Conditions: Cholestasis
Keywords: [14C]-linerixibat GSK2330672 Microtracer dose
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: yes

Brief summary:
Absorption, metabolism and excretion of linerixibat have been studied in previous clinical trials. However, no dedicated clinical studies of drug absorption, metabolism, and excretion have been conducted for linerixibat. The purpose of this study is to determine the PK, balance/excretion, and metabolism of radiolabeled 14 Carbon \[14C\]-linerixibat following a single intravenous (IV) radiolabeled microtracer dose (concomitant with a non-radiolabeled oral dose) and a single oral radiolabeled dose. This is a single group, two period, single sequence, and mass balance study will enroll 6 healthy male subjects. Each subject will be involved in the study for up to 10 weeks which includes screening period, two treatment periods (treatment Periods 1 and 2), separated by about 7 days (at least 13 days between oral doses), and a follow-up visit 1-2 weeks after the last assessment in treatment Period 2.

Detailed description:

Arms:
arm 1: Subjects will receive a single oral dose of linerixibat 90 milligram (mg) (2\*45 mg) tablets concomitantly with \[14C\]-linerixibat 100 microgram (approximately 9.25 kilobecquerel; 250 nano curie) IV infusion for 3 hours, after an overnight fast that continues for 2 hours after the oral dose/start of IV infusion, small standard high-fat meal will be given on Day 1 in treatment Period 1; followed by a single oral dose of \[14C\]-linerixibat 90 mg (approximately 4.96 megabecquerel; 134.1 micro curie) solution on Day 1 in treatment Period 2. A wash out period of at least 13 days will be maintained between oral doses of treatment periods.

Interventions: intervention 1: Linerixibat tablet intervention 2: [14C]-linerixibat intravenous infusion intervention 3: Linerixibat oral solution
Intervention descriptions: intervention 1: Linerixibat will be available as white to slightly colored film-coated round tablet to be administered as two tablets taken in the fasted state in the morning with 240 milliliter (mL) of room temperature water. intervention 2: \[14C\]-linerixibat will be available as clear, colorless solution free from visible particulates to be administered 25 mL IV over 3 hours immediately after the oral dose. intervention 3: Linerixibat will be available as clear, colorless solution free from visible particulates to be administered 60 mL solution in the fasted state in the morning.

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A two-period study in healthy male participants to determine the 
pharmacokinetics, balance/excretion, and metabolism of [14C]-linerixibat following a 
single intravenous radiolabeled microtracer dose (concomitant with a non-radiolabeled 
oral dose) and a single oral radiolabeled dose
Protocol Number: 205895
Compound Number:
GSK2330672
Study Phase: Phase 1 
Short Title: Pharmacokinetics and metabolism of radiolabelled linerixibat
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s):
IND: 130391
EudraCT:  2019-000875-18
Approval Date: 11-APR-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)..........................................................................9
2.
INTRODUCTION....................................................................................................16
2.1.
Study Rationale ..........................................................................................16
2.2.
Background ................................................................................................16
2.2.2.
Linerixibat (GSK2330672)............................................................17
2.3.
Benefit/Risk Assessment ............................................................................17
2.3.1.
Risk Assessment .........................................................................18
2.3.2.
Benefit Assessment.....................................................................18
2.3.3.
Overall Benefit: Risk Conclusion..................................................18
3.
OBJECTIVES AND ENDPOINTS...........................................................................19
4.
STUDY DESIGN ....................................................................................................20
4.1.
Overall Design ............................................................................................20
4.1.1.
Screening Period .........................................................................20
4.1.2.
Treatment Period 1 (oral tablets and intravenous infusion) ..........20
4.1.3.
Treatment Period 2 (oral solution)................................................21
4.1.4.
Demonstration of radioactivity recovery before discharge 
(Period 2).....................................................................................21
4.1.5.
Follow-up.....................................................................................22
4.2.
Scientific Rationale for Study Design ..........................................................22
4.3.
Justification for Dose ..................................................................................23
4.3.1.
Linerixibat Oral Dose (Periods 1 and 2) .......................................23
4.3.2.
Linerixibat Intravenous Dose (Period 1).......................................23
4.3.3.
Radiolabel Dose ..........................................................................24
4.3.4.
Total Radiation Exposure.............................................................24
4.4.
End of Study Definition ...............................................................................24
5.
STUDY POPULATION...........................................................................................25
5.1.
Inclusion Criteria.........................................................................................25
5.2.
Exclusion Criteria........................................................................................26
5.3.
Lifestyle Considerations..............................................................................28
5.3.1.
Meals and Dietary Restrictions ....................................................28
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................29
5.3.3.
Activity .........................................................................................29
5.4.
Screen Failures...........................................................................................29
6.
STUDY INTERVENTION........................................................................................29
6.1.
Study Intervention(s) Administered .............................................................30
6.2.
Preparation/Handling/Storage/Accountability..............................................30
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................31
6.4.
Study Intervention Compliance ...................................................................31
6.5.
Concomitant Therapy..................................................................................31
6.6.
Dose Modification .......................................................................................32
6.7.
Intervention after the End of the Study........................................................32


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7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................32
7.1.
Discontinuation of Study Intervention..........................................................32
7.1.1.
Liver Chemistry Stopping Criteria ................................................32
7.1.1.1.
Study Intervention Restart or Rechallenge after 
liver stopping criteria met............................................33
7.1.2.
QTc Stopping Criteria ..................................................................33
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................34
7.3.
Lost to Follow Up........................................................................................34
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................34
8.1.
Efficacy Assessments.................................................................................35
8.2.
Safety Assessments ...................................................................................35
8.2.1.
Physical Examinations.................................................................35
8.2.2.
Vital Signs....................................................................................36
8.2.3.
Electrocardiograms......................................................................36
8.2.4.
Clinical Safety Laboratory Assessments ......................................36
8.3.
Adverse Events and Serious Adverse Events.............................................37
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................37
8.3.2.
Method of Detecting AEs and SAEs.............................................37
8.3.3.
Follow-up of AEs and SAEs.........................................................37
8.3.4.
Regulatory Reporting Requirements for SAEs .............................38
8.3.5.
Pregnancy ...................................................................................38
8.4.
Treatment of Overdose...............................................................................38
8.5.
Pharmacokinetics .......................................................................................39
8.5.1.
Plasma Sample Collection ...........................................................39
8.5.2.
Urine Sample Collection ..............................................................39
8.5.3.
Fecal Sample Collection ..............................................................39
8.5.4.
Bile Sample Collection.................................................................40
8.5.5.
Sample Analysis ..........................................................................40
8.6.
Pharmacodynamics ....................................................................................40
8.7.
Genetics .....................................................................................................41
8.8.
Biomarkers .................................................................................................41
8.9.
Medical Resource Utilization and Health Economics ..................................41
9.
STATISTICAL CONSIDERATIONS........................................................................41
9.1.
Statistical Hypotheses.................................................................................41
9.2.
Sample Size Determination ........................................................................41
9.3.
Populations for Analyses ............................................................................41
9.3.1.
Statistical Analyses......................................................................42
9.3.2.
Efficacy Analyses.........................................................................42
9.3.3.
Safety Analyses...........................................................................42
9.4.
Pharmacokinetic Analyses..........................................................................42
9.5.
Metabolite profiling......................................................................................43
9.6.
Interim Analyses .........................................................................................44
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................45
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................45
10.1.1.
Regulatory and Ethical Considerations ........................................45


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10.1.2.
Financial Disclosure.....................................................................45
10.1.3.
Informed Consent Process ..........................................................45
10.1.4.
Data Protection............................................................................46
10.1.5.
Dissemination of Clinical Study Data ...........................................46
10.1.6.
Data Quality Assurance ...............................................................47
10.1.7.
Source Documents ......................................................................47
10.1.8.
Study and Site Closure ................................................................48
10.1.9.
Publication Policy.........................................................................48
10.2.
Appendix 2:  Clinical Laboratory Tests........................................................49
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................50
10.3.1.
Definition of AE............................................................................50
10.3.2.
Definition of SAE..........................................................................51
10.3.3.
Recording and Follow-Up of AE and SAE....................................52
10.3.4.
Reporting of SAE to GSK.............................................................53
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................55
10.4.1.
Contraception Guidance ..............................................................55
10.4.2.
Collection of Pregnancy Information: ...........................................55
10.5.
Appendix 5:  Risk Assessment....................................................................56
10.6.
Appendix 6:  An assessment of the radiation dose to male 
volunteers from the oral and IV administration of the study 
intervention.................................................................................................60
10.7.
Appendix 7 Genetics...................................................................................70
10.8.
Appendix 8: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................71
10.9.
Appendix 9: Abbreviations and Trademarks................................................73
11. REFERENCES.......................................................................................................75


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A two-period study in healthy male participants to determine the 
pharmacokinetics, balance/excretion, and metabolism of [14C]-linerixibat following a 
single intravenous radiolabeled microtracer dose (concomitantly with a non-radiolabelled 
oral dose) and a single oral radiolabeled dose
Short Title: Pharmacokinetics and metabolism of radiolabelled linerixibat
Rationale:
Absorption, metabolism and excretion of linerixibat (GSK2330672) 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. Using radiolabelled linerixibat with Accelerator Mass Spectrometry (AMS) 
will enable quantitative measurement of linerixibat concentrations and comprehensive 
identification and quantification of drug metabolites that would not otherwise be possible.
This open-label study in 6 healthy male participants will assess the pharmacokinetics, 
balance/excretion, and metabolism of linerixibat in humans using [14C]-radiolabelled 
drug substance administered as an intravenous (IV) infusion and orally.  [14C]-linerixibat
administered by IV infusion will be a microtracer dose; therefore, it will be administered 
concomitantly with an oral non-radiolabelled dose, to ensure that the pharmacokinetics 
(PK) are representative of a clinically-relevant dose. Use of a string bile collection device 
for sampling duodenal bile after IV [14C]-linerixibat infusion will enable a qualitative 
assessment of drug metabolites in this matrix to characterise biliary elimination pathways
(Guiney, 2011).  The study will also provide an assessment of linerixibat metabolism 
following administration of a [14C]-radiolabelled oral solution.


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Objectives and Endpoints:
Objectives
Endpoints1
Primary

To determine parent linerixibat and total 
drug-related radioactivity systemic 
concentrations following a single IV 
microtracer dose of [14C]-linerixibat
(concomitant with an oral dose of non-
radiolabelled linerixibat) and oral dose of 
[14C]-linerixibat1

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 of 
parent and total drug-related material 
(radioactivity) in plasma.

Volume (Vss) and clearance (CL) of parent 
after IV dose (Period 1 only).

Renal clearance of parent (CLr) after both 
IV and oral dose

To estimate the oral bioavailability of 
linerixibat

Direct estimation of F (absolute oral 
bioavailability), indirect calculation of Fh 
(fraction of drug escaping first pass hepatic 
clearance), and Fa (fraction absorbed)

To determine the rate and extent of 
excretion of total radioactivity in urine and 
feces and the total recovery of radioactivity, 
following IV and oral administrations of 
[14C]-linerixibat

Urinary and fecal cumulative excretion as a 
percentage of the total radioactive dose 
Secondary

To evaluate the safety and tolerability of 
linerixibat after single IV and oral doses in 
healthy participants.

Incidence and severity of adverse events.

Laboratory safety, 12-lead ECG, and vital 
signs parameters.
Exploratory

To generate samples that will be used to 
characterize the metabolite profile of 
linerixibat following a single IV microtracer 
dose of [14C]-linerixibat concomitant with an 
oral dose of non-radiolabelled linerixibat
(plasma, urine, feces, duodenal bile) and a 
single, oral dose of [14C]- linerixibat
(plasma, urine and feces).

Characterization and quantification of 
metabolites in plasma, urine, feces, and 
duodenal bile (qualitative identification in 
bile).  These analytical investigations will be 
conducted, and the results reported under 
a separate nonclinical GSK protocol.
1 For measured concentrations of linerixibat in plasma, the nomenclature [14C]-linerixibat describes the parent 
linerixibat concentration derived via analysis by liquid chromatography (LC) + Accelerator Mass Spectrometry 
(AMS), whereas linerixibat describes the parent linerixibat concentration derived via liquid chromatography-tandem 
mass spectrometry (LC/MS/MS).
Overall Design:
The aim of the study is to assess pharmacokinetics (PK), balance/excretion, and 
metabolism of linerixibat using [14C]-radiolabelled drug substance administered 
intravenously as a microtracer dose (concomitantly with an oral, non-radiolabelled dose) 


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and [14C]-radiolabelled drug substance administered orally. Safety data will include AE 
reporting, 12-lead ECG, vital signs, and laboratory safety tests. Blood will be sampled 
extensively on the day of dosing, and daily until Day 8 for assessment of the PK of 
linerixibat and its metabolites. Duodenal bile will be collected non-invasively using a 
suitable nylon string device in Period 1 only. 
Disclosure Statement: This is a single group, single center, [14C]-linerixibat mass 
balance study with a two-period, single sequence and no masking. 
Number of Participants:  Six participants will be screened and enrolled to achieve at 
least 4 participants completing the two treatment periods. 
If one or more participants prematurely discontinue the study, replacement participants 
will be enrolled at the discretion of the sponsor and in consultation with the investigator.
Any replacement participants will be required to complete both treatment periods. 
Intervention Groups and Duration:
Each participant will be involved in the study for up to 10 weeks.  He will have a 
screening visit, two inpatient treatment periods (Treatment Periods 1 and 2), separated by 
about 7 days (at least 13 days between doses), and a follow-up visit 1-2 weeks after the 
last assessment in Treatment Period 2.  During both treatment periods, participants will 
reside in the unit from the morning of Day -1 until all procedures are completed 168 h 
post-dose (on Day 8).  Participants may be asked to stay for up to 1 week longer in 
Treatment Period 2, if required to demonstrate sufficient recovery of drug-related 
material. Thereafter, if deemed necessary to demonstrate sufficient recovery of 
radioactivity, participants may be asked to collect excreta at home.
Data Monitoring Committee: No
Treatment Period 1 (oral tablets and 14C-intravenous infusion)
On Day 1 of Treatment Period 1, after an overnight fast of at least 8 h, each participant
will take a single 90 mg oral dose of linerixibat; participants will continue to fast for 2 h 
after dosing. Immediately after the oral dose, the IV infusion of 100 µg of [14C]-
linerixibat (approximately 9.25 kBq; 250 nCi) will begin and continue over 3 h.  Blood 
samples, all voided urine, and feces will be collected for 168 h after oral dosing (until 
Day 8), while duodenal bile will be collected as described below.  Participants will be 
discharged on study Day 8 after completion of the 168-h sample collection and other 
planned assessments. 
A non-invasive device to collect duodenal bile will be used only in Treatment Period 1.  
The collection string and small weight will be swallowed 3.5 h before the oral dose/start 
of IV infusion, a duration recommended to allow transit of the string to the duodenum, 
while participants are in a fasted state.  It will be removed about 3 h after the oral 
dose/start of IV infusion (immediately following the end of the 3 h IV infusion), a time 
when the oral dose is expected to have transitioned from the stomach to the duodenum.  
At 2 h after the start of IV infusion (i.e., 1 h before string withdrawal), a food cue (small 
standard high-fat meal) will be given to stimulate gall bladder emptying.


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Treatment Period 2 (oral solution)
On Day 1 of Treatment Period 2, after an overnight fast of at least 8 h, each participant
will receive 90 mg [14C]-linerixibat (approximately 4.96 MBq; 134.1 µCi) as an oral 
solution; this is considered 0 h for sample collection.  Participants will continue to fast for 
2 h after dosing, when the same small standard high-fat meal as in Period 1 will be given.  
Blood, urine and fecal samples will be collected for a minimum of 168 h after dosing,
(seven 24-h samples, which will complete on Day 8). Radioactivity quantification using 
liquid scintillation counting (LSC) will be performed on each 24-h urine collection and 
each 24-h fecal homogenate. Criteria for discharge for Period 2 are based on 
demonstrated cumulative recovery of radioactivity >90% or <1% in two consecutive 
samples (see Section 4.1.4). The inpatient stay may be extended by up to 7 days to meet
the discharge criteria. In the unlikely event that excretion is still >1% in the 24-h 
collection period prior to discharge on Day 15, the participant will continue to collect 
fecal samples only, at home, at 24-h intervals.  Samples will be returned to the unit every 
2 to 3 days for analysis.
Total Radiation Exposure
The total amount of radiation exposure in the study is 4.97 MBq (134.3 µCi).
1.2.
Schema
Figure 1
Study Intervention Schematic  
1.3.
Schedule of Activities (SoA)
The timing and number of planned study assessments, including safety and 
pharmacokinetic 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. Participants who withdraw from the study early should be subject 
to those assessments that would be required at discharge in that treatment period, if 
participants agree.


