A Phase 1, Open-label, Non-randomized, Parallel Group, Single-dose Adaptive Study in Adults With Hepatic Impairment and Matched, Healthy Control Participants With Normal Hepatic Function
Phase: PHASE1
Conditions: Anaemia
Sponsor: GlaxoSmithKline

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TITLE PAGE
Protocol Title: A Phase 1, open-label, non-randomized, parallel group, single-dose 
adaptive study in adults with hepatic impairment and matched, healthy control 
participants with normal hepatic function.
Protocol Number: 200231
Short Title: Daprodustat hepatic impairment study
Compound Number: GSK1278863
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 (SRM)
Regulatory Agency Identifying Number(s): IND Number: 101,291
Approval Date: 23-MAY-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorized copying or use of this information is prohibited.

PPD
PPD

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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................9
3.
INTRODUCTION....................................................................................................11
3.1.
Study Rationale ..........................................................................................11
3.2.
Background ................................................................................................12
3.3.
Benefit/Risk Assessment ............................................................................12
3.3.1.
Risk Assessment .........................................................................12
3.3.2.
Benefit Assessment.....................................................................12
3.3.3.
Overall Benefit:Risk Conclusion...................................................12
4.
OBJECTIVES AND ENDPOINTS...........................................................................13
5.
STUDY DESIGN ....................................................................................................13
5.1.
Overall Design ............................................................................................13
5.2.
Number of Participants ...............................................................................15
5.3.
Participant and Study Completion...............................................................16
5.4.
Scientific Rationale for Study Design ..........................................................16
5.5.
Dose Justification........................................................................................17
6.
STUDY POPULATION...........................................................................................18
6.1.
Inclusion Criteria.........................................................................................18
6.1.1.
Inclusion Criteria for All Participants.............................................18
6.1.1.1.
Additional Inclusion Criteria for Hepatically-
Impaired Participants..................................................19
6.1.1.2.
Additional Inclusion Criteria for Healthy Control 
Participants ................................................................19
6.2.
Exclusion Criteria........................................................................................20
6.2.1.
Exclusion Criteria for All Participants ...........................................20
6.2.1.1.
Additional Exclusion Criteria for Hepatically-
Impaired Participants..................................................21
6.2.1.2.
Additional Exclusion Criteria for Healthy 
Control Participants ....................................................22
6.3.
Lifestyle Restrictions...................................................................................22
6.3.1.
Meals and Dietary Restrictions ....................................................22
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................22
6.3.3.
Activity .........................................................................................23
6.4.
Screen Failures...........................................................................................23
7.
TREATMENTS.......................................................................................................23
7.1.
Treatments Administered............................................................................23
7.2.
Dose Modification .......................................................................................24
7.3.
Method of Treatment Assignment ...............................................................24
7.4.
Blinding.......................................................................................................24
7.5.
Preparation/Handling/Storage/Accountability..............................................24
7.6.
Treatment Compliance................................................................................24
7.7.
Concomitant Therapy..................................................................................25
7.7.1.
Permitted Medications and Non-Drug Therapies..........................25

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7.7.2.
Prohibited Medications and Non-Drug Therapies.........................25
7.8.
Treatment after the End of the Study ..........................................................25
8.
DISCONTINUATION CRITERIA.............................................................................26
8.1.
Discontinuation of Study Treatment ............................................................26
8.1.1.
Liver Chemistry Stopping Criteria ................................................26
8.2.
Withdrawal from the Study..........................................................................26
8.3.
Lost to Follow Up........................................................................................26
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................27
9.1.
Efficacy Assessments.................................................................................28
9.2.
Adverse Events...........................................................................................28
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................28
9.2.2.
Method of Detecting AEs and SAEs.............................................29
9.2.3.
Follow-up of AEs and SAEs.........................................................29
9.2.4.
Adverse Events of Special Interest (AESI)...................................29
9.2.5.
Regulatory Reporting Requirements for SAEs .............................29
9.2.6.
Cardiovascular and Death Events................................................30
9.2.7.
Possible Suicidality Related Adverse Events ...............................30
9.2.8.
Pregnancy ...................................................................................30
9.3.
Treatment of Overdose...............................................................................31
9.4.
Screening and Critical Baseline Assessments ............................................31
9.5.
Safety Assessments ...................................................................................31
9.5.1.
Physical Examinations.................................................................31
9.5.2.
Vital Signs....................................................................................32
9.5.3.
Electrocardiograms......................................................................32
9.5.4.
Clinical Safety Laboratory Assessments ......................................32
9.5.5.
Pregnancy Testing.......................................................................33
9.6.
Pharmacokinetics .......................................................................................33
9.6.1.
Blood sample collection ...............................................................33
9.6.2.
Sample Analysis ..........................................................................33
9.7.
Pharmacodynamics ....................................................................................34
9.8.
Genetics .....................................................................................................34
9.9.
Biomarkers .................................................................................................34
9.10.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................34
10. STATISTICAL CONSIDERATIONS........................................................................34
10.1.
Hypotheses.................................................................................................34
10.2.
Sample Size Determination ........................................................................34
10.2.1.
Sample Size Assumptions ...........................................................34
10.2.2.
Sample Size Sensitivity................................................................35
10.2.3.
Sample Size Re-estimation or Adjustment...................................35
10.3.
Data Analysis Considerations .....................................................................35
10.3.1.
Analysis Populations....................................................................35
10.3.1.1.
Enrolled Population ....................................................35
10.3.1.2.
Safety Population .......................................................35
10.3.1.3.
Pharmacokinetic Population .......................................36
10.3.2.
Interim Analysis ...........................................................................36
10.4.
Key Elements of Analysis Plan ...................................................................36
10.4.1.
Pharmacokinetic Analyses...........................................................37

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10.4.1.1.
Statistical Analysis of Pharmacokinetic 
Parameters.................................................................38
10.4.2.
Pharmacodynamic Analyses........................................................38
10.4.3.
Safety Analyses...........................................................................38
11. REFERENCES.......................................................................................................39
12. APPENDICES........................................................................................................40
12.1.
Appendix 1: Abbreviations and Trademarks................................................40
12.2.
Appendix 2: Risk Assessment.....................................................................43
12.3.
Appendix 3: Clinical Laboratory Tests.........................................................54
12.4.
Appendix 4: Study Governance Considerations..........................................56
12.5.
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................60
12.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................65
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................68
12.8.
Appendix 8:  Grades of Hepatic Encephalopathy........................................70

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1.
SYNOPSIS
Protocol Title: A Phase 1, open-label, non-randomized, parallel group, single-dose 
adaptive study in adults with hepatic impairment and matched, healthy control 
participants with normal hepatic function.
Short Title: Daprodustat hepatic impairment study
Rationale:
A recent study has shown that co-administration of daprodustat with a strong, irreversible 
inhibitor of the cytochrome (CYP) 2C8 enzyme (i.e., gemfibrozil) lead to marked 
increases in both daprodustat Cmax (4-fold) as well as AUC (19-fold).  This suggests that 
the liver is primarily involved in the clearance of daprodustat through the CYP2C8 
enzyme and, therefore hepatic impairment has the potential to affect daprodustat 
clearance and exposure.  Thus, the intent of this study is to assess the effect of hepatic 
impairment on the pharmacokinetics (PK) and pharmacodynamics (PD) of daprodustat.  
The results of this study are planned to provide guidance on administration of daprodustat 
to patients with impaired hepatic function.
Objectives and Endpoints:
Objective
Endpoint
Primary
To compare plasma PK parameters of 
daprodustat and its six metabolites (GSK2391220 
(M2), GSK2506104 (M3), GSK2487818 (M4), 
GSK2506102 (M5), GSK2531398 (M6), 
GSK2531401 (M13)) in participants with hepatic 
impairment to healthy controls matched in gender, 
age, and body mass index (BMI)
Daprodustat and its metabolites plasma area 
under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time [AUC(0-
∞)], percentage of AUC(0-) obtained by 
extrapolation (%AUCex), time zero (pre-dose) to 
last time of quantifiable concentration [AUC(0-t)], 
maximum observed concentration (Cmax) 
following a single oral dose of daprodustat, 
apparent terminal phase half-life (t½), and time of 
occurrence of Cmax (Tmax) following a single oral 
dose of daprodustat
To evaluate the impact of hepatic impairment on 
the plasma protein binding and unbound 
concentration of daprodustat in plasma
Unbound concentration and unbound fraction in 
plasma of daprodustat at 3, 12 and 24 h post dose 
(as data permit)
Secondary
To characterize the effect of hepatic impairment 
on the pharmacodynamics effect of daprodustat
Maximum observed effect (Emax) and and area 
under the effect curve from administration to the 
last measureable erythropoietin concentration 
[AUC(E, last)]
To assess the safety and tolerability of a single 6 
mg dose of daprodustat
Safety and tolerability parameters, including 
adverse events and clinical laboratory tests

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Overall Design:
This will be a Phase 1, open-label, non-randomized, parallel group, single-dose, adaptive 
study in adults with moderate (Part 1) and potentially either mild or severe (Part 2) 
hepatic impairment and matched, healthy control participants with normal hepatic 
function.
All participants will undergo screening assessments within 28 days of enrolment.  A 
decision to progress from Part 1 to 2 will be made based on the available study results, 
with the potential that Part 2 of the study will not be conducted.
In Part 1, healthy control participants (n=8) will be matched in gender, age (±10 years), 
and BMI (±15%) to participants with moderate hepatic impairment (Child-Pugh score of 
7-9).  All participants will receive 6 mg of daprodustat as a single oral dose in the fasted 
state followed by pharmacokinetic and pharmacodynamic sampling for total 
concentrations of daprodustat in plasma.  At sparse sampling times, unbound daprodustat 
concentrations will be assessed.
In Part 2, if the geometric mean total plasma AUC pharmacokinetic parameters of 
daprodustat is increased in Part 1 by ≥2-fold in moderately-impaired participants relative 
to matched controls, Part 2 may be conducted to evaluate daprodustat pharmacokinetics 
in participants with mild impairment (Child-Pugh score of 5-6; n=8) and matched, control 
participants (n=8).  Alternatively, if the geometric mean total plasma AUC(0-∞) of 
daprodustat is increased by <2-fold in moderately impaired participants relative to 
matched controls, Part 2 may be conducted to evaluate daprodustat pharmacokinetics in 
participants with severe impairment (Child-Pugh score of 10-13; n=8) and matched, 
control participants (n=8).  Similar to Part 1 of the study, all participants will receive 
6 mg of daprodustat followed by pharmacokinetic and pharmacodynamic blood
sampling.
Number of Participants:
A sufficient number of participants will be enrolled to ensure there are at least 8 
participants comprising the pharmacokinetic population per cohort.
Recruitment of Part 1 of this study will include the full range of participants with 
moderate hepatic impairment including at least one with a Child-Pugh score of 7, one 
with a score of 8 and one with a score of 9.  The recruitment will also include at least one 
female and at least one male participant in both the moderate hepatic impaired group and 
the healthy volunteer group to be part of the pharmacokinetic population as described.
Similar to the participants in Part 1, recruitment of Part 2 of this study, if conducted, will 
include a range of participants as follows:

If Part 2 is conducted, the study will recruit participants with mild hepatic 
impairment, recruitment will include at least one with a Child-Pugh score of 5 and 
one participant with a score of 6, and will also include at least one female and at 
least one male participant in both the moderate hepatic impaired group and the 
healthy volunteer group to be part of the pharmacokinetic population.

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
If Part 2 is conducted, the study will recruit participants with severe hepatic 
impairment, recruitment will include at least one with a Child-Pugh score of 10 or 
11 and one with a score of 12 or 13, and will also include at least one female and 
at least one male participant in both the severe hepatic impaired group and the 
healthy volunteer group to be part of the pharmacokinetic population.
Treatment Groups and Duration:
In both Part 1, and if conducted, Part 2, all participants will be administered 6 mg of 
daprodustat as a single oral dose, with assessments conducted for up to 48 h postdosing.
A follow-up visit will occur 10-14 days after the dose of study treatment.
A participant’s total involvement with the study will be up to 7 weeks.

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2.
SCHEDULE OF ACTIVITIES (SOA)
Procedure
Screening1
Day -1
Pre-Dose
0 h
0.5 h
1 h
1.5 h
2 h
3 h
4 h
6 h
8 h
10 h
12 h
24 h
36 h
48 h
Follow-up2
Informed 
Consent
X
Inclusion & 
Exclusion 
Criteria
X
X
Demography
X
Full physical 
exam
X
Medical 
history
X
Past/current 
medications
X
Laboratory
assessments
3
X
X
X
Drug/Alcohol 
Screen
X
X
12-lead ECG
X
X
X
X
Vital Signs 
and Weight
X
X
X
X
Pregnancy 
Test
X4
X4
Females 
only: 
Estrogen and 
FSH5
X

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Procedure
Screening1
Day -1
Pre-Dose
0 h
0.5 h
1 h
1.5 h
2 h
3 h
4 h
6 h
8 h
10 h
12 h
24 h
36 h
48 h
Follow-up2
Admission to 
Unit
X
Brief Physical 
Exam
X
X
X
Administratio
n of 
daprodustat
X
PK blood 
sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Protein 
binding 
sample
X
X
X
X
EPO blood 
sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse 
Events 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review 
Concomitant 
Medications
X
X
X
X
X
Discharge 
from Unit
X
1 All participants will undergo screening assessments within 28 days of enrolment.
2 A follow-up visit will occur 10-14 days after the dose of study treatment.
3 Laboratory assessment guidance can be found in Appendix 3.
4 For women of childbearing potential that are not using an approved method of contraception (see Appendix 6), one negative pregnancy test between Day -7 and Day -4 AND another 
negative pregnancy test on Day -1 is required.  Additional guidance can be found in Section 9.5.5.
5 All females are to have estrogen and FSH measured at screening.

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
The timing and number of planned study assessments, including safety, 
pharmacokinetic and pharmacodynamic assessments may be altered during the 
course of the study based on newly available data (e.g., to obtain data closer to the 
time of peak plasma concentrations) to ensure appropriate monitoring.

Any changes in the timing or addition of time points for any planned study 
assessments 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 IRB/IEC will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the ICF.
3.
INTRODUCTION
Daprodustat (GSK1278863) is a small molecule, oral hypoxia-inducible factor-prolyl 
hydroxylase enzymes inhibitor (HIF-PHI) currently in development for the treatment of 
anemia of chronic kidney disease (CKD).  Daprodustat may present several important 
advantages over currently-available recombinant human erythropoietins (rhEPOs) and 
analogs used in the treatment of anemia.  It is an oral medication and does not require 
cold-chain storage as do some rhEPOs, thus increasing ease of use for patients.  
Moreover, data indicate that daprodustat can effectively raise hemoglobin (Hgb)
concentrations with lower erythropoietin (EPO) levels than those observed after 
administration of rhEPOs [Holdstock, 2016].  Because of the increased cardiovascular 
(CV) risk associated with raising Hgb concentrations through large increases in EPO 
levels [Pfeffer, 2009], daprodustat may be able to provide a safer treatment alternative for 
these patients than rhEPOs.  Additional potential benefits include inproving iron 
availability for erythropoiesis, treating anemia without causing rhEPO-induced 
hypertension, and successfully treat rhEPO hypo-responders [Holdstock, 2016].
3.1.
Study Rationale
A recent study has shown that co-administration of daprodustat with a strong, irreversible 
inhibitor of the cytochrome (CYP) 2C8 enzyme (i.e., gemfibrozil) lead to marked 
increases in both daprodustat Cmax (4-fold) as well as AUC (19-fold).  This suggests that 
the liver is primarily involved in the clearance of daprodustat through the CYP2C8 
enzyme and, therefore hepatic impairment has the potential to affect daprodustat 
clearance and exposure [Johnson, 2013].  Thus, the intent of this study is to assess the 
effect of hepatic impairment on the pharmacokinetics (PK) and pharmacodynamics (PD)
of daprodustat.  The results of this study are planned to provide guidance on 
administration of daprodustat to patients with impaired hepatic function.
This study will use an adaptive study design, comprising Part 1 and potentially Part 2. 
Recruitment of Part 1 of this study will include the full range of Child-Pugh scores within 
the moderate hepatic impairment category including at least one with a Child-Pugh score 
of 7, one with a score of 8 and one with a score of 9. The recruitment will also include at 
least one female and at least one male participant in both the moderate hepatic impaired 
group and the healthy volunteer group.  If the geometric mean total plasma AUC of 
daprodustat is increased in Part 1 by ≥2-fold in moderately-impaired participants relative 
to matched controls, Part 2 may potentially be conducted to evaluate daprodustat 
pharmacokinetics in participants with mild impairment (Child-Pugh scores of 5-6) and 

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matched, control participants.  Alternatively, if the geometric mean total plasma AUC of 
daprodustat is increased by <2-fold in moderately-impaired participants relative to 
matched controls, Part 2 may potentially be conducted to evaluate daprodustat 
pharmacokinetics in participants with severe impairment (Child-Pugh scores of 10-13) 
and matched, control participants.  These levels of change in exposure as decision points 
are based on regulatory agency guidances [FDA Guidance for Industry, 2003; Committee 
for medicinal products for human use (CHMP), 2005], and the consideration that 
daprodustat has not been observed to possess a narrow therapeutic index.  A decision to 
progress from Part 1 to 2 will be made based on the available study results, with the 
potential that Part 2 of the study will not be conducted
3.2.
Background
Daprodustat is currently in Phase 3 development for the treatment of anemia of CKD.  
The clinical efficacy of daprodustat has been demonstrated in two Phase 2 studies.  In 
GSK study PHI113747 daprodustat achieved mean hemoglobin (Hgb) response in non-
dialysis dependent (ND) participants with CKD within a target range over a 24-week 
treatment period.  Participants in the daprodustat group achieved Hgb levels within the 
specific target range (8.0 to 11.0 g/dL; US only 8.0 to 10.0 g/dL), both in the 
recombinant, human (rh)-EPO naïve and rhEPO user groups.  In study PHI113633 
daprodustat achieved Hgb efficacy (maintenance of Hgb within the target range of 10.0 to 
11.5 g/dL) in a similar fashion as did rhEPO in hemodialysis-dependent (HD) 
participants with CKD [Holdstock, 2016].
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
daprodustat is provided in the Investigator’s Brochure (IB) and associated IB 
Supplements, if applicable.
3.3.
Benefit/Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
daprodustat can be found in the daprodustat IB and IB supplement(s), if applicable.
3.3.1.
Risk Assessment
The potential risks of clinical significance including AEs of special interest (Section 
9.2.4), and the mitigation strategies for this protocol taking into account the results of 
completed clinical and nonclinical studies with daprodustat, are outlined in Appendix 2.
3.3.2.
Benefit Assessment
As this is a single dose study, no clinical benefit is expected for participation.
3.3.3.
Overall Benefit:Risk Conclusion
Overall, the available data from nonclinical and clinical studies has not identified 
prohibitive risks associated with daprodustat at the exposures planned for this study.  
While there are a number of important potential risks identified for daprodustat, these can 

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be addressed in clinical trials with proper participant selection, close safety monitoring, 
and specific risk characterization and mitigation.
4.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary
To compare plasma PK parameters of 
daprodustat and its six metabolites (GSK2391220 
(M2), GSK2506104 (M3), GSK2487818 (M4), 
GSK2506102 (M5), GSK2531398 (M6), 
GSK2531401 (M13)) in participants with hepatic 
impairment to healthy controls matched in gender,
age, and body mass index (BMI)
Daprodustat and its metabolites plasma area 
under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time [AUC(0-
∞)], percentage of AUC(0-) obtained by 
extrapolation (%AUCex), time zero (pre-dose) to 
last time of quantifiable concentration [AUC(0-t)], 
maximum observed concentration (Cmax) 
following a single oral dose of daprodustat, 
apparent terminal phase half-life (t½), and time of 
occurrence of Cmax (Tmax) following a single oral 
dose of daprodustat
To evaluate the impact of hepatic impairment on 
the plasma protein binding and unbound 
concentration of daprodustat in plasma
Unbound concentration and unbound fraction in 
plasma of daprodustat at 3, 12 and 24 h post dose 
(as data permit)
Secondary
To characterize the effect of hepatic impairment 
on the pharmacodynamics effect of daprodustat
Maximum observed effect (Emax) and and area 
under the effect curve from administration to the 
last measureable erythropoietin concentration 
[AUC(E, last)]
To assess the safety and tolerability of a single 6 
mg dose of daprodustat
Safety and tolerability parameters, including 
adverse events and clinical laboratory tests
5.
STUDY DESIGN
5.1.
Overall Design
This will be a Phase 1, open-label, non-randomized, parallel group, single-dose, adaptive 
study in adults with moderate (Part 1) and potentially either mild or severe (Part 2)
hepatic impairment and matched, healthy control participants with normal hepatic 
function.
All participants will undergo screening assessments within 28 days of enrolment.  A 
decision to progress from Part 1 to 2 will be made based on the available study results, 
with the potential that Part 2 of the study will not be conducted.

