Clinical trial NCT02243306
Conditions: Anaemia
Keywords: pharmacokinetics Chronic kidney disease peritoneal dialysis hemoglobin Anemia GSK1278863 Prolyl hydroxylase inhibitor erythropoiesis stimulating agents
Sponsor: GlaxoSmithKline
Start date: 2014-10-24; Completion date: 2017-05-10
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
GSK1278863 is an orally-active, novel small molecule agent which inhibits hypoxia-inducible factor (HIF) prolyl -4- hydroxylases (PHDs) and is in development for the treatment of anaemia associated with chronic kidney disease (CKD). As the kidney represents a major site of elimination for many drugs and their metabolites, and GSK1278863 will be administered to subjects with various stages of renal disease, it is important to characterize the pharmacokinetics in this target patient population. The purpose of this study is to characterize the pharmacokinetics of GSK1278863 and its metabolites in subjects with end stage renal disease (ESRD) undergoing peritoneal dialysis. This will be a repeat-dose, open-label, parallel-group study. Approximately 30 subjects with ESRD will be enrolled in two cohorts (15 subjects in each cohort) to ensure that 6 subjects on continuous ambulatory peritoneal dialysis (CAPD) (cohort 1) and 6 subjects on automated peritoneal dialysis APD (cohort 2) complete dosing and critical assessments. GSK1278863 will be administered once daily for 14 days. Primary pharmacokinetic assessments will be made on Days 1 and 14.

Detailed description:

Arms: arm 1: Subjects on continuous ambulatory peritoneal dialysis (CAPD) will receive 5 mg of GSK1278863 orally, once daily for 14 days. arm 2: Subjects on automated peritoneal dialysis (APD) will receive 5 mg of GSK1278863 orally, once daily for 14 days
Interventions: intervention 1: GSK1278863
Intervention descriptions: intervention 1: Round, biconvex, white film coated tablet containing 5 mg GSK1278863.

Protocol documents:
Prot_000.pdf: 
2013N179529_07
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A repeat-dose, open-label, parallel-group study to assess the 
pharmacokinetics of GSK1278863 and metabolites in subjects 
with End Stage Renal Disease undergoing peritoneal dialysis
Compound Number:
GSK1278863
Development Phase:
I
Effective Date:
20-JUN-2016
Protocol Amendment Number:  6 
Author (s):
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2013N179529_00
2014-APR-11
Original
2013N179529_01
2014-JUN-06
Amendment No. 1
Section 4.2.1. Inclusion Criteria, Inclusion#8; hemoglobin levels are updated based on 
the feedback received from FDA. It was ≤11 g/dL for ESA naïve subjects, it is updated as 
<10.0 g/dL; it was ≤12.0 g/dL for subjects receiving ongoing ESA treatment, it is updated 
as ≤11.0 g/dL.
Section 4.2.2. Exclusion Criteria, the numbering of exclusion criteria was inadvertently 
incremented from previous section. The numbering now starts from “1”.
Section 5.3.3. Stopping Criteria; the stopping criteria related to the hemoglobin level is 
updated per the FDA’s feedback received. A previous criterion required subjects to have 
their absolute hemoglobin level ≥13.0 g/dL to stop the dosing. The hemoglobin level for 
stopping the dosing is now updated as >11.0 g/L.
Section 6.1. Time and Events Table, Protocol Activity “Urine Drug and Alcohol Screen” 
is updated as “Drug and Alcohol Screen” with a new footnote “m”. Majority of subjects 
with ESRD undergoing peritoneal dialysis will not be able to produce urine samples. For 
these subjects this screening test will be serum-based.
Section 6.3.2. Vital Signs; body temperature measurement was not included under vital 
signs assessment. It is now included as a part of vital signs assessment since it is a 
measurement performed as a standard practice at the site.Section 6.3.3. 
Electrocardiogram (ECG), instruction for Day -1 ECG measurement is updated as it 
indicated that ECG measurement should be done 2 h prior to dosing. The first dosing day 
is Day 1, and there will be no ECG measurement on the dosing day. This is now 
corrected.
2013N179529_02
2014-JUN-24
Amendment No. 2
Section 6.1. Time and Events Table, Footnote m is revised to make the Drug and Alcohol 
test type flexible. At screening and on Day -1, this test would have been performed urine 
based or alternatively serum based. However, it was recognized that each site has their 
standard tests for this assessment. At the discretion of the investigator, sites will be able 
to use their standard test in order to ensure that the test results will be ready for an 
evaluation prior the dosing. Test will also be performed on Day 13. 
Section 6.1. Time and Events Table, a new footnote, footnote n, is included to clarify 
how hemoglobin can be assessed on Day 3, Day 7, and Day 11 visits. 
2013N179529_03
2014-JUL-01
Amendment No. 3
Section 4.2.2., Inclusion and Exclusion Criteria, the numbering of each criterion was 
inadvertently changed starting from subtitles “Efficacy” and “Other”. After subtitle 


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“Safety”, the numbering was not consecutively increasing for the remaining inclusion and 
exclusion criteria. The inclusion and exclusion criteria numbers were changed to be 
consecutive.  Inclusion criteria numbers now starts from 1 and goes up to 12, exclusion 
criteria numbers start from 1 and goes up to 28.
Section 4.3.3. Caffeine, Alcohol, and Tobacco, the word “sample” was missing after the 
word “the final pharmacokinetic” in the last part of the first sentence, this is now 
included.
2013N179529_04
2014-DEC-12
Amendment No. 4
List of Abbreviations, the abbreviation for kilocalorie, kcal, is listed as it is now included 
in the text.
Regulatory Agency Identifying Number(s), the EudraCT number was inadvertently 
provided as 2013-002681-39 which belongs to phase II program of this compound. The 
EudraCT number is now updated as “2014-001197-34” with this amendment which is the 
correct number for this specific protocol.
Section 4.2.1 Inclusion Criteria, Efficacy, inclusion criteria#5; the urine output and Kt/V 
values were revised for subject’s eligibility after study investigators provided further 
information gathered about these conditions for the subjects who are on peritoneal 
dialysis.
Section 4.2.1. Inclusion Criteria, Efficacy, inclusion#8; hemoglobin levels are updated to 
meet with country specific requirements. For UK only site(s), hemoglobin value is 
updated as ≤11 g/dL for ESA naïve subjects and as ≤12.0 g/dL for subjects receiving 
ongoing ESA treatment.
Section 5.3.3. Stopping Criteria; the stopping criteria related to the hemoglobin level is 
updated to meet with country specific requirements. For UK only site(s), stopping 
criteria for absolute hemoglobin level now is ≥12.0 g/dL to stop the dosing. 
Section 4.2.2. Exclusion Criteria, Safety, exclusion criteria#15; it was revised to be 
flexible for those subjects who have not received their ophthalmology exam within 12 
months prior to Screening, so they may take their exam with a referral from the study 
investigators during Screening period.
Section 4.3.2 Meals and Dietary Restrictions; it was stated that subjects would not 
consume any food and drinks (except water) during 4 h fasting period after dosing on 
Day 1 and Day 14. Based on the initial feedback from one of study sites, some subjects 
on peritoneal dialysis are very hungry after they finish night portion therapy on peritoneal 
dialysis cycler. This is most likely due to the relatively high insulin dose required to 
mitigate high dextrose content in the peritoneal dialysis fluid needed to achieve adequate 
ultrafiltration. Thus this section was revised to allow subjects to have a light snack and a 
beverage which would not exceed 500 kcal during this 4 h fasting period after dosing.
Section 6.4.2. Dialysate Sample Collection, on Day 1 and Day 14, the volume of 
dialysate solution to be collected for analysis was specified as 10 mL aliquot. This is 
revised to 1.5 mL as 10 mL aliquot would have exceeded the required amount for the 
pharmacokinetic analysis.
Section 6.1, Time and Events Table, there was a typo error on the Day of Follow-up visit. 


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It was entered as Day 23. This is now corrected as Day 22.
2013N179529_05
2014-DEC-15
Amendment No. 4 
(Republishing)
The abbreviation “PD” included in Revision Chronology in 2013N179529_04 was 
required to change to “peritoneal dialysis” as “PD” in this protocol refers to 
“Pharmacodynamic”. The abbreviation “PD” in this section could have been 
misinterpreted if it was left as is. Thus, Amendment No. 4 was republished with this 
update in order to prevent any confusions.
2013N179529_06
2015-SEP-10
Amendment No. 5
This protocol amendment is to clarify several sections of protocol text and to confirm that 
there will be informal reviews of the available PK data to assist Phase III development of 
the compound.  Additionally, if during the informal review of the available PK data it is 
determined that there are no clinically-significant differences in PK between the CAPD 
and APD populations, the planned number of subjects may be reduced.  All changes are 
detailed in Appendix 5.   
In order to ensure transparent reporting of screen failure subjects to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and 
respond to queries from Regulatory authorities, a minimal set of screen failure 
information is required including Demography, Screen Failure details, Eligibility Criteria, 
and any Serious Adverse Events.  Section 4.4 has subsequently been updated to 
document that screen failure information is being collected.  The analysis populations 
(Section 9.3.1) have also been expanded to clarify the screen failure population.
Wording in Section 4.3.2 has been amended to clarify the duration for which subjects 
need to avoid consumption of red wine, grapefruit (juice), blood orange (juice), star fruit, 
onions, kale, broccoli, green beans, or apples, specifically are all prohibited from 7 days 
prior to the first dose of GSK1278863 until the Follow-Up visit, unless in the opinion of 
the investigator and GSK Medical Monitor this will not interfere with the study 
procedures and compromise subject safety
Wording in Section 5.10 has been amended to ensure the text is current regarding use of 
concomitant medications. 
The following protocol sections were updated accordingly:
Section 4.1, Section 4.3.2, Section 5.10, Section 9.3.1, Section 9.3.2. Section 11, 
Appendix 5
2013N179529_07
2016-JUN-20
Amendment No. 6
This protocol amendment is to reduce the number of subjects in the study (either cohort)
to a total of 8 completed subjects. This study has been active for 2 years and only 6 (1 
CAPD and 5 APD) subjects have completed the study. Given the recruitment challenges 
in general, and the CAPD population in particular, the protocol was amended to enroll 
ESRD subjects undergoing peritoneal dialysis from either the CAPD or APD population. 


PPD
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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
Fax Number
GSK Address
Primary Medical 
Monitor
M.D.
GlaxoSmithKline
UP4400
1250 S. Collegeville Rd.
Collegeville, 
PA 19426
Secondary 
Medical Monitor
 M.D.,
Ph.D.
GlaxoSmithKline
UP4400
1250 S. Collegeville Rd.
Collegeville, 
PA 19426
Tertiary Medical 
Monitor
M.D.
GlaxoSmithKline
UW2421
709 Swedeland Rd.
King of Prussia, PA 
19406
SAE fax number 
(for use ONLY 
when Inform is 
offline)
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Regulatory Agency Identifying Number(s):  
IND Number: 101, 291
EudraCT: 2014-001197-34
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200942:
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................11
1.
INTRODUCTION....................................................................................................14
1.1.
Rationale ....................................................................................................14
1.1.1.
Study Rationale ...........................................................................14
1.2.
Brief Background ........................................................................................15
1.3.
Clinical Experience to Date.........................................................................15
2.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
3.
STUDY DESIGN ....................................................................................................17
3.1.
Study Design Detail ....................................................................................17
3.2.
Discussion of Study Design ........................................................................18
3.2.1.
Dose Rationale ............................................................................19
3.3.
Risk Management.......................................................................................19
4.
STUDY POPULATION...........................................................................................20
4.1.
Number of Subjects ....................................................................................20
4.2.
Eligibility Criteria .........................................................................................20
4.2.1.
Inclusion Criteria..........................................................................21
4.2.2.
Exclusion Criteria.........................................................................22
4.3.
Lifestyle and/or Dietary Restrictions............................................................25
4.3.1.
Contraception Requirements .......................................................25
4.3.1.1.
Female Subjects.........................................................25
4.3.2.
Meals and Dietary Restrictions ....................................................25
4.3.3.
Caffeine, Alcohol, and Tobacco ...................................................26
4.3.4.
Activity .........................................................................................26
4.4.
Screen and Baseline Failures .....................................................................26
4.5.
Withdrawal Criteria and Procedures............................................................26
4.6.
Subject Completion.....................................................................................27
5.
STUDY TREATMENT ............................................................................................27
5.1.
Investigational Product (GSK1278863).......................................................27
5.2.
Treatment Assignment................................................................................28
5.3.
Subject Specific Dose Adjustment/Stopping Criteria ...................................28
5.3.1.
Liver Chemistry Stopping Criteria ................................................28
5.3.2.
QTc Withdrawal Criteria...............................................................28
5.3.3.
Stopping Criteria..........................................................................29
5.4.
Blinding.......................................................................................................30
5.5.
Packaging and Labeling..............................................................................30
5.6.
Preparation/Handling/Storage/Accountability..............................................30
5.7.
Assessment of Compliance ........................................................................31
5.8.
Treatment of Study Treatment Overdose....................................................32
5.9.
Treatment after the End of the Study ..........................................................32
5.10.
Concomitant Medications and Non-Drug Therapies....................................32
5.10.1.
Permitted Medications .................................................................33
5.10.1.1.
Inhibitors of BCRP......................................................33
5.10.1.2.
Non-Drug Therapies...................................................33
5.10.2.
Prohibited Medications and Non-Drug Therapies.........................33