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Any changes in the timing or addition of time points for any planned study assessments 
must be documented and approved by the relevant study team member and then archived 
in the sponsor and site study files but will not constitute a protocol amendment.  The 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment 
of the Informed Consent (ICF).
If assessments are scheduled for the same nominal time, the assessments should occur in 
the following order:
1. vital signs
2. 12-lead ECG 
3. blood draws
4. other assessments
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.


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Table 1
SoA: Treatment Period 1 (oral tablets and intravenous infusion)
Visit
Screening1
Day -1
Pre-dose
(incl. 0h)
Treatment Period 1
Day
-30 to -2
-1
1
2
3
4
5
6
7
8
Hrs Post-dose
Procedure
-3.5
0
0.5
1.0, 1.5
2.0, 2.5
3.0, 3.5
4.0, 4.5
5.0, 5.5
6
8
10
12
24
36
48
72
96
120
144
168
Informed consent
X
Adm. to unit pre-tx
X
Discharge from 
unit2
X
Medical history 
(including 
drug/alcohol use)
X
Demography
X
12-lead ECG 3
X
X
Vital signs 4
X
X
X
X
X
Drugs of abuse 
screen 
X
X
Alcohol, cotinine, & 
CO breath tests 
X
X
HIV and hepatitis B 
and C screen
X
Laboratory safety 
tests (incl. LFTs)
X
X
X
Physical exam 5
X-full
X
X
String bile collection 
test initiated 6
X
Oral linerixibat 7
X
14C-linerixibat IV
                                             3h 
Monitor local 
tolerability (IV)
                                              3h


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SoA: Treatment Period 1 (oral tablets and intravenous infusion) (Table 1 continued)
Visit
Screening1
Day 
-1
Pre-dose 
(incl. 0h)
Treatment Period 1
Day
-30 to -2
-1
1
2
3
4
5
6
7
8
Hrs Post-dose
Procedure
-3.5
0
0.5
1.0, 1.5
2.0, 2.5
3.0, 3.5
4.0, 4.5
5.0, 5.5
6
8
10
12
24
36
48
72
96
120
144
168
Standard small high 
fat meal8
X-2h
String bile collection 
device removed9
X 3h
Blood samples for 
plasma 
radioactivity10
X
X
X
X
X, X
X, X
X, X
X, X
X, X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for 
plasma drug assay10
X
X
X, X
X, X
X, X
X, X
X, X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for 
plasma 
metabolites11
X 1h
X 2h
X 3h
X 6h
Genetic sample
X
Fecal collection12
Day -2 or -1
Urine collection12
X
AE/SAE/Concom-
itant med. review13
Abbreviations: AE: adverse event; ECG: electrocardiogram; HIV: human immunodeficiency virus; IV: intravenous; LFTs: liver function tests; PGx: pharmacogenetics; Pre-tx: pre-treatment; 
SAE: serious adverse event.
Notes:
1Screening will be within 30 days before Day 1.
2 Participants will be discharged for a washout period prior to dosing in Treatment Period 2; there will be at least 13 days between a participant’s oral doses.  Participants who withdraw from the study 
early should be subject to those assessments that would be required at discharge in that treatment period, if participants agree.
3 Single ECG measurements will be obtained.   If any measurement is considered abnormal, then two additional ECGs will be taken. The mean of the triplicate measurements will be used.  The 
Screening measurement will be evaluated for eligibility and used as baseline. 


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4 Triplicate measurements of heart rate and systolic and diastolic blood pressure; single measurements of tympanic temperature and respiratory rate.
5 A full physical exam should be performed at baseline, including at minimum: assessments of the eyes, skin, joints, and the cardiovascular, respiratory, gastrointestinal and neurological systems; 
height, and weight should be measured and recorded, and BMI calculated and recorded.  Brief physical exams should be performed at later visits, including at minimum: assessments of the skin, 
lungs, cardiovascular system, abdomen (liver and spleen) and weight.
6 The string bile collection device will be swallowed 3.5 h before the oral dose/start of IV infusion, while participants are in a fasted state.  
7 Participants will fast for at least 8 h before oral dosing and continue to fast for 2 h after oral dosing. 
8 Meal time is specified for Day 1 mid-day only: approximately 2h (i.e., 2h ± 15 mins) after oral dose/start of IV infusion to stimulate gall bladder emptying. On all other days, meals will be served at the 
unit’s standard times. 
9 The string bile collection device will be removed 3 h after the oral dose/start of IV infusion (immediately after the end of the IV infusion). 
10 Background radiation will be measured in plasma samples obtained from blood collected at screening, on admission (Day –1), and pre-dose on Day1. Total radioactivity, [14C]-linerixibat analysis, and 
linerixibat analysis will be performed for all post-dosing plasma samples. All pre-dose plasma samples should be obtained from blood taken immediately prior to the oral dose/start of IV infusion; 
sampling times are relative to the oral dose on Day 1, unless otherwise indicated.
11 Plasma samples for metabolite profiling will be obtained from blood samples collected on Day 1 at 1h, 2h, 3h, and 6h post-dosing.
12 Urine and feces will be collected at pre-dose (up to 3 h pre-dose for the urine sample; up to 24 h pre-dose for the fecal sample). Starting at the time of oral dosing, all urine and feces will be collected as 
seven 24-h samples throughout Period 1 (total of 168 hours post-dose) in addition to pre-dose samples. 
13 AEs will be collected from the start of study intervention until the final follow-up visit.  All SAEs will be recorded from the time each participant consents to participate in the study,


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Table 2
SoA: Treatment Period 2 (oral solution)
Visit
Day -1
Pre-dose
(incl. 0h)
Treatment Period 2
F/up
Day
Day -1
1
2
3
4
5
6
7
81
14 –
212,3
Hrs Post-dose
Procedure
0
0.5
1
2
3
4
5
6
8
10
12
24
36
48
72
96
120
144
168
Admission to unit
X
Discharge from unit 4
X 4
12-lead ECG 5
X
X
(X)
Vital signs 6
X
X
X
X
X
Drugs of abuse screen 
X
Alcohol, cotinine, & CO 
breath tests
X
Laboratory safety tests 
(including LFTs)
X
X
(X)
[14C]-linerixibat oral 
solution
X
Brief physical exam 7
X
X
X
Standard small high fat 
meal 8
X
Blood samples for 
plasma radioactivity 9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for 
plasma drug assay 9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for 
plasma metabolites 10
X
X
X
X
Urine collection11
X
Fecal collection11
X
AE/SAE/concomitant 
medication review 12


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Abbreviations: AE: adverse event; ECG: electrocardiogram; FU: follow-up; HIV: human immunodeficiency virus; LFTs: liver function tests; SAE: serious adverse event; (X): at follow-up visit, these
assessments would only be performed to follow-up a result from the day of discharge.
Notes: 
1If discharge does not occur on Day 8, the following assessments should be performed on the day of discharge instead of Day 8:  vital signs, 12-lead ECG, brief physical examination.  
2 The follow-up will be between 7–14 days after the participant’s last assessment in Treatment Period 2.
3Participants who withdraw from the study early should be subject to those assessments that would be required at discharge in that treatment period, if participants agree.
4 Discharge from Period 2 will be contingent upon demonstration of adequate recovery of radioactivity (see Section 4.1.4). 
5 Single ECG measurements will be obtained. If any measurement is considered abnormal, then two additional ECGs will be taken, and the mean of the triplicate measurements used.  The Screening 
measurement will be evaluated for eligibility and used as baseline.
6 Triplicate measurements of heart rate and systolic and diastolic blood pressure; single measurements of tympanic temperature and respiratory rate.
7Brief physical exams should include at minimum assessments of the skin, lungs, cardiovascular system, abdomen (liver and spleen), and weight. 
8Participants will fast for at least 8 h before oral dosing and continue to fast for 2 h after dosing.  Meal time is specified for approximately 2h (i.e., 2h ± 15 mins) after the oral dose on Day 1, when the 
same small standard high fat meal as in Period 1 will be provided. On all other days, meals will be served at the unit’s standard times.
9 Total radioactivity, [14C]-linerixibat analysis, and linerixibat analysis will include predose and all post-dosing samples: at 0.5h post-dose, then every hour through 8h, then at 10h, 12h, 24h, 36h, 48h, 
and then daily until discharge. All pre-dose samples should be obtained immediately prior to the oral dose; sampling times are relative to the oral dose on Day 1, unless otherwise indicated. 
10 Plasma samples for metabolite profiling will be obtained from blood samples collected on Day 1 at 1h, 2h, 3h, and 6h post-dosing. 
11 Urine and feces will be collected at pre-dose (up to 3 h pre-dose for the urine sample; up to 24 h pre-dose for the fecal sample). Starting at the time of oral dosing, all urine and feces will be collected 
as 24-h samples throughout Period 2 (at minimum for168 hours post-dose) in addition to pre-dose samples. If subjects are required to stay after 168 h post-dose (Day 8), collections will continue at 24-
h intervals (see Section 4.1.4). 
12 AEs and SAEs will be collected until the final follow-up visit.


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2.
INTRODUCTION
Linerixibat is an oral small molecule inhibitor of the human ileal bile acid transporter 
(IBAT) that is located on the brush border of enterocytes lining the terminal ileum. 
Linerixibat is a highly soluble molecule, designed for gastrointestinal (GI) retention and 
minimal systemic exposure. It has the potential to improve symptoms of pruritus in 
cholestatic liver disease, such as primary biliary cholangitis (PBC). 
2.1.
Study Rationale
This study will assess the pharmacokinetics, balance/excretion, and metabolism of 
linerixibat in humans using [14C]-radiolabelled drug substance administered as an 
intravenous (IV) infusion and orally.  [14C]-linerixibat administered by IV infusion will 
be a microtracer dose; therefore, it will be administered concomitantly with an oral non-
radiolabelled dose, to ensure that the pharmacokinetics (PK) are representative of a 
clinically-relevant dose. Use of a string bile collection device for sampling duodenal bile 
after IV [14C]-linerixibat infusion will enable a qualitative assessment of drug metabolites 
in this matrix to characterise biliary elimination pathways. 
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. Using radiolabelled linerixibat with Accelerator Mass Spectrometry (AMS) 
will enable quantitative measurement of linerixibat concentrations and comprehensive 
identification and quantification of drug metabolites that would not otherwise be possible. 
2.2.
Background
Linerixibat belongs to a class of drugs that inhibit the ileal bile acid transporter. Located 
in the distal ileum of the gastrointestinal tract, IBAT is responsible for the active reuptake 
of bile acids from the gut lumen that are then returned to the liver via the portal vein, 
resulting in efficient enterohepatic conservation of bile acids, and negative feedback 
regulation of hepatic bile acid synthesis. No other IBAT inhibitors have been investigated 
as treatment for pruritus associated with primary biliary cholangitis (PBC). 
Because IBAT, the pharmacological target of linerixibat, is located on the brush border of 
enterocytes in the intestinal lumen, the investigational product was designed to have low 
permeability and high polar surface area, which limits absorption into the portal or 
systemic circulation. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of linerixibat
is provided in the Investigator’s Brochure (IB) (see GSK Document Number 
2010N111289_05).
2.2.1.
Pruritus associated with primary biliary cholangitis
PBC is a rare, chronic condition caused by the inflammatory destruction of the 
intrahepatic bile ducts giving rise to impaired bile acid flow and retention in the liver, 
which leads to hepatic scarring, fibrosis and ultimately cirrhosis and liver failure. Pruritus 


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is a major symptom associated with PBC. PBC pruritus is an intense itching that can 
occur anywhere on the body, often resulting in disturbed sleep and having a significant 
impact on a patient’s quality of life. Currently there is great unmet medical need, with
few therapies that provide limited relief of pruritus associated with PBC.
For patients with PBC, inhibition of IBAT by linerixibat is anticipated to increase 
excretion of bile acids, reduce bile acid concentrations in the liver and systemic 
circulation, and result in reduced pruritus and associated symptoms. 
2.2.2.
Linerixibat (GSK2330672)
Linerixibat was first administered to humans in June 2011. It has been evaluated in a 
series of nonclinical studies and clinical trials.  In vitro and in vivo studies established 
activity of linerixibat as an inhibitor of IBAT and confirmed the molecule has minimal 
systemic exposure.  Three Phase 1 studies in healthy participants (including one study in 
Japanese participants), two Phase 2 studies in Type 2 diabetic (T2D) patients, and one 
Phase 2 study in patients with pruritus secondary to PBC have been completed.  
In these studies, linerixibat, did not result in any findings during safety monitoring that 
would preclude conduct of planned short-term clinical trials in patient populations with 
T2D or PBC.  However, the high frequency of AEs of diarrhoea among T2D participants 
taking metformin 850 mg BID contributed to the decision to terminate development for
this condition. 
In a randomized, placebo-controlled, 14-day cross-over study (BAT117213), linerixibat
was given as 45 mg BID on Days 1 through 3 and as 90 mg BID on Days 4 through 14. 
Linerixibat treatment resulted in a statistically significant decrease in pruritus severity 
compared to placebo, along with decreases in fatigue, sleep disturbance and overall 
disability compared to placebo. No serious adverse events (SAEs) were reported. 
Diarrhoea was the most frequent adverse event (AE) during treatment with linerixibat:
seven with linerixibat vs one with placebo (Hegade, 2017). 
A Phase 2 dose-ranging study in participants with pruritus secondary to PBC is currently 
ongoing and will inform further development in PBC pruritus (see GSK IB, Section 1.1).
Detailed information relating to non-clinical pharmacology, safety pharmacology, PK 
and metabolism, toxicology and other pre-clinical data can be found in the linerixibat IB.
2.3.
Benefit/Risk Assessment
The potential clinically important risks of study intervention and trial procedures, and 
their mitigation, are given in Appendix 5 (see Section 10.5).
More detailed information about the known and expected benefits, risks, and reasonably 
expected AEs associated with linerixibat may be found in the IB, Section 6.


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2.3.1.
Risk Assessment
Potential risks of clinical significance, relevant supporting data and rationale, and 
mitigation strategy are presented in Appendix 5 (see Section 10.5). 
Justification of the use of healthy participants below the age of 50 years is required in 
accordance with the guidelines of the Administration of Radioactive Substances Advisory 
Committee (ARSAC) and the Association of the British Pharmaceutical Industry, as well 
as GSK internal policies. The assessment of the radiation dose to male participants from 
the oral and IV administration of the study intervention is within the lower end of 
exposure defined by the World Health Organization’s recommendation as acceptable for 
the general public (Public Health England, Appendix 6 [see Section 10.6]). Therefore, 
enrolling healthy male participants between 30 and 55 years in this study is acceptable. 
2.3.2.
Benefit Assessment
The healthy participants will receive no clinical benefit for participation in this study.
2.3.3.
Overall Benefit: Risk Conclusion
Overall, the available data from non-clinical and clinical studies have not identified 
prohibitive risks associated with linerixibat at the exposures planned for this study.  
While there are a number of important potential risks identified for linerixibat and the 
study procedures, these can be addressed in this clinical trial with proper participant
selection, close safety monitoring, and specific risk characterisation and mitigation 
(Appendix 5 [see Section 10.5]).


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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To determine parent linerixibat and total 
drug-related radioactivity systemic 
concentrations following a single IV 
microtracer dose of [14C]-linerixibat
(concomitantly with an oral dose of non-
radiolabelled linerixibat) and oral dose of 
[14C]-linerixibat1

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2
of parent and total drug-related material 
(radioactivity) in plasma.