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In Part 1, healthy control participants (n=8) will be matched in gender, age (±10 years), 
and BMI (±15%) to participants with moderate hepatic impairment (Child-Pugh score of 
7-9).  All participants will receive 6 mg of daprodustat as a single oral dose in the fasted 
state followed by pharmacokinetic and pharmacodynamic sampling for total 
concentrations of daprodustat in plasma.  At sparse sampling times, unbound daprodustat 
concentrations will be assessed.
In Part 2, if the geometric mean total plasma AUC pharmacokinetic parameters of 
daprodustat is increased in Part 1 by ≥2-fold in moderately-impaired participants relative 
to matched controls, Part 2 may be conducted to evaluate daprodustat pharmacokinetics 
in participants with mild impairment (Child-Pugh score of 5-6; n=8) and matched, control 
participants (n=8).  Alternatively, if the geometric mean total plasma AUC(0-∞) of 
daprodustat is increased by <2-fold in moderately impaired participants relative to 
matched controls, Part 2 may be conducted to evaluate daprodustat pharmacokinetics in 
participants with severe impairment (Child-Pugh score of 10-13; n=8) and matched, 
control participants (n=8).  Similar to Part 1 of the study, all participants will receive 
6 mg of daprodustat followed by pharmacokinetic and pharmacodynamic blood 
sampling.
A follow-up visit will occur 10-14 days after the dose of study treatment.
A participant’s total involvement with the study will be up to 7 weeks.
Table 1
Study Cohorts
Study Part
Cohort
Sample 
Size
Treatment1
Part 1
1 (Moderate Hepatic Impairment)2
8
Daprodustat 6 mg
2 (Matched Healthy Controls)3
8
Part 2
(if conducted)4
3 (either Mild OR Severe Hepatic 
Impairment)2
8
4 (Matched Healthy Controls)3
8
1 All participants will receive a single 6 mg oral dose of daprodustat.
2 Hepatic impairment categorized by Child-Pugh Classification system (See Table 2: Mild: Score 5-6; Moderate: 
Score 7-9; Severe: Score 10-13) in conjunction with the specifications listed in Section 6.
3 Healthy control participants are matched to the hepatic impairment participants in gender, age (±10 years), and 
BMI (±15%).
4 Part 2 of the study may be conducted dependent upon any observed difference in the geometric mean total plasma 
AUC(0-∞) of daprodustat in moderately impaired participants relative to matched controls as described in Section 
10.3.2.
A participant is classified with hepatic impairment based on the Child-Pugh classification 
as described in Table 2:

Mild hepatic impairment: Child-Pugh Class A, score of 5-6 points

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
Moderate hepatic impairment: Child-Pugh Class B, score of 7-9

Severe hepatic impairment: Child-Pugh Class C, score of 10-13
Table 2
Child-Pugh System of Hepatic Impairment Classification1
Parameter
Points Scored for Each Observed Finding
1 Point
2 Points
3 Points
Serum albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
Total serum bilirubin (mg/dL)
<2.0
2.0 to 3.0
>3.0
Prothrombin time INR (ratio)
<1.70
1.70 to 2.30
>2.30
Ascites
Absent
Slight
or
Participant on 1 
medication to 
control ascites
Moderate
or
Participant on 2 
medications to 
control ascites
Hepatic encephalopathy2
None
1 or 2
or
Participant currently 
receiving treatment 
with lactulose, 
neomycin, or other 
acceptable 
treatments
3 or 4
or
Continued 
encephalopathy 
while receiving 
treatment with 
lactulose, neomycin, 
and/or other 
acceptable 
treatments
1 Child-Pugh System of Hepatic Impairment: adapted from Child, 1964; Pugh, 1973.
2 A description of hepatic encephalopathy grades can be found in Appendix 8.
5.2.
Number of Participants
A sufficient number of participants will be enrolled to ensure there are at least 8 
participants comprising the pharmacokinetic population per cohort (See Section 
10.3.1.3).
Recruitment of Part 1 of this study will include the full range of participants with 
moderate hepatic impairment including at least one with a Child-Pugh score of 7, one 
with a score of 8 and one with a score of 9.  The recruitment will also include at least one 
female and at least one male participant in both the moderate hepatic impaired group and 
the healthy volunteer group to be part of the pharmacokinetic population as described
(See Section 10.3.1.3).

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Similar to the participants in Part 1, recruitment of Part 2 of this study, if conducted, will 
include a range of participants as follows:

If Part 2 is conducted, the study will recruit participants with mild hepatic 
impairment, recruitment will include at least one with a Child-Pugh score of 5 and 
one participant with a score of 6, and will also include at least one female and at 
least one male participant in both the moderate hepatic impaired group and the 
healthy volunteer group to be part of the pharmacokinetic population as described
(See Section 10.3.1.3).

If Part 2 is conducted, the study will recruit participants with severe hepatic 
impairment, recruitment will include at least one with a Child-Pugh score of 10 or 
11 and one with a score of 12 or 13, and will also include at least one female and 
at least one male participant in both the severe hepatic impaired group and the 
healthy volunteer group to be part of the pharmacokinetic population as described
(See Section 10.3.1.3).
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the follow up visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
This study will be an open label, single dose, parallel group, adaptive design for 
assessment of daprodustat PK and PD in participants with moderate hepatic impairment 
and matched control participants.  The design will permit daprodustat and its metabolites 
PK parameters to be determined in participants with moderate hepatic impairment (Child-
Pugh score 7-9), and compared to the PK parameters from matched healthy control 
participants with normal hepatic function.  Additionally, the unbound fraction of 
daprodustat will be determined to assess the impact of hepatic impairment on daprodustat 
plasma protein binding.  Finally, the effect of daprodustat on erythropoietin (EPO) levels 
will be described.

This study will be open label since the primary endpoint (PK) is an objective 
measure and unlikely to be influenced by the participant’s knowledge of the 
treatment received.

A single dose of daprodustat will be used in this study as daprodustat PK exhibits 
linear and time-independent PK.  Further, single-dose PK, as will be performed in 
this study, has consistently allowed reliable prediction of multiple-dose PK that 
would be observed with chronic administration.  Finally, as daprodustat (as well 
as predominant circulating metabolites) has a short half-life, PK on Day 1 is 
similar to PK at steady state. Multiple-dose study designs are only recommended 
if the PK changes over time; i.e., in cases of auto-induction or accumulation due 
to a long half-life.

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
The adaptive design of this study allows for subsequent study, if conducted, of
participants with either mild (Child-Pugh score 5-6) or severe (Child-Pugh score 
10-13) hepatic impairment to be implemented dependent upon the results from the 
participants with moderate hepatic impairment:
(i)
If a <2-fold change in daprodustat exposure (AUC) is observed in participants
with moderate hepatic impairment, the study may enrol participants with severe 
hepatic impairment and a healthy, matched control group;
(ii)
If a ≥2-fold change in daprodustat exposure (AUC) is observed in participants 
with moderate hepatic impairment, the study may enrol participants with mild 
hepatic impairment and a healthy, matched control group.

The Child-Pugh scoring system for hepatic impairment will be used for the 
classification of hepatically-impaired participants.  Currently, there are no well-
established biochemical markers to estimate the effects of hepatic impairment on 
the PK/PD of a drug.  Although the Child-Pugh classification system was not 
developed for the purpose of predicting drug elimination capacity, it is the most 
widely used and accepted method of categorizing the degree of hepatic 
impairment in participants included in a hepatic impairment PK study, and has 
been selected as the system to categorize the participants enrolled in this study 
[FDA Guidance for Industry, 2003; Pugh, 1973].  Because the clinical and 
biochemical criteria of the Child-Pugh classification system (i.e., encephalopathy, 
elevated bilirubin, increased INR, decreased albumin) are not specific only to 
liver disease, participants enrolled into the hepatic impairment cohorts must also 
exhibit clinical evidence of chronic liver disease and/or cirrhosis. This additional 
inclusion criteria will help to ensure the desired study population is recruited.
5.5.
Dose Justification
A single, oral 6 mg dose of daprodustat is planned to be used in this study.  This dose of 
daprodustat can be given by a single tablet, provides sufficient plasma levels for well-
defined pharmacokinetics and margins for potential increases in daprodustat exposure in 
hepatic impaired population.
The 6 mg dose is currently being evaluated in Phase 3 trials as well as doses up to 24 mg. 
As the PK of daprodustat is linear with dose, effects of hepatic impairment observed at 
6 mg can be extrapolated to the higher clinical doses.
Overall, single, oral doses of up to 150 mg administered to HD CKD participants and 
doses up to 500 mg administered to healthy participants has been generally well tolerated 
and no new safety concerns have been identified (GSK studies PHI112843 and 
PHI113635, respectively).
In the event that the 6 mg dose proves to be poorly tolerated by the study population, the 
dose of daprodustat may be reduced for participants yet to be enrolled.

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6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
6.1.1.
Inclusion Criteria for All Participants
AGE
1. Participant must be at least 18 years of age inclusive, at the time of signing the 
informed consent.
MEDICAL CONDITIONS
2. Hemoglobin values at screening ≤16.0 g/dL for males and ≤14.0 g/dL for females.
WEIGHT
3. Body weight 45 kg and body mass index (BMI) within the range 18-40 kg/m2
(inclusive).
SEX
4. Male or female
Female participants: A female participant is eligible to participate if she is not 
breastfeeding, and at least one of the following applies:
(i)
Not pregnant as confirmed by two pregnancy tests (see Section 9.5.5)
(ii)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 6
(iii)
For WOCBP that are currently utilizing a highly-effective contraceptive 
method prior to enrolment, agrees to follow the contraceptive guidance in 
Appendix 6 during the treatment period to the follow-up visit.  (Additional 
guidance can be found in Section 9.5.5.)
INFORMED CONSENT
5. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 

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protocol.
6.1.1.1.
Additional Inclusion Criteria for Hepatically-Impaired Participants
MEDICAL CONDITIONS
1. Part 1 Participants with Moderate Hepatic Impairment Only (Cohort 1): Is 
considered to have moderate hepatic impairment (of any etiology) and has been 
clinically stable for at least 1 month prior to screening.  To be classified as having 
moderate hepatic impairment, participants must have a Child-Pugh (Class B) 
score of 7-9 AND previous confirmation of liver cirrhosis by liver biopsy or other 
medical imaging technique (including laparoscopy, computerized tomography
(CT) scan, magnetic resonance imaging (MRI) or ultrasonography) associated 
with an unambiguous medical history (such as evidence of portal hypertension).
2. Part 2 Participants with Mild OR Severe Hepatic Impairment Only (Cohort 
3; if conducted): Is considered to have mild or severe hepatic impairment (of any 
etiology) and has been clinically stable for at least 1 month prior to screening.  To 
be classified as having mild OR severe hepatic impairment, participants must 
have:
(i)
Be classified as having mild hepatic impairment, participants must have a Child-
Pugh (Class A) score of 5-6 AND previous confirmation of chronic liver disease 
by liver biopsy or other medical imaging technique (including laparoscopy, CT 
scan, MRI or ultrasonography) associated with an unambiguous medical history 
(such as evidence of portal hypertension).
(ii)
Be classified as having severe hepatic impairment, participants must have Child-
Pugh (Class C) score of 10-13 AND previous confirmation of chronic liver 
disease by liver biopsy or other medical imaging technique (including 
laparoscopy, CT scan, MRI or ultrasonography) associated with an unambiguous 
medical history (such as evidence of portal hypertension).
3. Supplemental inclusion criteria for ALL hepatically-impaired participants:
Chronic (>6 months), stable (no acute episodes of illness due to deterioration in 
hepatic function within the previous 1 month prior to screening) hepatic 
impairment due to any etiology.  Participants must also remain stable throughout 
the Screening period.  Assessment of the stability of the participant’s hepatic 
function will be determined by the investigator.
6.1.1.2.
Additional Inclusion Criteria for Healthy Control Participants
AGE
1. Healthy control participants will be matched for age ±10 years to participants in 
the respective hepatic impairment cohort but must also be at least 18 years of age 
inclusive, at the time of signing the informed consent.

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MEDICAL CONDITIONS
2. Healthy as determined by the investigator or medically qualified designee based 
on a medical evaluation including medical history, physical examination, 
laboratory tests and cardiac monitoring.
3. A participant with a clinical abnormality or laboratory parameter(s) which is/are 
not specifically listed in the inclusion or exclusion criteria, outside the reference 
range for the population being studied may be included only if the investigator 
and/or the Medical Monitor agree and document that the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures.
WEIGHT
4. Healthy control participants will be matched for BMI ±15% to participants in the 
respective hepatic impairment cohort but must also remain in the range of body 
weight ≥45 kg and body mass index (BMI) within the range 18-38 kg/m2
(inclusive).
6.2.
Exclusion Criteria
6.2.1.
Exclusion Criteria for All Participants
Participants are excluded from the study if any of the following criteria apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY
1. QTcF >500 msec
NOTES:

The QTc must be the QT interval corrected for heart rate according to 
Fridericia’s formula (QTcF).

For purposes of data analysis, QTcB will be used as specified in the Reporting 
and Analysis Plan (RAP).
2. Recent history of deep vein thrombosis, pulmonary embolism or other thrombosis 
related condition. Any prior medical history in these areas will be reviewed and 
approved by the PI and the sponsor’s Medical Monitor on a case by case basis as 
needed.
3. Myocardial infarction or acute coronary syndrome, stroke or transient ischemic 
attack within the 12 weeks prior to enrollment.
4. Participants with a pre-existing condition (other than liver disease) interfering 
with normal gastrointestinal anatomy or motility that could interfere with the 
absorption, metabolism, and/or excretion of daprodustat.  Examples of conditions 

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that could interfere with normal gastrointestinal anatomy or motility can be found 
in the SRM.
5. Participants that have undergone cholecystectomy within the past 3 months.
6. Participants with chronic inflammatory joint disease (e.g., scleroderma, systemic 
lupus erythematosis, rheumatoid arthritis).
7. History of malignancy within the prior 2 years or known kidney mass >3cm (end-
stage renal disease patients only) OR currently receiving treatment for cancer, 
Note:  ONLY exception is localized squamous cell or basal cell carcinoma of the 
skin definitively treated 12 weeks prior to enrollment.
8. Class IV heart failure, as defined by the New York Heart Association (NYHA) 
functional classification system.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
9. Current enrolment or past participation (i.e., administration of last dose of 
investigational study treatment) within the last 30 days (or 5 half-lives, whichever 
is longer) before Day 1 in this or any other clinical study involving an 
investigational study treatment or any other type of medical research.
6.2.1.1.
Additional Exclusion Criteria for Hepatically-Impaired Participants
CONCURRENT CONDITIONS/MEDICAL HISTORY
1. Presence of 8 times ULN elevations in AST, ALT, or bilirubin.
2. Participants with any other medical condition which, in the judgment of the 
investigator and Medical Monitor, could jeopardize the integrity of the data 
derived from that participant or the safety of the participant.
3. Participants with advanced ascites (Grade 3).
4. Participants with refractory encephalopathy as judged by the investigator or 
significant Central Nervous System (CNS) disease (e.g., dementia, or seizures) 
which the investigator considers will interfere with the informed consent, conduct, 
completion, or results of this trial or constitutes an unacceptable risk to the 
participant.
5. Participants with functional Transjugular Intrahepatic Portosystemic Shunt (TIPS) 
placement.
6. Presence of hepatopulmonary or hepatorenal syndrome.
7. Presence of primarily cholestatic liver diseases.
8. History of liver transplantation.
9. Participants with signs of active infection, including active spontaneous bacterial 
peritonitis.

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10. Participants with unstable cardiac function or participants with hypertension 
whose blood pressure is not controlled (based on the investigator’s discretion).
11. Diabetic participants whose diabetes is not controlled (based on the investigator`s 
discretion).
6.2.1.2.
Additional Exclusion Criteria for Healthy Control Participants
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
1. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
DIAGNOSTIC ASSESSMENTS
2. 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 treatment.
3. Positive pre-study drug/alcohol screen.
4. Positive human immunodeficiency virus (HIV) antibody test.
5. Regular use of known drugs of abuse.
6. Regular alcohol consumption within 6 months prior to the study defined as an 
average weekly intake of >14 drinks.  One drink is equivalent to 12 g of alcohol: 
12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 
80 proof distilled spirits.  One unit is equivalent to 8 g of alcohol: a half-pint 
(~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Participants will refrain from any food and drink (except water) at least 8 h before 
dosing and 4 h after dosing of any investigational product.
6.3.2.
Caffeine, Alcohol, and Tobacco

Participants will be instructed to limit ingesting caffeine- or xanthine-containing 
products (e.g., coffee, tea, cola drinks, chocolate) for 24 h prior to the start of dosing 
until collection of the final pharmacokinetic blood sample.

Participants will abstain from alcohol for 24 h prior to the start of dosing until 
collection of the final pharmacokinetic blood sample.

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
Participants will be instructed to limit use of nicotine and/or nicotine containing 
products.  Up to 10 cigarettes/day is acceptable.
6.3.3.
Activity
Participants will abstain from strenuous exercise for 48 h prior to each blood collection 
for clinical laboratory tests.  Participants may participate in light recreational activities 
during studies (e.g., watch television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Rescreening of individuals will be in consultation with the Medical 
Monitor.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Product name:
Daprodustat (GSK1278863)
Dosage form:
Tablet
Unit dose strength(s)/Dosage 
level(s):
6 mg tablet strength/6 mg dosage level
Route of Administration:
Oral
Physical description:
9.0 mm round, compound radius, white film coated tablets
Packaging and Labelling:
Study Treatment will be provided in a bottle.  Each bottle will be 
labelled as required per country requirement.
Manufacturer
GlaxoSmithKline

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7.2.
Dose Modification
As this is a single dose study, no dosage modification for a participant can occur.
However, in the event that the 6 mg dose proves to be poorly tolerated by the study 
population, the dose of daprodustat may be reduced for participants yet to be enrolled.
7.3.
Method of Treatment Assignment
All participants will receive the same treatment of a single oral 6 mg dose of daprodustat.
7.4.
Blinding
This will be an open label study.
7.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the 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 treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  A Material Safety Data Sheet 
(MSDS)/equivalent document describing occupational hazards and recommended 
handling precautions either will be provided to the investigator, where this is required 
by local laws, or is available upon request from GSK.
7.6.
Treatment Compliance
As participants are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment 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 treatment.  
Study site personnel will examine each participant’s mouth to ensure that the study 
treatment was ingested.

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7.7.
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 
enrolment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
All concomitant medications will be reviewed by the GSK Medical Monitor and may be 
considered on a case by case basis.  A concomitant medication may be permitted by the 
GSK Medical Monitor if it will not jeopardize the interpretation of the data derived from 
that participant or the safety of the participant.
7.7.1.
Permitted Medications and Non-Drug Therapies
Acetaminophen, at doses of 2 g/day, is permitted for use any time during the study.  
Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the Medical Monitor.  See Appendix 7 for a list of 
permitted contraceptive methods for WOCBP.
7.7.2.
Prohibited Medications and Non-Drug Therapies
Healthy matched control participants must abstain from taking prescription or non-
prescription drugs (including vitamins and dietary or herbal supplements) within 7 days 
(or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) 
before the start of study treatment until completion of the follow-up visit, unless, in the 
opinion of the investigator and sponsor, the medication will not interfere with the study.
Use of any of the following prescription drugs from 28 days prior to Day 1 until 7 days 
after the last dose of study treatment is prohibited and will constitute a protocol violation:

Strong inhibitors of CYP2C8 (e.g., gemfibrozil)

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
7.8.
Treatment after the End of the Study
Healthy control and hepatically-impaired participants will not receive any additional 
treatment from GSK after completion of the study.
For participants with hepatic impairment, the investigator is responsible for ensuring that 
consideration has been given to the post-study care of the participant’s medical condition.