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5.10.2.1.
Supplements ..............................................................33
5.10.2.2.
NSAIDs ......................................................................34
5.10.2.3.
Immunosuppressants .................................................34
5.10.2.4.
Inhibitors and inducers of CYP2C8.............................34
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................34
6.1.
Time and Events Table...............................................................................36
6.1.1.
Study Procedures and Assessments for Plasma PK, EPO, 
Hepcidin & Protein Binding Sampling on Day 1 and Day 
14 ................................................................................................39
6.2.
Demographic/Medical History Assessments ...............................................40
6.3.
Safety .........................................................................................................40
6.3.1.
Physical Exams ...........................................................................40
6.3.2.
Vital Signs....................................................................................40
6.3.3.
Electrocardiogram (ECG).............................................................40
6.3.4.
Clinical Laboratory Assessments .................................................41
6.4.
Pharmacokinetics .......................................................................................42
6.4.1.
Blood Sample Collection..............................................................42
6.4.2.
Dialysate Sample Collection ........................................................43
6.4.3.
Sample Analysis ..........................................................................43
6.5.
Pharmacodynamic (PD) Markers................................................................43
6.5.1.
PD Sample Collection (EPO and Hepcidin)..................................43
6.6.
Pharmacogenetics......................................................................................44
7.
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, PREGNANCY AND 
MEDICAL DEVICES INCIDENTS...........................................................................44
7.1.
Adverse Events (AE) and Serious Adverse Events (SAEs).........................44
7.1.1.
Time period for collecting AE and SAE information......................44
7.1.2.
Method of Detecting AEs and SAEs.............................................45
7.1.3.
Definition of Adverse Events........................................................45
7.1.4.
Definition of Serious Adverse Events...........................................46
7.1.5.
Cardiovascular Events.................................................................47
7.1.6.
Death Events...............................................................................48
7.1.7.
Prompt Reporting of SAEs to GSK...............................................48
7.1.8.
Regulatory Reporting Requirements for SAEs .............................48
7.2.
Pregnancy ..................................................................................................48
7.2.1.
Time period for collecting pregnancy information.........................48
7.2.2.
Action to be taken if pregnancy occurs ........................................49
8.
DATA MANAGEMENT ...........................................................................................49
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................49
9.1.
Hypotheses and Treatment Comparisons...................................................50
9.2.
Sample Size Considerations.......................................................................50
9.2.1.
Sample Size Assumptions ...........................................................50
9.2.2.
Sample Size Sensitivity................................................................50
9.2.3.
Sample Size Re-estimation..........................................................50
9.3.
Data Analysis Considerations .....................................................................51
9.3.1.
Analysis Populations....................................................................51
9.3.2.
Interim Analysis ...........................................................................51
9.3.2.1.
Final Analyses............................................................51
9.3.2.2.
Safety Analyses..........................................................52


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9.3.2.3.
Pharmacokinetic Analyses..........................................52
9.3.2.3.1.
Plasma PK Parameters ..........................52
9.3.2.3.2.
Using the pooled estimate of 
variance, 90% confidence 
intervals will be calculated for Rs, 
and back-transformed to the 
original scale.Dialysate PK 
Parameters.............................................54
9.3.2.4.
Pharmacodynamic/Biomarker Analyses .....................54
9.3.2.5.
Pharmacogenetic Analysis .........................................54
10. STUDY GOVERNANCE CONSIDERATIONS........................................................54
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............54
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................54
10.2.1.
Urgent Safety Measures ..............................................................55
10.3.
Quality Control (Study Monitoring) ..............................................................55
10.4.
Quality Assurance.......................................................................................55
10.5.
Study and Site Closure ...............................................................................56
10.6.
Records Retention......................................................................................56
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................57
11. REFERENCES.......................................................................................................58
12. APPENDICES........................................................................................................60
12.1.
Appendix 1: Liver Safety Process ...............................................................60
12.2.
Appendix 2: Pharmacogenetic research .....................................................63
12.3.
Appendix 3: PK, EPO, Hepcidin, and Protein Binding Sampling 
Scheduled Times and Allowed Deviations ..................................................68
12.4.
Appendix 4: Procedures for Detection, Evaluation, Follow-Up and 
Reporting of Adverse Events and Medical Device Incidents .......................69
12.5.
Appendix 5: Investigational Product (GSK1278863) Information.................72
12.6.
Appendix 6: Protocol Amendment Changes................................................74


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LIST OF ABBREVIATIONS
-HCG
Beta-Human Chorionic Gonadotropin
µg
Microgram
µL
Microliter
AB
Antibody
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AMD
Age-related macular degeneration
APD
Automated peritoneal dialysis
AST
Aspartate aminotransferase (SGOT)
AUC(0-
)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
AUC(0-)
Area under the concentration-time curve over the dosing interval
BCRP
Breast Cancer Resistance Protein
BP
Blood pressure
BUN
Blood urea nitrogen
CAPD
Continuous ambulatory peritoneal dialysis
CI
Confidence Interval
CKD
Chronic kidney disease
CLCR
Creatinine clearance
CLr
Renal clearance
Cmax
Maximum observed concentration 
CO2
Carbondioxide
CPK
Creatine phosphokinase
CRF
Case Report Form
CV
Coefficient of variance
CYP
Cytochrome P450 enzyme
Cτ
Pre-dose (trough) concentration at the end of the dosing interval
DILI
Drug Induced Liver Injury
dL
decilitre
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
eGFR
Estimated Glomerular Filtration Rate
EGLN
Egg-laying deficiency protein nine-like protein
EPO
Erythropoietin
ESA
Erythropoiesis stimulating agent
ESRD
End stage renal disease
FDA
Food and Drug Administration
Fe
Iron
FSH
Follicle Stimulating Hormone
g
Gram
GCP
Good Clinical Practice


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GGT
Gamma glutamyl transferase
GI
Gastro intestine
GSK
GlaxoSmithKline
h
Hour(s)
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HDD
Hemodialysis-dependent
HIF
Hypoxia-inducible factor
HIV
Human Immunodeficiency Virus
HR
Heart rate
HRT
Hormone replacement therapy
HWE
Hardy-Weinberg Equilibrium
IB
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IDSL
Integrated Data Standards Library
IEC
Independent ethics committee
IND
Investigational New Drug
INR
International Normalized Ratio
IP
Investigational product
IRB
Institutional Review Board
IU
International units
IUD
Intrauterine device
IUS
Intrauterine system
K
Dialyzer clearance of urea
kcal
kilocalorie
KDOQI
Kidney Disease Outcomes Quality Initiative
Kg
Kilogram
L
Liter
LFTs
Liver function tests
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
Mg
Milligrams
mL
Milliliter
mmHg
Millimeters of mercury
MSDS
Material Safety Data Sheet
msec
Milliseconds
NDD
Non-dialysis dependent
NKF
National Kidney Foundation
nM 
nanomolar
NOAEL
No observed adverse effect level
NSAIDs
Non-steroidal anti-inflammatory drugs
NYHA
New York Heart Association


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OATP
Organic anion transporting polypeptide
ºC
Celsius
ºF
Fahrenheit
PD
Pharmacodynamic
pg
picogram
PGx
Pharmacogenetics
PHD
prolyl -4- hydroxylases
PK
Pharmacokinetic
pmol
picomoles
QTc
Corrected QT interval
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
R&D
Research and Development
RBC
Red blood cells
rhEPO
Recombinant erythropoietin
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SD
Standard deviation
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SPM
Study Procedures Manual
t
time
t½
Terminal phase half-life
TIBC
Total iron binding capacity
tmax
Time of occurrence of Cmax
UK
United Kingdom
ULN
Upper limit of normal
US
United States
V
volume
WBC
White blood cells
μM
micromolar
τ
Dosing interval
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Chiron RIBA
Procrit
WinNonlin


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1.
INTRODUCTION
1.1.
Rationale
1.1.1.
Study Rationale
The purpose of this study is to characterize the pharmacokinetics (PK) of GSK1278863 
and its metabolites in subjects with End Stage Renal Disease (ESRD) undergoing 
peritoneal dialysis, one of the target populations for Phase 3 studies.  
Peritoneal dialysis represents a treatment modality for subjects with ESRD as an 
alternative to hemodialysis for removal of waste from the blood normally eliminated by 
the kidneys.  Although peritoneal dialysis may allow greater freedom for subjects with 
ESRD to carry out normal activities of life, it is potentially less efficient at removing 
these wastes.  In particular, subjects undergoing peritoneal dialysis have different 
clearances of waste products that can affect the disposition of drugs.  As GSK1278863 is 
to be administered to anemic subjects with ESRD undergoing peritoneal dialysis, it is 
important to characterize the PK in this target patient population.
One modality of peritoneal dialysis is known as Continuous Ambulatory Peritoneal 
Dialysis (CAPD) and involves 3-5 manual exchanges per day of dialysis solution into the 
peritoneal cavity with a 4 to 8 hour dwell time. Automated Peritoneal Dialysis (APD) 
employs an automated peritoneal dialysis device, called cycler to perform between 4 and 
6 exchanges during the night time. Patients may drain completely or have additional 
dialysis solution fill in the morning after last drain on cycler. Additional automated or 
manual exchange may be added during the day.  
For the majority of patients, both peritoneal dialysis modalities are considered essentially 
equivalent, therefore, selection of modality typically is based on patient life style and
preference, with APD allowing more free time during the day. As the proportion of 
peritoneal dialysis patients using either modality is approximately equal globally, it is 
considered important to enroll ESRD subjects on both CAPD and APD.
In vitro pharmacology has shown that all major metabolites of GSK1278863 are 
pharmacologically active and show pIC50s > 8 (<10 nM), comparable to the parent 
compound GSK1278863 for human prolyl -4- hydroxylases (PHDs).  Therefore, there is 
the potential that the metabolites also may contribute to the clinical pharmacodynamics 
(PD) and therapeutic activity of GSK1278863.  While a previous clinical study of 
GSK1278863 in subjects with impaired renal function had demonstrated that parent 
GSK1278863 has similar pharmacokinetic characteristics to subjects with normal renal 
function (Study PHI112843). Preliminary PK data suggests that the major metabolites of 
GSK1278863 have prolonged half-lives compared to parent GSK1278863, with some 
metabolites accumulating upon repeat-dose administration in subjects with chronic 
kidney disease (CKD; Study PHI115573).  Full PK profiles of GSK1278863 and 
metabolites have not been collected following repeat-dose administration to the ESRD 
population undergoing peritoneal dialysis; therefore, the purpose of this study is to fully 
characterize the PK of GSK1278863 and metabolites following repeat-dose 
administration to this population.  This open-label study will evaluate the PK of parent 


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GSK1278863 and metabolites in two cohorts of ESRD subjects undergoing peritoneal 
dialysis.
The effective date of the original protocol is 11-APR-2014. In the 2 years that the study 
has been active, only 6 subjects have completed the study. This includes 1 CAPD and 5
APD subjects. Considering the difficulties with recruitment in general, and the CAPD 
population in particular, this protocol will be amended to enroll ESRD subjects 
undergoing peritoneal dialysis of either modality (i.e., CAPD or APD). In addition, in a 
previous study (PHI115573), the pharmacokinetic properties of daprodustat and the 
predominant metabolites were able to be adequately characterized in an ESRD population 
undergoing hemodialysis with 8 subjects. Finally, preliminary results from this study has 
shown that a subject using CAPD had similar PK to the 3 subjects using APD suggesting 
that, if there are differences in the PK of daprodustat depending upon the peritoneal 
dialysis modality, they are likely to be not considered clinically significant.
1.2.
Brief Background
Anemia is frequently present in patients with CKD, patients receiving chemotherapy, and 
patients with various chronic diseases.  Anemia may result from several causes, including 
factors which shorten red blood cell life span, vitamin deficiency, uremia, iron 
deficiency, inflammation, and insufficient production of erythropoietin (EPO).  
Erythropoiesis-stimulating agents (ESAs), such as recombinant human erythropoietin
(rhEPO), are commonly used in the treatment of patients with anemia, particularly 
anemia associated with chronic kidney disease.
Under hypoxic conditions, the hypoxia-inducible factor (HIF)-prolyl hydroxylases 
(PHDs) are inhibited, resulting in the accumulation of unhydroxylated HIFα subunits.  
These HIFα subunits dimerize with HIFβ subunits to effect the transcription of HIF-
responsive genes, including the gene responsible for the production of EPO and others 
involved in increasing oxygen utilization (e.g., transferrin, heme oxygenase 1).  Other 
functions regulated by HIFs include iron metabolism and utilization, angiogenesis, 
extracellular matrix metabolism, apoptosis, energy and glucose metabolism, vascular 
tone, cell adhesion, and motility (Haase, 2013).
GSK1278863 is a novel, orally-available, small molecule agent which stimulates 
erythropoiesis through inhibition of PHDs, mimicking the hypoxic state.  This activity 
leads to increased transcription of HIF-responsive genes including the gene responsible 
for the production of EPO.  This pharmacodynamic activity simulates components of the 
natural response to exposure to hypoxia.
1.3.
Clinical Experience to Date
As of 28 August 2015, GSK1278863 has been administered as single oral doses ranging 
from 2 to 500 mg to 235 healthy, adult male and female subjects in nine completed 
Clinical Pharmacology and Biopharmaceutical studies (PHX111427, PHI112842, 
PHI112843, PHI116008, PHI115573, PHI113635, PHI113634, PHI114703, PHI115385) 


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and administered once daily (15 to 100 mg) or 25 mg twice daily for up to 14 days 
duration to 20 healthy subjects in completed study PHI112842.
Additionally, oral GSK1278863 has been administered to 234 subjects with CKD.  
Twelve CKD subjects received two doses of up to 150 mg GSK1278863 (PHI112843).  
Fourteen CKD subjects received 5 mg GSK1278863 for up to 15 days (PHI115573).  
Sixty-one non-dialysis dependent (NDD; Stage 3 to 5) and 31 hemodialysis-dependent 
(HDD; Stage 5) anemic CKD subjects received 10 mg to 100 mg GSK1278863 for up to 
28 days in Study PHI112844.  Fifty-four subjects with anemia associated with CKD 
(Stage 3/4/5) who were not taking rhEPO and who were not undergoing dialysis received 
0.5, 2 or 5 mg GSK1278863 for up to 28 days (Study PHI116581).  Sixty-two Stage 5 
HDD subjects with anemia associated with CKD switching from stable rhEPO to 
GSK1278863 received 0.5, 2 or 5 mg GSK1278863 for up to 28 days (Study 
PHI116582).
Details of the completed studies, as well as available safety, pharmacokinetic and 
pharmacodynamic (PD) data, may be found in the Investigator’s Brochure (IB) for 
GSK1278863 [GlaxoSmithKline Document Number RM2008/00267/07] and associated 
IB Supplements [GlaxoSmithKline Document Number 2015N266524_00, 17-Dec-2015; 
GlaxoSmithKline Document Number 2015N266524_01, 08-Apr-2016].
2.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary
Characterize the steady-state PK of 
GSK1278863 and metabolites (GSK2391220 
(M2), GSK2506104 (M3), GSK2487818 (M4), 
GSK2506102 (M5), GSK2531398 (M6), 
GSK2531401 (M13) in ESRD subjects 
undergoing peritoneal dialysis