Volume (Vss) and clearance (CL) of 
parent after IV dose (Period 1 only).

Hepatic clearance (CLh) will be estimated 
from IV clearance (CLIV) and renal 
clearance (CLr)

To estimate the oral bioavailability of 
linerixibat

Direct estimation of F (absolute oral 
bioavailability), indirect calculation of Fh 
(fraction of drug escaping first pass 
hepatic clearance), and Fa (fraction 
absorbed)

To determine the rate and extent of 
excretion of total radioactivity in urine 
and feces and the total recovery of 
radioactivity, following IV and oral 
administration of [14C]-linerixibat

Urinary and fecal cumulative excretion as 
a percentage of the total radioactive dose 
Secondary

To describe the safety and tolerability of 
linerixibat after single IV and oral doses 
in healthy participants.

Characterize observed adverse events, and 
abnormal laboratory, 12-lead ECG, and 
vital signs assessments observed.
Exploratory

To generate samples that will be used to 
characterize the metabolite profile of 
linerixibat following a single IV 
microtracer dose of [14C]-linerixibat
concomitantly with an oral dose of non-
radiolabelled linerixibat (plasma, urine, 
feces, duodenal bile) and a single, oral 
dose of [14C]-linerixibat (plasma, urine 
and feces).

Characterization and quantification of 
metabolites in plasma, urine, feces, and 
duodenal bile (qualitative identification in 
bile). These analytical investigations will 
be conducted, and the results reported 
under a separate GSK nonclinical 
protocol.
AUC(0–inf): Area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time, 
AUC(0–t): Area under the plasma concentration-time curve from time zero (pre-dose) to last time of quantifiable 
concentration within a participant across all treatments, Cmax: Maximum observed plasma concentration, tmax: time of 
occurrence of Cmax, t1/2: terminal phase half-life. ECG: Electrocardiogram.
1 For measured concentrations of linerixibat in plasma, the nomenclature [14C]-linerixibat describes the parent 
linerixibat concentration derived via analysis by liquid chromatography (LC) + Accelerator Mass Spectrometry (AMS), 
whereas linerixibat describes the parent linerixibat concentration derived via liquid chromatography-tandem mass 
spectrometry (LC/MS/MS). 


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4.
STUDY DESIGN
4.1.
Overall Design
This is a single group, single center, [14C]-linerixibat mass balance study with a two-
period, single sequence, and no masking. 
This open-label, single-center, non-randomised, 2-period, single-sequence, mass balance 
study will enroll a cohort of 6 healthy male participants. The aim of the study is to assess 
the pharmacokinetics, balance/excretion, and metabolism of linerixibat using [14C]-
radiolabelled drug substance administered as an IV infusion of a microtracer dose 
(concomitant with an oral, non-radiolabelled dose) and orally.
Four to six healthy participants are deemed sufficient. To minimise the number of 
exposed to radiation, participants who discontinue early will not be replaced unless the 
total number of participants who complete dosing and all critical assessments drops 
below 4.
Each participant will be involved in the study for up to 10 weeks.  He will have a 
screening visit, two treatment periods (Treatment Periods 1 and 2), separated by about 7 
days (at least 13 days between oral doses), and a follow-up visit 1-2 weeks after the last 
assessment in Treatment Period 2.  During both treatment periods, participants will reside 
in the unit from the morning of Day -1 until all procedures are completed at 168 h post-
dose (on Day 8).  Participants may be asked to stay for up to 1 week longer in Treatment 
Period 2, if excretion of drug-related material takes longer than anticipated (see Figure 1). 
Safety data will include AE reporting, 12-lead ECG, vital signs, and laboratory safety 
tests.  Blood will be sampled extensively on the day of dosing and daily until Day 8, for 
assessing the PK of linerixibat and metabolites.
4.1.1.
Screening Period
Participants must be screened within 30 days before the first dose of linerixibat and must 
meet all eligibility criteria.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.
Baseline is defined as the value for clinical laboratory, ECG, VS, and physical exam 
results that is collected closest to but before the first dose on Day 1 in Period 1.
4.1.2.
Treatment Period 1 (oral tablets and intravenous infusion)
On Day 1 of Treatment Period 1, after an overnight fast of at least 8 h, each participant
will have a blood sample collected for time 0h, immediately followed by the single 90 mg 
oral dose of linerixibat and the IV infusion of 100 µg of [14C]-linerixibat (approximately 
9.25 kBq; 250 nCi). Participants will continue to fast for 2 h after dosing, and the IV 


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infusion will continue over 3 h.  All voided urine and feces will be collected in seven 24-
h samples for a total of 168 h after oral dosing (until the morning of Day 8). The last 
blood samples, vital signs, ECG, and brief physical examination of the treatment period 
will be obtained on Day 8. Duodenal bile will be collected on Day 1, as described below.  
A non-invasive device to collect duodenal bile will be used only in Treatment Period 1.  
The bile collection string and a small weight will be swallowed 3.5 h before the oral 
dose/start of IV infusion, a duration recommended to allow transit of the string to the 
duodenum, while participants are in a fasted state.  It will be removed about 3 h after the 
oral dose/start of IV infusion (immediately following the end of the 3 h IV infusion), a 
time when the oral dose is expected to have transitioned from the stomach to the 
duodenum.  At 2 h after the start of IV infusion (i.e., 1 h before string withdrawal), a food 
cue (small standard high-fat meal) will be given to stimulate gall bladder emptying.
Participants will be discharged on study Day 8 after completion of the 168-h sample 
collection and completion of other scheduled assessments. 
4.1.3.
Treatment Period 2 (oral solution)
On Day 1 of Treatment Period 2, after an overnight fast of at least 8 h, each participant
will have a blood sample collected for time 0h, immediately followed by the 90 mg [14C]-
linerixibat (approximately 4.96 MBq; 134.1 µCi) dose as an oral solution. Participants 
will continue to fast for 2 h after dosing, when the same small standard high-fat meal as 
in Period 1 will be provided. Urine and fecal samples will be collected for a minimum of 
168 h after dosing (Day 7 sample completing on Day 8). Radioactivity quantification 
using LSC will be performed on each of the 24-h urine collections and 24-h fecal 
homogenates. 
4.1.4.
Demonstration of radioactivity recovery before discharge 
(Period 2) 
LSC radioquantification results from samples collected for Days 1 through 6 (through 
144 h post-dose) will be reviewed on Day 8. The GSK In vitro / In vivo Translation 
(IV/IVT) Study Monitor should be consulted to agree with release of a participant. This 
process is outlined in detail in the Study Reference Manual (SRM). 

If >90% of the administered radioactivity has been recovered from the Day 1-6 
samples, then the participant may be discharged on Day 8 after all scheduled 
assessments have been completed, including complete collection of Day 7 urine and 
feces samples (24 h collection period ending on Day 8). 

If ≤90% has been recovered, then the radioquantification results will be re-evaluated 
on Day 9 with Day 7 results included. 
On Day 9, if >90% has been recovered or <1% of the dose has been excreted on both Day 
6 (120-144 h) and Day 7 (144-168 h), then the participant may be discharged on Day 9.   
If the participant is not eligible for discharge on Day 9, or if the results are inconclusive, 
the participant will remain at the unit. Urine and fecal collections will continue at 24-h 


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intervals for up to 7 additional days (until the morning of Day 15).  Once <1% of the dose 
is recovered in 2 consecutive 24-h periods where samples are provided (and the samples 
were of a sufficient size to make this assessment), or once >90% of the radioactivity has 
been recovered, the participant will be discharged.  
All remaining participants will be discharged from the unit no later than Day 15. In the 
unlikely event that excretion is still ≥1% in the 24-h collection period prior to discharge 
on Day 15, the participant will continue to collect fecal samples only, at home, over 24-h 
intervals.  Samples will be returned to the unit every 2 to 3 days for analysis.
4.1.5.
Follow-up
Follow-up procedures will be done 7-14 days after the participant’s last assessment in 
Treatment Period 2.  The follow-up period may be extended if:
(i)
radioactivity excretion is still higher than 1%;
(ii) a participant has an unresolved AE at the follow-up visit, which, in the opinion of 
the investigator, merits further follow-up; or
(iii) new information becomes available that supports an extended follow-up period.
The investigator and GSK IV/IVT Monitor and/or GSK Medical Monitor as appropriate 
will agree on the nature of the extended follow-up.  For example, participants may have a 
telephone follow-up at which they are asked about AEs, or participants may be asked to 
attend extra outpatient visits for additional monitoring of plasma radioactivity levels 
and/or for extra safety tests.  The extra safety tests might include tests that are not
described in this protocol.  The investigator reserves the right, during or after the study, to 
repeat safety tests or to do any extra safety tests that are in the best interest of the 
participants.  Those extra tests may or may not be described in this protocol. 
4.2.
Scientific Rationale for Study Design
In the first treatment period of this study, an IV microtracer dose of [14C]-linerixibat will 
be infused over 3 h, beginning concurrently with an oral dose of non-radiolabelled 
linerixibat.  The non-radiolabelled 90 mg dose of linerixibat is to ensure that the PK of 
the microdose represents a therapeutically relevant total body exposure to the drug. In the 
second treatment period, a 90 mg oral solution of [14C]-linerixibat will be used for 
comparison.
Biliary elimination pathways will be characterised after the IV dose by inclusion of 
duodenal bile collection in Period 1.  Complexities in human fecal sample analysis such 
as extraction, stability in the gastrointestinal tract, and endogenous contamination are 
minimised through assessment of the metabolite profile in duodenal bile after IV drug 
administration.


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4.3.
Justification for Dose
In Study BAT117213 (GSK Document Number 2015N268599_01), PBC participants 
received linerixibat at a dose of 45 mg twice daily increased to 90 mg twice daily after 3 
days and continued for 14 days in total.  Based on responses observed in these PBC 
participants and in relevant biomarkers (total serum bile acids and 7-α-hydroxy-4-
cholesten-3-one [C4]) measured in Type II diabetic (T2DM) participants, the currently 
expected therapeutic dose is 90 mg twice daily.  Further details of the findings in these 
studies are provided in the IB.
This 90 mg dose has adequate nonclinical toxicology cover for local gastrointestinal tract 
exposure (based on administered oral dose, i.e., 1.8 mg/kg/day assuming 50 kg body 
weight): 556-fold No Observed Adverse Effect Level (NOAEL) in the rat and 278-fold 
NOAEL in the dog for local gastrointestinal tract exposure (1000 mg/kg/day and 500 
mg/kg/day dose, respectively). Further information on nonclinical toxicology studies can 
be found in the IB.
The 100 μg microtracer dose administered as a 3-h IV infusion is projected (based on 
allometry) to achieve a linerixibat Cmax <0.5 ng/mL, which is >13-fold lower than the 
highest observed human Cmax following a 180 mg dose (Study 205808). This dose can 
be categorised as a microdose and as such required safety cover is detailed in ICH M3 
(R2) (International Conference on Harmonisation, 2009).
Preclinical toxicology species provide safety cover for systemic exposure to linerixibat. 
In vitro studies using hepatocytes from nonclinical species and humans show that there is 
generally no qualitative difference in metabolites formed. Preliminary non-radiolabelled 
studies detected no linerixibat metabolites in human plasma and urine following 90 mg 
BID dosing for two weeks (see IB, Section 1.1).
4.3.1.
Linerixibat Oral Dose (Periods 1 and 2)
The oral linerixibat dose is within the therapeutic range for the treatment of PBC pruritus. 
The 90 mg dose is half the highest once-daily dose currently under investigation in the 
ongoing Phase 2 study (180 mg), which is also the highest dose in clinical experience 
(see ).
4.3.2.
Linerixibat Intravenous Dose (Period 1)
The dose of [14C]-linerixibat to be administered intravenously is a microdose of 100 μg, 
which will be infused over 3 h.  A microdose was selected because linerixibat has not 
previously been administered by IV infusion to humans.  That dose level meets the 
criterion for a microdose, for the following reasons:
•
It is ≤ 100 µg.
•
It is ≤ 1/100th of the lowest pharmacologically-active oral dose in healthy participants 
with normal renal function (i.e., 10 mg single, oral dose) based on an increase in 
serum C4 (see GlaxoSmithKline Document Number 2016N306458_00 Study ID 
205808).


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•
It is ≤ 1/100,000th the no observed adverse effect level (NOAEL) of 500 mg/kg/day, 
the highest dose given in the 13-week dog study, where no adverse effects were 
observed. 
Systemic exposure (based on Cmax) at this NOAEL dose was >13-fold the maximum 
observed concentration of 6.64 ng/mL at a clinical dose of 180 mg/day in Study 205808.  
To ensure clinically-relevant systemic exposure during the microdose, the IV infusion of 
[14C]-linerixibat will be administered concomitantly with an oral non-radiolabelled dose 
of 90 mg linerixibat. 
The 100 μg microtracer dose administered as a 3-h IV infusion is projected (based on 
allometry) to achieve a linerixibat Cmax <0.5 ng/mL, which is >13-fold lower than the 
highest observed human Cmax following a 180 mg dose (Study 205808). This dose can 
be categorised as a microdose and as such required safety cover is detailed in ICH M3 
(R2).
4.3.3.
Radiolabel Dose
The effective dose of radiolabelled drug administered in human mass balance studies is 
calculated from data on the distribution and elimination of the radioactive drug from 
laboratory animals, considering the nature of the isotope, the concentration of 
radioactivity in individual tissues/organs and the residence or elimination half-life of the 
radioactivity from those tissues/organs.
4.3.4.
Total Radiation Exposure
In this study, each participant will receive the following doses of radioactivity:
•
approximately 9.25 kBq (250 nCi) in Treatment Period 1.
•
approximately 4.96 MBq (134.1 µCi) in Treatment Period 2.
The total amount of radiation exposure in the study is 4.97 MBq (134.3 µCi). 
It is estimated that the combined total effective dose for the two treatment periods will be 
<1mSv.  On this basis, the maximum administered activity would comply with the ICRP,
1992 recommendation of a 1 mSv maximum for Category IIa projects (further details are 
in Appendix 6 [see Section 10.6]). 
4.4.
End of Study Definition
A participant is considered to have completed the study if he has completed all phases of 
the study including the follow-up visit (end of study visit). 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 


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5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Aged 30 to 55 years, inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
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 and documents that the finding is unlikely to introduce additional 
risk factors and will not interfere with the study procedures.
3.
History of regular bowel movements (averaging one or more bowel movements per 
day).
4.
Non-smoker, or ex-smoker who hasn’t regularly smoked for the 6 months before 
screening.
Weight
5.
Body weight of 50 kg and above, and body mass index (BMI) within the range 19.0
to 31.0 kg/m2 (inclusive).
Sex
6.
Male only.
Participants must agree to use contraception as follows: participants with female 
partners of childbearing potential must agree to use a condom from the time of first 
dose of study intervention until 1 month after their last dose.  Further details are 
given in Appendix 4 (see Section 10.4.1).
Informed Consent
7.
Capable of giving signed informed consent as described in Appendix 5 (Section 
10.1.3), 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.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). Participants 
with a history of cholecystectomy must be excluded.
2.
Significant history of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, 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. 
3.
Any clinically relevant abnormality identified at the screening medical assessment 
(physical examination/medical history) clinical laboratory tests, or 12-lead ECG.
4. Current episode, recent history, or chronic history of diarrhoea. 
5. Lymphoma, leukemia, 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. 
6.
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.
7.
Regular use of known drugs of abuse or history of drug abuse or dependence within 
6 months of the study.
8.
Regular alcohol consumption within 6 months prior to the study defined as an 
average weekly intake of >21 units. 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.
9. History of or regular use of tobacco- or nicotine-containing products in the 6 months 
prior to screening. 
Prior/Concomitant Therapy
10. Past or intended use of over-the-counter or prescription medication, including 
analgesics (eg, paracetamol), herbal medications, or grapefruit and Seville orange 
juices within 14 days prior to the first dose of study intervention until completion of 
the follow-up visit.
11. Administration of any other IBAT inhibitor in the 3 months prior to screening.