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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests in the healthy control 
participant cohorts is required when:

a participant meets one of the conditions outlined in the algorithm;
OR

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the 
best interest of the participant.
The liver chemistry stopping criteria for healthy control participants can be found in 
Appendix 7.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

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
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
9.
STUDY ASSESSMENTS AND PROCEDURES
The following points must be noted:

If assessments are scheduled for the same nominal time, THEN the procedures 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws
NOTE: The timing of the assessments should allow the blood draw to occur as close 
as possible to the exact nominal time.

The timing and number of planned study assessments may be altered during the 
course of the study based on newly available data (e.g., to obtain data closer to the 
time of peak plasma concentrations) to ensure appropriate monitoring.

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 Informed Consent Form.

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

Study procedures and their timing are summarized in the SoA (Section 2).

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA
(Section 2), 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.
9.1.
Efficacy Assessments
Efficacy is not assessed in this study.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 5.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study (see Section 8).
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of treatment until the follow-up visit at the 
time points specified in the SoA (Section 2).  However, any SAEs assessed as related 
to study participation (e.g., study treatment, protocol-mandated procedures, invasive 
tests, or change in existing therapy) or related to a GSK product will be recorded from 
the time a participant consents to participate in the study.

All AEs will be collected from the start of treatment until the follow-up visit at the 
time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after obtaining
informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the 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 Section 12.5 Appendix 
5. 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 in former study 
participants. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in Appendix 
5.

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9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non serious AEs of special 
interest (as defined in Section 9.2.4), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 6.
9.2.4.
Adverse Events of Special Interest (AESI)
Adverse Events of Special Interest (AESI) have been identified based on non-clinical 
studies with daprodustat, clinical experience with recombinant, human erythropoietins
(rhEPOs), and current information regarding HIF-regulated pathways in mediating 
hypoxia-associated pathophysiology.  The currently identified AESI for daprodustat are 
as follows:

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis

Death, MI, stroke, heart failure, thromboembolic events, thrombosis of vascular 
access

Cardiomyopathy

Pulmonary artery hypertension

Cancer-related mortality and tumor progression and recurrence

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization

Exacerbation of rheumatoid arthritis
9.2.5.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study treatment under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

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.

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
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information e.g., summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.2.6.
Cardiovascular and Death Events
For any cardiovascular events listed below and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the electronic CRF
(eCRF) will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.7.
Possible Suicidality Related Adverse Events
If during the study there is an occurrence of an AE or SAE which in the investigator’s 
opinion, is possibly related to suicidality, the Possible Suicidality Related Adverse Events 
(PSRAE) eCRF form should be completed (in addition to the AE and SAE pages, as 
appropriate).
This event may include, but is not limited to, one that involves suicidal ideation, a 
preparatory act toward imminent suicidal behavior, a suicide attempt, or a completed 
suicide. The investigator will exercise his or her medical and scientific judgment in 
deciding whether an event is possibly related to suicidality.
9.2.8.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until the follow-up visit.

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
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 6.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
9.3.
Treatment of Overdose
For this study, any dose of daprodustat greater than 6 mg within a 24-h time period will 
be considered an overdose.  There is no specific antidote for overdose with daprodustat. 
The expected manifestations of daprodustat overdosage include signs and symptoms 
associated with an excessive and/or rapid increase in Hgb concentration.
In the event of a suspected overdose, it is recommended that the appropriate supportive 
clinical care be instituted, as dictated by the participant’s clinical status. Additionally, 
participants should be monitored closely for CV events, increased heart rate and 
hematologic abnormalities.
9.4.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
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 6.
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and was performed 
within the time frame defined in the SoA (Section 2).
9.5.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).
9.5.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, gastrointestinal and neurological systems. Height 
and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.

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9.5.2.
Vital Signs

Oral temperature, pulse, respiratory rate, and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed in a seated position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.

Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell 
phones).

Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 
pulse and 3 blood pressure measurements (3 consecutive blood pressure readings will 
be recorded at intervals of at least 1 minute). The average of the 3 blood pressure 
readings will be recorded on the CRF.
9.5.3.
Electrocardiograms

ECG measurements will be obtained as outlined in the SoA (Section 2)  Full 12-lead 
ECGs will be recorded with theparticipant 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, two additional ECGs are required if 
the initial ECG measurement indicates prolonged QTc (see Section 6.1) using the 
automated or manually calculated QTcF value.  The average QTcF value of all three 
ECGs will be used to determine eligibility.
9.5.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 3 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 2) for the timing and frequency.

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or at the follow-up visit should be repeated until the values 
return to normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 3, must be 
conducted in accordance with the laboratory manual and the SoA.

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9.5.5.
Pregnancy Testing
In this study, participants will have a drug exposure duration of <5 days including dosing 
plus 5 half-lives and dosing will occur in an inpatient setting.  Given this scenario, 
pregnancy risks are effectively mitigated by adequately ruling out pregnancy at the time 
of dosing.  Thus, it is not necessary to require participants to start a new contraceptive 
method if they are not already established on one.  To ensure capture of women of 
childbearing potential in this category who may have conceived but are just shy of being 
able to identify the pregnancy with current detection methods, it is recommended that two 
pregnancy tests are done in a short time span.
Therefore, for WOCBP that are not currently utilizing a highly-effective contraceptive 
method listed in Appendix 6, a negative pregnancy test on or between Day -7 to Day -4 
and again pre-dose (Day -1 or Day 0) is required.  WOCBP who are already using a 
highly effective contraceptive method listed in Appendix 6 (<1% failure rate per year 
when used consistently and correctly) should continue this method until the follow-up 
visit at a minimum.  In this case, a negative screening test within 28 days of dosing and 
again pre-dose (Day -1 to Day 0) is sufficient and the additional Day -7 to -4 test is not 
needed.
9.6.
Pharmacokinetics
9.6.1.
Blood sample collection
Blood samples for PK analysis of daprodustat and six predominant metabolites 
(GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), 
GSK2531398 (M6), GSK2531401 (M13) will be collected at the time points indicated in 
the SoA (Section 2).  The actual date and time of each blood sample collection will be 
recorded.  The timing of PK samples may be altered and/or PK samples may be obtained 
at additional time points to ensure thorough PK monitoring.
Additional blood samples will be collected for the assessment of protein binding for 
daprodustat at the timepoints in the SoA (Section 2).
Details of PK and protein binding blood sample collection (including volume to be 
collected), processing, storage and shipping procedures are provided in the SRM.
9.6.2.
Sample Analysis
Pharmacokinetic plasma analysis will be performed under the management of 
Bioanalytical Science and Toxicokinetics, Platform Technology & Science (PTS) Drug 
Metabolism & Pharmacokinetics (DMPK), GSK.  Concentrations and plasma protein 
binding of daprodustat and concentrations only of six predominant metabolites
(GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), 
GSK2531398 (M6), GSK2531401 (M13)) will be determined in samples using the 
currently approved analytical methodology.  Raw data will be stored in the archives at the 
site of bio-analysis.

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9.7.
Pharmacodynamics
Venous blood samples will be collected for measurement of plasma erythropoietin at the 
timepoints specified in the SoA (Section 2).  Details of pharmacodynamics (PD) blood 
sample collection (including volume to be collected), processing, storage and shipping 
procedures are provided in the SRM.
9.8.
Genetics
Genetics is not assessed in this study.
9.9.
Biomarkers
Biomarkers are not assessed in this study.
9.10.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
No formal hypotheses will be tested.  An estimation approach will be used to evaluate the 
effect of hepatic impairment (i.e., moderate and potentially either mild or severe) on the 
PK of daprodustat.  The comparisons of interest are the single dose PK parameters Cmax 
and AUC of daprodustat in each hepatic impaired cohort compared to the normal hepatic 
function cohort.
The point estimates of the geometric least squares (GLS) mean ratio for the PK 
parameters and associated 90% confidence intervals will be provided for cohort 
comparisons (hepatically impaired:healthy participants).  The PK parameters will be log-
transformed prior to analysis and cohort comparisons will be expressed as ratios on the 
original scale.  %AUCex and tmax and will be summarized descriptively.
10.2.
Sample Size Determination
10.2.1.
Sample Size Assumptions
The FDA Guidance for Industry “Pharmacokinetics in Patients with Impaired Hepatic 
Function: Study Design, Data Analysis, and Impact on Dosing and Labelling” 
recommends that a sufficient number of participants should be enrolled to provide 
evaluable data from at least eight participants in the control and moderate impairment 
groups. A sample size of eight evaluable participants per cohort was selected based upon 
this recommendation.

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Based on the recent GSK study PHI115573, the between participant CV (CVb) for 
AUC(0-inf) and Cmax of daprodustat (5 mg) is 41.9% (SD = 0.402) and 28.3% (SD = 
0.278) respectively from proc mixed model. Based on these estimates of CVb and a 
sample size of 8 in each cohort, it is estimated that the half width of the 90% confidence
interval will be 43% and 28% of the point estimates for AUC and Cmax, respectively. 
These calculations are based on the loge scale. If the point estimate of the ratio of 
geometric means is 1, then the 90% confidence interval will be approximately (0.70, 
1.43) and (0.78, 1.28) for AUC and Cmax, respectively.
10.2.2.
Sample Size Sensitivity
Table 3 shows the precision and 90% CI for a sample size of 8 in each group based on the 
observed SD in studies conducted among healthy and renal impairment participants.
Table 3
Precision and 90% CI Estimates
Study
Dose
Population
Parameter
SD
Precision
90% CI
PHX111427
5 mg
Healthy
AUC(0-inf)
0.362
38%
(0.73, 1.38)
Cmax
0.361
38%
(0.73, 1.38)
PHI112843
50 mg
Renal 
Impaired
AUC(0-inf)
0.294
30%
(0.77, 1.30)
Cmax
0.159
15%
(0.87, 1.15)
PHI112843
50 mg
Healthy
AUC(0-inf)
0.148
14%
(0.88, 1.14)
Cmax
0.109
11%
(0.90, 1.11)
10.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
10.3.
Data Analysis Considerations
10.3.1.
Analysis Populations
10.3.1.1.
Enrolled Population
All participants who were enrolled for the trial irrespective of whether they were 
randomized or not and for whom a record exist on the study database. This population 
will be used for summarizing screening failure reasons.
10.3.1.2.
Safety Population
All participants who received at least one dose of study medication. This will be the 
primary population for the safety analyses.

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10.3.1.3.
Pharmacokinetic Population
All participants in the ‘Safety’ population for 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.
10.3.2.
Interim Analysis
An interim analysis of the primary endpoint will be conducted following completion of 
Part 1 of the study, with possible progression to Part 2 based on the following criteria:

If a < 2-fold change in daprodustat exposure (AUC) is observed in participants with 
moderate hepatic impairment, the study may enrol participants with severe hepatic 
impairment and a healthy, matched control group.

If a ≥2-fold change in daprodustat exposure (AUC) is observed in participants with 
moderate hepatic impairment, the study may enrol participants with mild hepatic 
impairment and a healthy, matched control group.
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail.
10.4.
Key Elements of Analysis Plan
Final analyses will be performed after the completion of the study and final dataset 
authorization.
Data will be listed and summarized separately for each part of the study according to 
GSK reporting standards where applicable.  Listings will be sorted by participant, period, 
day, and time, noting treatment.  Summaries will be presented by treatment, day and 
time.
Unless stated otherwise, descriptive summaries for continuous variables will include n, 
mean, standard deviation (SD), coefficient of variation for the mean (%CV), median, 
minimum, maximum, geometric mean with associated 95% confidence interval (CI), and 
the between-participant CV (%CVb) for the geometric mean; whereas, n and percent will 
be used as summary statistics for categorical variables.
Baseline or pre-dose assessment is the last available assessment prior to time of the first 
dose unless it is specified otherwise.  If there are multiple assessments collected on the 
same scheduled time, the average of these assessments will be used.  For tabulated safety 
summaries, only the scheduled assessments will be included in the summary tables.
Version 9.4 or higher of the SAS system will be used to analyze data as well as to 
generate tables, listings, and figures.
Complete details will be documented in the Reporting and Analysis Plan (RAP).

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10.4.1.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed under the direct auspices of the Clinical 
Pharmacokinetics Modeling & Simulation department (CPMS), GlaxoSmithKline.  
Plasma concentration-time data for daprodustat and its six predominant metabolites
(GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), 
GSK2531398 (M6), GSK2531401 (M13)) will be analyzed by non-compartmental 
methods with WinNonlin version 5.22 or higher.  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, as data permit: maximum 
observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma 
concentration-time curve [AUC(0-t) and AUC(0-∞)], and apparent terminal phase half-
life (t½).
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively.  All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D.
Figures for individual plasma concentrations will be presented on both a linear and semi-
log scale daprodustat and its six predominant metabolites.  Linear and semi-log figures 
for mean and median plasma concentrations versus time will also be generated.
For each of the derived PK parameters of daprodustat and its six predominant 
metabolites, the following summary statistics will be calculated for each cohort: n 
(number of observations), arithmetic mean, standard deviation, median, minimum, 
maximum, and the 95% confidence interval of arithmetic mean.
In addition, summary statistics for log-transformed PK parameters of daprodustat and its 
six predominant metabolites [i.e., AUC(0-t), AUC(0-∞), Cmax, and t½],except tmax will 
include geometric mean, 95% confidence interval of the geometric mean, standard 
deviation of the logarithmically transformed data, and inter-participant coefficient of 
variation [CVb (%)].
The inter-participant CV [CVb (%)] will be calculated according to the following 
method:
Loge Transformed Data:
CVb(%) = SQRT(exp(SD2) – 1) x 100
where SD is the standard deviation on the loge scale.
Unbound fraction (fu) will be calculated using the total and unbound plasma 
concentration of daprodustat generated at 3, 12 and 24 h post dose for both normal and 
hepatic impaired participants using the following formula:
fu = Cunbound/Ctotal
where Cunbound and Ctotal are the unbound and total concentrations of daprodustat in 
plasma, respectively.

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Full details of the analysis will be provided in the RAP.
10.4.1.1.
Statistical Analysis of Pharmacokinetic Parameters
Statistical analyses of the pharmacokinetic parameter data will be performed under the 
direct auspices of Quantitative Sciences India, GSK.
For each log-transformed PK parameter (expect %AUCex and tmax), point estimate and 
its associated 90% CI will be constructed for the cohort (hepatically impaired – healthy 
participants) difference. The results will be exponentiated to obtain the ratio of GLS
means and its 90% CI.
As data permit, tmax will be analyzed non-parametrically using the Wilcoxon Rank Sum 
Test. The point estimates and 90% confidence intervals for the median differences will 
be calculated for the cohort difference (hepatically impaired – healthy participants).
Distributional assumptions underlying the statistical analyses will be assessed by visual 
inspection of residual plots.  Normality will be examined by normal probability plots, 
while homogeneity of variance will be assessed by plotting the residuals against the 
predicted values for the model.
A sensitivity analysis will be performed for log transformed PK parameters (except 
%AUCex and tmax) by analysis of covariance (ANCOVA) including terms cohort, 
gender, age and BMI. For each PK parameter, a point estimate and an associated 90% 
confidence interval (CI) will be constructed for the difference between participants with
hepatic impairment and healthy participants. The results will be exponentiated to obtain
the ratio of GLS means and its 90% CI.
Further details of analysis and reporting of PK data will be given in the RAP.
10.4.2.
Pharmacodynamic Analyses
Pharmacodynamic data will be presented in graphical and/or tabular form and will be 
summarized descriptively.
Descriptive statistics, where appropriate, (n, arithmetic mean, geometric mean, standard 
deviation, minimum, median and maximum) will be calculated for the pharmacodynamic 
endpoints.
10.4.3.
Safety Analyses
All safety analyses will be performed on the Safety Population. Safety data will be 
presented in tabular and/or graphical format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards.

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11.
REFERENCES
Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The liver 
and portal hypertension. Philadelphia: Saunders, 1964:50-64.
Committee for medicinal products for human use (CHMP): Guideline on the evaluation 
of the pharmacokinetics of medicinal products in patients with impaired hepatic function. 
February 2005.
FDA Guidance for Industry: Pharmacokinetics in patients with impaired hepatic function: 
Study design, data analysis, and impact on dosing and labelling. May 2003. 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
064982.htm
Holdstock L, Meadowcroft AM, Maier R, Johnson BM, Jones D, Rastogi A, Zeig S, 
Lepore JJ, Cobitz AR. Four-week studies of oral hypoxia-inducible factor-prolyl 
hydroxylase inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol. 2016; 
27:1234-1244.
Johnson BM, Stier BA, Caltabiano S. Effect of food and gemfibrozil on the 
pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863. Clin 
Pharmacol in Drug Devel. 2013;3:109-117.
Pfeffer MA, Burdmann EA, Chen C-Y, Cooper ME, de Zeeuw D, Eckart K-U, Feyzi JM, 
Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJV, Parfrey 
P, Parving H-H, Remuzzi G, Singh AJ, Solomon, SD, Toto R. A trial of darbepoetin alfa 
in Type 2 diabetes and chronic kidney disease. N Eng J Med. 2009; 361:2019-2032.
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973; 60:646-649.

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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Table 4
List of Abbreviations
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase (SGPT)
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the concentration-time curve
BCRP
Breast Cancer Resistance Protein
BMI
Body mass index
BUN
Blood urea nitrogen
CI
Confidence Interval
CKD
Chronic kidney disease
CIOMS
Council for International Organizations of Medical Sciences
Cmax
Maximum observed concentration
CNS
Central nervous system
CPK
Creatine phosphokinase
CONSORT
Consolidated Standards of Reporting Trials
CPMS
Clinical Pharmacokinetics Modeling & Simulation
CRF
Case Report Form
CPSR
Clinical study report
CT
Computerized tomography
Ctotal
Total concentration
Cunbound
Unbound concentration
CV
Cardiovascular
CVb
Between participant coefficient of variability
CYP
Cytochrome P450 enzyme
dL
decilitre
DMPK
Drug Metabolism & Pharmacokinetics
ECG
Electrocardiogram
ECHO
Echocardiographic
eCRF
Electronic Case Report Form
E,last
Last measurable concentration
Emax
Maximum observed effect
EPO
Erythropoietin
ex
Extrapolation
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
fu
Unbound fraction
g
Gram
GCP
Good Clinical Practice
GI
Gastrointestinal

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GLS
Geometric least squares
GSK
GlaxoSmithKline
h
Hour
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HD
Hemodialysis dependent
Hgb
Hgb
HIF
Hypoxia-inducible factor
HIV
Human Immunodeficiency Virus
HIPAA
Health Insurance Portability and Accountability Act
HPLC
High performance liquid chromatography
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICF
Informed Consent Form
IDSL
Integrated Data Standards Library
IEC
Independent ethics committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IND
Investigational new drug
INR
International normalization ratio
IP
Investigational product
IRB
Institutional Review Board
IU
International units
IUD
Intrauterine device
IUS
Intrauterine system
kg
Kilogram
LDH
Lactate dehydrogenase
LVEF
Left ventricular ejection fraction
MCH
Mean corpuscular Hgb
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
MI
Myocardial infarction
mL
Milliliter
mm
Millimeter
mmHg
Millimeters of mercury
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
msec
Milliseconds
μM
Micromolar
n
Number
ND
Nondialysis dependent
NOAEL
No observed adverse effect level

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NYHA
New York Heart Association
OATP
Organic anion transporting polypeptide
PAH
Pulmonary artery hypertension
PCI
Potential clinical importance
PD
Pharmacodynamic
%CV
Coefficient of variation of the mean
PHD
prolyl-4-hydroxylases
PK
Pharmacokinetic
PPD
Pharmaceutical Product Development
PRVP
Peak right ventricular pressure
PSRAE
Possible Suicidality Related Adverse Events
PTS
Platform Technology & Science
QTc
Corrected QT interval
QTcB
QT duration corrected for heart rate by Bazett’s formula
R&D
Research and development
RAP
Report and Analysis Plan
RBC
Red blood cells
rh
Recombinant human
RNA
Ribonucleic acid
SAE
Serious Adverse Event(s)
SD
Standard deviation
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SoA
Schedule of Activities
sPAP
systolic Pulmonary Artery Pressure
SRM
Study Reference Manual
SUSAR
Suspected unexpected serious adverse reactions
t½
Half life
TIPS
Transjugular Intrahepatic Portosystemic Shunt
Tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
UK
United Kingdom
µM
Micromolar
VEGF
Vascular endothelial growth factor
WBC
White blood cells
WOCBP
Woman of childbearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ADVAIR
Chiron RIBA
SAS
WinNonlin

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12.2.
Appendix 2: Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Excessive erythropoiesis (polycythemia) 
leading to thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis 
attributed to daprodustat was associated 
with vascular congestion, microthrombi, and 
tissue ischemia in a number of organs.
Phase 2 dose-ranging studies, and associated 
statistical and dose response modelling has 
informed Phase 3 dose rationale, starting 
doses, dose steps, and dose adjustment 
scheme to optimize Hgb management.
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat.