AUC(0-τ), AUC(0-∞) (Day 1 only), and 
Cmax of GSK1278863 and metabolites on 
Day 1 and Day 14
Secondary
Evaluate the safety and tolerability of 
GSK1278863 in ESRD subjects undergoing 
peritoneal dialysis

Subject incidence of treatment-emergent 
adverse events, including clinically-
significant changes in physical exams, 
laboratory safety tests, ECG and vital 
signs
Characterize the peritoneal dialysis clearance 
of GSK1278863 and metabolites in ESRD 
subjects undergoing peritoneal dialysis

Peritoneal dialysis clearance, tmax and t½ 
of GSK1278863 and metabolites on Day 1 
and Day 14 

Accumulation ratio and time invariance 
ratio (as data permit) of GSK1278863 and 
metabolites 


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Objectives
Endpoints
Characterize the plasma profile of 
erythropoietin and hepcidin after repeat-dose 
administration of GSK1278863 in ESRD 
subjects undergoing peritoneal dialysis

Erythropoietin and hepcidin plasma 
concentrations
Exploratory
Characterize the plasma protein binding of 
steady-state GSK1278863 and select 
metabolites in ESRD subjects undergoing 
peritoneal dialysis

Steady-state GSK1278863 and metabolite 
unbound concentration and free fraction
Exploratory
Characterize the effect of different peritoneal 
dialysis solutions on GSK1278863 and 
metabolites in ESRD subjects undergoing 
peritoneal dialysis

Descriptive summary of GSK1278863 and 
metabolite PK by different peritoneal 
dialysis solutions utilized
3.
STUDY DESIGN
3.1.
Study Design Detail
This is a repeat-dose, open label, 2 cohort study to assess the pharmacokinetics of 
GSK1278863 and metabolites in ESRD subjects undergoing peritoneal dialysis.
GSK1278863 (5 mg) will be orally administered once daily for 14 days to approximately 
12 ESRD subjects; 

Cohort 1 will enrol subjects on continuous ambulatory peritoneal dialysis 
(CAPD) to complete all dosing and critical assessments

Cohort 2 will enrol subjects on automated peritoneal dialysis (APD) to
complete all dosing and critical assessments.  
Once a total of 8 subjects across both cohorts collectively have completed the trial,
enrolment will be stopped and the study will be concluded. 
A sufficient number of ESRD subjects undergoing peritoneal dialysis will be enrolled in 
this study in order to ensure that at least 8 subjects total complete dosing and all critical 
assessments. However, if during an informal review of available PK data it is determined 
that the PK appears to be adequately characterized, the planned number of subjects may 
be reduced.
Blood samples for primary PK assessment will be collected on Day 1 and Day 14. 
To determine subject eligibility for enrolment in the study, a screening visit will be 
performed within 30 days of the start of dosing (prior to Day 1).  


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Subjects who are deemed eligible and sign the informed consent may remain in residence 
at the site from the afternoon of Day -1 through the last assessment on Day 17, at the 
discretion of the investigator or by request of the subject. Subjects will be offered to stay 
in residence at the study site (inpatient) or they are allowed to remain at home 
(outpatient) throughout the study. For subjects that choose to participate in the study as 
an outpatient, they will be released from the clinic and must return to the clinic for 
scheduled assessments.
At a minimum, study staff must ensure that subjects are in residence at the site on full PK 
Days (Day 1 and Day 14), as well as on Days 15, and16 for 48 and 72 h PK sampling.
All subjects are required to return to the unit 8 (+2) days from the last dose of 
GSK1278863 for a follow-up visit.
3.2.
Discussion of Study Design
The purpose of this study is to characterize the pharmacokinetics of GSK1278863 and 
metabolites in ESRD patients undergoing peritoneal dialysis.  To date, GSK1278863 has 
not been administered to this patient population, and there have been differences in the 
PK of the metabolites in subjects with CKD (Stage 3/4), both in subjects not on dialysis 
as well as in subjects undergoing hemodialysis, as compared to subjects with normal 
renal function.
In this study, subjects will receive GSK1278863 for 14 days.  Steady-state parent and 
metabolite PK have been evaluated after repeat-dose administration of 5 mg 
GSK1278863 in healthy subjects and subjects with renal impairment (Stage 3/4 NDD and 
Stage 5 HDD) in Study PHI115573.  PK of parent GSK1278863 was generally similar 
across healthy, NDD, and HDD subjects; slightly (16%) higher AUC was observed in 
HDD subjects on a dialysis day (GSK1278863 dosed ~2 h prior to dialysis) compared to 
a non dialysis day.
Compared to healthy subjects, steady-state metabolite exposures were 2.3 to 3.6-fold 
higher in NDD subjects, 1.8 to 3.3-fold higher in HDD subjects on a dialysis day, and 
3.0 to 6.9-fold higher in HDD subjects on a non-dialysis day.  
In HDD subjects, metabolites demonstrated 1.7 to 2.3-fold higher exposure on a non-
dialysis day compared to a dialysis day.  Metabolite PK reached steady-state by 14 days.
Since no placebo treatment group is required in this PK study, an open-label study design 
will be used.  
Plasma biomarker concentrations of on-target effects (erythropoietin and hepcidin) will 
be obtained to examine the time course of changes in erythropoietin and hepcidin after a 
5 mg dose.  
Samples for assessment of steady-state plasma protein binding will be collected (3 
samples to obtain approximate peak and trough concentrations of GSK1278863 and 
metabolites, M4 (GSK2487818) and M5 (GSK2506102).  Samples (aliquots) from the 


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peritoneal dialysis fluid (dialysate) will be collected for determination of clearance of 
GSK1278863 and metabolites at steady-state on Day 14.
3.2.1.
Dose Rationale
A 5 mg 14-day repeat dose schedule was selected for this study to allow direct 
comparison to a recent study with a similar study design in subjects with normal, Stage 
3/4, and Stage 5 (HDD) renal function (PHI115573).
In previous studies, single oral doses of 50 mg and 150 mg, and repeat oral doses 
between 0.5 mg and 100 mg for up to 28 days have been well tolerated in subjects with 
CKD.  
In a prior Phase IIa study, GSK1278863 was administered to Stage 5 HDD subjects who 
had been on rhEPO and switched to doses of 0.5 mg, 2 mg or 5 mg (Study PHI116582).  
In the study, switching from rhEPO to 5 mg GSK1278863 had a similar effect on 
maintaining Hgb over 4 weeks as continuing rhEPO.  To avoid a potential rapid increase 
in hemoglobin that has been observed with repeat doses > 10 mg, a 5 mg dose is 
appropriate for PK investigation in this study.  
Further, in a study (PHI115573) conducted in subjects with various stages of CKD, no 
safety concerns were found with a 5 mg oral dose.  
Finally, a 5 mg dose is anticipated to lead to quantifiable plasma levels of parent and 
metabolites, permitting characterization of the pharmacokinetics.
3.3.
Risk Management
Non-clinical data to date have not identified prohibitive risks associated with 
GSK1278863 at the exposures planned for this study.  Overall, the compound has been 
generally well tolerated with no clinically significant safety-related findings observed to 
date following administration of up to 500 mg single dose and up to 100 mg once daily 
for 14 days in healthy subjects and up to 100 mg once daily for 28 days in CKD patients.  
Please refer to the GlaxoSmithKline Investigator’s Brochure [GlaxoSmithKline 
Document Number. RM2008/00267/07, 14 October 2015] and associated IB 
Supplements for GSK1278863 [GlaxoSmithKline Document Number 2015N266524_00, 
17-Dec-2015; GlaxoSmithKline Document Number 2015N266524_01, 08-Apr-2016] for 
additional pre-clinical and clinical details.
To minimize risks to participants, eligibility criteria, safety monitoring, and stopping 
criteria are incorporated into the study design. 
Based on the non-clinical studies, the primary areas of interest for GSK1278863 are 
related to GI tolerability (e.g., stomach erosions with bleeding) and potential for 
thrombosis and/or tissue ischemia secondary to excessive erythropoiesis.  
In addition, several events of special interest have been identified based on clinical 
experience with ESAs including increased risk of cancer related morbidity and mortality 


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and increased risk of major cardiovascular events (e.g., death, stroke, myocardial 
infarction, congestive heart failure).  
Lastly based on what is currently known of the possible roles for HIF-regulated pathways 
in mediating hypoxia associated pathophysiology, pulmonary artery hypertension, 
cardiomyopathy, and tissue neo-vascularization (e.g., retinal, joint synovium) have also 
been identified as areas of special interest. 
Although no relevant safety findings related to these areas of special interest have been 
noted in animal or clinical studies conducted to date, where appropriate, specific 
eligibility criteria or monitoring instructions relevant to these theoretical concerns are 
included in the study protocol.  For example, subjects who are at high risk for thrombotic 
events or malignancy, or who have underlying significant retinal vascular disorders, 
significant pulmonary disease (including pulmonary hypertension), or inflammatory 
conditions such as rheumatoid arthritis are not eligible to participate.  
Hematologic parameters will be closely monitored throughout the dosing period with 
guidance provided regarding discontinuation of dosing.  Stopping criteria or specific 
suggestions for diagnostic evaluations are also provided for gastrointestinal, visual, 
pulmonary, and joint related adverse events.
4.
STUDY POPULATION
4.1.
Number of Subjects
Approximately 24 subjects with ESRD may be enrolled (12 subjects in each cohort) 
considering high dropout in the study to ensure completion of 8 evaluable subjects
complete dosing and critical assessments.  If subjects prematurely discontinue the study, 
additional subjects may be enrolled as replacement subjects at the discretion of the 
Sponsor in consultation with the investigator.
4.2.
Eligibility Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on GSK1278863 that may impact subject eligibility is 
provided in the GSK1278863 IB [GlaxoSmithKline Document Number 
RM2008/00267/07] and associated IB Supplements for GSK1278863 [GlaxoSmithKline 
Document Number 2015N266524_00, 17-Dec-2015; GlaxoSmithKline Document 
Number 2015N266524_01, 08-Apr-2016].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential.


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4.2.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
Safety
1.
Satisfactory medical evaluation based upon medical history, medication history, 
physical examination, and clinical laboratory data obtained at the Screening visit.  
The determination of clinical significance will be made by the Investigator and the 
GSK Medical Monitor and will require that the finding is unlikely to introduce 
additional risk factors or interfere with the study procedures, or the integrity of the 
study.
2.
QTc < 470 msec OR QTc < 480 msec in subjects with Bundle Branch Block. These 
should be based on average of triplicate values obtained over a brief recording period 
at Screening and on Day -1 and the single reading on Day 17.   The same QT 
correction formula should be used to determine inclusion and discontinuation for any 
individual subject throughout the study.
3.
Vitamin B12 and folate above the lower limit of normal at Screening.
4.
AST, ALT, and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%).
Efficacy
5.
A subject is eligible to enroll and participate in this study if he/she has ESRD and is 
on peritoneal dialysis for at least 2 months with a combined weekly (urine and 
peritoneal dialysis output) Kt/V urea > 1.7 measured at any time within last 3 
months.
6.
No history of peritoneal dialysis-associated peritonitis, peritoneal catheter tunnel 
(exit site) infection or leakage for at least 3 months before study.
7.
Meets the following erythropoiesis stimulating agent (ESA) criteria:

Is ESA naive (i.e., no ESA use within the previous 12 weeks of screening) 
OR

Agrees to discontinue ESA (if currently using ESA) for at least 7 days prior to 
first dose of GSK1278863 until completion of Follow-up visit.
a.
If the subject has a scheduled ESA interval which is ≤7 days, ESA 
treatment must be discontinued for at least 7 days prior to first dose of 
GSK1278863
b. If the subject has a scheduled ESA interval which is > 7 days, ESA 
treatment must be discontinued for at least the scheduled interval 
length (e.g., if ESA interval is 14 days, then ESA must be discontinued  
for 14 days) prior to the first dose of GSK1278863
8.
Has a hemoglobin value:

For ESA naïve subjects: <10.0 g/dL 


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
For subjects receiving ongoing ESA treatment: stable Hgb 9.0-11.5 g/dL. 
Other
9.
Subjects who are ≥ 18 years of age at the time of Screening.
10. A female subject is eligible to participate if she is of:

Childbearing potential, and agrees to use one of the contraception methods 
described in the protocol. This criterion must be followed from the time of 
Screening until completion of the Follow-up Visit.

Non-childbearing potential, defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy; or postmenopausal defined as 
12 months of spontaneous amenorrhea  (In questionable cases, a blood sample 
with simultaneous follicle stimulating hormone (FSH) 23.0-116.3 IU/L and 
estradiol ≤10 pg/mL (or ≤37 pmol/L) is confirmatory).  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the contraception methods described in the protocol if 
they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of post-menopausal status prior to study 
enrollment. For most forms of HRT, at least 2 months must elapse between the 
cessation of therapy and the blood draw; this interval depends on the type and 
dosage of HRT. Following confirmation of their post-menopausal status, they 
can resume use of HRT during the study without use of a contraceptive 
method.  
11. Body weight > 45 kg and < 140 kg at Screening.
12. The subject is mentally and legally able to comply with the requirements and 
restrictions of the protocol and has provided signed informed consent prior to 
participation in any protocol-specific procedures, including Screening procedures.
4.2.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
Safety
1.
A positive test for HIV antibody.
2.
Uncontrolled hypertension (diastolic BP >100 mmHg or systolic BP >170 mmHg) at 
Screening.
3.
History of drug abuse or dependence within 6 months of the study.
4.
History of sensitivity to GSK1278863, or its components thereof or a history of drug 
or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, 
contraindicates their participation.
5.
History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinical 
research unit uses heparin to maintain intravenous cannula patency).