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Prior/Concurrent Clinical Study Experience
12. Current enrolment in a clinical trial; recent participation in a clinical trial and has 
received an investigational product within 3 months before the first dose in the 
current study.
13. Exposure to more than 4 new chemical entities within 12 months before the first 
dose in the current study.
14. Participation in a clinical trial involving administration of 14C-labelled compound(s) 
within the last 12 months.  A participant’s previous effective dose will be reviewed 
by the medical investigator to ensure there is no risk of contamination/carryover into 
the current study.
15. Received a total body radiation dose of greater than 10.0 mSv (upper limit of IRCP
category II) or exposure to significant radiation (e.g., serial x-ray or computed 
tomography [CT] scans, barium meal, etc.) in the 3 years before this study.
Diagnostic assessments including clinical laboratory tests, or 12-lead ECG. 
16. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
17. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
18. Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C 
antibody test result at screening or within 3 months before the first dose of study 
intervention.
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.
19. Screening estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m² based on 
the Modification of Diet in Renal Disease (MDRD) Study equation (Levey, 2006). 
20. Positive pre-study drug/alcohol screen.
21. Urinary cotinine levels indicative of smoking.
22. Positive human immunodeficiency virus (HIV) antibody test.
23. QTcF >450 msec on ECG performed at Screening
NOTES:
The QTc must be the QT interval corrected for heart rate according to Fridericia’s
formula (QTcF).
For purposes of data analysis, QTcF will be used as specified in the Reporting and 
Analysis Plan (RAP).
24. At screening or prior to the first dose, a supine blood pressure (BP) that is persistently 
higher than 140/90 millimeters of mercury (mmHg) taken in triplicate, unless deemed 
not clinically significant by the investigator.


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25. At screening or prior to the first dose, a supine mean heart rate (HR) outside the range 
of 40–100 beats per minute, unless deemed not clinically significant by the
investigator.
Other Exclusions
26. Has had an occupation which requires monitoring for radiation exposure, nuclear 
medicine procedures, or excessive x-rays within the past 12 months. 
27. Unable to refrain from consumption of prohibited food and drinks (see Section 5.3) 
from 7 days before the first dose of study medication until the follow up visit. 
28. Loss of more than 400 mL blood during the 3 months before screening, eg as a blood 
donor, or plan to donate blood or blood products in the 3 months after the end of the trial.
29. Unwillingness or inability to follow the procedures outlines in the protocol, including 
the use of the string bile collection device. 
30. History of sensitivity to linerixibat, or their components thereof, or a history of drug 
or other allergy that, in the opinion of the investigator or GSK Medical Monitor, 
contraindicates their participation. 
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions
Participants will be required to fast for at least 5 h before laboratory safety tests, and for 
at least 8 h before dosing in both treatment periods.  In treatment period 1, participants 
will also be required to fast for 5.5 h after instillation of the string bile collection device 
(for 2 h after oral dose/start of infusion).  In treatment period 2, participants will also be 
required to fast for 2 h after the oral dose. A standard, small high-fat meal will be 
provided at 2 h after the oral dose in each period. Meal times are specified in both 
treatment periods for Day 1, please refer to the SoA (see Section 1.3); on all other days, 
meals will be served at the standard times of the clinical site.
Participants will refrain from consumption of Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or their fruit juices from 7 days 
before the start of study intervention until the follow-up visit. 
Participants will refrain from consumption of nuts, seeds, tomato skins, or other foods 
that may cause issues with homogenization of feces. 
No water is allowed until 2 h after oral dosing (apart from rinsing the oral solution dose 
of [14C]-linerixibat); water is allowed ad libitum at all other times.
Adequate hydration should be encouraged to help facilitate stool sample production.  If 
needed, participants may consume prunes or prune juice to facilitate stool samples.


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5.3.2.
Caffeine, Alcohol, and Tobacco
During each treatment period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) from 24 h 
before admission until discharge from the unit.
Participants will abstain from alcohol for 24 h before the screening visit until the follow-
up visit.
Participants must not be current smokers (no smoking for at least 6 months before the 
screening visit). Use of tobacco- or nicotine-containing products (including nicotine 
patches and other delivery devices such as vaporizers) will not be allowed from screening 
until after the final follow-up visit.
5.3.3.
Activity
Participants will abstain from strenuous exercise from 3 days before screening and until 
their final follow-up visit. Participants may participate in light recreational activities 
during studies (e.g., 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 enrolled 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, and any serious adverse 
events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol (see Table 3).


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6.1.
Study Intervention(s) Administered
Table 3
Treatments administered during the study
Study Intervention 
Name:
[14C]-linerixibat
solution for IV 
infusion
[14C]-linerixibat oral 
solution
Linerixibat
Dosage formulation:
IV solution
Oral solution
Oral tablets
Treatment Period
1
2
1
Unit dose strengths:
Strength:  4 µg/mL
Dosage Level: 100 µg
Strength:  1.5 mg/mL
Dosage Level: 90 mg
Strength: 45 mg tablet
Dosage Level: 90 mg
Route of 
Administration:
IV infusion
Oral
Oral
Dosing instructions:
Administer 25 mL 
intravenously over 3 h 
immediately after the 
oral dose
Administer 60 mL in the 
fasted state in the 
morning.  
Two tablets taken in the 
fasted state in the 
morning with 240 mL of 
room temperature 
water
Manufacturer:
Drug product:  HMR
Drug product:  HMR
Wuxi Apptec Co., Ltd.
Physical Description:
A clear, colourless 
solution free from 
visible particulates
A clear, colourless 
solution free from 
visible particulates
White to slightly 
coloured film-coated 
round tablet
6.2.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. 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).
A description of the methods and materials required for preparation of [14C]-linerixibat
solutions for IV infusion and oral administration is provided in the SRM and/or Technical 
Assessment (TA). A Quality Agreement will be in place with the CRO performing the 
manufacturing operations. 
Further guidance and information for the final disposition of unused study intervention 
are provided in the SRM. 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. In the case of 


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unintentional occupational exposure notify the monitor, Medical Monitor and/or GSK 
study contact.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.
Dose administrators must follow site-specific procedures for handling radiolabelled 
linerixibat. 
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label study with no randomization and no blinding of participants, site 
personnel, or sponsor personnel. 
Eligibility will be established during the Screening Period. A cohort of six participants 
will be admitted to the clinical research unit on the same day and will complete Period 1 
and Period 2 on the same schedule with the same study interventions. This approach 
minimizes potential bias associated with temporal effects. 
6.4.
Study Intervention Compliance
Individual doses will be prepared for each participant from a bulk supply and will be 
confirmed by a second member of the study site staff. 
All participants will receive their doses 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 and reported in the CRF.  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.  For oral doses, study site personnel will examine each participant’s mouth
to ensure that the study intervention was ingested. For IV doses, administration will be 
documented in the source documents and reported in the CRF.
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment must be discontinued by 15 days before the start of the study intervention.
These must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription and non-prescription drugs (including 
vitamins and dietary and herbal supplements) within 14 days before the start of study 
intervention until completion of the follow-up visit.


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Special warnings and precautions for use of linerixibat are given in the IB, Section 6.
6.6.
Dose Modification
No dose modification is allowed. 
6.7.
Intervention after the End of the Study
Participants will not receive any additional study intervention from GSK after completion 
of the study because only healthy participants are eligible for study participation. 
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
A participant may withdraw from the study at any time at his own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance or administrative reasons. Permanent discontinuation from study intervention 
is required for specific reasons (Section 7.1). 
If study intervention is permanently discontinued, the participant will remain in the study
for confirmation of excretion of radioactivity (see Section 4.1.4). Participants who are 
withdrawn from the study early should be subject to those assessments that would be 
required at discharge in that treatment period, if participants agree (see Section 1.3). 
7.1.
Discontinuation of Study Intervention
A participant must permanently discontinue study intervention for the pre-specified 
reasons below. 

Severe pain, redness, bleeding or swelling at the infusion site.

Liver chemistry abnormalities exceeding the threshold criteria (see Section 7.1.1).

QTc result meeting the stopping criteria (see Section 7.1.2)

SAE considered related to study intervention 
7.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met:


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Figure 2
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 8 (see Section 10.8). 
7.1.1.1.
Study Intervention Restart or Rechallenge after liver stopping criteria 
met
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
7.1.2.
QTc Stopping Criteria
The QT interval will be corrected using Fridericia’s formula and averaged from three 
ECGs obtained over a brief period to determine whether the participant should be 
discontinued from the study. 
If an automated reading is not available, the ECG should be manually over-read by the 
investigator or adequately trained physician. 
A participant who meets one or both bulleted criteria based on the average of triplicate 
ECG readings will be withdrawn from study intervention.  
•
QTcF >500 msec,
•
Change from baseline:  QTcF >60 msec


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7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time at his own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance or administrative reasons. Participants who withdraw from the study early 
should be subject to those assessments that would be required at discharge in that 
treatment period, if participants agree.
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 subject withdraws from the study, he may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records.
The investigator will record in the source documents the results of follow-up examination 
of withdrawn participants, if the participant gives their consent.  
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he will be considered to have 
withdrawn from the study. 
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (see Section 1.3).

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the GSK Medical Monitor
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
(see Section 1.3), is essential and required for study conduct.


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
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 and 
obtained before signing the 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 (see Section 1.3).

The timing and number of planned study assessments, including safety, and 
pharmacokinetic 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. 

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File which is approved by the relevant GSK 
study team member and then archived in the study sponsor and site study files, 
but this will not constitute a protocol amendment.

The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the ICF.

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 600 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

Discontinuation of the study is handled as part of Appendix 1.  
8.1.
Efficacy Assessments
Efficacy of linerixibat as a treatment for PBC pruritus or any other indication is not 
assessed in this study. 
8.2.
Safety Assessments
Safety assessments include AEs, SAEs, ECGs, vital signs, and clinical laboratory tests. 
Specific liver test results or QTc results that require discontinuation of study intervention
are presented in Section 7.1.1 and Section 7.1.2, respectively. 
8.2.1.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the eyes, 
skin, joints, and the cardiovascular, respiratory, gastrointestinal and neurological 
systems.  Height and weight will also be measured and recorded, and BMI 
calculated and recorded. 


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
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 and recorded. 

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include single measurements of tympanic temperature and respiratory rate and 
triplicate measurements of systolic and diastolic blood pressure and heart rate.

Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is 
not available.

For time points when blood pressure and heart rate are collected in triplicate, there 
should be about a 2-minute interval between readings.

Baseline will be defined as the mean of the 3 pre-dose measurements taken on Day 
1 in Treatment Period 1.
8.2.3.
Electrocardiograms

ECG measurements will be obtained as outlined in the SoA (see Section 1.3). Full 12 
lead ECGs will be recorded with the participant in a supine position.  Heart rate, PR 
interval, QRS duration, and QT (uncorrected) interval will be measured.  QTcF will 
be calculated (machine read or manually).

At each time point at which ECGs are required, single ECG measurements are 
appropriate; however, two additional ECGs are required if the initial ECG 
measurement indicates prolonged QTc (i.e., QTcF ≥ 500 msec) using the automated 
or manually calculated QTcF value.  The average QTcF value of all three ECGs will 
be used to determine eligibility.
8.2.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 4 (see Section 10.4) for the list of clinical laboratory tests to be 
performed and to the SoA (see 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.

All laboratory tests with values considered clinically-significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or GSK Medical Monitor.

If such values do not return to normal/baseline within a period judged reasonable by 
the investigator, the etiology should be identified, and the sponsor notified. 


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
All protocol-required laboratory assessments, as defined in Appendix 2 (see Section 
10.2), must be conducted in accordance with the laboratory manual and the SoA (see 
Section 1.3).
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3 (see Section 10.3).
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 (see Section 7). 
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 start of 
study intervention until the follow-up visit at the time points specified in the SoA (see 
Section 1.3).  

All AEs will be collected from start of study intervention until the follow-up visit at 
the time points specified in the SoA (see 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 h, as indicated in Appendix 3(see 
Section 10.3). The investigator will submit any updated SAE data to the sponsor 
within 24 h of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion of 
study participation.  However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he
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 (see Section 10.3).

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 


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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 (see Section 10.3). 
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of the study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

Investigator safety reports must be prepared for Suspected Unexpected Serious 
Adverse Reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary. 

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study intervention and until the participant’s final visit.

If a pregnancy is reported, the investigator should inform GSK within 24 h of
learning of the pregnancy and should follow the procedures outlined in Appendix 4
(see Section 10.4.2).

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.4.
Treatment of Overdose
For this study, any dose of linerixibat greater than 180 mg 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/SAE and laboratory abnormalities as agreed 
with the Medical Monitor on a case-by-case basis.


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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 CRF.
Decisions regarding dose interruptions or discontinuation will be made by the 
investigator in consultation with the GSK Medical Monitor based on the clinical 
evaluation of the participant.
8.5.
Pharmacokinetics
Pharmacokinetics will be assessed in plasma, urine, and faeces.  Samples collected as part 
of this study for metabolite profiling will be analysed under a separate nonclinical 
protocol. The results of those analyses will be reported separately.  
8.5.1.
Plasma Sample Collection
Blood samples will be collected for measurement of each of the following as specified in 
the SoA (Section 1.3): plasma total radioactivity, plasma [14C]-linerixibat, plasma 
concentrations of linerixibat, and plasma metabolite profiling. 
Details of PK blood sample collection (including the volumes to be collected), 
processing, storage and shipping procedures are provided in the SRM. 
For samples used to evaluate the PK of linerixibat (and [14C]-linerixibat), each plasma 
sample will be divided into 2 aliquots (1 each for PK and a back-up).  Samples collected 
for analyses of linerixibat plasma concentration may also be used to evaluate safety or 
efficacy aspects related to concerns that may arise during or after the study. 
Samples will be stored for no longer than 15 years after the end of the trial.
8.5.2.
Urine Sample Collection
Urine samples will be collected over the time periods specified in the SoA (see Section 
1.3). Urine samples will be used to determine total radioactivity excreted in urine and for 
subsequent metabolite profiling (to be conducted in a separate study). All participants 
will be asked to void their bladders before study intervention administration.  A blank 
urine sample will be collected pre-dose (up to 3 h before oral dosing) in Treatment 
Periods 1 and 2.  Details of urine sample collection, processing, storage and shipping 
procedures are provided in the SRM.
8.5.3.
Fecal Sample Collection
Fecal samples will be collected over the time periods specified in the SoA (see Section 
1.3).  Fecal samples will be used to determine total radioactivity excreted in feces and for 
subsequent metabolite profiling (to be conducted in a separate study).  A fecal sample 
will be collected from each participant before dosing in Treatment Periods 1 and 2 (the 


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pre-dose sample can be collected up to 48 h before oral dosing).  Details of fecal sample 
collection, processing, storage and shipping procedures are provided in the SRM.
8.5.4.
Bile Sample Collection
Bile samples will be collected via a non-invasive string device in Treatment Period 1 
only, as specified in the SoA (see Section 1.3).  The samples obtained will be used to 
investigate potential biliary metabolites (in a separate GSK study). 
The string bile collection device comprises a gelatine capsule which contains 90 cm or 
140 cm of nylon string attached to a 1 g steel weight.  One end of the string is attached to 
the outside of the mouth before swallowing the capsule, so that it can still be retrieved.  
The gelatine capsule dissolves in the stomach whilst the string and weight continue to the 
duodenum via peristalsis. 
A food cue will be used to stimulate gall bladder emptying at 2 h after the start of IV 
infusion, and the string will be withdrawn 1h later (IV infusion will be given over 3h).  
On withdrawal of the string through the mouth the steel weight separates from the string 
at the pyloric sphincter and is excreted in the feces.  Once the string has been removed 
from the participant it will be frozen and shipped for metabolite profiling (to be 
conducted in a separate study).  Full details of the bile sample collection, processing, 
storage and shipping procedures are provided in the SRM.
8.5.5.
Sample Analysis
Total radioactivity measurements in urine samples and fecal homogenates will be 
determined by LSC and/or by AMS.  Total radioactivity measurements from plasma 
derived from blood will be analysed, as appropriate, by AMS in Treatment Period 1 and 
by LSC and/or by AMS, for Treatment Period 2, as detailed in the SRM.
[14C]-linerixibat and linerixibat plasma concentrations will be analysed, as appropriate, as 
detailed in the SRM.
Aliquots of plasma, urine, fecal homogenates and duodenal bile will be provided for 
metabolite analysis.  Metabolite analysis will be performed and reported separately, 
under a separate nonclinical GSK study.
Analysis of all samples (plasma, urine, feces, and duodenal bile) will be performed under 
the control of Bioanalysis, Immunogenicity and Biomarkers (BIB) and Mechanistic 
Safety and Disposition (MSD), GlaxoSmithKline, the details of which will be included in 
the SRM.  Raw data will be archived at the bioanalytical site (detailed in the SRM).
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.


