboratory 
21.  
All 
Participants 
LB5xo 
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance 
ICH E3 
 
SAC [2] 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
22.  
All 
Participants 
LB5xo 
Listing of Laboratory Values of Potential Clinical Importance 
 
SAC [2] 
23.  
All 
Participants 
LB14 
Listing of Laboratory Data with Character Results 
ICH E3 
 
SAC [2] 
24.  
All 
Participants 
UR2xo 
Listing of Urinalysis Data for Participants with Any Value of 
Potential Clinical Importance 
ICH E3 
SAC [2] 
ECG 
25.  
All 
Participants 
EG3 
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance 
IDSL 
 
SAC [2] 
26.  
All 
Participants 
EG3 
Listing of ECG Values of Potential Clinical Importance 
IDSL 
 
SAC [2] 
27.  
All 
Participants 
EG5 
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding 
IDSL 
 
SAC [2] 
28.  
All 
Participants 
EG5 
Listing of Abnormal ECG Findings 
IDSL 
. 
SAC [2] 
Vital Signs 
29.  
All 
Participants 
VS5 
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance 
IDSL 
 
SAC [2] 
30.  
All 
Participants 
VS5 
Listing of Vital Signs of Potential Clinical Importance 
IDSL 
. 
SAC [2] 
 
 
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14.12.18. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
OCA 
31.  
Pharmacokinetic 
Concentrations 
PK07 
Listing of Total-OCA, OCA, Glyco-OCA, and Tauro-OCA 
Concentration-Time Data. 
Total-OCA will need to be calculated. 
A separate listing for each analyte. 
OCA and OCA+Linerixibat will be the 
periods.  
SAC [2] 
32.  
Pharmacokinetic 
Concentrations 
PK14 
Listing of Derived Total-OCA, OCA, Glyco-OCA, and Tauro-
OCA PK Parameters. 
Total-OCA will need to be calculated.  
A separate listing for each analyte. 
OCA and OCA+Linerixibat will be the 
periods. 
SAC [2] 
Linerixibat 
33.  
Pharmacokinetic 
Concentrations 
PK07 
Listing of Linerixibat Concentration-Time Data 
Day 20 and Day 33 will be the 
periods. 
SAC [2] 
34.  
Pharmacokinetic 
Concentrations 
PK14 
Listing of Derived Linerixibat PK Parameters. 
Day 20 and Day 33 will be the 
periods. 
SAC [2] 
 
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14.13. 
Appendix 13: Example Mock Shells for Data Displays 
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Example:    PK_T1 
 
 
 
 
 
 
 
 
 
 
 
 
                 Page 1 of n 
Protocol:     206224 
Population: Pharmacokinetic Parameters 
Table 4.5 
Analysis of Derived Plasma Total-OCA Pharmacokinetic Parameters 
Parameter 
N 
Mean 
OCA+Linerixibat 
Mean OCA  
Ratio: 
OCA+Linerixibat: 
OCA 
90% C.I. 
CVw(%) 
AUC(0-t) 
xx 
x.xx 
x.xx 
x.xx 
(x.xx,x.xx) 
xx.xx% 
AUC(0-24) 
xx 
x.xx 
x.xx 
x.xx 
(x.xx,x.xx) 
xx.xx% 
Cmax 
xx 
x.xx 
x.xx 
x.xx 
(x.xx,x.xx) 
xx.xx% 
Note: OCA+Linerixibat:OCA represents the ratio of adjusted geometric means between treatment regimens. 
Treatment Regimen Key: 
OCA+Linerixibat  = 10 mg OCA QD for 18 days + Linerixibat 90 mg BID for 18 days  
OCA  = 10 mg OCA QD for 18 days  
 
 
 
 
 
 
 
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Example:    PK_T2 
 
 
 
 
 
 
 
 
 
 
 
 
                 Page 1 of n 
Protocol:     206224 
Population: Pharmacokinetic Parameters 
Table 4.6 
Analysis of Ctrough of total-OCA Compared to 20 ng/mL Threshold 
Parameter 
N 
Mean 
OCA+Linerixibat 
90% C.I. 
20 ng/mL 
Threshold 
Average Ctrough 
xx 
x.xx 
(x.xx,x.xx) 
Above/Below 
 
 
 
   
  Note: Average Ctrough is the average Ctrough ng/mL from Study Days 35, 36, 37, and 38.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Example:    PK_T3 
 
 
 
 
 
 
 
 
 
 
 
 
                 Page 1 of n 
Protocol:     206224 
Population: Pharmacokinetic Parameters 
Table 4.6 
Summary of Derived Plasma Linerixibat Pharmacokinetic Accumulation Parameters by Day 20 and Day 33 
 
 
 
Parameter 
 
Summary 
Statistics 
 
Ratio:  
Day33/Day20 
 
 
 
RAUC 
N 
xxx 
 
n 
xxx 
 
Arith. Mean 
xxx.xx 
 
     95% CI  
(xxx.xx,xxx.xx) 
 
SD 
xxx.xxx 
 
Median 
xxx.xx 
 
Min 
xxx.x 
 
Max 
xxx.x 
 
 
 
RCmax 
N 
xxx 
 
n 
xxx 
 
Arith. Mean 
xxx.xx 
 
     95% CI  
(xxx.xx,xxx.xx) 
 
SD 
xxx.xxx 
 
Median 
xxx.xx 
 
Min 
xxx.x 
 
Max 
xxx.x 
 
Note: RAUC is the ratio of AUC(0-12) on Day 14 of the Linerixibat dosing interval (Study Day 
33) to the start of the Linerixibat dosing interval (Study Day 20). 
RCmax is the ratio of Cmax on Day 14 of the Linerixibat dosing interval (Study Day 33) to the 
start of the Linerixibat dosing interval (Study Day 20). 
 
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Example: SAFE_F1 
 
 
 
 
 
 
 
 
 
                                          
Page 1 of n 
Protocol: 206224 
Population: All Participants 
Figure 3.3 
Individual Plots of ALT at Day -1, 17, and 38 
 
 
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