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6.
History of thrombosis defined as deep vein thrombosis, stroke, pulmonary embolism 
or other thrombosis related condition within 3 months prior to Screening.
7.
History of myocardial infarction or acute coronary syndrome within 3 months prior 
to Screening.
8.
History of stroke or transient ischaemic attack within 3 months prior to Screening.
9.
Subjects with a pre-existing condition interfering with normal gastrointestinal 
anatomy or motility, and/or hepatic function that could interfere with the absorption, 
metabolism, and/or excretion of GSK1278863. Examples of conditions that could 
interfere with normal gastrointestinal anatomy or motility include gastrointestinal 
bypass surgery, partial or total gastrectomy, small bowel resection, vagotomy, 
malabsorption, Crohn’s disease, ulcerative colitis, or celiac sprue. Examples of 
conditions that could interfere with hepatic function include Gilbert’s syndrome.
10. Evidence of active peptic, duodenal or esophageal ulcer disease at Screening OR
history of clinically significant GI bleeding within 3 months prior to Screening.  
11. Subjects with chronic inflammatory disease that could impact erythropoiesis
(e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac 
disease).
12. Subjects with a history of symptomatic right heart failure.
13. Subjects with Class III or Class IV heart failure, as defined by the New York Heart 
Association (NYHA) functional classification system. 
14. Active malignancy or diagnosis of malignancy within 5 years prior to Screening 
(excluding successfully treated basal or squamous cell carcinoma).
15. History of proliferative vascular eye disease (e.g., choroidal or retinal disease, such 
as neovascular age-related macular degeneration, proliferative diabetic retinopathy or 
macular edema) based upon having had an ophthalmologic exam within 12 months 
prior to the end of the Screening period (The screening period is from the screening 
visit until Day -1). 
16. Pregnant females as determined by positive serum -hCG test at Screening or Day -1.
17. Lactating females.
18. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within a 56 day period prior to first dose.
19. Consumption of red wine, grapefruit (juice), blood orange (juice), star fruit, onions, 
kale, broccoli, green beans, or apples from 7 days prior to the first dose of 
investigational product until the Follow-up visit, unless in the opinion of the 
Investigator and GSK Medical Monitor this will not interfere with the study 
procedures and compromise subject safety. 
20. Use or planned use of any prescription or non-prescription drugs that are prohibited 
(see Section 5.10.2) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) prior to the first dose of GSK1278863 
until completion of the follow-up visit, unless in the opinion of the Investigator and 
GSK Medical Monitor the medication will not interfere with the study procedures or 
compromise subject safety.


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21. The following medications are specifically prohibited for the duration of the study 
(from Screening to the follow-up visit at the end of the study):

Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) with the 
exception of low dose (≤325 mg/day) aspirin/acetylsalicylic acid.  Occasional 
NSAID use is permitted (refer to Section 5.10.2.2).

Immunosuppressant drugs and drugs used to treat malignancies (including 
corticosteroids at doses >10 mg prednisolone per day or equivalent) within 2 
weeks of first dose of GSK1278863. 
Note: Failed transplant subjects back on peritoneal dialysis are eligible for 
participating in this study but should not be on immunosuppressive medications 
within 3 months prior to Screening.
22. The subject has participated in a clinical trial and has received an experimental 
investigational product within the following time period prior to the first dosing day 
in the current study: 30 days, 5 half-lives or twice the duration of the biological 
effect of the investigational product (whichever is longer).
Efficacy
23. The most recent values of ferritin and transferrin within 3 months prior to Screening 
are:
a. transferrin saturation < 20% 
b. serum ferritin < 100 μg/L
Other
24. A positive pre-dosing drug/alcohol screen. A minimum list of drugs that will be 
screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines. A positive pre-dosing screen for medications that are prescribed to 
a renal subject for pre-existing condition(s), may be allowed if in the opinion of the 
Investigator and GSK Medical Monitor the medication will not interfere with the 
study procedures or compromise subject safety.
25. History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of > 21 units for males or > 14 units for females. One unit is 
equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine 
or 1 (25 mL) measure of spirits.
26. History of regular use within 6 months of the study of tobacco- or nicotine-
containing products in excess of 20 cigarettes per day or equivalent.
27. Unwillingness or inability to follow the procedures, or lifestyle and/or dietary 
restrictions outlined in the informed consent and as directed by site staff.
28. Subject is either an immediate family member of a participating Investigator, study 
coordinator, employee of an Investigator; or is a member of the staff conducting the 
study.


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4.3.
Lifestyle and/or Dietary Restrictions
4.3.1.
Contraception Requirements
4.3.1.1.
Female Subjects
Female subjects of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%.  
Female subjects of childbearing potential with same sex partners (when this is their 
preferred and usual lifestyle) are not required to be abstinent or to use contraception.
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Contraceptive Methods with a Failure Rate of 1%

Oral contraceptive, either combined or progestogen alone

Injectable progestogen 

Implants of etonogestrel or levonorgestrel

Estrogenic vaginal ring

Percutaneous contraceptive patches

Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure 
rate as stated in the product label

Documented male partner sterilization prior to the female subject's entry into the 
study, and this male is the sole partner for that subject.  For this definition, 
“documented” refers to the outcome of the investigator's/designee’s review of the 
subject's medical history for study eligibility, as obtained via a verbal interview with 
the subject or from the subject’s medical records.
NOTE: These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label.  The Investigator is 
responsible for ensuring subjects understand how to properly use these methods of 
contraception.
4.3.2.
Meals and Dietary Restrictions

Consumption of red wine, grapefruit (juice), blood orange (juice), star fruit, onions, 
kale, broccoli, green beans, or apples is prohibited from 7 days prior to the first 
dose of GSK1278863 until the Follow-Up visit, unless in the opinion of the 
investigator and GSK Medical Monitor this will not interfere with the study 
procedures and compromise subject safety.


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
Subjects will refrain from any food and drink (except water) at least 4 h before 
dosing on Day 1 and Day 14.  On Day 1 and Day 14 subjects will be allowed a light 
snack (e.g., crackers and cheese or half a sandwich with a beverage which will not 
exceed 500 kcal) upon request.

Subjects will be required to adhere to a balanced meal plan of the study site’s choice 
while in the study site.  The same meals served on Day 1 will also be served on 
Day 14.
4.3.3.
Caffeine, Alcohol, and Tobacco
During each dosing session, subjects will abstain from 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 sample during each session. 
During each dosing session, subjects will abstain from alcohol for 24 h prior to the start 
of dosing until collection of the final pharmacokinetic and/or pharmacodynamic sample 
during each session.
Subjects who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical 
research unit. 
4.3.4.
Activity
Subjects will abstain from strenuous exercise for 48 h prior to each blood collection for 
clinical laboratory tests.  Subjects may participate in light recreational activities during 
studies (e.g., watch television, read).
4.4.
Screen and Baseline Failures
Any subject who signs an Informed Consent Form but does not satisfy 
Inclusion/Exclusion criteria during the Screening Period will be considered a Screen 
Failure.  
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any Serious Adverse Events.
4.5.
Withdrawal Criteria and Procedures
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the Investigator for safety, behavioral or 
administrative reasons.


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Refer to Section 5.3.3 for stopping criteria based on safety, tolerability, preliminary 
pharmacokinetic, and preliminary pharmacodynamic data and Section 5.3 for subject 
specific dose adaptation/stopping criteria including Liver Chemistry and QTc. 
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance).  See Section 5.3.1 for details.
In the event that a subject withdraws or is withdrawn from the study, the investigator will 
make every effort to have the subject return to the clinic to complete follow up 
assessments.
A subject who withdraws from the study may be replaced with another subject (see 
Section 4.1).  
All data will be listed and will be valid for clinical safety and tolerability evaluation.
4.6.
Subject Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
5.
STUDY TREATMENT
5.1.
Investigational Product (GSK1278863)
Study Treatment
Product name:
GSK1278863
Dosage form:
Tablet
Unit dose strength(s)/Dosage level(s):
5 mg/5 mg
Route/Administration/
Duration:
Oral, once daily in the morning for 14 days
Dosing instructions:
Take one tablet with approximately half a glass 
of water daily in the morning (Day 1 dosing time 
1h). On Day 1 and Day14, the dose will be 
administered within 30 min after completion of 
night APD treatment or morning last fill of 
peritoneal dialysis fluid; on any other study 
days, the dose will be administered within 2 h 
after completion of night APD treatment or 
morning last fill of peritoneal dialysis fluid. 
Physical description:
A round, biconvex, white film coated tablet
Manufacturer:
GlaxoSmithKline


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5.2.
Treatment Assignment
All subjects will be assigned to 5 mg GSK1278863 once daily. 
For detail information about dosage and administration, refer to Appendix 5.
5.3.
Subject Specific Dose Adjustment/Stopping Criteria
5.3.1.
Liver Chemistry Stopping Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance). 
Study treatment will be stopped for a subject if the following liver chemistry stopping 
criteria is met: 

ALT 3xULN
NOTE: Refer to Appendix 1 for details of the required assessments if a subject meets the 
above criteria.
5.3.2.
QTc Withdrawal Criteria

A subject that meets any of the criteria below will be withdrawn from the study.  
The same QT correction formula should be used to determine inclusion and 
discontinuation for any individual subject throughout the study.  Uncorrected QT 
>600 msec,

Change from baseline:  QTcB or QTcF >60 msec

QTcB or QTcF ≥500 msec (for subjects without underlying bundle branch block)
For subjects with underlying bundle branch block the following withdrawal criteria 
should be used 
Baseline QTc value (with 
underlying bundle branch block)
QTc withdrawal 
criteria
<470 msec
>500 msec
470-480 msec
>530 msec
Withdrawal of subjects is to be based on an average QTc value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period of 
time and then use the averaged QTc values of the 3 ECGs to determine whether the 
subject should be discontinued from the study.


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Note: The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the subject has been enrolled.
For example, if a subject is eligible for the protocol based on QTcB, then QTcB must be 
used for discontinuation of this individual subject as well.
5.3.3.
Stopping Criteria
Dosing in the study may be stopped if three or more subjects receiving GSK1278863 
experience any of the safety criteria listed below.  An individual subject may also be 
withdrawn at the discretion of the Investigator and the GSK Medical Monitor for other 
safety reasons not listed below.  
The subject will be followed at the discretion of the Investigator, and the GSK Medical 
Monitor will be notified.  In the event one or more subjects are withdrawn, additional 
subjects may be enrolled (upon consultation with the GSK protocol contact, see Section 
4.1) to ensure an adequate number of subjects complete the study. For an individual study 
participant, stopping criteria include, but are not limited to:

Severe signs or symptoms, or significant changes in any of the safety 
assessments, that put the safety of the individual at risk (e.g., ECG, vital signs, 
laboratory tests, etc), as judged by the Investigator in consultation with the 
Medical Monitor if necessary.

Pregnancy.

Active GI bleeding or new diagnosis of peptic or duodenal ulcer disease.

Diagnosis of cancer, with the exception of squamous cell and basal cell 
carcinoma.

Cardiovascular ischemic event or thrombotic events (e.g., myocardial infarction 
(MI), acute coronary syndrome, stroke, deep venous thrombosis, pulmonary 
embolism, new onset or worsening limb ischemia) excluding events associated 
with vascular access.

New onset or clinically significant worsening right heart failure or right heart 
strain not explained by fluid intake.

Treatment emergent pulmonary hypertension, new onset or worsening 
retinopathy (e.g., proliferative retinopathy or macular edema), or new onset or 
worsening nontraumatic joint inflammation (e.g., rheumatic or psoriatic 
arthritis).

Subjects with new onset or worsening clinically-significant signs or symptoms 
affecting:
a.
the gastrointestinal system (e.g., evidence of GI bleeding, new onset positive 
fecal occult blood test, abdominal pain other than transient, minor abdominal 
pain, etc.)


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b. vision (e.g., persistent blurred or diminished vision)
c.
the pulmonary system (e.g., persistent significant dyspnea)
d. the musculoskeletal system (e.g., significant myalgias or joint inflammation)

New onset or clinically significant worsening of hypertension inadequately 
responsive to change in anti-hypertensive therapy, OR BP ≥180/110 mmHg (on a 
study visit day) which persists for >48 h despite optimal treatment.

Non- hypertensive subjects with normal baseline blood pressure that experience an 
increase in blood pressure to ≥ 160/100 mmHg that persists over 24 h.  Any subject 
who demonstrates this increase in blood pressure will be followed to resolution, until 
any antihypertensive therapy is withdrawn.

Subjects with stable elevated blood pressure at baseline that further increases above 
baseline by either >20 mmHg systolic, >10 mmHg diastolic, or achieves ≥ 180/110 
mmHg.  To meet this criterion these elevations must persist longer than 24 h.  Any 
subject who develops worsening hypertension requiring intervention will be 
followed to resolution, until any intervention therapy is withdrawn.

On Days 3, 7 and 11, subject’s hemoglobin will be assessed prior to dosing using a 
HemoCue device.  Should subjects have an absolute hemoglobin level > 11.0 g/dL, a 
second hemoglobin measurement will be obtained at the same study visit to confirm.  
If confirmed, permanently discontinue GSK1278863 and withdraw subject from the 
study.

On Days 3, 7 and 11, subject’s hemoglobin will be assessed prior to dosing using a 
HemoCue device.  Should subjects have an absolute hemoglobin level of <8.5 g/dL, 
a second hemoglobin measurement will be obtained at the same study visit.  If 
confirmed, permanently discontinue GSK1278863 and withdraw subject from the 
study. 

CPK level >5xULN without confirmed alternative etiology or if deemed clinically 
significant by the Investigator.
5.4.
Blinding
This will be an open-label study. 
5.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
5.6.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK1278863 is 
provided in Appendix 5.
No special preparation of study treatment is required.


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Study treatment will be dispensed or administered according to procedures described 
herein.  Only subjects enrolled in the study will receive study treatment.  Only authorized 
site staff will supply or administer study treatment.  
All study treatment must be stored in a secure area with access limited to the investigator 
and authorized site staff.  Study treatment is to be stored to up 30C (86F).  Maintenance 
of a temperature log (manual or automated) is required.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance.  
The Investigator or the head of the medical institution (where applicable), or designated 
site staff (e.g., storage manager, where applicable) must maintain study treatment 
accountability records throughout the course of the study.  The responsible person(s) will 
document the amount of study treatment received from and returned to GSK and the 
amount administered to subjects.  The required accountability unit for this study will be 
tablet.  Discrepancies are to be reconciled or resolved.  Procedures for final disposition of 
unused study treatment are listed in the Appendix 5.
GSK1278863 is not expected to pose significant occupational safety risk to site staff 
under normal conditions of use and administration.  Take adequate precautions to avoid 
direct eye or skin contact.  
In the case of unintentional occupational exposure notify the study monitor, GSK 
Medical Monitor and/or protocol contact.  
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.  
Precaution will be taken to avoid direct contact with GSK1278863.
5.7.
Assessment of Compliance
When the individual dose for a subject is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff. 
When subjects are dosed at the study 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 subject’s mouth to ensure that the study treatment 
was ingested.