Specific eligibility criteria related to 
requirements for entry Hgb are detailed 
in Section 6.1.1

Monitoring of emerging safety data by 
an internal GSK Safety Review Team.
Death, MI, stroke, heart failure, 
thromboembolic events, thrombosis of 
vascular access at Hgb levels which are 
within the normal range (i.e. not 
polycythemic conditions)
Marketed rhEPOs have been associated with 
an increased risk for death and serious 
cardiovascular events when used in patients 
with anemia of CKD.
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat.

Specific eligibility criteria related to CV 
risk are outlined in Section 6.2.1.

Monitoring of emerging safety data by 
an internal GSK Safety Review Team.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Esophageal and gastric erosions
In animal studies, undesirable GI effects 
including emesis, abnormal feces and/or 
decreased food consumption/body weight 
loss and stomach erosions/ulcers with 
hemorrhage were observed with 
daprodustat.
In rodents stomach erosions were observed 
with intravenous and oral administration of 
daprodustat.
Gender-averaged systemic exposure (AUC) 
at the no observed adverse effect levels 
(NOAEL) are 3.3 -fold (monkeys) and 737 -
fold (rats) above human exposure (25 mg 
daprodustat).
In clinical trials to date with daprodustat, 
mild-moderate GI signs and symptoms 
represent the most frequently reported 
adverse event, however causal association 
has not been established.
Following review of clinical data received 
to date, GI erosions have not been identified 
as a safety concern for daprodustat.

Suspected GI bleeding or significant 
symptoms consistent with erosions or 
ulcers should be investigated 
diagnostically (i.e. endoscopic 
examination) as clinically warranted.

Monitoring of emerging safety data by 
an internal GSK Safety Review Team.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cancer-related mortality and tumor 
progression and recurrence
Marketed rhEPOs have been associated with 
increased risk of cancer related morbidity 
and mortality when used in patients with 
cancer.
Administration of 60 mg/kg daprodustat to 
mice caused minimal increases in 
circulating VEGF while significant EPO 
increases were observed.
In clinical studies conducted to date , 
administration of daprodustat has been 
associated with:

In studies up to 4 weeks duration, a 
dose-ordered increase in VEGF plasma 
concentrations was observed at doses 
ranging from 10 to 150 mg.  In studies 
up to 24 weeks duration at doses up to 
25 mg, changes in VEGF plasma 
concentrations were variable but similar 
relative to control.

Systemic EPO concentrations within the 
physiologic range
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat.

Specific eligibility criteria related to 
personal history of malignancy are 
outlined in Section 6.2.1.

Monitoring of emerging safety data by 
an internal GSK Safety Review Team.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Pulmonary artery hypertension (PAH)
A role for HIF-regulated pathways in the 
pathophysiology of PAH has been 
suggested based on well-established effects 
of acute and chronic hypoxia in man on the 
pulmonary vasculature (vasoconstriction), 
and by findings in patients with naturally 
occurring mutations that result in decreased 
HIF degradation [Smith, 2006; Formenti, 
2011].
There have been no histopathologic findings 
suggestive of PAH in pre-clinical safety 
studies with daprodustat (up to 13 weeks 
duration in mice and dog, up to 26 weeks in 
rat, and up to 39 weeks in monkeys.
Acute hypoxic challenge (rats):  
Daprodustat produced increases in peak 
right ventricular pressure (PRVP) during 
acute hypoxia that were slightly higher than 
the vehicle control group.  These hypoxia-
induced PRVP changes fall within the range 
of PRVP differences noted among non-
treated rats.
Results from a clinical study of acute 
hypoxic challenge in healthy volunteers 
demonstrated that short-term (5 days) 
therapy with daprodustat 5 mg or 100 mg 
had no clinically significant effect on 

Monitoring of emerging safety data by 
an internal GSK Safety Review Team.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
transthoracic Echocardiographic (ECHO)
estimates of systolic pulmonary artery 
pressure (sPAP) under either normoxic or 
hypoxic conditions.
ECHO assessments performed in Phase 2b 
studies (24 weeks treatment duration) did 
not identify any clinically-meaningful 
changes in sPAP in participants not on 
dialysis for daprodustat.  In hemodialysis 
participants, mean absolute change from 
baseline in sPAP was similar for both 
treatment groups; however, there was a 
numeric imbalance (Daprodustat: 8 [7%]; 
Control 0) in participants reaching the sPAP 
PCI (>20 mmHg increase from baseline).  
Regarding this imbalance, there were a 
number of confounding factors in the study, 
most notably a 4.5:1 randomization scheme 
and inconsistency in timing of ECHOs 
relative to dialysis day.  Additionally, 2 of 3 
participants with resolution of sPAP on 
safety follow-up ECHOs had confounding 
conditions that could contribute to 
resolution other than discontinuation of 
study treatment; and there was no dose 
relationship for participants meeting the 
sPAP potential clinical importance (PCI)
criterion.  Overall, there is insufficient 
evidence to conclude a relationship to 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
treatment with daprodustat.
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat.
Cardiomyopathy
Published data suggest that cardiac effects 
of HIF stabilization are likely a function of 
the mechanism, extent, and duration of the 
effects, and can range from protective to 
detrimental depending upon the specific 
model and experimental conditions utilized.
Small increases in cardiac troponin in 6 
month rat study with daprodustat were 
consistent with the background finding of 
spontaneous rodent cardiomyopathy
independent of exposure to daprodustat.  
There were no elevations observed in 
cardiac troponin in 9 month monkey study 
with daprodustat.
Cardiomyopathy has not been associated 
with naturally occurring mutation in man 
which results in increased HIF stabilization.
ECHO assessments performed in phase 2b 
studies (24 weeks treatment duration) did 
not identify any clinically meaningful 
changes in LVEF for daprodustat.

Monitoring of emerging safety data by 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat.
Proliferative retinopathy, macular edema, 
choroidal neovascularization
Increases in local (ocular) VEGF production 
with retinal neovascularization and macular 
edema observed in diabetic retinopathy and 
to choroidal leakage, edema and 
neovascularization seen in age-related 
macular degeneration [Campochiaro, 2006].
Administration of 60 mg/kg daprodustat to 
mice caused minimal increases in 
circulating VEGF while significant EPO 
increases were observed.
No ocular abnormalities with daprodustat 
were seen in non-clinical studies of up to 13 
weeks duration in mice and dogs, 26 weeks 
in rats, and 39 weeks in monkeys.
In clinical studies up to 4 weeks duration, a 
dose-ordered increase in VEGF plasma 
concentrations was observed at doses 
ranging from 10 to 150 mg.  In studies up to 
24 weeks duration at doses up to 25 mg, 
changes in VEGF plasma concentrations 
were variable but similar relative to control.
Ophthalmologic assessments performed in 
phase 2b studies (24 weeks treatment 

Suspected proliferative retinopathy, 
macular edema, choroidal 
neovascularization or symptoms 
consistent with these events should be 
investigated by ophthalmologic 
consultation as clinically warranted.

Monitoring of emerging safety data by 
an internal GSK Safety Review Team.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
duration) did not identify any clinically 
meaningful changes in proliferative 
retinopathy, macular edema, or choroidal 
neovascularization with daprodustat.
Following review of clinical data with 
daprodustat received to date, this has not 
been identified as a safety concern for 
daprodustat.
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of 
HIF-related genes secondary to decreased 
oxygen and pro-inflammatory cytokines has 
been postulated to contribute to the neo-
angiogenesis, proliferation and infiltration 
of rheumatoid synovial fibroblasts [Westra
2010; Muz, 2009].
No abnormalities seen in non-clinical 
studies conducted to date for daprodustat.
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat.

Monitoring of emerging safety data by 
an internal GSK Safety Review Team.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Drug-drug interactions
Co-administration of daprodustat with the 
strong CYP2C8 inhibitor, gemfibrozil 
increased the Cmax and AUC of 
daprodustat, 4- and 19-fold, respectively, 
while co-administration of the weak 
inhibitor, trimethoprim increased the Cmax 
and AUC of daprodustat by 1.3- and 1.5-
fold, respectively.  Population PK analysis 
from completed Phase 2 studies suggests 
that co-administration of daprodustat with a 
moderate CYP2C8 inhibitor (clopidogrel) 
leads to a ~2-fold increase in AUC, with no 
clinically-significant increase in the
measured Hgb response.
Daprodustat is an inhibitor of CYP2C8 in 
vitro, with an IC50 value of 21 µM.
Population PK analysis from completed 
Phase 2 studies suggests that co-
administration of daprodustat with 
clopidogrel (a moderate CYP2C8 inhibitor) 
leads to a ~ 2-fold increase in AUC, with no 
clinically-significant increase in the 
measured Hgb response.
Co-administration of daprodustat with 
BCRP inhibitors has the potential to 
increase exposure of daprodustat.  Use of 
BCRP inhibitors was not a significant
covariate of daprodustat exposure, but was 

Co-administration of daprodustat with 
the strong CYP2C8 inhibitor, 
gemfibrozil and inducer, 
rifampin/rifampicin is not permitted as 
outlined in Section 7.7.2.

Co-administration of daprodustat with 
moderate CYP2C8 inhibitors (i.e., 
clopidogrel, teriflunomide, deferasirox) 
should be performed with caution.

Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in 
Section 7.7.

Monitoring of emerging safety data by 
an internal GSK Safety Review Team.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
found to result in a small change in 
metabolite exposure (20% increase in 
AUC).  Co-administration of daprodustat
with BCRP inhibitors [e.g., cyclosporine, 
HIV antivirals (atazanavir, lopinavir, 
ritonavir, tipranavir), lapatanib and 
curcumin] is not expected to produce 
clinically relevant increases in daprodustat 
exposure.
Daprodustat is an inhibitor of organic anion 
transporter polypeptide (OATP) 1B1/1B3 in 
vitro, with IC50 values of 6 µM and 11 µM, 
respectively.  A clinical drug interaction 
study between 100 mg daprodustat with 
either a CYP2C8 substrate or an 
OATP1B1/1B3 substrate showed that there 
is no PK interaction at this dose of 
daprodustat.
References
Campochiaro PA and the first ARVO/Pfizer Institute Working Group et al. Ocular versus extraocular neovascularization: Mirror images 
or vague resemblances. Invest Ophthalmol & Vis Sci. 2006; 47:462-474.
Formenti F, Beer PA, Croft QPP, Dorrington KL, Gale DP, Lappin TRJ, Lucas GS, Maher ER, Maxwell PH, McMullin MF, O’Connor 
DF, Percy MJ, Pugh CW, Ratcliffe PJ, Smith TG, Talbot NP, Robbins PA. Cardiopulmonary function in two human disorders of the 
hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2α gain-of-function mutation. FASEB J. 2011; 25:2001-
2011.

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Muz B, Khan MN, Kiriakidis S, Paleolog EM. The role of hypoxia and HIF-dependent signalling events in rheumatoid arthritis. Arthritis 
Research & Therapy 2009; 11:201-209.
Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Leedham DL, Liu C, Maxwell PH, Treacy M, Robbins PA. Mutations of 
von Hippel-Lindau tumour suppressor and heman cardiopulmonary physiology. PLos Med. 2006; 3:3290.
Westra J, Molema G, Kallenberg CG. Hypoxia-inducible factor-1 as regulator of angiogenesis in rheumatoid arthritis - therapeutic 
implications. Curr Med Chem. 2010; 17:254-63.

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12.3.
Appendix 3: Clinical Laboratory Tests

The tests detailed in Table 5 will be performed by the central laboratory.

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined
necessary by the investigator or required by local regulations.
Table 5
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Count
Hemoglobin
Hematocrit
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and 
direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose 
(nonfasting)
Calcium
Alkaline 
phosphatase
Albumin
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 

Follicle-stimulating hormone and estradiol (as needed in women of 

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Laboratory 
Assessments
Parameters
Tests
non-childbearing potential only)

Serum or urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)

Serum or urine human chorionic gonadotropin (hCG) pregnancy 
test2

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody) or specify other tests if applicable 

PT/INR
The results of each test must be entered into the CRF.
NOTES :
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Section 8.1 and Appendix 7 All events of ALT 3 × upper limit 
of normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international 
normalized ratio (INR) >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), 
must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).
2 Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.

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12.4.
Appendix 4: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, 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
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study 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. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.

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Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study 
participants, as appropriate.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, 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. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the 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 Pharmacology Study Report (CPSR)/ equivalent summary unless local 
regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.

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Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the 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.

Definition of what constitutes source data can be found in the SRM.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development

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12.5.
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, 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 

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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
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 

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jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording 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 sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.

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

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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 h.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the
relationship of each SAE to IP/study participation (causality) within 72 h 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 by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SRM.

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12.6.
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range is to be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female participants
Female participants of childbearing potential that are not currently utilizing a highly-
effective contraceptive method are eligible to participate if a pregnancy test conducted on 
or between Day -7 to Day -4 and again pre-dose (Day -1 or Day 0) is negative.  It is not 
necessary to require participants to start a new contraceptive method if they are not already 
established on one.
Female participants of childbearing potential that are currently utilizing a highly-effective 
contraceptive method are eligible to participate if they agree to continue to use this 
method consistently and correctly as described in Table 6.  In this instance a negative 

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pregnancy test on or between Day -7 to Day -4 and again pre-dose (Day -1 or Day 0) 
would not be required.
Table 6
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent1
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal

transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation2

injectable
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
1Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies.
2 Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the 
contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 48 h  after the last dose of study treatment 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test at the times listed in the SoA (Section 2)

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
Additional pregnancy testing is not required during the treatment period and at 48 h
after the last dose of study treatment

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected

Pregnancy testing, with a sensitivity of 2 mIU/mL will be performed using the test 
kit provided by the central laboratory.
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 h of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 6. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating will be withdrawn 
from the study.

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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
For the purposes of this protocol, please refer to the guidelines below for the required 
action, monitoring and follow-up assessments if a participant meets any of the criteria 
listed below, after dosing with the study medication.
Phase I liver chemistry stopping criteria and required follow up assessments for 
Healthy Volunteer Participants
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

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 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 

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, obtained 48 h of last dose4 

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

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

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Liver Chemistry Stopping Criteria 
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
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.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week
[James, 2009]

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.
Includes: 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.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos. 2009; 37:1779-1784.

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12.8.
Appendix 8:  Grades of Hepatic Encephalopathy
Grade
Description
1
Trivial lack of awareness, euphoria or anxiety; shortened attention span; impairment of 
addition or subtraction
2
Lethargy; disorientation for time; obvious personality changes; inappropriate beharior
3
Somnolence to semistupor; responsive to stimuli; confused; gross disorientation; 
bizarre behavior
4
Coma; unable to test mental state
References
Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL. 
Comparison of lactulose and neomycin in the treatment of chronic portalsystemic 
encephalopathy. A double-blind controlled trial. Gastroenterology. 1977; 72:573-583.

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TITLE PAGE 
Protocol Title: A Phase 1, open-label, non-randomized, parallel group, single-dose 
adaptive study in adults with hepatic impairment and matched, healthy control 
participants with normal hepatic function. 
Protocol Number: 200231 
Short Title: Daprodustat hepatic impairment study 
Compound Number: GSK1278863 
 
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 (SRM) 
Regulatory Agency Identifying Number(s): IND Number: 101,291 
Approval Date: 15-NOV-2017 
 
 
 
 
 
 
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorized copying or use of this information is prohibited. 

PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment  1 
15-NOV-2017 
Original Protocol 
23-May-2017 
 
Amendment 1 15-Nov-2017 

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Section # and 
Name 
Description of Change 
Brief Rationale 
1 Synopsis 
Chages as described in main 
protocol sections below 
As below.  
4. Objectives 
and Endpoints 
Second primary objective and 
associate endpoint adds 
daprodustat AND its metabolites to 
plasma protein binding and 
unbound concentration in plasma 
Secondary PD enpoint is revised 
to say Cmax, EPO instead of 
Emax; and specifies AUC(0-t, 
EPO) instead of AUC(last) 
For robustness of data in the hepatic 
impairment population, metabolite protein 
binding has been added 
 
 
Correction of PD endpoint to specify EPO 
 
5.1 Overall 
Design 
Part 1 adds metabolites to 
unbound daprodustat 
For robustness of data in the hepatic 
impairment population, metabolite protein 
binding has been added. 
 
5.4 Scientific 
Rationale for 
Study Design 
Adds metabolites to unbound 
fraction of daprodustat, and also to 
plasma protein binding 
For robustness of data in the hepatic 
impairment population, metabolite protein 
binding has been added. 
9.6.1. Blood 
sample 
collection 
Adds metabolites to protein 
binding assessement of 
daprodustat 
For robustness of data in the hepatic 
impairment population, metabolite protein 
binding has been added. 
9.6.2. Sample 
Analysis 
Changes responsible GSK 
department name from 
Bioanalytical Science and 
Toxicokinetics and Drug 
Metabolism & Pharmacokinetics 
(DMPK) to Bioanalysis, 
Immunogenicity and Biomarkers 
and In Vitro/In Vivo Translation 
 
Remove “concentrations only of” 
six predominant metabolites… 
Update of GSK responsible department 
names 
 
 
 
 
 
 
Updated to include protein binding of the 
six predominant metabolites 
10.3.1. Analysis 
Populations 
Enrolled and PK populations 
clarified; PD and Screened 
population descriptions added. 
Additional and clarifying summarizations 
have been added to Enrolled and PK 
population descriptions; PD and Screened 
have population descriptions have been 
added (previously omitted in error).  