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8.7.
Genetics
A 6 mL blood sample for DNA isolation will be collected, prior to the first dose, 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.
See Appendix 7 (Section 10.7) for Information regarding genetic research]. Details on 
processes for collection and shipment and destruction of these samples can be found in 
the SRM. 
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
9.
STATISTICAL CONSIDERATIONS
Final analyses will be performed after the completion of the study and final dataset 
authorization. 
9.1.
Statistical Hypotheses
This study is not designed for statistical testing and therefore has no formal statistical 
hypothesis. The primary objectives and associated endpoints are presented in Section 1.1
and Section 3. 
9.2.
Sample Size Determination
No formal sample size calculation has been performed for this study.  The primary 
objective of the study is to gain a better understanding of the compound’s 
pharmacokinetic, excretory, and metabolic profile and 4 to 6 participants are deemed 
sufficient for this purpose.  Six participants will be enrolled into the study.  To minimise 
the number of participants exposed to radiation, those participants that discontinue early 
will not be replaced unless the total number of participants who complete both Periods 1 
and 2 drops below 4.
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Screened Population
All participants who sign the ICF.  This 
will be the population for reporting 
screened population data.


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All Participants Population
All participants who take at least 1 dose of 
study intervention.  Participants will be 
analysed according to the treatment they 
received.  This will be the population for 
reporting safety and study population 
data.
Pharmacokinetic Population
All participants whom sufficient data are 
available to calculate the derived 
pharmacokinetic parameters on an as-
treated basis.  This will be the population 
used for all the pharmacokinetic displays.
9.3.1.
Statistical Analyses
Details of the planned statistical reporting are described in the RAP. 
9.3.2.
Efficacy Analyses
This is not applicable. 
9.3.3.
Safety Analyses
All safety analyses will be performed on the All Participants Population. Safety data will 
be presented in tabular format and summarized descriptively according to GSK’s 
Integrated Data Standards Library (IDSL.  Further details will be given in the RAP. 
9.4.
Pharmacokinetic Analyses
Plasma linerixibat concentration-time data will be listed for each subject and summarised 
by treatment and planned sampling time.  [14C]-linerixibat and radioactivity 
concentrations in plasma will be reported similarly.  Individual subject, mean and median 
plasma linerixibat, [14C]-linerixibat, and total radioactivity concentration–time profiles 
will be plotted for each treatment on both a linear and semi-log scale.
Pharmacokinetic analysis will be performed by or under the direct auspices of Clinical 
Pharmacology Modelling & Simulation, GSK.  Plasma linerixibat, [14C]-linerixibat, and 
total radioactivity concentration–time data will be analysed by non-compartmental 
methods with WinNonlin Version 6.3 or above.  Calculations will be based on the actual 
sampling times recorded during the study.  From the plasma concentration-time data the 
following pharmacokinetic parameters will be determined, for linerixibat, 
[14C]-linerixibat, and total radioactivity, as data permits: maximum observed plasma  
concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve 
[AUC(0–t) and AUC(0-inf)], terminal phase rate constant (λz), and apparent terminal 
phase half-life (t1/2) following oral and IV dosing.  Additionally, volume of distribution at 
steady state (Vss), renal clearance (CLr), and total systemic clearance (CL) will be 
derived following IV dosing.  These parameters will be summarised descriptively.


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Calculation of bioavailability (F), Fraction of drug escaping first-pass hepatic 
clearance (Fh), and Fraction absorbed (Fa) for study 205895
Absolute oral bioavailability (F)
F = (AUCpo/Dosepo)/(AUCiv/Doseiv)
Note:  All AUC terms refer to AUC(0-inf)
Equation 1
Fraction of drug escaping first-
pass hepatic clearance (Fh)
Fh = (1-ERh)
Where ERh = Hepatic extraction ratio 
ERh = CLh / Qh
Where, CLh = CLiv - CLrenal
Hepatic blood flow (Qh) =87 L/h (Davies, 1993)
Equation 2a
Equation 2b
Equation 2c
Fraction of drug absorbed and 
fraction escaping gut clearance 
(Fa)
Fa = F/Fh    
Equation 3
Derivation of the urine and fecal radioactivity parameters will be the responsibility, or 
under the direct auspices, of the BIB department within GSK.  The following 
radioactivity parameters will be determined from the urine and fecal radiolabelled drug-
related material (total radioactivity) data, and will be listed and summarised by treatment:

Percentage excreted in urine (Fe%[urine]) within each collection period and 
cumulative urinary recovery and fraction excreted over the total collection period.

Percentage excreted in feces (Fe%[fecal]) with each collection period and 
cumulative fecal recovery and fraction excreted over the total collection period 
and cumulatively over the collection period.

Total excretion (sum of urine and fecal excretion), Fe% [total] will be calculated 
by collection interval for each subject. 
The urine, fecal and total radioactivity parameters will be listed, summarised and plotted, 
as appropriate.
All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals, R&D.  Production of the summaries, listings and figures of the plasma, 
urine and feces data will be performed under the direct auspices of Clinical Statistics, 
GSK. 
Further details regarding the tables, figures and listings to be produced for the study 
report will be given in the RAP.
9.5.
Metabolite profiling
The metabolic profiling/structural characterisation aspect of this work will be performed 
by GSK (or a GSK representative) in a separate nonclinical study and reported separately.


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9.6.
Interim Analyses
No interim analyses will be performed. 


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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, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, 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.
10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 


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
Participants must be informed that their participation is voluntary. 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 center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
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. 

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 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 participant-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. 


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10.1.6.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 

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 CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final Clinical 
Study Report (CSR)/ equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
10.1.7.
Source Documents

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

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.

Definition of what constitutes source data can be found in the SRM. 


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10.1.8.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. The study site 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
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.

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. 

The requirement for fasting before laboratory sample collection will be determined by 
the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
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
Hemoglobin
Haematocrit
Clinical Chemistry1
Urea
Creatinine
Uric acid
Fasting glucose
Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides
Potassium
Sodium
Chloride
Calcium
Phosphate
Aspartate 
Aminotransferase
(AST)/ Serum Glutamic-
Oxaloacetic 
Transaminase (SGOT)
Alanine 
Aminotransferase
(ALT)/ Serum Glutamic-
Pyruvic Transaminase
(SGPT)
Alkaline phosphatase
Total and 
direct bilirubin
Total Protein
Albumin
Globulin
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick

Microscopic examination (if leukocyte esterase, nitrites, blood or protein is 
abnormal)
Screening only Tests

Alcohol breath test, urine cotinine test

Carbon Monoxide (CO) breath test

Drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)
NOTES :
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.1 and Appendix 8 (Section 10.8). 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. 


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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.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).


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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:
Results in death
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 fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
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 


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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 (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

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 CRF 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.
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.


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
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 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.
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.


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
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 SAE coordinator by telephone.

Contacts for SAE reporting can be found in the SRM. 
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor 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 the SRM.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
10.4.1.
Contraception Guidance

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in (see Section 5.1):

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to 
remain abstinent

Agree to use a male condom when having penile-vaginal intercourse with 
a woman of childbearing potential

Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the protocol-defined time frame.

In addition, male participants must refrain from donating sperm for during the 
protocol-defined time frame.
10.4.2.
Collection of Pregnancy Information:
For male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 


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10.5.
Appendix 5:  Risk Assessment 
Potential Risks of Clinical Significance, Relevant Data, and Mitigation 
Strategy
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Study Intervention: Linerixibat
Systemic exposure to 
linerixibat greater than that 
previously tested in humans
The total systemic exposure of 
linerixibat from either treatment
period (90 mg) is predicted to 
be below the systemic 
exposure from the highest 
dose of linerixibat tested in 
previous human studies 
(repeat oral doses of 180 mg).  
The 100 μg microtracer dose 
administered as a 3-h IV 
infusion is projected (based on 
allometry) to achieve a 
linerixibat Cmax <0.5ng/mL, 
which is 13-fold lower than the 
highest observed human Cmax 
following a 180 mg dose 
(Study 205808). 
Preclinical toxicology species 
provide safety cover for 
systemic exposure to 
linerixibat. The in vitro studies 
using hepatocytes from 
nonclinical species and 
humans show that there is 
generally no qualitative 
difference in metabolites 
formed. Preliminary non-
radiolabelled studies detected 
no linerixibat metabolites in 
human plasma and urine 
following 90 mg BID dosing for 
two weeks (Study 200185). 
Haematology and clinical 
chemistry, ECG, and vital signs
will be monitored.
Gastrointestinal effects,
including diarrhoea.
Animal studies including fecal 
alterations, e.g., nonformed, 
liquid (see IB, Section 4.5).
AEs in humans including loose 
Exclusion of participants with 
current episode, recent history, 
or chronic history of diarrhoea
(see Section 5.2).


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
stools (see IB Section 5.3).
Only two doses of 
GSK23320672 separated by at 
least 13 days will be 
administered in this study. 
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, Section 5.3.1). 
A nonfatal SAE of acute 
cholecystitis leading to 
hospitalization for 
cholecystectomy and 
withdrawal from study 
intervention: Prior to dosing 
with metformin + 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
(see IB Section 5.3.1).
Exclusion of participants with 
current symptomatic 
cholelithiasis or inflammatory 
gall bladder disease (see 
Section 5.2).
Study subjects will also 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.
Participants will be informed of 
the signs and symptoms of 
cholelithiasis in the Informed 
Consent Form.
Radiolabelled Investigational Product: [14C]-linerixibat]
Radioactivity exposure risk 
([14C]-linerixibat
The total effective dose 
associated with IV and oral 
administrations of [14C]-
linerixibat is 0.99 mSv. On this 
basis, the maximum 
administered activity would 
comply with the ICRP, 1992 
recommendation of a 1 mSv 
maximum for Category IIa 
projects and well within the
dose limits for members of the 
public, as per WHO Category II 
(further details are in Appendix 
6, Table 2).. The total effective 
dose is also below the 
GlaxoSmithKline Global Safety 
Board level of radiation (10
The Period 1 dose is a 
microdose for which the 
associated radioactivity is less 
than the International 
Commission on Radiological 
Protection (ICRP, 1992)
recommended threshold for 
clinical research projects with 
intermediate level of societal 
benefit. It is below the level 
identified as trivial risk by the 
ICRP, 1992) and below the 
maximum exposure threshold 
for the level of risk that is 
within variations of natural 
background radiation


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
mSv).
according to the World Health 
Organization (WHO, 1977). 
See Section 4.3 and Appendix 
6 (Section 10.6). 
In Period 2, participants will be 
monitored for recovery of 
radioactivity (see Section 
4.1.4).
Study Procedures
Local extravasation of 
intravenous microdose at the 
infusion site
Linerixibat has not previously 
been administered by IV 
infusion in humans. 
In a single dose IV rat study, 
redness was observed around 
the injection site in a single rat: 
Male rats (n=4/group) were 
given single IV doses of 
linerixibat at 5, 15 or 30 mg/kg 
(slow bolus) and 30 or 60 
mg/kg (3 or 4-hour infusion, 
respectively).  All doses were 
well tolerated. One rat given 30 
mg/kg by slow bolus injection 
had redness around the 
injection site.  However, no 
injection site findings were 
reported in a repeat dose IV 
study where male rats 
(n=4/group) were given 
linerixibat IV at 2, 15 or 60 
mg/kg/day once daily for 6 or 7 
days. 
Linerixibat was also given to 
dogs as a single escalating IV 
dose at 5 or 15 mg/kg (slow 
bolus to 2 males and 1 female) 
or at 15, 30 or 60 mg/kg (4-
hour infusion to 1 male and 2 
females).  A washout period of 
at least 3 days was allowed 
between initial and subsequent 
doses.  
Participants will avoid 
moderate or strenuous 
physical activity during the 
infusion.
Usual iv care will include 
flushing the iv before 
administration of the dose 
and monitoring for correct 
positioning of the iv. 
Study medication must be 
discontinued if the subject 
develops severe pain, 
redness, bleeding or swelling 
at the infusion site. 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
No irritancy at site of injection 
was reported. 
String test for bile collection 
risk
Streaks of blood on the string 
due to local irritation have 
been infrequently noted. 
Gagging upon retrieval of the 
string can occur.
On a few occasions, an entire 
string has been swallowed 
without ill effects and passes 
out from the body in the 
faeces.  
The string will be securely 
taped in place (to the cheek of 
each individual) during the 
collection time to minimise risk 
of swallowing the entire string.  


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10.6.
Appendix 6:  An assessment of the radiation dose to male 
volunteers from the oral and IV administration of the study 
intervention


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PPD
PPD
PPD


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10.7.
Appendix 7 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 linerixibat, pruritus associated with 
PBC, and related diseases. They may also be used to develop tests/assays (including 
diagnostic tests) related to linerixibat, drugs of this class, or PBC pruritus. Genetic 
research may consist of the analysis of one or more candidate genes or the analysis 
of genetic markers throughout the genomic analysis of the entire genome (as 
appropriate).

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data obtained from this study. 

DNA samples will be analyzed by using appropriate descriptive and/or statistical 
analysis methods. A detailed description of any planned analyses will be documented 
in a RAP prior to initiation of the analysis

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study intervention 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 linerixibat continues but no longer 
than 15 years after the last participant’s last visit or shorter period as per local 
requirements.

The samples will be retained while research on linerixibat, study interventions of this 
class, or PBC pruritus continues but no longer than 15 years after the last subject last 
visit or other period as per local requirements.


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10.8.
Appendix 8: 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 aetiology.
These protocol guidelines are in alignment with FDA premarketing clinical liver safety 
guidance.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Table 5
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 treatment

Report the event to GSK within 24 h

Complete the liver event CRF, 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, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
h

Monitor participants twice weekly until liver 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis if requested by the Medical 
Monitor (determined on a case-by-case 
basis)4 

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 form


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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 perform 
liver event follow up assessments within 24-
72 h

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

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 treatment 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, 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); INR measurement is not required and the threshold value stated will not apply to 
participants receiving anticoagulants.
3 Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing); Hepatitis E IgM antibody 
4 Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention. Sample 
handling and shipping instructions are in the SRM.