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5.8.
Treatment of Study Treatment Overdose
No specific antidote for GSK1278863 is known. The expected manifestations of 
GSK1278863 overdosage include signs and symptoms associated with an excessive 
and/or rapid increase in Hgb concentration. GSK1278863 is highly protein bound; thus, 
clearance of GSK1278863 by HD or PD is very low and these are not effective methods 
to enhance the elimination of GSK1278863. GSK1278863 metabolites are, in part, 
cleared via hemodialysis. 
In the event of suspected overdose:

collect blood samples for pharmacokinetics and safety laboratory immediately.

it is recommended that the appropriate supportive clinical care be instituted, as 
dictated by the subject’s clinical status. Additionally, subjects should be 
monitored closely for CV events, increased heart rate and hematologic 
abnormalities.
5.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study. 
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition, whether or not GSK is providing specific 
post-study treatment.
5.10.
Concomitant Medications and Non-Drug Therapies
All concomitant medications (including rhEPO) taken in the 4 weeks before and during 
the study will be recorded in the eCRF.  The minimum requirement is that drug name, 
dose administered and dates of administration are to be recorded.
In vitro characterization of GSK1278863 distribution and biotransformation has 
identified potential mechanisms for clinical drug-drug interactions.  GSK1278863 is 
primarily metabolized via the CYP2C8 pathway, with minor involvement of the CYP3A4 
pathway.  Data from a study (PHI113634) to assess the interaction potential between 
GSK1278863 and a CYP2C8 inhibitor (gemfibrozil) showed a clinically-significant 
increase in GSK1278863 exposure following co-administration.
  In vitro studies showed the potential for inhibition of CYP2C8 (IC50: 21 µM) by 
GSK1278863, while there was no evidence of concentration- or metabolism-dependent 
inhibitory potential towards human CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6 or 3A4.  In a 
recent drug-drug interaction, there was no apparent evidence of a drug interaction 
between GSK1278863, at doses up to 100 mg, with pioglitazone, a CYP2C8 substrate.


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GSK1278863 was also observed to be an inhibitor of organic anion transporting 
polypeptide (OATP) 1B1 and 1B3 in vitro with IC50s of ~6 μM and ~11 μM, 
respectively.  The average Cmax observed after single dose administration of 5 mg 
GSK1278863 to healthy subjects was 0.24 μM, suggesting a low risk of an interaction. In 
a recent drug-drug interaction, there was no apparent evidence of a drug interaction 
between GSK1278863, at doses up to 100 mg, with rosuvastatin, an OATP1B1 substrate.
GSK1278863 is a substrate of human breast cancer resistance protein (BCRP) in vitro.  
Therefore, there may be the potential for interactions when GSK1278863 is co-
administered with drugs which are inhibitors of human-BCRP, however, GSK1278863 
has moderate to high passive permeability, potentially mitigating any BCRP inhibition 
effects.
5.10.1.
Permitted Medications
Paracetamol or Acetaminophen, at doses of ≤ 2 grams/day is permitted for use from 48 h 
prior to the first dose of GSK1278863 and until completion of follow-up procedures. 
Use of low dose (≤325mg/day) aspirin/acetylsalicylic acid is permitted for the duration of 
the study (from Screening to the follow-up visit at the end of the study).
Concomitant medications other than specified in Section 5.10 may be considered on a 
case by case basis by the Investigator in consultation with the GSK Medical Monitor.
Subjects receiving HRT and other drugs not specifically prohibited (see Section 5.10.2) 
are permitted to continue while on study.  
5.10.1.1.
Inhibitors of BCRP
Medications that are inhibitors of BCRP will be permitted in the study.  These 
medications include omeprazole, lansoprazole, rabeprazole, and pantoprazole.
5.10.1.2.
Non-Drug Therapies
Calcium, Vitamin D, and other vitamins and minerals may be permitted at the discretion 
of the Investigator or his/her designee.  Refer to Study Procedural Manual (SPM) for an 
extended list. 
5.10.2.
Prohibited Medications and Non-Drug Therapies
5.10.2.1.
Supplements
Subjects must abstain from taking supplements (with the exception of vitamin or 
minerals), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-
lives (whichever is longer) prior to the first dose of GSK1278863 until completion of the 


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follow-up visit, unless in the opinion of the Investigator and sponsor it will not interfere 
with the study. 
5.10.2.2.
NSAIDs
Chronic use of NSAIDs will not be permitted with the exception of low dose 
(≤325mg/day) aspirin/acetylsalicylic acid for the duration of the study (from Screening to 
the follow-up visit at the end of the study). 
5.10.2.3.
Immunosuppressants
Immunosuppressant drugs and drugs used to treat malignancies (including corticosteroids 
at doses >10 mg prednisolone per day or equivalent) within 2 weeks of first dose of 
GSK1278863 are specifically prohibited from Screening through the follow-up visit.   
Note: Failed transplant subjects who are on peritoneal dialysis are eligible for 
participation in this study but should not be on immunosuppressive medications within 3 
months prior to Screening.
5.10.2.4.
Inhibitors and inducers of CYP2C8
The primary route of metabolism of GSK1278863 involves CYP2C8.
Strong inhibitors and inducers of CYP2C8 are prohibited from 14 days prior to the first 
dose of GSK1278863 until 7 days after the last dose of GSK1278863.  These medications 
include gemfibrozil, rifampin/rifampicin, phenytoin, hyperforin supplements (e.g., St 
John’s Wort), Phenobarbital/phenobarbitone.
6.
STUDY ASSESSMENTS AND PROCEDURES
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 6.1. 
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 

12-lead ECG

vital signs

blood draws
The timing of the assessments is required to allow the blood draw to occur as close as 
possible to the nominal time.
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 


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specified in the Time and Events Table (Section 6.1), are essential and required for study 
conduct.
The timing and number of planned study assessments and procedures 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 approved and 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.  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 (ICF). 
Additional safety tests (such as vital signs, physical exams, and clinical laboratory tests) 
may also be obtained during the course of the study based on newly available data, to 
ensure appropriate safety monitoring.  
No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
Refer to Appendix 3 for details regarding PK sample time windows that will not be 
regarded as protocol deviations.
During the Follow-up Period, deviations of up to +2 days for clinical research unit visits 
will not be regarded as Protocol Deviations.
The actual date and time will be recorded for all procedures and the Investigator will 
make every effort to perform procedures at the scheduled nominal dates and times.


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6.1.
Time and Events Table
Informed consent for optional PGx (pharmacogenetics) research must be obtained before collecting a sample.
Protocol Activity
Screening 
(refer to 
Section 
3.1) 
Treatment
Follow 
Up 
(refer 
to 
Section 
3.1)
~Day -30
Day -1
Day 1
Day 
2
Day 3
Day 
4-6
Day 
7
Day 
8-10
Day 
11
Day 
12-13
Day 14
Day 
15
Day 16
Day 17
Day 22
Window
+2 
days
Informed Consent Process
X
Demographics
X
Medical/medication/drug/alcohol 
history
X
Safety Assessments
Concomitant Medications a
=============================================X===============================================
Complete Physical
X
Vital Signs
X
X
X
X
12 - Lead ECG(refer to Section 
6.3.3)
X
X
X
Adverse Events Assessment/ 
SAE's a
==============================================X===============================================
Brief Physical
X
X
Laboratory Assessments
Chemistry
X
X
X
Hematology
X
X
X
PGx Sampling
                           collect one PGx sample after the start of dosing (preferably on Day 1)                               
Serum Pregnancy Test
X
X
X


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Protocol Activity
Screening 
(refer to 
Section 
3.1) 
Treatment
Follow 
Up 
(refer 
to 
Section 
3.1)
~Day -30
Day -1
Day 1
Day 
2
Day 3
Day 
4-6
Day 
7
Day 
8-10
Day 
11
Day 
12-13
Day 14
Day 
15
Day 16
Day 17
Day 22
Window
+2 
days
Hepatitis B Surface Antigen 
(HBsAg)
X
Hepatitis C Antibody (HCVAb)
X
Admission to Clinic (optional)b
X
X
IP dosing (oral)c
X
X
X
X
X
X
X
X
X
Discharge
X
X
Blood PK samples
Xd
Xe
Xe
Xe
Xd
Xf
Xg
Xh
Dialysate PK samples
Xi
Xj
Xj
Iron Binding Capacity (TIBC)
X
Creatine Kinase (CPK)k
X
X
X
X
ALTl
X
X
X
X
Iron (Fe)
X
Transferrin
X
Ferritin
X
Drug and Alcohol Screenm
X
X
X
Estradiol (E2) (refer to Section 
6.3.4)
X
Follicle Stimulating Hormone 
(FSH) (refer to Section 6.3.4)
X
Serum Vitamin B12 and folate
X
EPO and Hepcidin
Xd
Xe
Xe
Xe
Xd
HIV Ab
X
Hemoglobin (Hb)n
X
X
X
Protein Binding
Xd


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a
Both Adverse event monitoring and Concomitant Medication reviews will be conducted throughout the study starting from Day -1.
b
Subjects may remain in residence at the site from the afternoon of Day -1 through the last assessment on Day 17, at the discretion of the investigator or by request of the subject 
(refer to Section 3.1). Outpatients must return to the site for scheduled PK assessments.
c
Each dose will be administered within 30 min after completion of the night APD treatment or morning last fill of peritoneal dialysis fluid. Outpatients can self administer their daily 
dose
d
Sampling schedules within the day are given in Section 6.1.1.
e
Sample to be taken predose only.
f
g
h
i
j
Sample to be taken 24 h post Day 14 dose.
Sample to be taken 48 h post Day 14 dose.
Sample to be taken 72 h post Day 14 dose.
Aliquot of dialysate from the last drained dwell prior to dosing on Day 1. Aliquot for APD subjects may be collected from automated cycler drain/drain bag prior to dosing onDay1. 
In CAPD subjects, record volume and take aliquots of dialysate from each drain bag over 24 h dosing period starting at time of Day 14 dose. Aliquot for APD subjects is to be 
collected from APD collection drain bag over 24 h dosing period starting at time of Day 14 dose.
k
Measurement in addition to clinical chemistry assessment.
l
m
n
Measurement in addition to hematology assessment.
Test will be performed for drug and alcohol at Screening, Day-1, and Day 13 visits check-in for subjects who participate in the study as outpatient, and it must be negative prior to 
dosing.
Hemoglobin assessment will be by a HemoCue device.


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6.1.1.
Study Procedures and Assessments for Plasma PK, EPO, Hepcidin & Protein Binding Sampling on Day 1 
and Day 14
Procedure
Time (in h relative to dosing)
Predose
0.5
1
2
3
4
6
8
12
16
24
48
72
DAY 1
PK blood sample
X
X
X
X
X
X
X
X
X
X
X
EPO and Hepcidin
X
X
X
X
X
DAY 14
PK blood sample
X
X
X
X
X
X
X
X
X
X
X
X
X
EPO and Hepcidin
X
X
X
X
X
Protein Binding
X
X
X


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6.2.
Demographic/Medical History Assessments
The following demographic parameters will be captured: date of birth (only year), 
gender, race and ethnicity.
Medical/medication/alcohol history will be assessed as related to the eligibility criteria 
listed in Section 4.2.  
Baseline assessments are defined as the last pre-dose timepoint of each assessment 
(except ECG, which will be the average of the 3 ECGs obtained at that timepoint).
6.3.
Safety
Planned timepoints for all safety assessments are listed in the Time and Events Table 
(Section 6.1).  
Additional time points for safety tests such as vital signs, physical exams and laboratory 
safety tests may be added during the course of the study based on newly available data to 
ensure appropriate safety monitoring.
6.3.1.
Physical Exams

A complete physical examination will include assessments of the head, eyes, ears, 
nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and 
spleen), lymph nodes and extremities.  
Height and weight will also be measured and recorded.

A brief physical examination will include assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
6.3.2.
Vital Signs

Vital sign measurements will be measured in supine position after 5 min rest and 
will include systolic and diastolic blood pressure, body temperature, and pulse rate.
6.3.3.
Electrocardiogram (ECG)

12-lead ECGs will be obtained at each timepoint during the study using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals.  
Subjects are required to rest quietly at supine position for at least10 min before and 
during each ECG reading (subjects should remain comfortable).  
Repeat measurements may be performed if there are any clinical abnormalities observed 
or if artifacts are present.  


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Below is the number of ECGs will be obtained at each timepoint:

Screening:  Three ECGs will be taken, at least 5 min apart. Take average of the three 
intervals to determine subject eligibility.    

Day -1:  Three ECGs will be taken, at least 5 min apart. The average of the intervals 
from the three ECGs will determine the baseline (HR, PR, QRS, QTc).  