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Section # and 
Name 
Description of Change 
Brief Rationale 
10.4.1. 
Pharmacokinetic 
Analyses 
Metabolites added to unbound 
plasma concentration of 
daprodustat and calculations 
For robustness of data in the hepatic 
impairment population, metabolite protein 
binding has been added 
12.1. Appendix 
1 Abbreviations 
and Trademarks 
Cmax, EPO added 
Clarification of abbreviation 
 
 

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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
SYNOPSIS ................................................................................................................. 9 
2. 
SCHEDULE OF ACTIVITIES (SOA) ........................................................................ 12 
3. 
INTRODUCTION ..................................................................................................... 14 
3.1. 
Study Rationale ............................................................................................ 14 
3.2. 
Background .................................................................................................. 15 
3.3. 
Benefit/Risk Assessment .............................................................................. 15 
3.3.1. 
Risk Assessment .......................................................................... 15 
3.3.2. 
Benefit Assessment ...................................................................... 15 
3.3.3. 
Overall Benefit:Risk Conclusion .................................................... 15 
4. 
OBJECTIVES AND ENDPOINTS ............................................................................ 16 
5. 
STUDY DESIGN ...................................................................................................... 16 
5.1. 
Overall Design .............................................................................................. 16 
5.2. 
Number of Participants ................................................................................. 18 
5.3. 
Participant and Study Completion ................................................................ 19 
5.4. 
Scientific Rationale for Study Design ........................................................... 19 
5.5. 
Dose Justification ......................................................................................... 20 
6. 
STUDY POPULATION ............................................................................................. 21 
6.1. 
Inclusion Criteria .......................................................................................... 21 
6.1.1. 
Inclusion Criteria for All Participants ............................................. 21 
6.1.1.1. 
Additional Inclusion Criteria for Hepatically-
Impaired Participants ................................................... 22 
6.1.1.2. 
Additional Inclusion Criteria for Healthy Control 
Participants .................................................................. 22 
6.2. 
Exclusion Criteria ......................................................................................... 23 
6.2.1. 
Exclusion Criteria for All Participants ............................................ 23 
6.2.1.1. 
Additional Exclusion Criteria for Hepatically-
Impaired Participants ................................................... 24 
6.2.1.2. 
Additional Exclusion Criteria for Healthy 
Control Participants ..................................................... 25 
6.3. 
Lifestyle Restrictions .................................................................................... 25 
6.3.1. 
Meals and Dietary Restrictions ..................................................... 25 
6.3.2. 
Caffeine, Alcohol, and Tobacco .................................................... 25 
6.3.3. 
Activity ........................................................................................... 26 
6.4. 
Screen Failures ............................................................................................ 26 
7. 
TREATMENTS ......................................................................................................... 26 
7.1. 
Treatments Administered ............................................................................. 26 
7.2. 
Dose Modification ......................................................................................... 27 
7.3. 
Method of Treatment Assignment ................................................................ 27 
7.4. 
Blinding ........................................................................................................ 27 
7.5. 
Preparation/Handling/Storage/Accountability ............................................... 27 
7.6. 
Treatment Compliance ................................................................................. 27 

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7.7. 
Concomitant Therapy ................................................................................... 28 
7.7.1. 
Permitted Medications and Non-Drug Therapies .......................... 28 
7.7.2. 
Prohibited Medications and Non-Drug Therapies ......................... 28 
7.8. 
Treatment after the End of the Study ........................................................... 28 
8. 
DISCONTINUATION CRITERIA .............................................................................. 29 
8.1. 
Discontinuation of Study Treatment ............................................................. 29 
8.1.1. 
Liver Chemistry Stopping Criteria ................................................. 29 
8.2. 
Withdrawal from the Study ........................................................................... 29 
8.3. 
Lost to Follow Up ......................................................................................... 29 
9. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................... 30 
9.1. 
Efficacy Assessments .................................................................................. 31 
9.2. 
Adverse Events ............................................................................................ 31 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .................................................................................... 31 
9.2.2. 
Method of Detecting AEs and SAEs ............................................. 32 
9.2.3. 
Follow-up of AEs and SAEs .......................................................... 32 
9.2.4. 
Adverse Events of Special Interest (AESI) ................................... 32 
9.2.5. 
Regulatory Reporting Requirements for SAEs ............................. 32 
9.2.6. 
Cardiovascular and Death Events ................................................ 33 
9.2.7. 
Possible Suicidality Related Adverse Events ................................ 33 
9.2.8. 
Pregnancy ..................................................................................... 33 
9.3. 
Treatment of Overdose ................................................................................ 34 
9.4. 
Screening and Critical Baseline Assessments ............................................. 34 
9.5. 
Safety Assessments ..................................................................................... 34 
9.5.1. 
Physical Examinations .................................................................. 34 
9.5.2. 
Vital Signs ..................................................................................... 35 
9.5.3. 
Electrocardiograms ....................................................................... 35 
9.5.4. 
Clinical Safety Laboratory Assessments ....................................... 35 
9.5.5. 
Pregnancy Testing ........................................................................ 36 
9.6. 
Pharmacokinetics ......................................................................................... 36 
9.6.1. 
Blood sample collection ................................................................ 36 
9.6.2. 
Sample Analysis ........................................................................... 36 
9.7. 
Pharmacodynamics ...................................................................................... 37 
9.8. 
Genetics ....................................................................................................... 37 
9.9. 
Biomarkers ................................................................................................... 37 
9.10. 
Health Economics OR Medical Resource Utilization and Health 
Economics .................................................................................................... 37 
10. STATISTICAL CONSIDERATIONS ......................................................................... 37 
10.1. 
Hypotheses .................................................................................................. 37 
10.2. 
Sample Size Determination .......................................................................... 37 
10.2.1. 
Sample Size Assumptions ............................................................ 37 
10.2.2. 
Sample Size Sensitivity ................................................................. 38 
10.2.3. 
Sample Size Re-estimation or Adjustment ................................... 38 
10.3. 
Data Analysis Considerations ...................................................................... 38 
10.3.1. 
Analysis Populations ..................................................................... 38 
10.3.1.1. Enrolled Population ..................................................... 38 
10.3.1.2. Safety Population ........................................................ 38 
10.3.1.3. Pharmacokinetic Population ........................................ 39 
10.3.1.4. Pharmacodynamic Population ..................................... 39 

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10.3.1.5. Screened Population ................................................... 39 
10.3.2. 
Interim Analysis ............................................................................. 39 
10.4. 
Key Elements of Analysis Plan ..................................................................... 39 
10.4.1. 
Pharmacokinetic Analyses ............................................................ 40 
10.4.1.1. Statistical Analysis of Pharmacokinetic 
Parameters .................................................................. 41 
10.4.2. 
Pharmacodynamic Analyses ......................................................... 41 
10.4.3. 
Safety Analyses ............................................................................ 42 
11. REFERENCES ........................................................................................................ 43 
12. APPENDICES .......................................................................................................... 44 
12.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 44 
12.2. 
Appendix 2: Risk Assessment ...................................................................... 47 
12.3. 
Appendix 3: Clinical Laboratory Tests .......................................................... 58 
12.4. 
Appendix 4: Study Governance Considerations ........................................... 60 
12.5. 
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ........................................ 64 
12.6. 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................................... 69 
12.7. 
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ................................................................................................ 72 
12.8. 
Appendix 8:  Grades of Hepatic Encephalopathy ......................................... 74 
12.9. 
Appendix 9: Protocol Amendment History .................................................... 75 
 

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1. 
SYNOPSIS 
Protocol Title: A Phase 1, open-label, non-randomized, parallel group, single-dose 
adaptive study in adults with hepatic impairment and matched, healthy control 
participants with normal hepatic function. 
Short Title: Daprodustat hepatic impairment study 
Rationale: 
A recent study has shown that co-administration of daprodustat with a strong, irreversible 
inhibitor of the cytochrome (CYP) 2C8 enzyme (i.e., gemfibrozil) lead to marked 
increases in both daprodustat Cmax (4-fold) as well as AUC (19-fold).  This suggests that 
the liver is primarily involved in the clearance of daprodustat through the CYP2C8 
enzyme and, therefore hepatic impairment has the potential to affect daprodustat 
clearance and exposure.  Thus, the intent of this study is to assess the effect of hepatic 
impairment on the pharmacokinetics (PK) and pharmacodynamics (PD) of daprodustat.  
The results of this study are planned to provide guidance on administration of daprodustat 
to patients with impaired hepatic function. 
Objectives and Endpoints: 
Objective 
Endpoint 
Primary 
To compare plasma PK parameters of daprodustat 
and its six metabolites (GSK2391220 (M2), 
GSK2506104 (M3), GSK2487818 (M4), 
GSK2506102 (M5), GSK2531398 (M6), 
GSK2531401 (M13)) in participants with hepatic 
impairment to healthy controls matched in gender, 
age, and body mass index (BMI) 
Daprodustat and its metabolites plasma area under 
the concentration-time curve from time zero (pre-
dose) extrapolated to infinite time [AUC(0-∞)], 
percentage of AUC(0-∞) obtained by extrapolation 
(%AUCex), time zero (pre-dose) to last time of 
quantifiable concentration [AUC(0-t)], maximum 
observed concentration (Cmax) following a single 
oral dose of daprodustat, apparent terminal phase 
half-life (t½), and time of occurrence of Cmax 
(Tmax) following a single oral dose of daprodustat 
To evaluate the impact of hepatic impairment on the 
plasma protein binding and unbound concentration 
of daprodustat and its metabolites in plasma 
Unbound concentration and unbound fraction in 
plasma of daprodustat and its metabolites at 3, 12 
and 24 h post dose (as data permit) 
Secondary 
To characterize the effect of hepatic impairment on 
the pharmacodynamics effect of daprodustat 
Maximum observed erythropoietin concentration 
(Cmax, EPO), Time of the maximum observed 
erythropoietin concentration (Tmax, EPO) and 
erythropoietin area under the concentration-time 
curve from time zero (pre-dose) to the last time 
of quantifiable concentration [AUC (0-t, EPO)]. 
To assess the safety and tolerability of a single 6 mg 
Safety and tolerability parameters, including adverse 

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Objective 
Endpoint 
dose of daprodustat 
events and clinical laboratory tests 
Overall Design: 
This will be a Phase 1, open-label, non-randomized, parallel group, single-dose, adaptive 
study in adults with moderate (Part 1) and potentially either mild or severe (Part 2) 
hepatic impairment and matched, healthy control participants with normal hepatic 
function. 
All participants will undergo screening assessments within 28 days of enrolment.  A 
decision to progress from Part 1 to 2 will be made based on the available study results, 
with the potential that Part 2 of the study will not be conducted. 
In Part 1, healthy control participants (n=8) will be matched in gender, age (±10 years), 
and BMI (±15%) to participants with moderate hepatic impairment (Child-Pugh score of 
7-9).  All participants will receive 6 mg of daprodustat as a single oral dose in the fasted 
state followed by pharmacokinetic and pharmacodynamic sampling for total 
concentrations of daprodustat in plasma.  At sparse sampling times, unbound daprodustat 
and its metabolites’ concentrations will be assessed. 
In Part 2, if the geometric mean total plasma AUC pharmacokinetic parameters of 
daprodustat is increased in Part 1 by ≥2-fold in moderately-impaired participants relative 
to matched controls, Part 2 may be conducted to evaluate daprodustat pharmacokinetics 
in participants with mild impairment (Child-Pugh score of 5-6; n=8) and matched, control 
participants (n=8).  Alternatively, if the geometric mean total plasma AUC(0-∞) of 
daprodustat is increased by <2-fold in moderately impaired participants relative to 
matched controls, Part 2 may be conducted to evaluate daprodustat pharmacokinetics in 
participants with severe impairment (Child-Pugh score of 10-13; n=8) and matched, 
control participants (n=8).  Similar to Part 1 of the study, all participants will receive 
6 mg of daprodustat followed by pharmacokinetic and pharmacodynamic blood 
sampling. 
Number of Participants: 
A sufficient number of participants will be enrolled to ensure there are at least 8 
participants comprising the pharmacokinetic population per cohort. 
Recruitment of Part 1 of this study will include the full range of participants with 
moderate hepatic impairment including at least one with a Child-Pugh score of 7, one 
with a score of 8 and one with a score of 9.  The recruitment will also include at least one 
female and at least one male participant in both the moderate hepatic impaired group and 
the healthy volunteer group to be part of the pharmacokinetic population as described. 
Similar to the participants in Part 1, recruitment of Part 2 of this study, if conducted, will 
include a range of participants as follows: 
• If Part 2 is conducted, the study will recruit participants with mild hepatic 
impairment, recruitment will include at least one with a Child-Pugh score of 5 and 

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one participant with a score of 6, and will also include at least one female and at 
least one male participant in both the moderate hepatic impaired group and the 
healthy volunteer group to be part of the pharmacokinetic population. 
• If Part 2 is conducted, the study will recruit participants with severe hepatic 
impairment, recruitment will include at least one with a Child-Pugh score of 10 or 
11 and one with a score of 12 or 13, and will also include at least one female and 
at least one male participant in both the severe hepatic impaired group and the 
healthy volunteer group to be part of the pharmacokinetic population. 
Treatment Groups and Duration: 
In both Part 1, and if conducted, Part 2, all participants will be administered 6 mg of 
daprodustat as a single oral dose, with assessments conducted for up to 48 h postdosing. 
A follow-up visit will occur 10-14 days after the dose of study treatment. 
A participant’s total involvement with the study will be up to 7 weeks. 
 

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2. 
SCHEDULE OF ACTIVITIES (SOA) 
Procedure 
Screening1 
Day -1 
Pre-Dose 
0 h 
0.5 h 
1 h 
1.5 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
12 h 
24 h 
36 h 
48 h 
Follow-up2 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion & 
Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past/current 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
assessments
3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Drug/Alcohol 
Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital Signs 
and Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy 
Test 
X4 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Females 
only: 
Estrogen and 
FSH5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Procedure 
Screening1 
Day -1 
Pre-Dose 
0 h 
0.5 h 
1 h 
1.5 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
12 h 
24 h 
36 h 
48 h 
Follow-up2 
Admission to 
Unit 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Physical 
Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Administratio
n of 
daprodustat 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood 
sampling 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Protein 
binding 
sample 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
 
 
EPO blood 
sampling 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse 
Events 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review 
Concomitant 
Medications 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Discharge 
from Unit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1 All participants will undergo screening assessments within 28 days of enrolment. 
2 A follow-up visit will occur 10-14 days after the dose of study treatment. 
3 Laboratory assessment guidance can be found in Appendix 3. 
4 For women of childbearing potential that are not using an approved method of contraception (see Appendix 6), one negative pregnancy test between Day -7 and Day -4 AND another 
negative pregnancy test on Day -1 is required.  Additional guidance can be found in Section 9.5.5. 
5 All females are to have estrogen and FSH measured at screening. 

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• 
The timing and number of planned study assessments, including safety, 
pharmacokinetic and pharmacodynamic assessments may be altered during the 
course of the study based on newly available data (e.g., to obtain data closer to the 
time of peak plasma concentrations) to ensure appropriate monitoring. 
• 
Any changes in the timing or addition of time points for any planned study 
assessments 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 IRB/IEC will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the ICF. 
3. 
INTRODUCTION 
Daprodustat (GSK1278863) is a small molecule, oral hypoxia-inducible factor-prolyl 
hydroxylase enzymes inhibitor (HIF-PHI) currently in development for the treatment of 
anemia of chronic kidney disease (CKD).  Daprodustat may present several important 
advantages over currently-available recombinant human erythropoietins (rhEPOs) and 
analogs used in the treatment of anemia.  It is an oral medication and does not require 
cold-chain storage as do some rhEPOs, thus increasing ease of use for patients.  
Moreover, data indicate that daprodustat can effectively raise hemoglobin (Hgb) 
concentrations with lower erythropoietin (EPO) levels than those observed after 
administration of rhEPOs [Holdstock, 2016].  Because of the increased cardiovascular 
(CV) risk associated with raising Hgb concentrations through large increases in EPO 
levels [Pfeffer, 2009], daprodustat may be able to provide a safer treatment alternative for 
these patients than rhEPOs.  Additional potential benefits include inproving iron 
availability for erythropoiesis, treating anemia without causing rhEPO-induced 
hypertension, and successfully treat rhEPO hypo-responders [Holdstock, 2016]. 
3.1. 
Study Rationale 
A recent study has shown that co-administration of daprodustat with a strong, irreversible 
inhibitor of the cytochrome (CYP) 2C8 enzyme (i.e., gemfibrozil) lead to marked 
increases in both daprodustat Cmax (4-fold) as well as AUC (19-fold).  This suggests that 
the liver is primarily involved in the clearance of daprodustat through the CYP2C8 
enzyme and, therefore hepatic impairment has the potential to affect daprodustat 
clearance and exposure [Johnson, 2013].  Thus, the intent of this study is to assess the 
effect of hepatic impairment on the pharmacokinetics (PK) and pharmacodynamics (PD) 
of daprodustat.  The results of this study are planned to provide guidance on 
administration of daprodustat to patients with impaired hepatic function. 
This study will use an adaptive study design, comprising Part 1 and potentially Part 2.  
Recruitment of Part 1 of this study will include the full range of Child-Pugh scores within 
the moderate hepatic impairment category including at least one with a Child-Pugh score 
of 7, one with a score of 8 and one with a score of 9.  The recruitment will also include at 
least one female and at least one male participant in both the moderate hepatic impaired 
group and the healthy volunteer group.  If the geometric mean total plasma AUC of 
daprodustat is increased in Part 1 by ≥2-fold in moderately-impaired participants relative 
to matched controls, Part 2 may potentially be conducted to evaluate daprodustat 
pharmacokinetics in participants with mild impairment (Child-Pugh scores of 5-6) and 

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matched, control participants.  Alternatively, if the geometric mean total plasma AUC of 
daprodustat is increased by <2-fold in moderately-impaired participants relative to 
matched controls, Part 2 may potentially be conducted to evaluate daprodustat 
pharmacokinetics in participants with severe impairment (Child-Pugh scores of 10-13) 
and matched, control participants.  These levels of change in exposure as decision points 
are based on regulatory agency guidances [FDA Guidance for Industry, 2003; Committee 
for medicinal products for human use (CHMP), 2005], and the consideration that 
daprodustat has not been observed to possess a narrow therapeutic index.  A decision to 
progress from Part 1 to 2 will be made based on the available study results, with the 
potential that Part 2 of the study will not be conducted 
3.2. 
Background 
Daprodustat is currently in Phase 3 development for the treatment of anemia of CKD.  
The clinical efficacy of daprodustat has been demonstrated in two Phase 2 studies.  In 
GSK study PHI113747 daprodustat achieved mean hemoglobin (Hgb) response in non-
dialysis dependent (ND) participants with CKD within a target range over a 24-week 
treatment period.  Participants in the daprodustat group achieved Hgb levels within the 
specific target range (8.0 to 11.0 g/dL; US only 8.0 to 10.0 g/dL), both in the 
recombinant, human (rh)-EPO naïve and rhEPO user groups.  In study PHI113633 
daprodustat achieved Hgb efficacy (maintenance of Hgb within the target range of 10.0 to 
11.5 g/dL) in a similar fashion as did rhEPO in hemodialysis-dependent (HD) 
participants with CKD [Holdstock, 2016]. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
daprodustat is provided in the Investigator’s Brochure (IB) and associated IB 
Supplements, if applicable. 
3.3. 
Benefit/Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with 
daprodustat can be found in the daprodustat IB and IB supplement(s), if applicable. 
3.3.1. 
Risk Assessment 
The potential risks of clinical significance including AEs of special interest (Section 
9.2.4), and the mitigation strategies for this protocol taking into account the results of 
completed clinical and nonclinical studies with daprodustat, are outlined in Appendix 2. 
3.3.2. 
Benefit Assessment 
As this is a single dose study, no clinical benefit is expected for participation. 
3.3.3. 
Overall Benefit:Risk Conclusion 
Overall, the available data from nonclinical and clinical studies has not identified 
prohibitive risks associated with daprodustat at the exposures planned for this study.  
While there are a number of important potential risks identified for daprodustat, these can 

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be addressed in clinical trials with proper participant selection, close safety monitoring, 
and specific risk characterization and mitigation. 
4. 
OBJECTIVES AND ENDPOINTS 
Objective 
Endpoint 
Primary 
To compare plasma PK parameters of daprodustat 
and its six metabolites (GSK2391220 (M2), 
GSK2506104 (M3), GSK2487818 (M4), 
GSK2506102 (M5), GSK2531398 (M6), 
GSK2531401 (M13)) in participants with hepatic 
impairment to healthy controls matched in gender, 
age, and body mass index (BMI) 
Daprodustat and its metabolites plasma area under 
the concentration-time curve from time zero (pre-
dose) extrapolated to infinite time [AUC(0-∞)], 
percentage of AUC(0-∞) obtained by extrapolation 
(%AUCex), time zero (pre-dose) to last time of 
quantifiable concentration [AUC(0-t)], maximum 
observed concentration (Cmax) following a single 
oral dose of daprodustat, apparent terminal phase 
half-life (t½), and time of occurrence of Cmax 
(Tmax) following a single oral dose of daprodustat 
To evaluate the impact of hepatic impairment on the 
plasma protein binding and unbound concentration 
of daprodustat and its metabolites in plasma 
Unbound concentration and unbound fraction in 
plasma of daprodustat and its metabolites at 3, 12 
and 24 h post dose (as data permit) 
Secondary 
To characterize the effect of hepatic impairment on 
the pharmacodynamics effect of daprodustat 
Maximum observed erythropoietin concentration 
(Cmax, EPO), Time of the maximum observed 
erythropoietin concentration (Tmax, EPO) and 
erythropoietin area under the concentration-time 
curve from time zero (pre-dose) to the last time 
of quantifiable concentration [AUC (0-t, EPO)]. 
To assess the safety and tolerability of a single 6 mg 
dose of daprodustat 
Safety and tolerability parameters, including adverse 
events and clinical laboratory tests 
 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
This will be a Phase 1, open-label, non-randomized, parallel group, single-dose, adaptive 
study in adults with moderate (Part 1) and potentially either mild or severe (Part 2) 
hepatic impairment and matched, healthy control participants with normal hepatic 
function. 
All participants will undergo screening assessments within 28 days of enrolment.  A 
decision to progress from Part 1 to 2 will be made based on the available study results, 
with the potential that Part 2 of the study will not be conducted. 