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10.9.
Appendix 9: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase 
AMS
Accelerator Mass Spectrometry
AUC
Area under concentration-time curve
AUC(0–inf)
Area under the concentration-time curve from time zero (pre-dose)
extrapolated to infinite time
AUC(0–t)
Area under the concentration-time curve from time zero (pre-dose) 
to last time of quantifiable concentration within a participant 
across all treatments
BIB
Bioanalysis, Immunogenicity and Biomarkers
BID
Bis In Die (Twice A Day)
BMI
Body mass index
BP
Blood Pressure
Bq
Becquerel
Cmax
Maximum observed concentration
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
CFR
Code of Federal Regulations (US)
CRF
Case Report Form
CSR
Clinical Study Report
CV
Cardiovascular 
DCSI
Development Core Safety Information
ECG
Electrocardiogram
F
Absolute bioavailability
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GSK
GlaxoSmithKline
h
Hour(s)
HBsAg 
Hepatitis B Surface Antigen 
Hep B
Hepatitis B
Hep C
Hepatitis C
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HMR
Hammersmith Medicines Research
IB
Investigator’s Brochure
IBAT
Ileal bile acid transporter
ICF
Informed Consent Form
ICRP
International Commission on Radiological Protection


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IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
Intravenous
IVIVT
In vitro / In vivo Translation - Investigative Safety & Drug 
Metabolism, GSK
LC
Liquid Chromatography
LC/MS/MS
Liquid Chromatography–Tandem Mass Spectrometry
LSC
Liquid Scintillation Counting
LFTs
Liver Function Tests
MBq
Megabecquerel
μCi
Micro Curie
μg
Microgram
μSv
Microsievert
mg
Milligrams
mL
Millilitre
MSDS
Material Safety Data Sheet
mSv
Millisievert
nCi
Nano Curie
NOAEL
No Observed Adverse Effect Level
PK
Pharmacokinetic(s)
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event
SoA
Schedule of Activities
SRM
Study Reference Manual
tmax
Time of occurrence of Cmax
t½
Terminal phase half-life
UK
United Kingdom
ULN
Upper Limit of Normal
WHO
World Health Organisation
z
Lambda-z (Terminal Phase Rate Constant)
Trademark Information
Trademarks of the GlaxoSmithKline group of 
companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
WinNonlin


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11.
REFERENCES
Davies, B and Morris, T., Physiological Parameters in Laboratory Animals and Humans. 
Pharmaceutical Research Vol 10.  No.7; 1093-1095. 1993
GlaxoSmithKline Document Number 2010N111289_05. GSK2330672 Investigator's 
Brochure. 2018.
GlaxoSmithKline Document Number 2015N268599_01 Study ID BAT117213.  A 
randomised, double-blind, placebo-controlled study to evaluate the safety, tolerability, 
pharmacokinetics and pharmacodynamics of repeat doses of GSK2330672 administration 
in patients with primary biliary cirrhosis (PBC) and symptoms of pruritus. 2016.
GlaxoSmithKline Document Number 2013N186306_00 Study 200185. A Randomized, 
Double-Blind (Sponsor Unblinded), Placebo Controlled, Repeat Dose Study Investigating 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2330672 in Type 
2 Diabetes Patients Taking Metformin. 2014
GlaxoSmithKline Document Number 2016N306458_00 Study ID 205808.  A double-
blind, randomized, placebo controlled, dose escalating crossover study to evaluate the 
safety, tolerability, pharmacokinetic and pharmacodynamic parameters of single doses of 
GSK2330672 in Japanese healthy male volunteers. 2017.
Guiney WJ, Beaumont C, Thomas SR, Robertson DC, McHugh SM, Koch A, Richards 
D. Use of Entero-Test, a simple approach for non-invasive clinical evaluation of the 
biliary disposition of drugs.  Br J Clin Pharmacol. 2011; 72:133-142.
Hegade VS, Kendrick SFW, Dobbins RL, Miller SR, Thompson D, Richards D, et al.
Effect of ileal bile acid transporter inhibitor linerixibat on pruritus in primary biliary 
cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. 
Lancet 2017; 389: 1114–23. 
ICRP. Radiological Protection in Biomedical Research. ICRP Publication 62. Ann ICRP 
1992; 22(3).
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. Guidance on Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals M3 
(R2). 2009.
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplin
ary/M3_R2/Step4/M3_R2__Guideline.pdf. Accessed 15 February 2019.  
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Chronic 
Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine values 
in the modification of diet in renal disease study equation for estimating glomerular 
filtration rate. Ann Intern Med. 2006 Aug 15;145(4):247-54.


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World Health Organization (WHO). Use of ionizing radiation and radionuclides on 
human beings for medical research, training and nonmedical purposes. Technical report 
series No. 611. 1977, Geneva. 

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205895
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A two-period study in 
healthy male participants to determine the pharmacokinetics, 
balance/excretion, and metabolism of [14C]-linerixibat 
following a single intravenous radiolabeled microtracer dose 
(concomitant with a non-radiolabeled oral dose) and a single 
oral radiolabeled dose.
Compound Number 
:
GSK2330672
Effective Date 
:
17-JAN-2020
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol [205895].

This RAP is intended to describe and to assess pharmacokinetics (PK), mass 
balance/excretion, metabolism of safety and tolerability 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.
RAP Author(s):
Approver
Date
17-01-2020
Principal Statistician (FPD, Clinical Statistics)
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


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RAP Team Approvals:
Approver
Date
Approval Method
17-01-2020
Email
Clinical Development Director, Clinical Science 
(Respiratory & Specialty)
17-01-2020
Email
Global Clinical Development Manager, PCPS 
GCSD
Drug Transporter SME, Global Disposition & 
Biotransformation
17-01-2020
Email
Senior Programmer, Biostatistics (Bangalore, 
India), Clinical Programming
17-01-2020
Email
On behalf of CPMS, GSK, 
Director, Quantitative Clinical Development, 
(Parexel International)
16-01-2020
Email
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
Director (FPD, Clinical Statistics)
17-01-2020
Email
16-01-2020
Email
Programming Manager (FPD, Clinical 
Programming)
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................5
2.2.
Study Objective(s) and Endpoint(s)...............................................................5
2.3.
Study Design ................................................................................................7
2.4.
Statistical Hypotheses / Statistical Analyses .................................................8
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS .....................................................................................9
4.1.
Protocol Deviations.....................................................................................10
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................11
5.1.
Study Treatment & Sub-group Display Descriptors.....................................11
5.2.
Baseline Definitions ....................................................................................11
5.3.
Multicentre Studies .....................................................................................12
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................12
6.
STUDY POPULATION ANALYSES .......................................................................13
6.1.
Overview of Planned Study Population Analyses........................................13
7.
EFFICACY ANALYSES..........................................................................................14
8.
SAFETY ANALYSES .............................................................................................15
8.1.
Adverse Events Analyses ...........................................................................15
8.2.
Clinical Laboratory Analyses.......................................................................15
8.3.
Other Safety Analyses ................................................................................15
9.
PHARMACOKINETIC ANALYSES.........................................................................16
9.1.
Primary Pharmacokinetic Analyses.............................................................16
9.1.1.
Endpoints / Variables...................................................................16
9.1.1.1.
Drug Concentration Measures....................................17
9.1.1.2.
Derived Plasma, Urine and Fecal 
Pharmacokinetic Parameters......................................18
9.1.2.
Summary Measure ......................................................................19
9.1.3.
Population of Interest...................................................................20
9.1.4.
Statistical Analyses / Methods .....................................................20
9.1.4.1.
Statistical Methodology Specification..........................21
9.2.
Metabolite Profiling Analyses in Plasma, Urine, Feces and Bile..................22
10. REFERENCES.......................................................................................................23
11. APPENDICES........................................................................................................24


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11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................24
11.2.
Appendix 2: Schedule of Activities ..............................................................25
11.2.1.
Protocol Defined Schedule of Events...........................................25
11.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................27
11.3.1.
Study Phases ..............................................................................27
11.3.1.1.
Study Phases for Concomitant Medication .................27
11.3.1.2.
Treatment Phases for AE Data...................................27
11.3.2.
Treatment Emergent Flag for Adverse Events .............................28
11.4.
Appendix 4: Data Display Standards & Handling Conventions....................29
11.4.1.
Reporting Process .......................................................................29
11.4.2.
Reporting Standards....................................................................29
11.4.3.
Reporting Standards for Pharmacokinetic....................................30
11.4.4.
General........................................................................................30
11.4.5.
Study Population..........................................................................31
11.4.6.
Safety ..........................................................................................31
11.4.7.
Pharmacokinetic ..........................................................................32
11.5.
Appendix 5: Reporting Standards for Missing Data.....................................33
11.5.1.
Premature Withdrawals................................................................33
11.5.2.
Handling of Missing Data.............................................................33
11.5.2.1.
Handling of Missing and Partial Dates ........................33
11.6.
Appendix 6: Values of Potential Clinical Importance ...................................35
11.6.1.
Laboratory Values........................................................................35
11.6.2.
ECG.............................................................................................36
11.6.3.
Vital Signs....................................................................................36
11.7.
Appendix 7: Abbreviations & Trade Marks ..................................................37
11.7.1.
Abbreviations...............................................................................37
11.7.2.
Trademarks .................................................................................38
11.8.
Appendix 8: List of Data Displays ...............................................................39
11.8.1.
Data Display Numbering..............................................................39
11.8.2.
Mock Example Shell Referencing ................................................39
11.8.3.
Deliverables.................................................................................39
11.8.4.
Study Population Tables..............................................................40
11.8.5.
Safety Tables...............................................................................41
11.8.6.
Pharmacokinetic Tables...............................................................43
11.8.7.
Pharmacokinetic Figures .............................................................44
11.8.8.
ICH Listings .................................................................................45
11.8.9.
Non-ICH Listings..........................................................................48
11.9.
Appendix 9: Example Mock Shells for Data Displays ..................................49


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 205895:
Revision Chronology:
205895
11-APR-2019
Original critical component
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the 205895 protocol Dated: 11/April/2019.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To determine parent linerixibat 
and total drug-related 
radioactivity systemic 
concentrations following a 
single IV microtracer dose of 
[14C]-linerixibat (concomitantly 
with an oral dose of 
nonradiolabelled linerixibat) 
and oral dose of [14C]-
linerixibat1

AUC(0–inf), AUC(0–t), Cmax, tmax and t1/2 of 
parent and total drug-related material 
(radioactivity) in plasma.

Volume (Vss) and clearance (CL) of parent 
after IV dose (Period 1 only).

Hepatic clearance (CLh) will be estimated from 
IV clearance (CLIV) and renal clearance (CLr)

To estimate the oral 
bioavailability of linerixibat

Direct estimation of F (absolute oral 
bioavailability), indirect calculation of Fh 
(fraction of drug escaping first pass hepatic 
clearance), and Fa (fraction absorbed)

To determine the rate and 
extent of excretion of total 
radioactivity in urine and feces 
and the total recovery of 
radioactivity, following IV and 
oral administration of [14C]-
linerixibat

Urinary and fecal cumulative excretion as a 
percentage of the total radioactive dose
Secondary Objectives
Secondary Endpoints

To describe the safety and
tolerability of linerixibat after 
single IV and oral doses in 
healthy participants.

Characterize observed adverse events, and 
abnormal laboratory, 12-lead ECG, and vital 
signs assessments observed.


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Objectives
Endpoints
Exploratory Objectives
Exploratory Endpoints

To generate samples that will 
be used to characterize the 
metabolite profile of linerixibat 
following a single IV
microtracer dose of [14C]-
linerixibat concomitantly with 
an oral dose of 
nonradiolabelled linerixibat 
(plasma, urine, feces, duodenal 
bile) and a single, oral dose of 
[14C]-linerixibat (plasma, urine 
and feces).

Characterization and quantification of
metabolites in plasma, urine, feces, and
duodenal bile (qualitative identification in bile). 
These analytical investigations will be 
conducted, and the results reported under a 
separate GSK nonclinical protocol.
1 For measured concentrations of linerixibat in plasma, the nomenclature [14C]-linerixibat describes the 
parent linerixibat concentration derived via analysis by liquid chromatography (LC) + Accelerator Mass 
Spectrometry (AMS), whereas linerixibat describes the parent linerixibat concentration derived via liquid 
chromatography-tandem mass spectrometry (LC/MS/MS).


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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features
This is a single group, single center, [14C]-linerixibat mass balance study 
with a two period, single sequence, and no masking.
This open-label, single-center, non-randomised, 2-period, single-sequence, 
mass balance study will enroll a cohort of 6 healthy male participants. The 
aim of the study is to assess the pharmacokinetics, balance/excretion, and 
metabolism of linerixibat using [14C]- radiolabelled drug substance 
administered as an IV infusion of a microtracer dose (concomitant with an 
oral, non-radiolabelled dose) and orally.
Dosing

90 mg Linerixibat Oral Tablets and Oral solution Dose (Periods 1 and 
2).

Linerixibat Intravenous (IV) Micro-Dose (Period 1) The dose of [14C]-
linerixibat to be administered intravenously is a microdose of 100 μg, 
which will be infused over 3 hours.

Radiolabelled doses will be individualized for the 14C-IV infusion 
(period 1) and 14C 90 mg oral solution dose (period 2).  Each dose is 
slightly different from the nominal dose.
Time & 
Events

[Refer to Appendix 2: Schedule of Activities]
Treatment 
Assignment

Linerixibat 90mg ORAL tablets or solution and [14C]-Linerixibat IV
Interim 
Analysis

No interim analysis will be performed for this study.


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2.4.
Statistical Hypotheses / Statistical Analyses
This is an investigative study to determine the pharmacokinetics (absorption, distribution, 
metabolism and excretion; ADME), mass balance excretion, and metabolism of 
linerixibat (GSK2330672) using [14C]- radiolabelled drug substance administered as an 
IV infusion of a microtracer dose (concomitant with an oral, non-radiolabelled dose of 90 
mg linerixibat tablets) Period 1 and 90 mg Linerixibat oral solution Period 2.
Due to its descriptive nature, there will be no formal statistical hypothesis tested; an 
estimation approach will be adopted to assess the study objectives.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
No formal 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.
3.
Final PK analyses will be completed as the final merged plasma concentration and 
actual time files become available.  There will be one to two ARM releases via 
BIB/DMPK for plasma concentration data.
4.
The urine and feces reports for mass balance recovery of total radioactivity will be 
provided by Pharmaron and Covance.  These reports will be appended to the final 
clinical study report.
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
Enrolled

Enrolled: All participants who 
passed screening and entered the 
study. Participants who were 
assigned a treatment in a non-
randomised study.

Note screening failures (who never 
passed screening even if 
rescreened) and participants 
screened but never enrolled into the 
study (Reserve, Not Used) are 
excluded from the Enrolled 
population as they did not enter the 
study.

Study 
Population
Safety

All participants who take at least 1 
dose of study treatment.  

Participants will be analysed 
according to the treatment they 
actually received.

Safety and 
Study 
population


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Population
Definition / Criteria
Analyses Evaluated
Pharmacokinetic (PK)

All participants in the Safety 
population who had at least 1 non-
missing PK assessment (Non-
quantifiable [NQ] values will be 
considered as non-missing values).

PK
Refer to Appendix 8: 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.
Include the following text only if a Per Protocol Population is being defined: Important 
deviations which result in exclusion from the analysis population will also be summarised
and listed. (Please refer to Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population).

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan [27-June-2019 
and versionV1]. 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
o 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 CRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
The treatment groups will be labelled and administered as follows:
Treatment Group Descriptions
Treatment Description
Data Displays for Reporting 
Code
Description
Description
(Safety)
Description
(PK Analysis)
Order [1]
A
Linerixibat 90 mg Oral Tablets
+ [14C]-Linerixibat 100 µg IV
infusion
A
A1
A2
1
2
B
[14C]-Linerixibat 90 mg Oral
solution
B
B
3
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
Study population displays will be summarized by total column.
Please add footnote in all the displays as follows for the treatment group

Note: For Safety Displays
A: 90 mg Linerixibat Oral Tablets + 100 µg [14C]-Linerixibat IV infusion
B: 90 mg [14C]-Linerixibat Oral Solution

Note: For PK displays:
A1: 90 mg Linerixibat Oral Tablets
A2: 100 µg [14C]-Linerixibat IV infusion
B:   90 mg [14C]-Linerixibat Oral Solution
5.2.
Baseline Definitions
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
[Safety]
Vital Signs
X
X
X [1]
Day 1 (mean pre-
dose) [2]
Laboratory safety tests
X
X
Day -1
12-lead ECG
X
PK
X
X
X
Mean of Day -1 & 1
[1] Taken in triplicate
[2] Mean of the triplicate pre-dose assessments on Day 1 in Treatment Period.


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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.
5.4.
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
11.1
Appendix 1: Protocol Deviation Management and Definitions 
11.2
Appendix 2: Schedule of Activities
11.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
11.4
Appendix 4: Data Display Standards & Handling Conventions
11.5
Appendix 5: Reporting Standards for Missing Data
11.6
Appendix 6: Values of Potential Clinical Importance
11.7
Appendix 7: Abbreviations & Trade Marks
11.8
Appendix 8: List of Data Displays
11.9
Appendix 9: Example Mock Shells for Data Displays


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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/Enrolled/Safety/PK 
population, unless otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 8: List of Data Displays.