Day 17: A single ECG will be taken.
Refer to Section 5.3.2 for QTc withdrawal criteria and additional QTc readings that may 
be necessary.
6.3.4.
Clinical Laboratory Assessments
Blood samples for Clinical Laboratory Assessments will be collected in the fasted state 
during the study at the time points indicated in the Time and Events Table (Section 6.1).  
Subjects are to be fasted for a minimum of 6 h prior to blood sample collections.
If screening results suggest that the blood sample was obtained without an appropriate 
fasting period, the clinical chemistry may be repeated once at the Investigator discretion.
The total volume of blood collected for planned Clinical Laboratory Assessments, 
pharmacodynamic and pharmacokinetic assessments from all subjects will not exceed 
500 mL during the entire study period.
Hematology, clinical chemistry, and additional parameters to be tested are listed below.  
Details for the preparation and shipment of samples will be provided by Quest.
Reference ranges for all safety parameters will be provided to the site by the laboratory.
If additional non-protocol specified laboratory assessments are performed at the site’s 
local laboratory and result in a change in subject management or are considered clinically 
significant by the Investigator (for example SAE or AE or dose modification) the results 
must be captured and sent to GSK along with other study data as defined in Appendix 4 .
Hematology, clinical chemistry, and additional parameters to be tested are listed below:
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils


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Clinical Chemistry
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Chloride
ALT (SGPT)
Uric Acid
Glucose, fasting
Total CO2
GGT
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
CPK
NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are 
given in Section 5.3.1.
Other screening/lab tests
HIV
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody – if second generation Hepatitis C antibody positive, a hepatitis C 
RNA assay (or other third generation immunoassay) should be reflexively performed on the same 
sample to confirm the result) 
FSH and Estradiol (as needed in women of non-child bearing potential only)
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines).
Erythropoietin
TIBC
Serum iron
Serum Ferritin
Serum transferrin
Vitamin B-12
Folate
Out of range laboratory results may be repeated at the discretion of the Investigator.  
When hemoglobin values achieve the threshold values defined in Section 5.3.3 (Safety 
Stopping Criteria), appropriate procedures (e.g., venesection or erythrocytapheresis) will 
be considered and implemented at the discretion of the Investigator until the values return 
below the thresholds.
6.4.
Pharmacokinetics
6.4.1.
Blood Sample Collection
Blood samples (approximately 3 mL) for pharmacokinetic analysis of GSK1278863 and 
metabolites (GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 
(M5), GSK2531398 (M6), and GSK2531401 (M13) will be collected at the time points 
indicated in Section 6.1, Time and Events Table.  
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 (approximately 3 mL) will be collected for assessment of protein 
binding of GSK1278863 and metabolites, M4 (GSK2487818) and M5 (GSK2506102), at 
the time points indicated in the Time and Events Table in Section 6.1. 


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Processing, storage and shipping procedures are provided in the SPM.
6.4.2.
Dialysate Sample Collection
Peritoneal dialysate samples for pharmacokinetic analysis of GSK1278863 and 
metabolites (GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 
(M5), GSK2531398 (M6), and GSK2531401 (M13) will be collected on the days listed in 
Section 6.1, Time and Events Table.  
On Day 1:
After mixing, approximately 1.5 mL aliquot of dialysate from the last drained dwell prior 
to GSK1278863 dosing will be collected (aliquot for APD subjects may be collected 
from automated cycler drain/drain bag).
On Day 14:
All drained dialysate will be collected over a 24 h period, starting at the time of 
GSK1278863 dosing.  The volume of each drained dwell needs to be recorded, and an 
aliquot taken for analysis.
CAPD subjects: After mixing and measurement of drained dialysate volume, 
approximately 1.5 mL aliquot of dialysate from each drained dwell will be collected.
APD subjects: After mixing and measurement of drained dialysate volume, 
approximately 1.5 mL aliquot of dialysate from the cycler drain bag (and any manual 
peritoneal dialysis exchanges during the day) will be collected.
Details of PK dialysate sample processing, storage and shipping procedures are provided 
in the SPM.
6.4.3.
Sample Analysis
All samples will be shipped at the end of dosing period and appropriately analyzed for 
plasma or dialysate GSK1278863 and metabolite concentrations and protein binding (free 
fraction, plasma if technically feasible) using validated methods.
Once the plasma has been analyzed for GSK1278863 and metabolites, and protein 
binding, any remaining plasma may be analyzed for other compound-related metabolites 
and the results reported under a separate PTS-DMPK, GlaxoSmithKline protocol.
6.5.
Pharmacodynamic (PD) Markers
6.5.1.
PD Sample Collection (EPO and Hepcidin)
Blood samples for PD analysis of EPO and hepcidin will be collected at the time points 
indicated in the Time and Events Table in Section 6.1.


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The actual date and time of each blood sample collection will be recorded. Details of PD 
blood sample collection, processing, storage, and shipping procedures are provided in the 
SPM.
6.6.
Pharmacogenetics
Information regarding pharmacogenetic (PGx) research is included in Appendix 2
The IRB/IEC and, where required, the applicable regulatory agency must approve the 
PGx assessments before these can be conducted at the site.  
In some cases, approval of the PGx assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
PGx assessments is being deferred and in most cases, the study, except for PGx 
assessments, can be initiated.  
When PGx assessments will not be approved, then the approval for the rest of the study 
will clearly indicate this and therefore, PGx assessments will not be conducted.
7.
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, 
PREGNANCY AND MEDICAL DEVICES INCIDENTS
7.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The Investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
7.1.1.
Time period for collecting AE and SAE information
AEs will be collected from the start of Study Treatment and until the follow-up contact.  
Medical occurrences that begin prior to the start of study treatment but after obtaining 
informed consent may be recorded on the Medical History/Current Medical Conditions 
CRF.
SAEs will be collected over the same time period as stated above for AEs.  However, any 
SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a GSK product will be recorded 
from the time a subject consents to participate in the study up to and including any 
follow-up contact.  All SAEs will be recorded and reported to GSK within 24 h, as 
indicated in Appendix 4. 
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 
subject has been discharged from the study, and he/she considers the event reasonably 
related to the study treatment or study participation, the investigator would promptly 
notify GSK.


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NOTE: The method of, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.1.3.
Definition of Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
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 medicinal product.  
Events meeting the definition of an AE include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the Investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae.).
Events that do not meet the definition of an AE include:


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
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’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 subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
7.1.4.
Definition of Serious Adverse Events
If an event is not an AE per Section 7.1.3, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
An SAE is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject 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 hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during hospitalization are 
AEs.  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 disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.


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e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are 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.
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick.  If fractionation is unavailable 
and ALT 3xULN and total bilirubin 2xULN, then the event is still to be reported 
as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
7.1.5.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.


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7.1.6.
Death Events
In addition, all deaths, whether or not they are considered SAEs, will require a specific 
death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (including sudden cardiac death) and 
noncardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
7.1.7.
Prompt Reporting of SAEs to GSK
Once the investigator determines that an event meets the protocol definition of an SAE, 
the SAE will be reported to GSK within 24 h.  Any follow-up information on a 
previously reported SAE will also be reported to GSK within 24 h.
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying GSK of the event and completing the 
appropriate data collection tool.  The investigator will always provide an assessment of 
causality at the time of the initial report as described in Appendix 4 .
7.1.8.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to 
regulatory authorities, IRBs/IECs and Investigators.  
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to Investigators as necessary.  An Investigator who receives an Investigator safety report 
describing an SAE(s) or other specific safety information (e.g., summary or listing of 
SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
7.2.
Pregnancy
7.2.1.
Time period for collecting pregnancy information
All pregnancies in female subjects will be collected after the start of dosing and until the 
time period that is 5 terminal half-lives after the last dose.


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7.2.2.
Action to be taken if pregnancy occurs
The Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  The Investigator will record pregnancy 
information on the appropriate form and submit it to GSK within 2 weeks of learning of a 
subject's pregnancy.  The subject will also be followed to determine the outcome of the 
pregnancy.  Information on the status of the mother and child will be forwarded to GSK.  
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.  Any premature termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE.
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to GSK1278863 by the Investigator, will be reported to GSK as 
described in Section 7.1.7.  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 subject who becomes pregnant while participating will discontinue 
GSK1278863.
8.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined electronic case report forms 
(eCRFs), transmitted electronically to GSK and combined with data provided from other 
sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA (Medical Dictionary for Regulatory Activities) and 
an internal validated medication dictionary, GSKDrug.  eCRFs (including queries and 
audit trails) will be retained by GSK, and copies will be sent to the Investigator to 
maintain as the Investigator copy.  Subject initials will not be collected or transmitted to 
GSK according to GSK policy.
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
Statistical analyses of the pharmacokinetic data will be provided by, or under the direct 
auspices of Quantitative Sciences (QSci), GSK.


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9.1.
Hypotheses and Treatment Comparisons
This study is designed to estimate pharmacokinetic endpoints of GSK1278863 and 
metabolites in ESRD patients undergoing peritoneal dialysis following repeat 
administration of 5 mg once daily GSK1278863.  
There will be two cohorts of subjects in this study: subjects with CAPD and subjects with 
APD.  
No formal statistical hypotheses will be tested. An estimation approach will be used to 
evaluate the comparisons of interest, with point estimates and associated 90% confidence 
intervals presented to provide a range of plausible values for the comparisons.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
As this study is descriptive in nature and no formal statistical comparisons of PK data 
will be performed, the sample size of 24 subjects (12 in each cohort) will be recruited 
such that at least 8 subjects complete the trial. Based on PK parameter CV% of ~50% in 
subjects with renal impairment or ESRD [refer to GlaxoSmithKline Document Number
RM2008/00267/07, 14-Oct-2015.GSK1278863 IB and associated IB supplements for 
GSK1278863 [GlaxoSmithKline Document Number 2015N266524_00, 17-Dec-2015; 
GlaxoSmithKline Document Number 2015N266524_01, 08-Apr-2016]] for a sample size 
of at least 8 statistically evaluable subjects, the half width of the 90% confidence interval
will be within 56% of the point estimate.
9.2.2.
Sample Size Sensitivity
Not applicable.
9.2.3.
Sample Size Re-estimation
No sample size re-estimation will be performed.


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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
All Screened Population
The “All Screened” population will be defined as all subjects screened.
All Subjects Population
The ‘All Subjects Population’ is defined as all subjects who receive at least one dose of 
study treatment.  This population will be used for the study population and safety 
analyses.
Pharmacokinetic Population
The ‘PK Population' is defined as subjects in the ‘All Subjects’ population for whom a 
pharmacokinetic sample was obtained and analyzed.  This will be the population used for 
all the pharmacokinetic displays.
9.3.2.
Interim Analysis
Informal PK reviews will be conducted throughout the study to assist Phase III 
development of the compound 
9.3.2.1.
Final Analyses
Descriptive statistics (n, arithmetic mean and associated 95% confidence interval (CI), 
standard deviation, minimum, median, maximum) will be calculated for all 
pharmacokinetic endpoints of GSK1278863 and metabolites separately by cohort and 
overall (CAPD, APD, and both combined) 
In addition, geometric means, associated 95% CIs, and estimates of between-subject CVs 
(CVb(%)) will be calculated for AUC (0-τ), AUC (0-∞), Cmax, clearance, and t½where 
Geometric mean = exp(mean on loge scale)
CVb(%) = SQRT(exp(SD**2 – 1) * 100, where SD is the standard deviation of 
the loge-transformed data.
Similar descriptive summaries will be created for the steady-state GSK1278863 and 
metabolite unbound concentration and free fraction, erythropoietin, and hepcidin plasma 
concentration.
At a minimum, descriptive statistics (n, mean and associated 95% CI, standard deviation, 
minimum, median, maximum) will be calculated at each relevant time point.


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9.3.2.2.
Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to CDISC standards.
9.3.2.3.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling & Simulation department within GSK. 
Plasma GSK1278863 and metabolites GSK2391220 (M2), GSK2506104 (M3), 
GSK2487818 (M4), GSK2506102 (M5), GSK2531398 (M6), and GSK2531401 (M13) 
concentration-time data will be analyzed by non-compartmental methods with Phoenix 
WinNonlin Version 6.3 or higher.  Calculations will be based on the actual sampling 
times recorded during the study. 
Pharmacokinetic data will be listed and may be presented in graphical form and will be 
summarized descriptively.  All pharmacokinetic data will be stored in the Archives, GSK, 
R&D.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Clinical Statistics, GSK.
9.3.2.3.1.
Plasma PK Parameters
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit
Day 1:  Maximum observed plasma concentration (Cmax), time to Cmax (tmax), area 
under the plasma concentration-time curve AUC(0-τ) and AUC(0-∞), and apparent 
terminal phase half-life (t½).  
Day 14: Cmax, tmax, AUC(0-τ), and apparent terminal phase half-life (t½).  
AUC(0-∞), AUC(0-τ) and Cmax following single (Day 1) and repeat doses (Day 14) will 
be used for determination of accumulation and time-invariance ratios.
Day 12 to 15:  Trough concentration (Ctau, or C) samples collected on Days 12 to 15 
will be used to assess attainment of steady state. 
Other Plasma PK Analyses: GSK1278863 and metabolite unbound concentration and 
free fraction (as a percentage) will be presented in tabular form and will be summarized 
descriptively.  Metabolite-to-parent exposure ratios (corrected for molecular weight) will 
also be calculated and summarized descriptively.
Steady State Assessment
Trough concentration (C) samples collected on the specified days will be used to assess 
attainment of steady state.  Individual trough concentration data Cwill be plotted and 


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listed.  Cwill be summarized by day and cohort, and the mean and median plots will be 
provided. 
Steady state will be assessed separately for GSK1278863 and metabolites in each cohort. 
A linear mixed effects ANOVA model will be used to evaluate steady state for 
GSK1278863 and each metabolite.  The dependent variable will be log-transformed pre-
dose (trough) concentrations (Cτ) on Days 12 to 15.  Independent variables in the model 
include day (as a continuous variable) as a fixed effect and subject as a random effect. 
Assessment of plasma GSK1278863 and metabolites steady state will be assessed by 
evaluating the estimated slope for the day parameter and associated 90% CI for both the 
cohorts combined.
Secondary Comparisons:
Assessment of Accumulation
To estimate the extent of accumulation for GSK1278863 and metabolites after repeat 
dosing, the observed accumulation ratio R0 will be determined.