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In Part 1, healthy control participants (n=8) will be matched in gender, age (±10 years), 
and BMI (±15%) to participants with moderate hepatic impairment (Child-Pugh score of 
7-9).  All participants will receive 6 mg of daprodustat as a single oral dose in the fasted 
state followed by pharmacokinetic and pharmacodynamic sampling for total 
concentrations of daprodustat in plasma.  At sparse sampling times, unbound daprodustat 
and its metabolites’ concentrations will be assessed. 
In Part 2, if the geometric mean total plasma AUC pharmacokinetic parameters of 
daprodustat is increased in Part 1 by ≥2-fold in moderately-impaired participants relative 
to matched controls, Part 2 may be conducted to evaluate daprodustat pharmacokinetics 
in participants with mild impairment (Child-Pugh score of 5-6; n=8) and matched, control 
participants (n=8).  Alternatively, if the geometric mean total plasma AUC(0-∞) of 
daprodustat is increased by <2-fold in moderately impaired participants relative to 
matched controls, Part 2 may be conducted to evaluate daprodustat pharmacokinetics in 
participants with severe impairment (Child-Pugh score of 10-13; n=8) and matched, 
control participants (n=8).  Similar to Part 1 of the study, all participants will receive 
6 mg of daprodustat followed by pharmacokinetic and pharmacodynamic blood 
sampling. 
A follow-up visit will occur 10-14 days after the dose of study treatment. 
A participant’s total involvement with the study will be up to 7 weeks. 
Table 1 
Study Cohorts 
Study Part 
Cohort 
Sample 
Size 
Treatment1 
Part 1 
1 (Moderate Hepatic Impairment)2 
8 
Daprodustat 6 mg 
2 (Matched Healthy Controls)3 
8 
Part 2 
(if conducted)4 
3 (either Mild OR Severe Hepatic 
Impairment)2 
8 
4 (Matched Healthy Controls)3 
8 
1 All participants will receive a single 6 mg oral dose of daprodustat. 
2 Hepatic impairment categorized by Child-Pugh Classification system (See Table 2: Mild: Score 5-6; Moderate: 
Score 7-9; Severe: Score 10-13) in conjunction with the specifications listed in Section 6. 
3 Healthy control participants are matched to the hepatic impairment participants in gender, age (±10 years), and 
BMI (±15%). 
4 Part 2 of the study may be conducted dependent upon any observed difference in the geometric mean total plasma 
AUC(0-∞) of daprodustat in moderately impaired participants relative to matched controls as described in Section 
10.3.2. 
A participant is classified with hepatic impairment based on the Child-Pugh classification 
as described in Table 2: 
• 
Mild hepatic impairment: Child-Pugh Class A, score of 5-6 points 

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• 
Moderate hepatic impairment: Child-Pugh Class B, score of 7-9 
• 
Severe hepatic impairment: Child-Pugh Class C, score of 10-13 
Table 2 
Child-Pugh System of Hepatic Impairment Classification1 
Parameter 
Points Scored for Each Observed Finding 
1 Point 
2 Points 
3 Points 
Serum albumin (g/dL) 
>3.5 
2.8 to 3.5 
<2.8 
Total serum bilirubin (mg/dL) 
<2.0 
2.0 to 3.0 
>3.0 
Prothrombin time INR (ratio) 
<1.70 
1.70 to 2.30 
>2.30 
Ascites 
Absent 
Slight 
or 
Participant on 1 
medication to 
control ascites 
Moderate 
or 
Participant on 2 
medications to 
control ascites 
Hepatic encephalopathy2 
None 
1 or 2 
or 
Participant currently 
receiving treatment 
with lactulose, 
neomycin, or other 
acceptable 
treatments 
3 or 4 
or 
Continued 
encephalopathy 
while receiving 
treatment with 
lactulose, neomycin, 
and/or other 
acceptable 
treatments 
1 Child-Pugh System of Hepatic Impairment: adapted from Child, 1964; Pugh, 1973. 
2 A description of hepatic encephalopathy grades can be found in Appendix 8. 
 
5.2. 
Number of Participants 
A sufficient number of participants will be enrolled to ensure there are at least 8 
participants comprising the pharmacokinetic population per cohort (See Section 
10.3.1.3). 
Recruitment of Part 1 of this study will include the full range of participants with 
moderate hepatic impairment including at least one with a Child-Pugh score of 7, one 
with a score of 8 and one with a score of 9.  The recruitment will also include at least one 
female and at least one male participant in both the moderate hepatic impaired group and 
the healthy volunteer group to be part of the pharmacokinetic population as described 
(See Section 10.3.1.3). 

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Similar to the participants in Part 1, recruitment of Part 2 of this study, if conducted, will 
include a range of participants as follows: 
• If Part 2 is conducted, the study will recruit participants with mild hepatic 
impairment, recruitment will include at least one with a Child-Pugh score of 5 and 
one participant with a score of 6, and will also include at least one female and at 
least one male participant in both the moderate hepatic impaired group and the 
healthy volunteer group to be part of the pharmacokinetic population as described 
(See Section 10.3.1.3). 
• If Part 2 is conducted, the study will recruit participants with severe hepatic 
impairment, recruitment will include at least one with a Child-Pugh score of 10 or 
11 and one with a score of 12 or 13, and will also include at least one female and 
at least one male participant in both the severe hepatic impaired group and the 
healthy volunteer group to be part of the pharmacokinetic population as described 
(See Section 10.3.1.3). 
5.3. 
Participant and Study Completion 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the follow up visit. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5.4. 
Scientific Rationale for Study Design 
This study will be an open label, single dose, parallel group, adaptive design for 
assessment of daprodustat PK and PD in participants with moderate hepatic impairment 
and matched control participants.  The design will permit daprodustat and its metabolites 
PK parameters to be determined in participants with moderate hepatic impairment (Child-
Pugh score 7-9), and compared to the PK parameters from matched healthy control 
participants with normal hepatic function.  Additionally, the unbound fraction of 
daprodustat and its metabolites will be determined to assess the impact of hepatic 
impairment on daprodustat and its metabolites plasma protein binding.  Finally, the effect 
of daprodustat on erythropoietin (EPO) levels will be described. 
• This study will be open label since the primary endpoint (PK) is an objective 
measure and unlikely to be influenced by the participant’s knowledge of the 
treatment received. 
• A single dose of daprodustat will be used in this study as daprodustat PK exhibits 
linear and time-independent PK.  Further, single-dose PK, as will be performed in 
this study, has consistently allowed reliable prediction of multiple-dose PK that 
would be observed with chronic administration.  Finally, as daprodustat (as well 
as predominant circulating metabolites) has a short half-life, PK on Day 1 is 
similar to PK at steady state.  Multiple-dose study designs are only recommended 
if the PK changes over time; i.e., in cases of auto-induction or accumulation due 
to a long half-life. 

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• The adaptive design of this study allows for subsequent study, if conducted, of 
participants with either mild (Child-Pugh score 5-6) or severe (Child-Pugh score 
10-13) hepatic impairment to be implemented dependent upon the results from the 
participants with moderate hepatic impairment: 
(i) 
If a <2-fold change in daprodustat exposure (AUC) is observed in participants 
with moderate hepatic impairment, the study may enrol participants with severe 
hepatic impairment and a healthy, matched control group; 
(ii) 
If a ≥2-fold change in daprodustat exposure (AUC) is observed in participants 
with moderate hepatic impairment, the study may enrol participants with mild 
hepatic impairment and a healthy, matched control group. 
• The Child-Pugh scoring system for hepatic impairment will be used for the 
classification of hepatically-impaired participants.  Currently, there are no well-
established biochemical markers to estimate the effects of hepatic impairment on 
the PK/PD of a drug.  Although the Child-Pugh classification system was not 
developed for the purpose of predicting drug elimination capacity, it is the most 
widely used and accepted method of categorizing the degree of hepatic 
impairment in participants included in a hepatic impairment PK study, and has 
been selected as the system to categorize the participants enrolled in this study 
[FDA Guidance for Industry, 2003; Pugh, 1973].  Because the clinical and 
biochemical criteria of the Child-Pugh classification system (i.e., encephalopathy, 
elevated bilirubin, increased INR, decreased albumin) are not specific only to 
liver disease, participants enrolled into the hepatic impairment cohorts must also 
exhibit clinical evidence of chronic liver disease and/or cirrhosis.  This additional 
inclusion criteria will help to ensure the desired study population is recruited. 
5.5. 
Dose Justification 
A single, oral 6 mg dose of daprodustat is planned to be used in this study.  This dose of 
daprodustat can be given by a single tablet, provides sufficient plasma levels for well-
defined pharmacokinetics and margins for potential increases in daprodustat exposure in 
hepatic impaired population. 
The 6 mg dose is currently being evaluated in Phase 3 trials as well as doses up to 24 mg.  
As the PK of daprodustat is linear with dose, effects of hepatic impairment observed at 
6 mg can be extrapolated to the higher clinical doses. 
Overall, single, oral doses of up to 150 mg administered to HD CKD participants and 
doses up to 500 mg administered to healthy participants has been generally well tolerated 
and no new safety concerns have been identified (GSK studies PHI112843 and 
PHI113635, respectively). 
In the event that the 6 mg dose proves to be poorly tolerated by the study population, the 
dose of daprodustat may be reduced for participants yet to be enrolled. 

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6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
6.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
6.1.1. 
Inclusion Criteria for All Participants 
AGE 
1. Participant must be at least 18 years of age inclusive, at the time of signing the 
informed consent. 
 
MEDICAL CONDITIONS 
2. Hemoglobin values at screening ≤16.0 g/dL for males and ≤14.0 g/dL for females. 
 
WEIGHT 
3. Body weight ≥45 kg and body mass index (BMI) within the range 18-40 kg/m2 
(inclusive). 
 
SEX 
4. Male or female 
Female participants: A female participant is eligible to participate if she is not 
breastfeeding, and at least one of the following applies: 
(i) 
Not pregnant as confirmed by two pregnancy tests (see Section 9.5.5) 
(ii) 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 6 
(iii) 
For WOCBP that are currently utilizing a highly-effective contraceptive 
method prior to enrolment, agrees to follow the contraceptive guidance in 
Appendix 6 during the treatment period to the follow-up visit.  (Additional 
guidance can be found in Section 9.5.5.) 
 
INFORMED CONSENT 
5. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 

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protocol. 
 
6.1.1.1. 
Additional Inclusion Criteria for Hepatically-Impaired Participants 
MEDICAL CONDITIONS 
1. Part 1 Participants with Moderate Hepatic Impairment Only (Cohort 1): Is 
considered to have moderate hepatic impairment (of any etiology) and has been 
clinically stable for at least 1 month prior to screening.  To be classified as having 
moderate hepatic impairment, participants must have a Child-Pugh (Class B) 
score of 7-9 AND previous confirmation of liver cirrhosis by liver biopsy or other 
medical imaging technique (including laparoscopy, computerized tomography 
(CT) scan, magnetic resonance imaging (MRI) or ultrasonography) associated 
with an unambiguous medical history (such as evidence of portal hypertension). 
2. Part 2 Participants with Mild OR Severe Hepatic Impairment Only (Cohort 
3; if conducted): Is considered to have mild or severe hepatic impairment (of any 
etiology) and has been clinically stable for at least 1 month prior to screening.  To 
be classified as having mild OR severe hepatic impairment, participants must 
have: 
(i) 
Be classified as having mild hepatic impairment, participants must have a Child-
Pugh (Class A) score of 5-6 AND previous confirmation of chronic liver disease 
by liver biopsy or other medical imaging technique (including laparoscopy, CT 
scan, MRI or ultrasonography) associated with an unambiguous medical history 
(such as evidence of portal hypertension). 
(ii) 
Be classified as having severe hepatic impairment, participants must have Child-
Pugh (Class C) score of 10-13 AND previous confirmation of chronic liver 
disease by liver biopsy or other medical imaging technique (including 
laparoscopy, CT scan, MRI or ultrasonography) associated with an unambiguous 
medical history (such as evidence of portal hypertension). 
3. Supplemental inclusion criteria for ALL hepatically-impaired participants: 
Chronic (>6 months), stable (no acute episodes of illness due to deterioration in 
hepatic function within the previous 1 month prior to screening) hepatic 
impairment due to any etiology.  Participants must also remain stable throughout 
the Screening period.  Assessment of the stability of the participant’s hepatic 
function will be determined by the investigator. 
 
6.1.1.2. 
Additional Inclusion Criteria for Healthy Control Participants 
AGE 
1. Healthy control participants will be matched for age ±10 years to participants in 
the respective hepatic impairment cohort but must also be at least 18 years of age 
inclusive, at the time of signing the informed consent. 

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MEDICAL CONDITIONS 
2. Healthy as determined by the investigator or medically qualified designee based 
on a medical evaluation including medical history, physical examination, 
laboratory tests and cardiac monitoring. 
3. A participant with a clinical abnormality or laboratory parameter(s) which is/are 
not specifically listed in the inclusion or exclusion criteria, outside the reference 
range for the population being studied may be included only if the investigator 
and/or the Medical Monitor agree and document that the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures. 
 
WEIGHT 
4. Healthy control participants will be matched for BMI ±15% to participants in the 
respective hepatic impairment cohort but must also remain in the range of body 
weight ≥45 kg and body mass index (BMI) within the range 18-38 kg/m2 
(inclusive). 
 
6.2. 
Exclusion Criteria 
6.2.1. 
Exclusion Criteria for All Participants 
Participants are excluded from the study if any of the following criteria apply: 
CONCURRENT CONDITIONS/MEDICAL HISTORY 
1. QTcF >500 msec 
NOTES: 
• 
The QTc must be the QT interval corrected for heart rate according to 
Fridericia’s formula (QTcF). 
• 
For purposes of data analysis, QTcB will be used as specified in the Reporting 
and Analysis Plan (RAP). 
2. Recent history of deep vein thrombosis, pulmonary embolism or other thrombosis 
related condition.  Any prior medical history in these areas will be reviewed and 
approved by the PI and the sponsor’s Medical Monitor on a case by case basis as 
needed. 
3. Myocardial infarction or acute coronary syndrome, stroke or transient ischemic 
attack within the 12 weeks prior to enrollment. 
4. Participants with a pre-existing condition (other than liver disease) interfering 
with normal gastrointestinal anatomy or motility that could interfere with the 
absorption, metabolism, and/or excretion of daprodustat.  Examples of conditions 
that could interfere with normal gastrointestinal anatomy or motility can be found 

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in the SRM. 
5. Participants that have undergone cholecystectomy within the past 3 months. 
6. Participants with chronic inflammatory joint disease (e.g., scleroderma, systemic 
lupus erythematosis, rheumatoid arthritis). 
7. History of malignancy within the prior 2 years or known kidney mass >3cm (end-
stage renal disease patients only) OR currently receiving treatment for cancer, 
Note:  ONLY exception is localized squamous cell or basal cell carcinoma of the 
skin definitively treated 12 weeks prior to enrollment. 
8. Class IV heart failure, as defined by the New York Heart Association (NYHA) 
functional classification system. 
 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
9. Current enrolment or past participation (i.e., administration of last dose of 
investigational study treatment) within the last 30 days (or 5 half-lives, whichever 
is longer) before Day 1 in this or any other clinical study involving an 
investigational study treatment or any other type of medical research. 
 
6.2.1.1. 
Additional Exclusion Criteria for Hepatically-Impaired Participants 
CONCURRENT CONDITIONS/MEDICAL HISTORY 
1. Presence of 8 times ULN elevations in AST, ALT, or bilirubin. 
2. Participants with any other medical condition which, in the judgment of the 
investigator and Medical Monitor, could jeopardize the integrity of the data 
derived from that participant or the safety of the participant. 
3. Participants with advanced ascites (Grade 3). 
4. Participants with refractory encephalopathy as judged by the investigator or 
significant Central Nervous System (CNS) disease (e.g., dementia, or seizures) 
which the investigator considers will interfere with the informed consent, conduct, 
completion, or results of this trial or constitutes an unacceptable risk to the 
participant. 
5. Participants with functional Transjugular Intrahepatic Portosystemic Shunt (TIPS) 
placement. 
6. Presence of hepatopulmonary or hepatorenal syndrome. 
7. Presence of primarily cholestatic liver diseases. 
8. History of liver transplantation. 
9. Participants with signs of active infection, including active spontaneous bacterial 
peritonitis. 
10. Participants with unstable cardiac function or participants with hypertension 

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whose blood pressure is not controlled (based on the investigator’s discretion). 
11. Diabetic participants whose diabetes is not controlled (based on the investigator`s 
discretion). 
 
6.2.1.2. 
Additional Exclusion Criteria for Healthy Control Participants 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
1. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day. 
 
DIAGNOSTIC ASSESSMENTS 
2. 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 treatment. 
3. Positive pre-study drug/alcohol screen. 
4. Positive human immunodeficiency virus (HIV) antibody test. 
5. Regular use of known drugs of abuse. 
6. Regular alcohol consumption within 6 months prior to the study defined as an 
average weekly intake of >14 drinks.  One drink is equivalent to 12 g of alcohol: 
12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 
80 proof distilled spirits.  One unit is equivalent to 8 g of alcohol: a half-pint 
(~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits. 
 
6.3. 
Lifestyle Restrictions 
6.3.1. 
Meals and Dietary Restrictions 
• Participants will refrain from any food and drink (except water) at least 8 h before 
dosing and 4 h after dosing of any investigational product. 
6.3.2. 
Caffeine, Alcohol, and Tobacco 
• Participants will be instructed to limit ingesting caffeine- or xanthine-containing 
products (e.g., coffee, tea, cola drinks, chocolate) for 24 h prior to the start of dosing 
until collection of the final pharmacokinetic blood sample. 
• Participants will abstain from alcohol for 24 h prior to the start of dosing until 
collection of the final pharmacokinetic blood sample. 

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• Participants will be instructed to limit use of nicotine and/or nicotine containing 
products.  Up to 10 cigarettes/day is acceptable. 
6.3.3. 
Activity 
Participants will abstain from strenuous exercise for 48 h prior to each blood collection 
for clinical laboratory tests.  Participants may participate in light recreational activities 
during studies (e.g., watch television, reading). 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study.  A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened.  Rescreening of individuals will be in consultation with the Medical 
Monitor. 
7. 
TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
7.1. 
Treatments Administered 
Product name: 
Daprodustat (GSK1278863) 
Dosage form: 
Tablet 
Unit dose strength(s)/Dosage 
level(s): 
6 mg tablet strength/6 mg dosage level 
Route of Administration: 
Oral 
Physical description: 
9.0 mm round, compound radius, white film coated tablets 
Packaging and Labelling: 
Study Treatment will be provided in a bottle.  Each bottle will be 
labelled as required per country requirement. 
Manufacturer 
GlaxoSmithKline 
 

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7.2. 
Dose Modification 
As this is a single dose study, no dosage modification for a participant can occur.  
However, in the event that the 6 mg dose proves to be poorly tolerated by the study 
population, the dose of daprodustat may be reduced for participants yet to be enrolled. 
7.3. 
Method of Treatment Assignment 
All participants will receive the same treatment of a single oral 6 mg dose of daprodustat. 
7.4. 
Blinding 
This will be an open label study. 
7.5. 
Preparation/Handling/Storage/Accountability 
No special preparation of study treatment is required. 
• The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
• Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the 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 treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
• Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM. 
• Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  A Material Safety Data Sheet 
(MSDS)/equivalent document describing occupational hazards and recommended 
handling precautions either will be provided to the investigator, where this is required 
by local laws, or is available upon request from GSK. 
7.6. 
Treatment Compliance 
As participants are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment 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 treatment.  
Study site personnel will examine each participant’s mouth to ensure that the study 
treatment was ingested. 