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7.
EFFICACY ANALYSES
This is not applicable for this study.


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8.
SAFETY ANALYSES
No formal statistical analysis of safety data will be performed. Safety data will be 
descriptively summarized and presented in a tabular form. In addition, listings of the 
safety data will be provided. The safety analyses will be based on the Safety population, 
unless otherwise specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 8: List of Data Displays.
8.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 8: List of Data Displays.
8.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 8: List of Data Displays.


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9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
9.1.1.
Endpoints / Variables
Period 1 - 205895
Total radioactivity in plasma from IV dose in Period 1

AUC(0–inf),iv14C, AUC(0–t),iv14C, Cmax,iv14C, tmax,iv14C, z,iv14C, and t½,iv14C of total drug-related 
material (radioactivity) in plasma.
[14C]-linerixibat in plasma following IV infusion dose 100ug over 3 hours

AUC(0–inf),iv14C-L, AUC(0–t),iv14C-L, AUC(0-24),iv14C-L, %AUCex,iv14C-L,Cmax,iv14C-L, tmax,iv14C-L, 
z,iv14C-L, and t½,ivC14-L CLiv, Vss,iv, CLrenal,iv of [14C]-linerixibat (L) in plasma.
Linerixibat in plasma following oral tablet dose of linerixibat 90mg in Period 1

AUC(0–inf),poP1, AUC(0–t),poP1, %AUCex,poP1, Cmax,poP1, tmax,poP1, z,poP1 and t½,poP1of linerixibat in 
plasma.
Ratio of [14C] linerixibat / total radioactivity for Cmax, AUC(0-t) and AUC(0-inf) for Period 1
Cmax, ratio P1 -(pg/mL)/(pgEq/mL
AUC(0-t), ratio P1 (h*pg/mL)/h*pgEq/mL)
AUC(0-inf), ratio P1 (h*pg/mL)/h*pgEq/mL)
Absolute bioavailability (F) from the oral tablet and IV doses administered in Period1 for AUC(0-inf) and AUC(0-t) PK 
parameter calculated as:
(linerixibat AUC,poP1/Dose,poP1 (90mg))
_________________________________
(14C linerixibat AUC,iv14C-L / Dose,iv14C-L(100g)
Oral and IV Dose (100g) will be converted into same units (pg or ng) using conversion values as needed below.  The 
100 g dose will vary slightly for each subject and final corrected doses will be provided in Covance/Pharmaron reports
1mg=1000 mcg (or µg)
1mcg (or g) = 1000 ng
1ng = 1000 pg
1 pg = 1000 femtograms (fg)
Clearance (CLiv)
Total systemic clearance will be calculated as:
Dose 100g (iv14C-L)/AUC(0-inf)(iv14C-L)
Period 1, analyte: [14C]- linerixibat.
Cumulative amount of [14C]-linerixibat in urine at 24 hours
(Ae(0-24) iv14C-L) (data derived from GSK DMPK metabolite profiling study 19DMM027)
Renal Clearance (CLrenal,iv)
[14C] linerixibat-Ae(0-24),iv14C-L / AUC(0-24),iv14C-L
(t=available time interval is 24hours), (i.e., Amount of [14C]-linerixibat from pooled urine samples (0-24 hours) for all 
subjects divided by each subject’s AUC(0-24) in plasma resulting in 6 values.
Hepatic Clearance (CLhepatic or CLh)
CLh,iv = CLiv – CLrenal,iv
If [14C] linerixibat-Ae(0-24), iv 14C-L is BQL, it will be assumed to be zero for the calculation of CLrenal,iv and 
subsequently CLh,iv,


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CLh,iv,in plasma divided by linerixibat blood-to-plasma ratio (B:P) = CLiv,h,blood [Mehvar, 2016]
The blood-to-plasma ratio for human = 0.678 (GSK Report Number: 2017N342697_00)
Hepatic extraction ratio (Eh)
Eh = CLh,iv blood / hepatic blood flow 
Human hepatic blood flow estimate = 1200-1450 mL/min [Edginton, 2006, Davies and Morris, 1993], liver blood flow 
estimate used will be reported in the CPSR.
Fraction of linerixibat that escapes first pass liver extraction = Fh = 1 – Eh
Fraction of linerixibat absorbed (includes fraction escaping gut extraction) = Fabs = F/Fh
Period 2 – 205895
Total radioactivity in plasma following oral dose in Period 2

AUC(0–inf)po14C, AUC(0–t)po14C, Cmax,po14C, tmax,po14C, z,po14C, and t½,po14C of total drug-related 
material (radioactivity) in plasma.
Linerixibat in plasma following oral dose of linerixibat 90mg

AUC(0–inf),poP2, AUC(0–t),poP2, %AUCex,poP2, Cmax,poP2, tmax,poP2, z,poP2 and t1/2,poP2 of linerixibat in 
plasma.
Ratio of linerixibat / total radioactivity for Cmax, AUC(0-t) and AUC(0-inf) for Period 2
Cmax, ratio P2 (pg/mL)/(pgEq/mL)
AUC(0-t), ratio P2 (h*pg/mL)/h*pgEq/mL)
AUC(0-inf), ratio P2 (h*pg/mL)/h*pgEq/mL)
Radioactivity Mass Balance in Periods 1 and 2 - Parameter Endpoints and Description
Fe%[urine]
% of total dose excreted as total radioactivity for each collection interval 
Data will be provided by Covance/Pharmaron:
Fe%[feces]
% of total dose excreted as total radioactivity for each collection interval 
Data will be provided by Covance/Pharmaron:
Fe%[total]
% of total dose excreted as radioactivity will be estimated in each collection interval as:
Sum of Fe%[urine] and Fe%[feces] – Data to be provided by Covance/Pharmaron
9.1.1.1.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.4.3
Reporting Standards for Pharmacokinetic).
Plasma linerixibat, [14C]-linerixibat, plasma total radioactivity, concentration-time data 
will be listed for each participant and standard summary statistics will be calculated (i.e. 
arithmetic mean, standard deviation, median, minimum and maximum) by period, 
analyte, treatment dose and planned sampling time.


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Individual subject, mean and median plasma linerixibat, [14C]-linerixibat, plasma total 
radioactivity concentration-time profiles will be plotted for each period and treatment on 
both a linear and semi-log scale.
9.1.1.2.
Derived Plasma, Urine and Fecal Pharmacokinetic Parameters
PK parameters will be calculated by standard non-compartmental analysis according to 
current working practices (GUI_51487 (4.0)) and using the currently supported version of 
PhoenixWinNonlin Version 6.4 or above. All calculations of non-compartmental 
parameters will be based on actual sampling times. PK parameters listed will be 
determined from the plasma linerixibat, [14C]-linerixibat, and plasma total radioactivity 
concentration-time data, as data permits.  The calculation of CLh,in blood for the purpose 
of estimating Fh is shown below.
Derivation of the urine and fecal total radioactivity mass balance parameters will be the 
responsibility or under the direct auspices, of the BIB/DMPK department within GSK. 
All mass balance parameters for urine and fecal radiolabelled drug-related material (total 
radioactivity) will be provided in QC/QA reports provided by Pharmaron and Covance.  
Urine and feces analytical data will not be entered into the SMS2000 system.  No further 
data manipulation will be required and those reports will be used to write the clinical 
study report.
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.
AUC (0-inf)
Area under the concentration-time curve extrapolated to infinity will 
be calculated as: 
AUC = AUC(0-t) + C(t) / λz
%AUCex
The percentage of AUC (0-∞) obtained by extrapolation (%AUCex) 
will be calculated as:
[AUC(0-inf) – AUC(0-t)] / AUC(0-inf) x 100
Cmax
Maximum observed concentration, determined directly from the 
concentration-time data.
Cmax ratio
AUC(0-t) ratio
AUC (0-inf)
Ratios for period 1 = [14C] linerixibat /Total radioactivity for Cmax, 
AUC(0-t) and AUC(0-inf)
Ratios for period 2 = linerixibat / total radioactivity for Cmax, 
AUC(0-t) and AUC(0-inf) for Period 2
CLiv
Total clearance will be calculated as:
Dose(iv)/AUC(0-inf)iv
Treatment period 1, analyte [14C]- linerixibat only.
CLh,iv,plasma
Hepatic Clearance (CLhepatic or CLh) in plasma following IV dose
CLh,iv = CLiv – CLrenal,iv
If CLrenal,iv is not available, assume 0.00
CLh,iv,blood
Hepatic Clearance in blood following IV dose


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Parameter 
Parameter Description
CLh,plasma divided by blood to plasma ratio = CLh, blood
CLrenal,iv
Renal Clearance (CLrenal,iv)
14C linerixibat-Ae(0-t),iv14C-L/AUC(0-t),iv14C-L
As data permits, (t=available time interval, Ae(0-24) may be a pooled 
estimate from 6 subjects in Period 1
B:P ratio (blood to 
plasma ratio)
In vitro estimate of human blood-to-plasma ratio for linerixibat
F
Absolute bioavailability from the oral tablets and IV doses 
administered in Period1 for AUC(0-inf) and AUC(0-t)
Fh
Fraction of linerixibat that escapes first pass liver extraction = Fh = 1 
– Eh
Fabs
Fraction of linerixibat absorbed (includes fraction escaping gut 
extraction) = Fabs = F/Fh
z
The first order rate constant associated with the terminal (log-linear) 
portion of the concentration-time curve.
Tmax
Time to reach Cmax, determined directly from the concentration-time 
data.
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / λz
Vss,iv
Volume of distribution of at steady-state will be calculated as:
CL*MRTiv
where the mean residence time (MRT) is calculated as AUMC(0-inf) 
(area under the first moment curve)/AUC(0-inf).
Treatment period 1, analyte [14C]- linerixibat.
Radioactivity Mass Balance in Periods 1 and 2 - Parameter Endpoints and Description
Parameter
Description
Fe%[urine]
% of total dose excreted as total radioactivity for each collection interval :
Data provided by Covance/Pharmaron.
Fe%[feces]
% of total dose excreted as total radioactivity for each collection interval:
Data provided by Covance/Pharmaron.
.
Fe%[total]
% of total dose excreted as radioactivity will be estimated in each collection interval as:
Sum of Fe%[urine] and Fe%[feces] - Data provided by Covance/Pharmaron.
9.1.2.
Summary Measure

Summary measures of PK parameters detailed in above table 9.1.1

Derived PK parameter estimates from plasma linerixibat, plasma14C-linerixibat and 
plasma total radioactivity in plasma for IV and oral along with other derived PK 
parameters will be listed and summarised.


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
Urinary and fecal recovery, cumulative excretion as percentage of the total 
radioactive dose over time will be listed and summarised (Treatment Periods 1 and 2 
as data permits) in reports provided by Pharmaron and Covance and appended to the 
Clinical Study Report

Absolute bioavailability after oral and IV dosing (Treatment Period 1) will be 
analysed by using AUC(0-t), AUC (0-inf) parameters.
9.1.3.
Population of Interest 
The PK analyses will be based on the PK population, unless otherwise specified.
9.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 8: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
Plasma linerixibat concentration-time data will be listed for each subject and summarized 
by period, analyte, treatment and planned sampling time. [14C]-linerixibat and total 
radioactivity concentrations in plasma will be reported similarly. Individual subject, mean 
and median plasma linerixibat, [14C]-linerixibat, and total radioactivity concentration–
time profiles will be plotted for each treatment on both a linear and semi-log scale. 
Pharmacokinetic analysis will be performed by or under the direct auspices of Clinical 
Pharmacology Modelling & Simulation, GSK. Plasma linerixibat, [14C]-linerixibat, and 
total radioactivity concentration–time data will be analysed by non-compartmental 
methods with Phoenix WinNonlin Version 6.4 or above. Calculations will be based on 
the actual sampling times recorded during the study. From the plasma concentration-time 
data the following pharmacokinetic parameters will be determined, for linerixibat, [14C]-
linerixibat, and total radioactivity, as data permits: maximum observed plasma 
concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time 
curve [AUC(0–t) and AUC(0-inf)], terminal phase rate constant (λz), and apparent 
terminal phase half-life (t1/2) following oral and IV dosing. Additionally, volume of 
distribution at steady state (Vss), renal clearance (CLr), and total systemic clearance (CL) 
will be derived following IV dosing. These parameters will be summarized descriptively.
All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKlinePharmaceuticals, R&D. Production of the summaries, tables, figures 
and listings of the plasma data will be performed under the direct auspices of Clinical 
Statistics, GSK.  The urine and fecal data for dose recovery estimations will be provided 
by Pharmaron and Covance under the auspices of BIB/DMPK, GSK.


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9.1.4.1.
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

AUC(0-inf)/dose

AUC(0-t)/dose
Model Specification

Will be statistically analyzed using a mixed model (MM) for Period1.

Terms fitted in the mixed effect ANOVA model will include:
o
Fixed effect                   : Treatment (IV dose/Oral dose in Period1)
o
Random Effect              : Subject

The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used.
Point estimates for the adjusted means on the loge scale, the mean difference between 
treatments and associated 90% confidence interval for the contrast (test-reference) will be 
constructed using the residual variance. 
Model Checking & Diagnostics

Dose normalized PK parameters should be used for the analysis.

For the Mixed Model analysis, Model assumptions will be applied, but appropriate 
adjustments may be made based on the data.

Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable. 
-
If there are any departures from the distributional assumptions, alternative 
transformations, such as data squared, or square root of data, will be explored.
Model Results Presentation

The point estimate and confidence interval obtained from MM analysis will be 
exponentially back-transformed to obtain adjusted (least square) geometric means for 
each treatment. 

Point estimates (Absolute Bioavailability of Linerixibat and associated 90% 
confidence interval for the ratio Oral dose/IV dose (see 9.1.1 for equation)) along 
with within-subject variability (%CVw) will be reported.
Where %CVw=100*(SQRT (EXP(σw2)-1)) and σw2 is the mean squares error (MSE) 
from the statistical Mixed model.


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9.2.
Metabolite Profiling Analyses in Plasma, Urine, Feces and 
Bile
The metabolic profiling/structural characterization aspect of this work will be performed
by GSK (or a GSK representative) in a separate BIB/DMPK study report.  Data from the 
quantification of unchanged linerixibat in urine following IV administration will be used 
in the estimate of renal clearance, as detailed above.


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10.
REFERENCES
Covance Study Number 8412194. GSK2330672: Absorption and elimination following 
administration of [14C]-linerixibat to human subjects, 2019.
Davies, B.; Morris, T. Physiological parameters in laboratory animals and humans. 
Pharm. Res. 1993,10, 1093–1095.
Edginton, A.N., Schmitt, W., Willmann, S. Development and evaluation of a generic 
physiologically based pharmacokinetic model for children. Clin Pharmacokinetics, 2006, 
45(10), 1013-1034.
GlaxoSmithKline Document Number 2010N111289_06. Linerixibat (GSK2330672) 
Investigator's Brochure, 29-AUG-2019.
GlaxoSmithKline Document Number 2018N388243_00. A two-period study in healthy 
male volunteers to determine the pharmacokinetics, balance/excretion, and metabolism of 
[14C]-GSK2330672 following a single intravenous radiolabeled microtracer dose 
(concomitant with a non-radiolabelled oral dose) and a single oral radiolabeled dose, 22-
FEB-2019.
GlaxoSmithKline Study Protocol 19DMM027. Quantification and characterization of 
[14C]-GSK2330672 and its major metabolites in healthy adult male subjects following a 
single intravenous radiolabelled microtracer dose (concomitant with a non-radiolabelled 
oral dose) and a single oral radiolabelled dose.
GlaxoSmithKline Study Report Number 2017N342697_00 and Protocol Number 
8367797.  A Study to Investigate the In Vitro Plasma Protein Binding and Blood-to-
Plasma Partitioning of 14C-GSK2330672 in Mouse, Rat,Rabbit, Dog, and Human Plasma 
and Blood
GUI_137354: Information for Authors – Reporting and Analysis Plan, Global; GSK.
GUI_51487 (4.0) Non-Compartmental Analysis of Pharmacokinetic Data, CPMS Global.
Mehvar R. Application of organ clearance to estimation of the in vivo hepatic extraction 
ratio. Curr Clin Pharmacol. 2016,11(1),47-52. doi: 
10.2174/1574884710666150817104746.
Pharmaron Study Number 001/039. Determination of total radioactivity in urine and 
feces samples derived from humans administered an IV dose of 250 nCi / 100 µg 14C-
linerixibat, 2019.
SOP_54838: Development, Review & Approval of Reporting & Analysis Plan, Global; 
GSK.