0
R
)
0
(
)
0
(




AUC
AUC
ss
where  
ss
AUC
)
0
(


is AUC from time zero to t h under steady state and  
)
0
(


AUC
is 
AUC from time zero to dosing interval at Day 1.
To evaluate the accumulation ratio, statistical analysis of GSK1278863 and metabolites
for both the cohorts combined will be performed after a log transformation of the data. 
A mixed effect model will be fitted with day (single and repeat dose), as fixed effects and 
subject as a random effect.  Day 14 will be compared to Day 1 in order to estimate the 
accumulation ratios, Ro= (AUC (0- τ, Day14): AUC (0- τ, Day1).  The ratios will be 
calculated by back-transforming the difference between the LS means. 
Using the pooled estimate of variance, 90% confidence intervals will be calculated for   
Ro, and back-transformed to the original scale.
Assessment of Time Invariance
To evaluate the time invariance ratio, statistical analysis of (AUC (0-∞) Day 1) and AUC 
(0- τ) (Day14), of GSK1278863 and metabolites for both the cohorts combined will be 
performed after a log transformation of the data. 
A mixed effect model will be fitted with day as fixed effects and subject as a random 
effect.  Day 14 AUC (0- τ) will be compared to Day 1 AUC (0-∞) n order to estimate the 


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time invariance ratios, RS= AUC (0- τ, Day 14): AUC (0-∞, Day 1). The ratios will be 
calculated by back-transforming the difference between the LS means. 
9.3.2.3.2.
Using the pooled estimate of variance, 90% confidence intervals will be 
calculated for Rs, and back-transformed to the original scale.Dialysate 
PK Parameters
Peritoneal dialysis excretion amounts and clearance of GSK1278863 and metabolites will 
be calculated from Day 14 dialysate excretion data (total amount excreted over 24 h) 
divided by plasma AUC(0-τ).  
9.3.2.4.
Pharmacodynamic/Biomarker Analyses
Plasma erythropoietin and hepcidin concentrations will be presented in graphical and/or 
tabular form and will be summarized descriptively.
9.3.2.5.
Pharmacogenetic Analysis
Samples will be collected and stored.  No prospective analyses will be performed.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will also be conducted in accordance with ICH GCP, all applicable subject 
privacy requirements, and, the guiding principles of the 2008 Declaration of Helsinki.  
This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval to conduct the study and of any 
subsequent relevant amended documents

Written informed consent (and any amendments) must be obtained for each subject 
before participation in the study


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Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol deviations to 
IRB/IEC). 
Detailed information regarding pharmacogenetic research conduct is included in 
Section 6.6 and in Appendix 2.
10.2.1.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the 
study treatment, and this new event is likely to affect the safety of subjects, the sponsor 
and the Investigator will take appropriate urgent safety measures to protect subjects 
against any immediate hazard.
The sponsor will work with the Investigator to ensure the IEC/IRB is notified.
10.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and GSK procedures, GSK 
monitors will contact the site prior to the start of the study to review with the site staff the 
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and 
GSK requirements.  When reviewing data collection procedures, the discussion will also 
include identification, agreement and documentation of data items for which eCRFs will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.

The Investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study.  In the event of an assessment, audit or inspection, the Investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.


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10.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the Investigator or site staff, as appropriate, in accordance with 
applicable regulations including GCP, and GSK procedures.
In addition, GSK reserves the right to temporarily suspend or prematurely discontinue 
this study at any time for reasons including, but not limited to, safety or ethical issues or 
severe non-compliance.  For multicenter studies, this can occur at one or more or at all 
sites.  If GSK determines such action is needed, GSK will discuss this with the 
Investigator or the head of the medical institution (where applicable), including the 
reasons for taking such action.  When feasible, GSK will provide advance notification to 
the Investigator or the head of the medical institution, where applicable, of the impending 
action prior to it taking effect.
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform Investigators or the head of the medical institution (where applicable) 
and the regulatory authorities of the suspension or premature discontinuation of the study 
and the reason(s) for the action.  If required by applicable regulations, the Investigator or 
the head of the medical institution (where applicable) must inform the IRB/IEC promptly 
and provide the reason for the suspension or premature discontinuation.
10.6.
Records Retention
Following closure of the study, the Investigator or the head of the medical institution 
(where applicable) must maintain all site study records, except for those required by local 
regulations to be maintained by someone else, in a safe and secure location.  The records 
must be maintained to allow easy and timely retrieval, when needed (e.g., audit or 
inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and staff.  Where 
permitted by local laws/regulations or institutional policy, some or all of these records 
can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  The 
Investigator must assure that all reproductions are legible and are a true and accurate 
copy of the original, and meet accessibility and retrieval standards, including re-
generating a hard copy, if required.  Furthermore, the Investigator must ensure there is an 
acceptable back-up of these reproductions and that an acceptable quality control process 
exists for making these reproductions.
GSK will inform the Investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, or GSK standards/procedures; otherwise, the 
retention period will default to 15 years.
The Investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership of the 
records in the event the Investigator leaves the site.


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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical study report.  The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the Investigator with the full summary of the study results.  The 
Investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the Investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.  
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.


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11.
REFERENCES
Dmitrieva O, de Lusignan S, Mcdougall IC, Gallagher H, Tomson C, Harris K, 
Desombre T Goldsmith D. 2013. Association of anaemia in primary care patients with 
chronic kidney disease: Cross sectional study of quality improvement in chronic kidney 
disease (QICKD) trial data.  BMC Nephrology, 14:24-31.
GlaxoSmithKline Document Number RM2008/00267/06GSK1278863 Investigator’s 
Brochure, 04-MAR-2014.
GlaxoSmithKline Document Number RM2008/00267/07, Investigator’s Brochure, 14 
October 2015. 
GlaxoSmithKline Document Number: 2015N266524_00, Investigator’s Supplement, 17-
Dec-2015; 
GlaxoSmithKline Document Number: 2015N266524_01, Investigator’s Supplement, 08-
Apr-2016.
GlaxoSmithKline Document Number RM2009/00585/00. A Phase I, Randomized, 
Single-blind, Placebo-controlled, Dose-escalation Study to Evaluate the Safety, 
Pharmacokinetics, and Pharmacodynamics of Repeat Oral Doses of GSK1278863A in 
Healthy Subjects 01 FEB 2010.
Haase VH. Mechanisms of Hypoxia Responses in Renal Tissue. JASN, 2013 24:537-541
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.
Levey AS, Coresh J, Balk, E, Kausz, AT, Levin, A, et al. 2003. National Kidney 
Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, 
and Stratification. Ann Intern Med, 139:137-47.
Lundby C, Hellsten Y, Jensen MBF, Munch, AS, Pilegaard H.  2008.  Erythropoietin 
receptor in human skeletal muscle and the effects of acute and long-term injections with 
recombinant human erythropoietin on the skeletal muscle.  J Appl Physiol 104:1154-
1160.
Rule AD, Larson TS, Bergstrahl EJ, Slezak JM, et al.  2004. Using Serum Creatinine to 
Estimate Glomerular Filtration Rate: Accuracy in Good Health and in Chronic Kidney 
Disease.  Ann Intern Med, 141:929-37.
Steinjans VW, Diletti E. 1983. Statistical analysis of bioavailability studies: parametric 
and nonparametric confidence intervals, Eur J Clin Pharmacol, 24:127-136.
The Australasian Creatinine Consensus Working Group (ACCWG). 2005. Chronic 
kidney disease and automatic reporting of estimated Glomerular filtration rate: a position 
statement.  Med J Australia, 183(3): 138-41.


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Thomsen JJ, Rentsch RL, Robach P, Calbet JAL, Boushel R, Rasmussen P, Juel C, 
Lundby C.  2007.  Prolonged administration of recombinant human erythropoietin 
increases submaximal performance more than maximal aerobic capacity.  Eur J Appl 
Physiol, 101:481-486.


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12.
APPENDICES
12.1.
Appendix 1: Liver Safety Process
The procedures listed below are to be followed if a subject meets the liver chemistry 
stopping criteria defined in Section 5.3.1:

Immediately withdraw the subject from study treatment 

Notify the GSK medical monitor within 24 h of learning of the abnormality to 
confirm the subject’s study treatment cessation and follow-up.

Complete the “Safety Follow-Up Procedures” listed below.

Complete the liver event case report forms.  If the event also meets the criteria of an 
SAE (see Section 7.1.4), the SAE data collection tool will be completed separately 
with the relevant details.

Upon completion of the safety follow-up withdraw the subject from the study unless 
further safety follow up is required  

Do not restart study treatment 

Refer to the Flow chart for a visual presentation of the procedures listed below.
Safety Follow-Up Procedures for subjects with ALT 3xULN:

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.
Safety Follow-Up Procedures for subjects with ALT 3xULN and total bilirubin 
2xULN (>35% direct bilirubin); or ALT 3xULN and INR1 > 1.5:

This event is considered an SAE (see Section 7.1.4.  Serum bilirubin fractionation 
should be performed if testing is available. If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury).

Make every reasonable attempt to have subjects return to the clinic within 24 h for 
repeat liver chemistries, additional testing, and close monitoring (with specialist or 
hepatology consultation recommended).

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
In addition, for all subjects with ALT 3xULN, every attempt must be made to also 
obtain the following:

Viral hepatitis serology including:
                                                
1 INR testing not required per protocol and the threshold value does not apply to subjects receiving 
anticoagulants.


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Hepatitis A IgM antibody.
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM). 
Hepatitis C RNA. 
Cytomegalovirus IgM antibody.
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).
Hepatitis E IgM antibody.

Blood sample for pharmacokinetic (PK) analysis, obtained within 24 h of last dose. 
Record the date/time of the PK blood sample draw and the date/time of the last dose 
of study treatment prior to blood sample draw on the CRF.  If the date or time of the 
last dose is unclear, provide the subject’s best approximation.  If the date/time of the 
last dose cannot be approximated OR a PK sample cannot be collected in the time 
period indicated above, do not obtain a PK sample.  Instructions for sample 
handling and shipping are included in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Assess eosinophilia

Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) 
on the AE CRF.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the Concomitant Medications 
CRF.

Record alcohol use on the Liver Events CRF.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN 
(>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in the 
preceding week (James, 2009).

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.

The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these tests 
are performed.


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Refer to the diagram below for a visual presentation of the procedures listed above.
ALT≥3xULN ?
Bilirubin ≥ 2xULN
(or INR > 1.5 if 
measured)* ?
No
No
Yes
Yes
Continue investigational product (IP)
Instruct subject to stop IP
Notify GSK within 24 hrs 
Obtain weekly liver chemistries until resolved, stabilized or returned 
to baseline values
Perform liver event follow up assessments (serology, PK sample, etc 
as in protocol) 
Complete liver event CRF
Withdraw subject from study after liver chemistry monitoring 
complete + do not re-challenge with IP
Instruct subject to stop IP
Notify GSK and arrange clinical followup within 24 hrs
Perform liver event follow up assessments (serology, PK sample etc 
as in protocol) 
Report as SAE (excl. hepatic impairment or cirrhosis studies); 
complete SAE & liver event CRF + liver imaging  
and biopsy CRFs (if these tests are performed)
Obtain twice weekly liver chemistries until resolved, stabilized or 
returned to baseline values 
Consultation with hepatologist/specialist recommended
Withdraw subject from study after liver chemistry monitoring 
complete + do not re-challenge with IP
*INR threshold does not apply to 
subjects receiving anticoagulants.


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12.2.
Appendix 2: Pharmacogenetic research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations.  There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
PGx associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington,
2002; Mallal, 
2002; 
Mallal, 2008]
HLA-B* 57:01 
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir.  
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity.  Treatment guidelines and 
abacavir product labeling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity.  HLA-B*57:01 
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.
Carbamaze
pine
Seizure, Bipolar 
disorders & 
Analgesia Chung, 
2010; Ferrell, 
2008
HLA-B*15:02
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02 
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis.  
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine.


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Drug
Disease
Gene Variant
Outcome
Irinotecan
Cancer 
[Innocenti, 2004; 
Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects that 
include neutropenia following initiation of 
Irinotecan treatment.  The irinotecan drug 
label indicates that individuals who have two 
copies of the UGT1A1*28 variant are at 
increased risk of neutropenia.  A genetic blood 
test is available that can detect variations in 
the gene.    
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable PGx analysis to be conducted if at any time it appears that there is a potential 
unexpected or unexplained variation in response to [insert the name of the study 
treatment]. 
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to 
GSK1278863 .  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with GSK1278863, the following objectives 
may be investigated – the relationship between genetic variants and study treatment with 
respect to:

Pharmacokinetics and/or pharmacodynamics of study treatment

Safety and/or tolerability 

Efficacy
Study Population
Any subject, who is enrolled in the clinical study, can participate in PGx research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study or result in any penalty or loss of benefits to 
which the subject would otherwise be entitled.


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Study Assessments and Procedures
Blood samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in 
PGx assessments.
In addition to any blood samples taken for the clinical study, a whole blood sample 
(~6ml) will be collected for the PGx research using a tube containing EDTA.  It is 
recommended that the blood sample be taken at the first opportunity after a subject has 
been randomized and provided informed consent for PGx research, but may be taken at 
any time while the subject is participating in the clinical study.

The PGx sample is labelled (or “coded”) with a study specific number that can be 
traced or linked back to the subject by the investigator or site staff.  Coded samples 
do not carry personal identifiers (such as name or social security number).  The 
blood sample is taken on a single occasion unless a duplicate sample is required due 
to inability to utilize the original sample.  
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
GSK1278863 has been completed and the clinical study data reviewed.  In some cases, 
the samples may not be studied; e.g., no questions are raised about how people respond to 
GSK1278863.
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research withdraws from the clinical 
study for any reason other than being lost to follow-up, the subject will be given a choice 
of one of the following options concerning the PGx sample, if already collected:

Continue to participate in the PGx research with the PGx sample retained for 
analysis 

Withdraw from the PGx research and destroy the PGx sample 
If a subject withdraws consent for PGx research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. The investigator should forward the Pharmacogenetic Sample 
Destruction Request Form to GSK as directed on the form. This can be done at any time 


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when a subject wishes to withdraw from the PGx research or have their sample destroyed 
whether during the study or during the retention period following close of the main study.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent 
and sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Pharmacogenetics Analyses
Pharmacogenetics Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene 
variants or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to [insert the name of the study treatment].  
The genes that may code for these proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results
of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data.  A detailed description of the analysis 
to be performed will be documented in the study reporting and analysis plan (RAP) or in 
a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any blood being taken for 
PGx research.


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Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarize the PGx research results in the clinical study report, or separately, 
or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, insurers, or employers) of individual 
genotyping results that are not known to be relevant to the subject’s medical care at the 
time of the study, unless required by law. This is due to the fact that the information 
generated from PGx studies is generally preliminary in nature, and therefore the 
significance and scientific validity of the results are undetermined.
References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-46.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-2.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-40.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-32.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-78
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-66.