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7.7. 
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 
enrolment or receives during the study must be recorded along with: 
• reason for use 
• dates of administration including start and end dates 
• dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
All concomitant medications will be reviewed by the GSK Medical Monitor and may be 
considered on a case by case basis.  A concomitant medication may be permitted by the 
GSK Medical Monitor if it will not jeopardize the interpretation of the data derived from 
that participant or the safety of the participant. 
7.7.1. 
Permitted Medications and Non-Drug Therapies 
Acetaminophen, at doses of ≤2 g/day, is permitted for use any time during the study.  
Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the Medical Monitor.  See Appendix 7 for a list of 
permitted contraceptive methods for WOCBP. 
7.7.2. 
Prohibited Medications and Non-Drug Therapies 
Healthy matched control participants must abstain from taking prescription or non-
prescription drugs (including vitamins and dietary or herbal supplements) within 7 days 
(or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) 
before the start of study treatment until completion of the follow-up visit, unless, in the 
opinion of the investigator and sponsor, the medication will not interfere with the study. 
Use of any of the following prescription drugs from 28 days prior to Day 1 until 7 days 
after the last dose of study treatment is prohibited and will constitute a protocol violation: 
• Strong inhibitors of CYP2C8 (e.g., gemfibrozil) 
• Strong inducers of CYP2C8 (e.g., rifampin/rifampicin) 
7.8. 
Treatment after the End of the Study 
Healthy control and hepatically-impaired participants will not receive any additional 
treatment from GSK after completion of the study. 
For participants with hepatic impairment, the investigator is responsible for ensuring that 
consideration has been given to the post-study care of the participant’s medical condition. 

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8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
8.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).  These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Discontinuation of study treatment for abnormal liver tests in the healthy control 
participant cohorts is required when: 
• a participant meets one of the conditions outlined in the algorithm; 
OR 
• when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the 
best interest of the participant. 
The liver chemistry stopping criteria for healthy control participants can be found in 
Appendix 7. 
8.2. 
Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance or administrative reasons. 
• If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
8.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 

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• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9. 
STUDY ASSESSMENTS AND PROCEDURES 
The following points must be noted: 
• If assessments are scheduled for the same nominal time, THEN the procedures 
should occur in the following order: 
1. 12-lead ECG 
2. vital signs 
3. blood draws 
NOTE: The timing of the assessments should allow the blood draw to occur as close 
as possible to the exact nominal time. 
• The timing and number of planned study assessments may be altered during the 
course of the study based on newly available data (e.g., to obtain data closer to the 
time of peak plasma concentrations) to ensure appropriate monitoring. 
• 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 Informed Consent Form. 
• No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required. 
• Study procedures and their timing are summarized in the SoA (Section 2). 
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 2), 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. 
9.1. 
Efficacy Assessments 
Efficacy is not assessed in this study. 
9.2. 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 5. 
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study (see Section 8). 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All SAEs will be collected from the start of treatment until the follow-up visit at the 
time points specified in the SoA (Section 2).  However, any SAEs assessed as related 
to study participation (e.g., study treatment, protocol-mandated procedures, invasive 
tests, or change in existing therapy) or related to a GSK product will be recorded from 
the time a participant consents to participate in the study. 
• All AEs will be collected from the start of treatment until the follow-up visit at the 
time points specified in the SoA (Section 2). 
• Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the 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 Section 12.5 Appendix 
5.  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 in former study 
participants.  However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor. 
• The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in Appendix 
5. 

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9.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE.  Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs, and non serious AEs of special 
interest (as defined in Section 9.2.4), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3).  Further information on follow-up procedures is given in Appendix 6. 
9.2.4. 
Adverse Events of Special Interest (AESI) 
Adverse Events of Special Interest (AESI) have been identified based on non-clinical 
studies with daprodustat, clinical experience with recombinant, human erythropoietins 
(rhEPOs), and current information regarding HIF-regulated pathways in mediating 
hypoxia-associated pathophysiology.  The currently identified AESI for daprodustat are 
as follows: 
• Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 
• Death, MI, stroke, heart failure, thromboembolic events, thrombosis of vascular 
access 
• Cardiomyopathy 
• Pulmonary artery hypertension 
• Cancer-related mortality and tumor progression and recurrence 
• Esophageal and gastric erosions 
• Proliferative retinopathy, macular edema, choroidal neovascularization 
• Exacerbation of rheumatoid arthritis 
9.2.5. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study treatment under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• 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. 

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• An investigator who receives an investigator safety report describing a SAE or other 
specific safety information e.g., summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
9.2.6. 
Cardiovascular and Death Events 
For any cardiovascular events listed below and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the electronic CRF 
(eCRF) will be required to be completed.  These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
9.2.7. 
Possible Suicidality Related Adverse Events 
If during the study there is an occurrence of an AE or SAE which in the investigator’s 
opinion, is possibly related to suicidality, the Possible Suicidality Related Adverse Events 
(PSRAE) eCRF form should be completed (in addition to the AE and SAE pages, as 
appropriate). 
This event may include, but is not limited to, one that involves suicidal ideation, a 
preparatory act toward imminent suicidal behavior, a suicide attempt, or a completed 
suicide.  The investigator will exercise his or her medical and scientific judgment in 
deciding whether an event is possibly related to suicidality. 
9.2.8. 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of 
study treatment and until the follow-up visit. 

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• 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 6. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
9.3. 
Treatment of Overdose 
For this study, any dose of daprodustat greater than 6 mg within a 24-h time period will 
be considered an overdose.  There is no specific antidote for overdose with daprodustat. 
The expected manifestations of daprodustat overdosage include signs and symptoms 
associated with an excessive and/or rapid increase in Hgb concentration. 
In the event of a suspected overdose, it is recommended that the appropriate supportive 
clinical care be instituted, as dictated by the participant’s clinical status.  Additionally, 
participants should be monitored closely for CV events, increased heart rate and 
hematologic abnormalities. 
9.4. 
Screening and Critical Baseline Assessments 
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening. 
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 6. 
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and was performed 
within the time frame defined in the SoA (Section 2). 
9.5. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 2). 
9.5.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, gastrointestinal and neurological systems.  Height 
and weight will also be measured and recorded. 
• A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 

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9.5.2. 
Vital Signs 
• Oral temperature, pulse, respiratory rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed in a seated position with a 
completely automated device.  Manual techniques will be used only if an automated 
device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell 
phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 
pulse and 3 blood pressure measurements (3 consecutive blood pressure readings will 
be recorded at intervals of at least 1 minute).  The average of the 3 blood pressure 
readings will be recorded on the CRF. 
9.5.3. 
Electrocardiograms 
• ECG measurements will be obtained as outlined in the SoA (Section 2)  Full 12-lead 
ECGs will be recorded with theparticipant 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, two additional ECGs are required if 
the initial ECG measurement indicates prolonged QTc (see Section 6.1) using the 
automated or manually calculated QTcF value.  The average QTcF value of all three 
ECGs will be used to determine eligibility. 
9.5.4. 
Clinical Safety Laboratory Assessments 
• Refer to Appendix 3 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 2) for the timing and frequency. 
• The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or at the follow-up visit should be repeated until the values 
return to normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor. 
• If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
• All protocol-required laboratory assessments, as defined in Appendix 3, must be 
conducted in accordance with the laboratory manual and the SoA. 

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9.5.5. 
Pregnancy Testing 
In this study, participants will have a drug exposure duration of <5 days including dosing 
plus 5 half-lives and dosing will occur in an inpatient setting.  Given this scenario, 
pregnancy risks are effectively mitigated by adequately ruling out pregnancy at the time 
of dosing.  Thus, it is not necessary to require participants to start a new contraceptive 
method if they are not already established on one.  To ensure capture of women of 
childbearing potential in this category who may have conceived but are just shy of being 
able to identify the pregnancy with current detection methods, it is recommended that two 
pregnancy tests are done in a short time span. 
Therefore, for WOCBP that are not currently utilizing a highly-effective contraceptive 
method listed in Appendix 6, a negative pregnancy test on or between Day -7 to Day -4 
and again pre-dose (Day -1 or Day 0) is required.  WOCBP who are already using a 
highly effective contraceptive method listed in Appendix 6 (<1% failure rate per year 
when used consistently and correctly) should continue this method until the follow-up 
visit at a minimum.  In this case, a negative screening test within 28 days of dosing and 
again pre-dose (Day -1 to Day 0) is sufficient and the additional Day -7 to -4 test is not 
needed. 
9.6. 
Pharmacokinetics 
9.6.1. 
Blood sample collection 
Blood samples for PK analysis of daprodustat and its six predominant metabolites 
(GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), 
GSK2531398 (M6), GSK2531401 (M13) will be collected at the time points indicated in 
the SoA (Section 2).  The actual date and time of each blood sample collection will be 
recorded.  The timing of PK samples may be altered and/or PK samples may be obtained 
at additional time points to ensure thorough PK monitoring. 
Additional blood samples will be collected for the assessment of protein binding for 
daprodustat and metabolites at the timepoints in the SoA (Section 2). 
Details of PK and protein binding blood sample collection (including volume to be 
collected), processing, storage and shipping procedures are provided in the SRM. 
9.6.2. 
Sample Analysis 
Pharmacokinetic plasma analysis will be performed under the management of 
Bioanalysis, Immunogenicity and Biomarkers, Platform Technology & Science (PTS) In 
Vitro/In Vivo Translation, GSK.  Concentrations and plasma protein binding of 
daprodustat six predominant metabolites (GSK2391220 (M2), GSK2506104 (M3), 
GSK2487818 (M4), GSK2506102 (M5), GSK2531398 (M6), GSK2531401 (M13)) will 
be determined in samples using the currently approved analytical methodology.  Raw 
data will be stored in the archives at the site of bio-analysis. 

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9.7. 
Pharmacodynamics 
Venous blood samples will be collected for measurement of plasma erythropoietin at the 
timepoints specified in the SoA (Section 2).  Details of pharmacodynamics (PD) blood 
sample collection (including volume to be collected), processing, storage and shipping 
procedures are provided in the SRM. 
9.8. 
Genetics 
Genetics is not assessed in this study. 
9.9. 
Biomarkers 
Biomarkers are not assessed in this study. 
9.10. 
Health Economics OR Medical Resource Utilization and 
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Hypotheses 
No formal hypotheses will be tested.  An estimation approach will be used to evaluate the 
effect of hepatic impairment (i.e., moderate and potentially either mild or severe) on the 
PK of daprodustat.  The comparisons of interest are the single dose PK parameters Cmax 
and AUC of daprodustat in each hepatic impaired cohort compared to the normal hepatic 
function cohort. 
The point estimates of the geometric least squares (GLS) mean ratio for the PK 
parameters and associated 90% confidence intervals will be provided for cohort 
comparisons (hepatically impaired:healthy participants).  The PK parameters will be log-
transformed prior to analysis and cohort comparisons will be expressed as ratios on the 
original scale.  %AUCex and tmax and will be summarized descriptively. 
10.2. 
Sample Size Determination 
10.2.1. 
Sample Size Assumptions 
The FDA Guidance for Industry “Pharmacokinetics in Patients with Impaired Hepatic 
Function: Study Design, Data Analysis, and Impact on Dosing and Labelling” 
recommends that a sufficient number of participants should be enrolled to provide 
evaluable data from at least eight participants in the control and moderate impairment 
groups.  A sample size of eight evaluable participants per cohort was selected based upon 
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Based on the recent GSK study PHI115573, the between participant CV (CVb) for 
AUC(0-inf) and Cmax of daprodustat (5 mg) is 41.9% (SD = 0.402) and 28.3% (SD = 
0.278) respectively from proc mixed model.  Based on these estimates of CVb and a 
sample size of 8 in each cohort, it is estimated that the half width of the 90% confidence 
interval will be 43% and 28% of the point estimates for AUC and Cmax, respectively.  
These calculations are based on the loge scale.  If the point estimate of the ratio of 
geometric means is 1, then the 90% confidence interval will be approximately (0.70, 
1.43) and (0.78, 1.28) for AUC and Cmax, respectively. 
10.2.2. 
Sample Size Sensitivity 
Table 3 shows the precision and 90% CI for a sample size of 8 in each group based on the 
observed SD in studies conducted among healthy and renal impairment participants. 
Table 3 
Precision and 90% CI Estimates 
Study 
Dose 
Population 
Parameter 
SD 
Precision 
90% CI 
PHX111427 
5 mg 
Healthy 
AUC(0-inf) 
0.362 
38% 
(0.73, 1.38) 
Cmax 
0.361 
38% 
(0.73, 1.38) 
PHI112843 
50 mg 
Renal 
Impaired 
AUC(0-inf) 
0.294 
30% 
(0.77, 1.30) 
Cmax 
0.159 
15% 
(0.87, 1.15) 
PHI112843 
50 mg 
Healthy 
AUC(0-inf) 
0.148 
14% 
(0.88, 1.14) 
Cmax 
0.109 
11% 
(0.90, 1.11) 
 
10.2.3. 
Sample Size Re-estimation or Adjustment 
No sample size re-estimation will be performed. 
10.3. 
Data Analysis Considerations 
10.3.1. 
Analysis Populations 
10.3.1.1. 
Enrolled Population 
All participants who were successfully screened and enrolled for the trial and for whom a 
record exists on the study database. This population will be used for summarize number 
of subjects by Country and Site ID and age ranges. 
10.3.1.2. 
Safety Population 
All participants who received at least one dose of study medication. This will be the 
primary population for the safety analyses. 

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10.3.1.3. 
Pharmacokinetic Population 
All participants in the ‘Safety Population’ for whom a PK sample has been obtained and 
analyzed will be included in the PK population. This population will be used in the 
evaluation of PK data. PK samples that may be affected by protocol deviations will be 
reviewed by the study team to determine whether or not the sample will be excluded from 
the analyses of PK data. 
10.3.1.4. 
Pharmacodynamic Population 
All participants in the ‘Safety Population’ who had at least 1 PD assessment. PD samples 
that may be affected by protocol deviations will be reviewed by the study team to 
determine whether or not the sample will be excluded from the analyses of PD data. 
10.3.1.5. 
Screened Population 
All participants who were screened will be considered for this population. This 
population will be used for summarizing screening status. 
10.3.2. 
Interim Analysis 
An interim analysis of the primary endpoint will be conducted following completion of 
Part 1 of the study, with possible progression to Part 2 based on the following criteria: 
• If a < 2-fold change in daprodustat exposure (AUC) is observed in participants with 
moderate hepatic impairment, the study may enrol participants with severe hepatic 
impairment and a healthy, matched control group. 
• If a ≥ 2-fold change in daprodustat exposure (AUC) is observed in participants with 
moderate hepatic impairment, the study may enrol participants with mild hepatic 
impairment and a healthy, matched control group. 
The Reporting and Analysis Plan will describe the planned interim analyses in greater 
detail. 
10.4. 
Key Elements of Analysis Plan 
Final analyses will be performed after the completion of the study and final dataset 
authorization. 
Data will be listed and summarized separately for each part of the study according to 
GSK reporting standards where applicable.  Listings will be sorted by participant, period, 
day, and time, noting treatment.  Summaries will be presented by treatment, day and 
time. 
Unless stated otherwise, descriptive summaries for continuous variables will include n, 
mean, standard deviation (SD), coefficient of variation for the mean (%CV), median, 
minimum, maximum, geometric mean with associated 95% confidence interval (CI), and 
the between-participant CV (%CVb) for the geometric mean; whereas, n and percent will 
be used as summary statistics for categorical variables. 

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Baseline or pre-dose assessment is the last available assessment prior to time of the first 
dose unless it is specified otherwise.  If there are multiple assessments collected on the 
same scheduled time, the average of these assessments will be used.  For tabulated safety 
summaries, only the scheduled assessments will be included in the summary tables. 
Version 9.4 or higher of the SAS system will be used to analyze data as well as to 
generate tables, listings, and figures. 
Complete details will be documented in the Reporting and Analysis Plan (RAP). 
10.4.1. 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be performed under the direct auspices of the Clinical 
Pharmacokinetics Modeling & Simulation department (CPMS), GlaxoSmithKline.  
Plasma concentration-time data for daprodustat and its six predominant metabolites 
(GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), 
GSK2531398 (M6), GSK2531401 (M13)) will be analyzed by non-compartmental 
methods with WinNonlin version 5.22 or higher.  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, as data permit: maximum 
observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma 
concentration-time curve [AUC(0-t) and AUC(0-∞)], and apparent terminal phase half-
life (t½). 
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively.  All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D. 
Figures for individual plasma concentrations will be presented on both a linear and semi-
log scale daprodustat and its six predominant metabolites.  Linear and semi-log figures 
for mean and median plasma concentrations versus time will also be generated. 
For each of the derived PK parameters of daprodustat and its six predominant 
metabolites, the following summary statistics will be calculated for each cohort: n 
(number of observations), arithmetic mean, standard deviation, median, minimum, 
maximum, and the 95% confidence interval of arithmetic mean. 
In addition, summary statistics for log-transformed PK parameters of daprodustat and its 
six predominant metabolites [i.e., AUC(0-t), AUC(0-∞), Cmax, and t½],except tmax will 
include geometric mean, 95% confidence interval of the geometric mean, standard 
deviation of the logarithmically transformed data, and inter-participant coefficient of 
variation [CVb (%)]. 
The inter-participant CV [CVb (%)] will be calculated according to the following 
method: 
Loge Transformed Data: 
CVb(%) = SQRT(exp(SD2) – 1) x 100 
where SD is the standard deviation on the loge scale. 

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Unbound fraction (fu) will be calculated using the total and unbound plasma 
concentration of daprodustat and its metabolites generated at 3, 12 and 24 h post dose for 
both normal and hepatic impaired participants using the following formula: 
fu = Cunbound/Ctotal 
where Cunbound and Ctotal are the unbound and total concentrations of daprodustat and 
its metabolites in plasma, respectively. 
Full details of the analysis will be provided in the RAP. 
10.4.1.1. 
Statistical Analysis of Pharmacokinetic Parameters 
Statistical analyses of the pharmacokinetic parameter data will be performed under the 
direct auspices of Quantitative Sciences India, GSK. 
For each log-transformed PK parameter (expect %AUCex and tmax), point estimate and 
its associated 90% CI will be constructed for the cohort (hepatically impaired – healthy 
participants) difference.  The results will be exponentiated to obtain the ratio of GLS 
means and its 90% CI. 
 
As data permit, tmax will be analyzed non-parametrically using the Wilcoxon Rank Sum 
Test.  The point estimates and 90% confidence intervals for the median differences will 
be calculated for the cohort difference (hepatically impaired – healthy participants). 
Distributional assumptions underlying the statistical analyses will be assessed by visual 
inspection of residual plots.  Normality will be examined by normal probability plots, 
while homogeneity of variance will be assessed by plotting the residuals against the 
predicted values for the model. 
A sensitivity analysis will be performed for log transformed PK parameters (except 
%AUCex and tmax) by analysis of covariance (ANCOVA) including terms cohort, 
gender, age and BMI. For each PK parameter, a point estimate and an associated 90% 
confidence interval (CI) will be constructed for the difference between participants with 
hepatic impairment and healthy participants. The results will be exponentiated to obtain 
the ratio of GLS means and its 90% CI. 
 
Further details of analysis and reporting of PK data will be given in the RAP. 
10.4.2. 
Pharmacodynamic Analyses 
Pharmacodynamic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. 
Descriptive statistics, where appropriate, (n, arithmetic mean, geometric mean, standard 
deviation, minimum, median and maximum) will be calculated for the pharmacodynamic 
endpoints. 

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10.4.3. 
Safety Analyses 
All safety analyses will be performed on the Safety Population.  Safety data will be 
presented in tabular and/or graphical format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards. 

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11. 
REFERENCES 
Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The liver 
and portal hypertension. Philadelphia: Saunders, 1964:50-64. 
Committee for medicinal products for human use (CHMP): Guideline on the evaluation 
of the pharmacokinetics of medicinal products in patients with impaired hepatic function. 
February 2005. 
FDA Guidance for Industry: Pharmacokinetics in patients with impaired hepatic function: 
Study design, data analysis, and impact on dosing and labelling. May 2003. 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
064982.htm 
Holdstock L, Meadowcroft AM, Maier R, Johnson BM, Jones D, Rastogi A, Zeig S, 
Lepore JJ, Cobitz AR. Four-week studies of oral hypoxia-inducible factor-prolyl 
hydroxylase inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol. 2016; 
27:1234-1244. 
Johnson BM, Stier BA, Caltabiano S. Effect of food and gemfibrozil on the 
pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863. Clin 
Pharmacol in Drug Devel. 2013;3:109-117. 
Pfeffer MA, Burdmann EA, Chen C-Y, Cooper ME, de Zeeuw D, Eckart K-U, Feyzi JM, 
Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJV, Parfrey 
P, Parving H-H, Remuzzi G, Singh AJ, Solomon, SD, Toto R. A trial of darbepoetin alfa 
in Type 2 diabetes and chronic kidney disease. N Eng J Med. 2009; 361:2019-2032. 
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973; 60:646-649. 