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11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
A Per Protocol Population is not being defined for this study. 
Please Refer to Section 4.1 for handling and Reporting of Protocol Deviations.


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11.2.
Appendix 2: Schedule of Activities
11.2.1.
Protocol Defined Schedule of Events
Period 1


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Period 2 Oral solution


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11.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
11.3.1.
Study Phases
11.3.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 15 days prior to screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 5: 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.
11.3.1.2.
Treatment Phases for AE Data
Treatment State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment stop 
date.
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 1 
day
Post-Treatment
If AE onset date is after the treatment stop date.
AE Start Date > Study Treatment Stop Date + 1 day
Onset Time 
Since 1st Dose 
(Days, hours,
mins)
Start/Stop Time is Collected: (AE Onset Date/time - Treatment Start Date/time) / 
60
Start or Stop Time is missing:
If Treatment Start Date ˃ AE Onset Date = AE Onset Date - Treatment Start 
Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date 
+1 day
Missing otherwise.
Duration (Days, 
hours,
Mins)
Start/Stop Time is Collected: Onset Time = (AE Resolution Date/time – AE Onset 
Date/time) / 60
Start or Stop Time is missing:
AE Resolution Date – AE Onset Date + 1 day
Drug-related
If relationship is marked ‘YES’ on [Inform/CRF OR value is missing].
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.


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11.3.2.
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.

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date+ 1 day

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 
+ 1 day
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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11.4.
Appendix 4: Data Display Standards & Handling 
Conventions
11.4.1.
Reporting Process
Software

The SAS Version 9.4 or above and Phoenix WinNonlin Version 6.4 or above will be used.
Reporting Area
HARP Server
: us1salx00259
HARP Compound
: \ARPROD\ GSK2330672\mid205895
Analysis Datasets 

Analysis datasets will be created according to CDISC standards SDTM IG Version 3.1.3 ADaM IG 
Version 1.1. 

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for final SAC.
11.4.2.
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
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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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.
11.4.3.
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 as per GUI_51487
(4.0), Noncompartmental Analysis of Pharmacokinetic Data.
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer

Ratios will be provided by CPMS.  [AUC/Dose, (dose from IV infusion of [14C]-
linerixibat in Period 1 (~100 µg) and oral dose of [14C]-linerixibat in Period 2 
(~90 mg) will be slightly different for each participant and will be corrected, 
calculated and provided in Pharmaron and Covance reports.  A listing of dose 
will not be needed for CSR.

Ratio of plasma [14C] linerixibat / total radioactivity for Cmax, AUC(0-inf), 
AUC(0-t) for periods 1 and 2 (refer to 9.1.1 for calculation of ratio)

Total radioactivity only - Fe%[urine], Fe%[feces], Fe%[total] – These will be
provided by Pharmaron and Covance
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.
Refer to IDSL Statistical Principle 6.06.1.
11.4.4.
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.


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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    
11.4.5.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:

Any subject with a missing day will have this imputed as day ‘15’.

Since Year of Birth is recorded in pCRF, date and month will be imputed as ‘30th June’ of that year.

Birth date will be presented in listings as ‘YYYY’.

The Date of Birth will be assumed to be 30 June YYYY and age will be calculated at screening visit 
using this assumed date of birth.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)]2
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

For each period consider start date and stop date for duration of exposure. Subjects who 
were allocated to treatment but did not report a treatment start date will be categorized as 
having zero days of exposure.
11.4.6.
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 decimal places in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 

Example 1: 2 Decimal Places = ‘< x’ becomes x – 0.01

Example 2: 1 Decimal Places = ‘> x’ becomes x + 0.1

Example 3: 0 Decimal Places = ‘< x’ becomes x – 1
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :


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ECG Parameters
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.

Machine read values of RR should not be replaced with derived values.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as : 
11.4.7.
Pharmacokinetic
PK Endpoints
Listed in 9.1.1

PK endpoints used to assess the bioavailability i.e. AUC(0-t) and AUC (0-∞) will be divided by 
corresponding dose (converted into pg and assuming AUC is h*pg/mL) before passing to MM model for 
estimation of mean and 90% confidence intervals for absolute bioavailability(F).  AUC/Dose ratios will 
be provided by CPMS.  Actual doses for radiolabelled doses will be provided in Pharmaron and 
Covance reports.

The ratio of plasma [14C] linerixibat/total radioactivity for Cmax, AUC(0-inf),and AUC(0-t) will be 
calculated and summarized for radiolabelled dose in periods 1 and 2.  (see calculation in 9.1.1)


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11.5.
Appendix 5: Reporting Standards for Missing Data
11.5.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as one who has 
completed all phases of the study including the last follow-up visit.

The end of the study is defined as the date of the last contact with the last participant in 
the study.

Withdrawn subjects will not be replaced unless the total number of participants who 
complete dosing and all critical assessments drops below 4.

All available data from subjects 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.
11.5.2.
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:
o
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. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.5.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events
o
The pCRF 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:
o
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 3: Study Phases 
and Treatment Emergent Adverse Events.
o
Missing Start Month: January will be used as the Month unless this is
before the Month of start of the study treatment; in that case the Month of 
study treatment start will be used.
o
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.
o
Missing Month of Stop: December will be used as the Month unless this
is after the Month of stop of the study treatment; in that case the Month
of study treatment stop, will be used.
o
Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be missing.


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Element
Reporting Detail
o
Start or end dates which are completely missing (i.e. no year specified) will remain 
missing, with no imputation applied.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the pCRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
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.

The recorded partial date will be displayed in listings.


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11.6.
Appendix 6: Values of Potential Clinical Importance
11.6.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
∆ from BL
↓0.075
Hemoglobin 
g/L
Male
180
∆ from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
White 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
2.75
Creatinine
µmol/L
∆ from BL
>30% increase from Baseline 
Glucose
mmol/L
3
9
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT


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11.6.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTcF
msec
500
Absolute PR Interval
msec
110 
240 
Absolute QRS Interval
msec
120 
11.6.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
85
160
Diastolic Blood Pressure
mmHg
40
90
Heart Rate
bpm
35
100
Respiration Rate
BREATHS/mi
n
8
20


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11.7.
Appendix 7: Abbreviations & Trade Marks
11.7.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
AUC(0–inf)
Area under the concentration-time curve from time zero (pre-dose)
extrapolated to infinite time
AUC(0–t)
Area under the concentration-time curve from time zero (pre-dose) to
last time of quantifiable concentration within a participant across all
treatments
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
DR
Dry Run
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
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control


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Abbreviation
Description
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 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
11.7.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
Excel
Phoenix WinNonlin
SAS


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11.8.
Appendix 8: List of Data Displays
11.8.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.10
Safety
2.1 to 2.12
Pharmacokinetic
3.1 to 3.7
3.1 to 3.6
Section
Listings
ICH Listings
1 to 25
Other Listings
26 to 34
11.8.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 9: 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.’
11.8.3.
Deliverables
Delivery 
Description
DR
Dry Run
SAC 
Final Statistical Analysis Complete


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11.8.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1xo
Summary of Participant Disposition for the Participant 
Conclusion Record
DR, SAC
1.2.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
DR, SAC
1.3.
Enrolled
NS1
Summary of Number of Participant by Country and Site ID
DR, SAC
Protocol Deviation
1.4.
Safety
DV1
Summary of Important Protocol Deviations
DR, SAC
Population Analysed
1.5.
Screened
SP1A
Summary of Study Populations 
DR, SAC
Demographic and Baseline Characteristics
1.6.
Safety
DM1xo
Summary of Demographic Characteristics
Include height, weight 
& BMI.
DR, SAC
1.7.
Enrolled
DM11
Summary of Age Ranges
DR, SAC
1.8.
Safety
DM5
Summary of Race and Racial Combinations
DR, SAC
Prior and Concomitant Medications
1.9.
Safety
CM1
Summary of Concomitant Medications
ICH E3
DR, SAC
Exposure and Treatment Compliance
1.10.
Safety
EX1 
Summary of Exposure to Study Treatment
ICH E3
DR, SAC


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11.8.5.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.1.
Safety
AE1xo
Summary of All Adverse Events by System Organ Class and 
Preferred Term
DR, SAC
2.2.
Safety
AE1xo
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and by Overall Frequency
DR, SAC
Serious and Other Significant Adverse Events
2.3.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
DR, SAC
Laboratory: Chemistry 
2.4.
Safety
LB1
Summary of Chemistry Changes from Baseline 
Includes baseline 
values.
DR, SAC
2.5.
Safety
LB1
Summary of Chemistry Values
DR, SAC
2.6.
Safety
LB15
Summary of Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline 
DR, SAC
Laboratory: Hematology
2.7.
Safety
LB1
Summary of Hematology Changes from Baseline
Includes baseline 
values.
DR, SAC
2.8.
Safety
LB1
Summary of Hematology values 
DR, SAC
2.9.
Safety
LB15
Summary of Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline
DR, SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
2.10.
Safety
EG1
Summary of ECG Findings 
DR, SAC
2.11.
Safety
EG2
Summary of ECG Values
DR, SAC
Vital Signs
2.12.
Safety
VS1
Summary of Change from Baseline in Vital Signs
Includes baseline 
values.
DR, SAC


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11.8.6.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Plasma linerixibat and Plasma [14C] linerixibat
3.1.
PK
pkct1
Summary of Plasma Linerixibat and [14C] Linerixibat Concentration by 
period, treatment and time 
Linerixibat: Summarized for A1 and B
[14C] linerixibat: Summarized for A2 
and if available for B treatment
Group by period and dose
DR, SAC
3.2.
PK
pkpt1
Summary of Untransformed Plasma Linerixibat and [14C] Linerixibat 
Pharmacokinetic Parameters
Linerixibat : Summarized for A1 and B
[14C] linerixibat: Summarized for A2 
and if available for B
Group by period and treatment
DR, SAC
3.3.
PK
pkpt3
Summary of Loge-transformed Plasma Linerixibat and [14C] Linerixibat 
Pharmacokinetic Parameters 
Linerixibat: Summarized for A1 and B
[14C] linerixibat: Summarized for A2 
and if available for B treatment group
Group by period and treatment
DR, SAC
Total Radioactivity
3.4.
PK
pkct1
Summary of Plasma Total Radioactivity Concentration by Period, 
Treatment and Time
Summarized by Period A1 and B
Group by period and treatment
DR, SAC
3.5.
PK
pkpt1
Summary of Untransformed Plasma Total Radioactivity 
Pharmacokinetic Parameters
Summarized by Period A1 and B
Group by period and treatment
DR, SAC
Other Output
3.6.
PK
pkpt3
Summary of Loge-transformed Plasma Total Radioactivity 
Pharmacokinetic Parameters
Same as Table 3.3
Group by period
DR, SAC
PK Statistical Analysis
3.7.
PK
PK_T2
Summary of Statistical Analysis of Loge-transformed Plasma 
Linerixibat PK Parameter
Summarize for Period 1
DR, SAC


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11.8.7.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Plasma linerixibat and Plasma [14C] linerixibat
3.1.
PK
pkcf6
Individual Subject Plasma Linerixibat and [14C] Linerixibat
Concentration-time Plot (Linear and Semi-log) by Period and 
Treatment
Different plot symbols will be used for 
each subject
DR, SAC
3.2.
PK
pkcf2
Arithmetic Mean Plasma Linerixibat and [14C] Linerixibat 
Concentration-time Plot (Linear and Semi-log) by Period and 
Treatment
DR, SAC
3.3.
PK
pkcf3
Median Plasma Linerixibat and [14C] Linerixibat Concentration -time 
Plot (Linear and Semi-log) by Period and Treatment
DR, SAC
Total Radioactivity
3.4.
PK
pkcf6
Individual Subject Plasma Total Radioactivity Concentration-time Plot 
(Linear and Semi-log) by Period and Treatment
DR, SAC
3.5.
PK
pkcf2
Arithmetic Mean Plasma Total Radioactivity Concentration-time Plot 
(Linear and Semi-log) by Period and Treatment
DR, SAC
3.6.
PK
pkcf3
Median Plasma Total Radioactivity Concentration -time Plot (Linear 
and Semi-log) by Treatment
DR, SAC


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11.8.8.
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
DR, SAC
2.
Safety
ES2xo
Listing of Reasons for Study or Treatment Withdrawal
DR, SAC
Protocol Deviations
3.
Safety
DV2xo
Listing of Important Protocol Deviations 
DR, SAC
4.
Safety
IE3xo
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
DR, SAC
Demographic and Baseline Characteristics
5.
Safety
DM2xo
Listing of Demographic Characteristics
DR, SAC
6.
Safety
DM9xo
Listing of Race
DR, SAC
Prior and Concomitant Medications
7.
Safety
CM10xo
Listing of Concomitant Medications
DR, SAC
Exposure and Treatment Compliance
8.
Safety
EX3xo
Listing of Exposure Data
DR, SAC
Adverse Events
9.
Safety
AE8CPxo
Listing of All Adverse Events
DR, SAC
10.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
DR, SAC
11.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
DR, SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
12.
Safety
AE8CPAxo
Listing of Serious Adverse Events
DR, SAC
13.
Safety
AE8CPxo
Listing of Adverse Events Leading to Withdrawal from Study
DR, SAC
14.
Safety
AE8CPxo
Listing of Treatment Emergent AEs
DR, SAC
Hepatobiliary (Liver)
15.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
DR, SAC
16.
Safety
MH2xo
Listing of Medical Conditions for Subjects with Liver Stopping
DR, SAC
17.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping
Events
DR, SAC
All Laboratory
18.
Safety
LB5xo
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance/Outside Normal Range
DR, SAC
19.
Safety
LB5xo
Listing of Laboratory Values of Potential Clinical Importance
DR, SAC
20.
Safety
UR2xo
Listing of Urinalysis Data for Subjects with Positive Dipstick
Results 
DR, SAC
ECG
21.
Safety
EG3xo
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
DR, SAC
22.
Safety
EG3xo
Listing of ECG Values of Potential Clinical Importance
DR, SAC
23.
Safety
EG5xo
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding
DR, SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
24.
Safety
VS4xo
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance
IDSL
Required for ClinPharm studies 
only. Display ALL Vital Signs for a 
subject who experienced a value of 
potential clinical importance.
DR, SAC
25.
Safety
VS4xo
Listing of Vital Signs of Potential Clinical Importance
IDSL
Required for ClinPharm studies 
only.
DR, SAC


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11.8.9.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK
26.
PK
pkcl1x
Listing of Plasma Linerixibat and [14C] – Linerixibat Concentration-
Actual Time Data by period, treatment and time
DR, SAC
27.
PK
pkpl1x
Listing of Plasma Linerixibat and [14C] – Linerixibat Pharmacokinetic 
Parameters by period and treatment
DR, SAC
28.
PK
pkcl1x
Listing of Plasma Total-Radioactivity Concentration -Actual Time 
Data by period, treatment and time
DR, SAC
29.
PK
pkpl1x
Listing of Plasma Total -Radioactivity Pharmacokinetic Parameters 
by period and treatment
DR, SAC
30.
PK
N/A
Supportive SAS Output from Statistical Analysis of Loge-
transformed Plasma Linerixibat GSK Pharmacokinetic Parameters
DR , SAC


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11.9.
Appendix 9: Example Mock Shells for Data Displays
Data Display Specification will be made available on request.