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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
Table 4 
List of Abbreviations 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase (SGPT) 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the concentration-time curve 
BCRP 
Breast Cancer Resistance Protein 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CI 
Confidence Interval 
CKD 
Chronic kidney disease 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum observed concentration 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
CONSORT Consolidated Standards of Reporting Trials 
CPMS 
Clinical Pharmacokinetics Modeling & Simulation 
CRF 
Case Report Form 
CPSR 
Clinical study report 
CT 
Computerized tomography 
Ctotal 
Total concentration 
Cunbound 
Unbound concentration 
CV 
Cardiovascular 
CVb 
Between participant coefficient of variability 
CYP 
Cytochrome P450 enzyme 
dL 
decilitre 
DMPK 
Drug Metabolism & Pharmacokinetics 
ECG 
Electrocardiogram 
ECHO 
Echocardiographic 
eCRF 
Electronic Case Report Form 
E,last 
Last measurable concentration 
Cmax, 
EPO 
Maximum observed EPO concetration 
EPO 
Erythropoietin 
ex 
Extrapolation 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
fu 
Unbound fraction 
g 
Gram 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 

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GLS 
Geometric least squares 
GSK 
GlaxoSmithKline 
h 
Hour 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HD 
Hemodialysis dependent 
Hgb 
Hgb 
HIF 
Hypoxia-inducible factor 
HIV 
Human Immunodeficiency Virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HPLC 
High performance liquid chromatography 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICF 
Informed Consent Form 
IDSL 
Integrated Data Standards Library 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IND 
Investigational new drug 
INR 
International normalization ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
IU 
International units 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
MCH 
Mean corpuscular Hgb 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MI 
Myocardial infarction 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeters of mercury 
MRI 
Magnetic resonance imaging 
MSDS 
Material Safety Data Sheet 
msec 
Milliseconds 
μM 
Micromolar 
n 
Number 
ND 
Nondialysis dependent 
NOAEL 
No observed adverse effect level 

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NYHA 
New York Heart Association 
OATP 
Organic anion transporting polypeptide 
PAH 
Pulmonary artery hypertension 
PCI 
Potential clinical importance 
PD 
Pharmacodynamic 
%CV 
Coefficient of variation of the mean 
PHD 
prolyl-4-hydroxylases 
PK 
Pharmacokinetic 
PPD 
Pharmaceutical Product Development 
PRVP 
Peak right ventricular pressure 
PSRAE 
Possible Suicidality Related Adverse Events 
PTS 
Platform Technology & Science 
QTc 
Corrected QT interval 
QTcB 
QT duration corrected for heart rate by Bazett’s formula 
R&D 
Research and development 
RAP 
Report and Analysis Plan 
RBC 
Red blood cells 
rh 
Recombinant human 
RNA 
Ribonucleic acid 
SAE 
Serious Adverse Event(s) 
SD 
Standard deviation 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SoA 
Schedule of Activities 
sPAP 
systolic Pulmonary Artery Pressure 
SRM 
Study Reference Manual 
SUSAR 
Suspected unexpected serious adverse reactions 
t½ 
Half life 
TIPS 
Transjugular Intrahepatic Portosystemic Shunt 
Tmax 
Time of occurrence of Cmax 
ULN 
Upper limit of normal 
UK 
United Kingdom 
µM 
Micromolar 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cells 
WOCBP 
Woman of childbearing potential 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
ADVAIR 
 
Chiron RIBA 
 
 
SAS 
 
 
WinNonlin 
 

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12.2. 
Appendix 2: Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Excessive erythropoiesis (polycythemia) 
leading to thrombosis and/or tissue ischemia 
In animal studies, excessive erythropoiesis 
attributed to daprodustat was associated 
with vascular congestion, microthrombi, and 
tissue ischemia in a number of organs. 
 
Phase 2 dose-ranging studies, and associated 
statistical and dose response modelling has 
informed Phase 3 dose rationale, starting 
doses, dose steps, and dose adjustment 
scheme to optimize Hgb management. 
 
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat. 
• Specific eligibility criteria related to 
requirements for entry Hgb are detailed 
in Section 6.1.1 
• Monitoring of emerging safety data by 
an internal GSK Safety Review Team. 
Death, MI, stroke, heart failure, 
thromboembolic events, thrombosis of 
vascular access at Hgb levels which are 
within the normal range (i.e. not 
polycythemic conditions) 
Marketed rhEPOs have been associated with 
an increased risk for death and serious 
cardiovascular events when used in patients 
with anemia of CKD. 
 
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat. 
• Specific eligibility criteria related to CV 
risk are outlined in Section 6.2.1. 
• Monitoring of emerging safety data by 
an internal GSK Safety Review Team. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Esophageal and gastric erosions 
In animal studies, undesirable GI effects 
including emesis, abnormal feces and/or 
decreased food consumption/body weight 
loss and stomach erosions/ulcers with 
hemorrhage were observed with 
daprodustat. 
 
In rodents stomach erosions were observed 
with intravenous and oral administration of 
daprodustat. 
 
Gender-averaged systemic exposure (AUC) 
at the no observed adverse effect levels 
(NOAEL) are 3.3 -fold (monkeys) and 737 -
fold (rats) above human exposure (25 mg 
daprodustat). 
 
In clinical trials to date with daprodustat, 
mild-moderate GI signs and symptoms 
represent the most frequently reported 
adverse event, however causal association 
has not been established. 
 
Following review of clinical data received 
to date, GI erosions have not been identified 
as a safety concern for daprodustat. 
• Suspected GI bleeding or significant 
symptoms consistent with erosions or 
ulcers should be investigated 
diagnostically (i.e. endoscopic 
examination) as clinically warranted. 
• Monitoring of emerging safety data by 
an internal GSK Safety Review Team. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Cancer-related mortality and tumor 
progression and recurrence 
Marketed rhEPOs have been associated with 
increased risk of cancer related morbidity 
and mortality when used in patients with 
cancer. 
 
Administration of 60 mg/kg daprodustat to 
mice caused minimal increases in 
circulating VEGF while significant EPO 
increases were observed. 
 
In clinical studies conducted to date , 
administration of daprodustat has been 
associated with: 
• In studies up to 4 weeks duration, a 
dose-ordered increase in VEGF plasma 
concentrations was observed at doses 
ranging from 10 to 150 mg.  In studies 
up to 24 weeks duration at doses up to 
25 mg, changes in VEGF plasma 
concentrations were variable but similar 
relative to control. 
• Systemic EPO concentrations within the 
physiologic range 
 
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat. 
• Specific eligibility criteria related to 
personal history of malignancy are 
outlined in Section 6.2.1. 
• Monitoring of emerging safety data by 
an internal GSK Safety Review Team. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Pulmonary artery hypertension (PAH) 
A role for HIF-regulated pathways in the 
pathophysiology of PAH has been 
suggested based on well-established effects 
of acute and chronic hypoxia in man on the 
pulmonary vasculature (vasoconstriction), 
and by findings in patients with naturally 
occurring mutations that result in decreased 
HIF degradation [Smith, 2006; Formenti, 
2011]. 
 
There have been no histopathologic findings 
suggestive of PAH in pre-clinical safety 
studies with daprodustat (up to 13 weeks 
duration in mice and dog, up to 26 weeks in 
rat, and up to 39 weeks in monkeys. 
 
Acute hypoxic challenge (rats):  
Daprodustat produced increases in peak 
right ventricular pressure (PRVP) during 
acute hypoxia that were slightly higher than 
the vehicle control group.  These hypoxia-
induced PRVP changes fall within the range 
of PRVP differences noted among non-
treated rats. 
 
Results from a clinical study of acute 
hypoxic challenge in healthy volunteers 
demonstrated that short-term (5 days) 
therapy with daprodustat 5 mg or 100 mg 
had no clinically significant effect on 
• Monitoring of emerging safety data by 
an internal GSK Safety Review Team. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
transthoracic Echocardiographic (ECHO) 
estimates of systolic pulmonary artery 
pressure (sPAP) under either normoxic or 
hypoxic conditions. 
 
ECHO assessments performed in Phase 2b 
studies (24 weeks treatment duration) did 
not identify any clinically-meaningful 
changes in sPAP in participants not on 
dialysis for daprodustat.  In hemodialysis 
participants, mean absolute change from 
baseline in sPAP was similar for both 
treatment groups; however, there was a 
numeric imbalance (Daprodustat: 8 [7%]; 
Control 0) in participants reaching the sPAP 
PCI (>20 mmHg increase from baseline).  
Regarding this imbalance, there were a 
number of confounding factors in the study, 
most notably a 4.5:1 randomization scheme 
and inconsistency in timing of ECHOs 
relative to dialysis day.  Additionally, 2 of 3 
participants with resolution of sPAP on 
safety follow-up ECHOs had confounding 
conditions that could contribute to 
resolution other than discontinuation of 
study treatment; and there was no dose 
relationship for participants meeting the 
sPAP potential clinical importance (PCI) 
criterion.  Overall, there is insufficient 
evidence to conclude a relationship to 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
treatment with daprodustat. 
 
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat. 
Cardiomyopathy 
Published data suggest that cardiac effects 
of HIF stabilization are likely a function of 
the mechanism, extent, and duration of the 
effects, and can range from protective to 
detrimental depending upon the specific 
model and experimental conditions utilized. 
 
Small increases in cardiac troponin in 6 
month rat study with daprodustat were 
consistent with the background finding of 
spontaneous rodent cardiomyopathy 
independent of exposure to daprodustat.  
There were no elevations observed in 
cardiac troponin in 9 month monkey study 
with daprodustat. 
 
Cardiomyopathy has not been associated 
with naturally occurring mutation in man 
which results in increased HIF stabilization. 
 
ECHO assessments performed in phase 2b 
studies (24 weeks treatment duration) did 
not identify any clinically meaningful 
changes in LVEF for daprodustat. 
 
• Monitoring of emerging safety data by 
an internal GSK Safety Review Team 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat. 
Proliferative retinopathy, macular edema, 
choroidal neovascularization 
Increases in local (ocular) VEGF production 
with retinal neovascularization and macular 
edema observed in diabetic retinopathy and 
to choroidal leakage, edema and 
neovascularization seen in age-related 
macular degeneration [Campochiaro, 2006]. 
 
Administration of 60 mg/kg daprodustat to 
mice caused minimal increases in 
circulating VEGF while significant EPO 
increases were observed. 
 
No ocular abnormalities with daprodustat 
were seen in non-clinical studies of up to 13 
weeks duration in mice and dogs, 26 weeks 
in rats, and 39 weeks in monkeys. 
 
In clinical studies up to 4 weeks duration, a 
dose-ordered increase in VEGF plasma 
concentrations was observed at doses 
ranging from 10 to 150 mg.  In studies up to 
24 weeks duration at doses up to 25 mg, 
changes in VEGF plasma concentrations 
were variable but similar relative to control. 
 
Ophthalmologic assessments performed in 
phase 2b studies (24 weeks treatment 
• Suspected proliferative retinopathy, 
macular edema, choroidal 
neovascularization or symptoms 
consistent with these events should be 
investigated by ophthalmologic 
consultation as clinically warranted. 
• Monitoring of emerging safety data by 
an internal GSK Safety Review Team. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
duration) did not identify any clinically 
meaningful changes in proliferative 
retinopathy, macular edema, or choroidal 
neovascularization with daprodustat. 
 
Following review of clinical data with 
daprodustat received to date, this has not 
been identified as a safety concern for 
daprodustat. 
Exacerbation of rheumatoid arthritis 
In inflamed rheumatic joints, activation of 
HIF-related genes secondary to decreased 
oxygen and pro-inflammatory cytokines has 
been postulated to contribute to the neo-
angiogenesis, proliferation and infiltration 
of rheumatoid synovial fibroblasts [Westra 
2010; Muz, 2009]. 
 
No abnormalities seen in non-clinical 
studies conducted to date for daprodustat. 
 
Following review of clinical data received 
to date, this has not been identified as a 
safety concern for daprodustat. 
• Monitoring of emerging safety data by 
an internal GSK Safety Review Team. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Drug-drug interactions 
Co-administration of daprodustat with the 
strong CYP2C8 inhibitor, gemfibrozil 
increased the Cmax and AUC of 
daprodustat, 4- and 19-fold, respectively, 
while co-administration of the weak 
inhibitor, trimethoprim increased the Cmax 
and AUC of daprodustat by 1.3- and 1.5-
fold, respectively.  Population PK analysis 
from completed Phase 2 studies suggests 
that co-administration of daprodustat with a 
moderate CYP2C8 inhibitor (clopidogrel) 
leads to a ~2-fold increase in AUC, with no 
clinically-significant increase in the 
measured Hgb response. 
 
Daprodustat is an inhibitor of CYP2C8 in 
vitro, with an IC50 value of 21 µM. 
Population PK analysis from completed 
Phase 2 studies suggests that co-
administration of daprodustat with 
clopidogrel (a moderate CYP2C8 inhibitor) 
leads to a ~ 2-fold increase in AUC, with no 
clinically-significant increase in the 
measured Hgb response. 
 
Co-administration of daprodustat with 
BCRP inhibitors has the potential to 
increase exposure of daprodustat.  Use of 
BCRP inhibitors was not a significant 
covariate of daprodustat exposure, but was 
• Co-administration of daprodustat with 
the strong CYP2C8 inhibitor, 
gemfibrozil and inducer, 
rifampin/rifampicin is not permitted as 
outlined in Section 7.7.2. 
• Co-administration of daprodustat with 
moderate CYP2C8 inhibitors (i.e., 
clopidogrel, teriflunomide, deferasirox) 
should be performed with caution. 
• Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in 
Section 7.7. 
• Monitoring of emerging safety data by 
an internal GSK Safety Review Team. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
found to result in a small change in 
metabolite exposure (20% increase in 
AUC).  Co-administration of daprodustat 
with BCRP inhibitors [e.g., cyclosporine, 
HIV antivirals (atazanavir, lopinavir, 
ritonavir, tipranavir), lapatanib and 
curcumin] is not expected to produce 
clinically relevant increases in daprodustat 
exposure. 
 
Daprodustat is an inhibitor of organic anion 
transporter polypeptide (OATP) 1B1/1B3 in 
vitro, with IC50 values of 6 µM and 11 µM, 
respectively.  A clinical drug interaction 
study between 100 mg daprodustat with 
either a CYP2C8 substrate or an 
OATP1B1/1B3 substrate showed that there 
is no PK interaction at this dose of 
daprodustat. 

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References 
Campochiaro PA and the first ARVO/Pfizer Institute Working Group et al. Ocular versus 
extraocular neovascularization: Mirror images or vague resemblances. Invest Ophthalmol 
& Vis Sci. 2006; 47:462-474. 
Formenti F, Beer PA, Croft QPP, Dorrington KL, Gale DP, Lappin TRJ, Lucas GS, 
Maher ER, Maxwell PH, McMullin MF, O’Connor DF, Percy MJ, Pugh CW, Ratcliffe 
PJ, Smith TG, Talbot NP, Robbins PA. Cardiopulmonary function in two human 
disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and 
HIF-2α gain-of-function mutation. FASEB J. 2011; 25:2001-2011. 
Muz B, Khan MN, Kiriakidis S, Paleolog EM. The role of hypoxia and HIF-dependent 
signalling events in rheumatoid arthritis. Arthritis Research & Therapy 2009; 11:201-
209. 
Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Leedham DL, Liu C, 
Maxwell PH, Treacy M, Robbins PA. Mutations of von Hippel-Lindau tumour 
suppressor and heman cardiopulmonary physiology. PLos Med. 2006; 3:3290. 
Westra J, Molema G, Kallenberg CG. Hypoxia-inducible factor-1 as regulator of 
angiogenesis in rheumatoid arthritis - therapeutic implications. Curr Med Chem. 2010; 
17:254-63. 
 

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12.3. 
Appendix 3: Clinical Laboratory Tests 
• 
The tests detailed in Table 5 will be performed by the central laboratory. 
• 
Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 5 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Count 
Hemoglobin 
Hematocrit 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and 
direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose 
(nonfasting) 
Calcium 
Alkaline 
phosphatase 
Albumin 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
• Follicle-stimulating hormone and estradiol (as needed in women of 

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Laboratory 
Assessments 
Parameters 
Tests 
non-childbearing potential only) 
• Serum or urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines) 
• Serum or urine human chorionic gonadotropin (hCG) pregnancy 
test2 
• Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody) or specify other tests if applicable  
• PT/INR 
The results of each test must be entered into the CRF. 
NOTES : 
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Section 8.1 and Appendix 7 All events of ALT ≥3 × upper limit 
of normal (ULN) and bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT ≥3 × ULN and international 
normalized ratio (INR) >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), 
must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
2 Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
 

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12.4. 
Appendix 4: Study Governance Considerations 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, 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 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  

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• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study 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.  
• 
Participants who are rescreened are required to sign a new ICF. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings.  If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• 
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 

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Dissemination of Clinical Study Data 
• Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location. 
• GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study 
participants, as appropriate. 
• The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, 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.  
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the 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 Pharmacology Study Report (CPSR)/ equivalent summary unless local 
regulations or institutional policies require a longer retention period.  No records 
may be destroyed during the retention period without the written approval of the 
sponsor.  No records may be transferred to another location or party without 
written notification to the sponsor. 

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Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the 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. 
• 
Definition of what constitutes source data can be found in the SRM. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study treatment development 

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12.5. 
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (eg, 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 

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convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
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 

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jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
Recording 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 sufficiently discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
 

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

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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 h. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 h 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 by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in the SRM. 
 

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12.6. 
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in 
the postmenopausal range is to be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Female participants 
Female participants of childbearing potential that are not currently utilizing a highly-
effective contraceptive method are eligible to participate if a pregnancy test conducted on 
or between Day -7 to Day -4 and again pre-dose (Day -1 or Day 0) is negative.  It is not 
necessary to require participants to start a new contraceptive method if they are not already 
established on one. 
Female participants of childbearing potential that are currently utilizing a highly-effective 
contraceptive method are eligible to participate if they agree to continue to use this 
method consistently and correctly as described in Table 6.  In this instance a negative 

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pregnancy test on or between Day -7 to Day -4 and again pre-dose (Day -1 or Day 0) 
would not be required. 
Table 6 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent1 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb  
• oral 
• intravaginal 
• transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation2 
• injectable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)  
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)  
NOTES:  
1 Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies. 
2 Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the 
contraceptive method.  In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 48 h  after the last dose of study treatment  
 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test at the times listed in the SoA (Section 2) 

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• 
Additional pregnancy testing is not required during the treatment period and at 48 h 
after the last dose of study treatment 
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
• 
Pregnancy testing, with a sensitivity of 2 mIU/mL will be performed using the test 
kit provided by the central laboratory. 
Collection of Pregnancy Information 
Female Participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.  
• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 h of learning of a participant's pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. 
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 6.  While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
Any female participant who becomes pregnant while participating will be withdrawn 
from the study. 
 
 
 
 

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12.7. 
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments 
For the purposes of this protocol, please refer to the guidelines below for the required 
action, monitoring and follow-up assessments if a participant meets any of the criteria 
listed below, after dosing with the study medication. 
Phase I liver chemistry stopping criteria and required follow up assessments for 
Healthy Volunteer Participants 
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 
• 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 
chemistries resolve, stabilise or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
If ALT≥3xULN AND bilirubin < 2xULN  and 
• 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, obtained 48 h of last dose4  
• 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 
• 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 

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Liver Chemistry Stopping Criteria  
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 
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. 
• Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009] 
• 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. Includes: 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. PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the CRF.  If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample.  Instructions for sample handling and 
shipping are in the SRM. 
 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos. 2009; 37:1779-1784. 
 

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12.8. 
Appendix 8:  Grades of Hepatic Encephalopathy 
Grade 
Description 
1 
Trivial lack of awareness, euphoria or anxiety; shortened attention span; impairment of 
addition or subtraction 
2 
Lethargy; disorientation for time; obvious personality changes; inappropriate beharior 
3 
Somnolence to semistupor; responsive to stimuli; confused; gross disorientation; 
bizarre behavior 
4 
Coma; unable to test mental state 
 
References 
Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL. 
Comparison of lactulose and neomycin in the treatment of chronic portalsystemic 
encephalopathy. A double-blind controlled trial. Gastroenterology. 1977; 72:573-583. 
 

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12.9. 
Appendix 9: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).