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12.3.
Appendix 3: PK, EPO, Hepcidin, and Protein Binding 
Sampling Scheduled Times and Allowed Deviations
Procedures
Time 
Allowed deviation
For PK, 
EPO /hepcidin, 
and 
protein binding samples
Pre-dose
within 1 h of dosing
0.5 h post dose
10 min
1 h post dose
10 min
2 h post dose
15 min
3 h post dose
15 min
4 h post dose
15 min
6 h post dose
30 min
8 h post dose
30 min
12 h post dose
30 min
16 h post dose
30 min
24 h post dose
30 min
48 h post dose
60 min
72 h post dose
60 min


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12.4.
Appendix 4: Procedures for Detection, Evaluation, Follow-
Up and Reporting of Adverse Events and Medical Device 
Incidents
Recording of AEs and SAEs
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative 
to the event.  The investigator will then record all relevant information regarding an 
AE/SAE in the appropriate data collection tool. 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE data collection tool.  
However, there may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to submission 
of to GSK.
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
Subject-completed health outcomes questionnaires and the collection of AE data are 
independent components of the study.  Responses to each question in the health outcomes 
questionnaire will be treated in accordance with standard scoring and statistical 
procedures detailed by the scale’s developer.  The use of a single question from a 
multidimensional health survey to designate a cause-effect relationship to an AE is 
inappropriate.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities.
Moderate:  An event that is sufficiently discomforting to interfere with normal everyday 
activities.
Severe:  An event that prevents normal everyday activities.
An AE that is assessed as severe will not be confused with an SAE.  Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.  An event is defined as ‘serious’ when it meets at least one of the pre-
defined outcomes as described in the definition of an SAE.


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Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE.  A "reasonable possibility" is meant to convey that there are 
facts/evidence 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 natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study treatment will be considered and investigated.  The investigator will also consult 
the Investigator Brochure (IB) and/or Product Information, for marketed products, in the 
determination of 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 when 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 prior to the initial 
transmission of the SAE data to GSK.  The investigator may change his/her opinion of 
causality in light of follow-up information, amending the SAE data collection tool 
accordingly.  The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All AEs and SAEs will be followed until 
resolution, until the condition stabilizes, until the event is otherwise explained, or until 
the subject is lost to follow-up.
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.   The 
investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.  If a subject 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 data collection 
tool.  The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
Reporting of SAEs to GSK
The primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool. If the electronic system is unavailable for greater than 24 hr, the site will use the 
paper SAE data collection tool and fax it to the GSK Medical Monitor and/or protocol 


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contact.  Then the site will enter the serious adverse event data into the electronic system 
as soon as it becomes available.
After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) 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, the site can report this information on a paper SAE form or to their 
GSK protocol contact by telephone.
GSK contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
Facsimile transmission of the SAE data collection tool is the preferred method to transmit 
this information to the project contact for SAE receipt.  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.  Initial notification via the telephone 
does not replace the need for the investigator to complete and sign the SAE data 
collection tool within the designated reporting time frames.
GSK contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of all required information sent by overnight mail.


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12.5.
Appendix 5: Investigational Product (GSK1278863) 
Information
Shipping, Receipt, and Storage of GSK1278863
The shipment of GSK1278863 will contain a Clinical Supplies Shipping Invoice. 
Upon receipt of a shipment, check that the contents correspond to the form. If all of the 
contents are present exactly as listed on the form, the pharmacist or designee signs and 
dates the form. The form will be retained in the pharmacy and/or study site records.
The initial shipment of GSK1278863 will only occur after all of the appropriate 
regulatory and IRB documents have been received and reviewed for completeness by 
GSK.
In the event additional GSK1278863 supplies are needed, contact the GSK protocol 
contact and allow a minimum of 5 days for delivery.
GSK1278863 tablets are to be stored at up to 30°C, and in the original container(s), 
unless being prepared for administration.
Dosage and Administration
GSK1278863 will be supplied in 5 mg tablet strength, supplied as 35 tablets per bottle in 
a white, HDPE 45cc bottle with CR cap. Each bottle will be labelled with an open label, 
single panel label without container numbers.
The tablets are packaged for the site to dispense the medication to the subjects daily 
while at the clinic.
Study drug will be administered with small amount of water. 
Subjects need to refrain from any food and drink (except water) at least 4 h before dosing 
and 4 h after dosing on Day 1 and Day14.
Drug Accountability and Reconciliation
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for GSK1278863 accountability, reconciliation, and record maintenance. 
In accordance with all applicable regulatory requirements, the Investigator or the head of 
the medical institution (where applicable), or designated site staff (e.g., storage manager, 
where applicable) must maintain GSK1278863 accountability records throughout the 
course of the study. 
The responsible person(s) will document the amount of GSK1278863 received from and 
returned to GSK (when applicable), the amount supplied and/or administered to and 
returned by subjects, if applicable.


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GSK1278863 Returns
At the conclusion of the study, a final inventory will be performed by a Study Monitor 
and site pharmacy staff. 
Unused bottles of GSK1278863 must be destroyed locally according to local 
requirements after full review and reconciliation of GSK1278863 accountability records.


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12.6.
Appendix 6: Protocol Amendment Changes
AMENDMENT 1
This amendment will apply to all the study sites and all countries.
This amendment will serve to implement
Summary of Amendment Changes with Rationale
List of Specific Changes
Section 4.2.1. Inclusion Criteria, Inclusion#8, 
Hemoglobin levels are updated based on the feedback received from FDA. It was ≤11.0 
g/dL for ESA naïve subjects, it is updated as <10.0 g/dL; it was ≤12.0 g/dL for subjects 
receiving ongoing ESA treatment, it is updated as ≤11.0 g/dL.
PREVIOUS TEXT
Inc#8: Has a hemoglobin value:

For ESA naïve subjects: 11.0 g/dL

For subjects receiving ongoing ESA treatment: 12.0 g/dL at Screening with a 
re-check value of 11.0 g/dL after appropriate discontinuation according to 
Inclusion Criterion #7 and prior to commencing GSK1278863 dosing.
REVISED TEXT
Inc# 8: Has a hemoglobin value:

For ESA naïve subjects: <10.0 g/dL

For subjects receiving ongoing ESA treatment: 11.0 g/dL at Screening.
Section 4.2.2. Exclusion Criteria, 
The numbering of exclusion criteria was incremented from previous section. The 
numbering now is updated and starts from “1”.
PREVIOUS TEXT
The numbering was from 13 through 40.
REVISED TEXT
The numbering now starts from 1 and goes up to 28.


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Section 5.3.3. Stopping Criteria 
The stopping criteria related to the hemoglobin level is updated per the FDA’s feedback 
received. A previous criterion required subjects to have their absolute hemoglobin level 
≥13.0 g/dL to stop the dosing. The hemoglobin level for stopping the dosing is now 
updated as >11.0 g/L.
PREVIOUS TEXT

On Days 3, 7 and 11, subject’s hemoglobin will be assessed prior to dosing using a 
HemoCue device.  Should subjects have an absolute hemoglobin level 13.0 g/dL, a 
second hemoglobin measurement will be obtained at the same study visit to confirm.  
If confirmed, permanently discontinue GSK1278863 and withdraw subject from the 
study.
REVISED TEXT

On Days 3, 7 and 11, subject’s hemoglobin will be assessed prior to dosing using a 
HemoCue device.  Should subjects have an absolute hemoglobin level > 11.0 g/dL, a 
second hemoglobin measurement will be obtained at the same study visit to confirm.  
If confirmed, permanently discontinue GSK1278863 and withdraw subject from the 
study.
Section 6.1. Time and Events Table, 
Protocol Activity “Urine Drug and Alcohol Screen” is updated as “Drug and Alcohol 
Screen” with a new footnote “m”. Majority of subjects with ESRD undergoing perinoteal 
dialysis will not be able to produce urine samples. For these subjects this screening test 
will be serum-based.
PREVIOUS TEXT
Urine Drug and Alcohol Screen
REVISED TEXT
Drug and Alcohol Screenm
Footnote m: “Urine test will be performed for drug and alcohol screening at Screening (it 
must be negative prior to dosing) and Day-1 visits. For subjects who are not able to 
produce the required amount of urine sample, serum based test will be performed as an 
alternative.”
Section 6.3.2. Vital Signs 
Body temperature measurement was not included under vital signs assessment. It is now 
included as a part of vital signs assessment since it is a measurement performed as a 
standard practice at the site.


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PREVIOUS TEXT

Vital sign measurements will be measured in supine position after 5 min rest and 
will include systolic and diastolic blood pressure, and pulse rate.
REVISED TEXT

Vital sign measurements will be measured in supine position after 5 min rest and 
will include systolic and diastolic blood pressure, body temperature, and pulse rate.
Section 6.3.3. Electrocardiogram (ECG)
On Day -1, ECG measurement will be taken; however, it indicated that this ECG 
measurement should be taken 2 h prior to dosing. 
The first dosing will take place on Day 1, and there will be no ECG measurement on that 
day. This logical error is now corrected.
PREVIOUS TEXT
Day -1:  Three ECGs will be taken, at least 5 min apart within 2 h prior to dosing.  
REVISED TEXT
Day -1:  Three ECGs will be taken, at least 5 min apart.  


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AMENDMENT 2
This amendment will apply to all the study sites and all countries.
This amendment will serve to implement
Summary of Amendment Changes with Rationale
List of Specific Changes
Section 6.1. Time and Events Table, Footnote m
Section 6.1. Time and Events Table, Footnote m is revised to make the Drug and Alcohol 
test type flexible. At screening and on Day -1, this test would have been performed urine 
based or alternatively serum based. However, it was recognized that each site has their 
standard tests for this assessment. At the discretion of the investigator, sites will be able 
to use their standard test in order to ensure that the test results will be ready for an 
evaluation prior the dosing. Test will also be performed on Day 13. 
PREVIOUS TEXT
Urine test will be performed for drug and alcohol screening at Screening (it must be 
negative prior to dosing) and Day-1 visits. For subjects who are not able to produce the 
required amount of urine sample, serum based test will be performed as an alternative.
REVISED TEXT
Test will be performed for drug and alcohol at Screening, Day-1, and Day 13 visits 
check-in for subjects who participate in the study as outpatient, and it must be negative 
prior to dosing.
Section 6.1. Time and Events Table, Footnote
A new footnote, footnote n, is included to clarify how hemoglobin can be assessed on 
Day 3, Day 7, and Day 11 visits. 
PREVIOUS TEXT
N/A
REVISED TEXT
Hemoglobin assessment will be by a HemoCue device.


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AMENDMENT 3
This amendment will apply to all the study sites and all countries.
This amendment will serve to implement
Summary of Amendment Changes with Rationale
List of Specific Changes
Section 4.2.2., Inclusion and Exclusion Criteria, the numbering of each criterion was 
inadvertently changed starting from subtitles “Efficacy” and “Other”. After subtitle 
“Safety”, the numbering was not consecutively increasing for the remaining inclusion and 
exclusion criteria. The inclusion and exclusion criteria numbers were changed to be 
consecutive.  Inclusion criteria numbers now starts from 1 and goes up to 12, exclusion 
criteria numbers start from 1 and goes up to 28.
PREVIOUS TEXT
After the subtitle “Safety”, the numbering for the additional inclusion and exclusion 
criteria under the next subtitles “Efficacy” and “Other” was starting from 1 again, and 
was not consecutive.
REVISED TEXT
Numbering of both inclusion and exclusion criteria is updated after the subtitle “Safety”. 
It is now starting from 1 and goes up to 12 for inclusion criteria and it start from 1 and 
goes up to 28 for exclusion criteria.
Section 4.3.3. Caffeine, Alcohol, and Tobacco, the word “sample” was missing after the 
word “the final pharmacokinetic” in the last part of first sentence, this is now included.
PREVIOUS TEXT
During each dosing session, subjects will abstain from 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 during each session. 
REVISED TEXT
During each dosing session, subjects will abstain from 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 sample during each session. 


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AMENDMENT 4
This amendment will apply to all the study sites and all countries.
This amendment will serve to implement
Summary of Amendment Changes with Rationale
List of Specific Changes
List of Abbreviations
The abbreviation for kilocalorie, kcal, is included in the list.
PREVIOUS TEXT
The abbreviation kcal was not listed.
REVISED TEXT
The abbreviation kcal is now listed.
Regulatory Agency Identifying Number(s), the EudraCT number was provided as 2013-
002681-39. The EudraCT number is now updated as “2014-001197-34” which is the 
correct number for this specific protocol.
PREVIOUS TEXT
EudraCT: 2013-002681-39
REVISED TEXT
EudraCT: 2014-001197-34
Section 4.2.1 Inclusion Criteria, Efficacy, inclusion criteria#5
The urine output and Kt/V values were revised for subject’s eligibility after study 
investigators provided further information gathered about these conditions for the 
subjects who are on peritoneal dialysis.
PREVIOUS TEXT
Inclusion#5: A subject is eligible to enroll and participate in this study if he/she has 
ESRD and is on peritoneal dialysis for at least 2 months with estimated minimal residual 
kidney function (average urine output < 100 mL/daily) with stable Kt/V urea > 1.7 
weekly.
REVISED TEXT
Inclusion#5: A subject is eligible to enroll and participate in this study if he/she has 
ESRD and is on peritoneal dialysis for at least 2 months with an average urine output of < 


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750 mL/daily with a combined weekly (urine and peritoneal dialysis output) Kt/V urea > 
1.7 measured at any time within last 3 months.
Section 4.2.1. Inclusion Criteria, Efficacy, inclusion#8
Hemoglobin levels are updated to meet with country specific requirements. For UK only 
site(s), hemoglobin value is updated as ≤11 g/dL for ESA naïve subjects and as ≤12.0 
g/dL for subjects receiving ongoing ESA treatment.
PREVIOUS TEXT
Inclusion#8 
Has a hemoglobin value:

For ESA naïve subjects: <10.0 g/dL For subjects receiving ongoing ESA 
treatment: 11.0 g/dL at Screening. 
REVISED TEXT
Inclusion#8
Has a hemoglobin value:

For ESA naïve subjects: <10.0 g/dL (UK site(s) only: ≤11.0 g/dL)

For subjects receiving ongoing ESA treatment: 11.0 g/dL at Screening (UK 
site(s) only: 12.0 g/dL at Screening).
Section 4.2.2. Exclusion Criteria, Safety, exclusion criteria#15
The exclusion criteria was revised to be flexible for those subjects who have not received 
their ophthalmology exam within 12 months prior to Screening, so they may take their 
exam with a referral from the study investigators during Screening period.
PREVIOUS TEXT
Exclusion#15: History of proliferative vascular eye disease (e.g., choroidal or retinal 
disease, such as neovascular age-related macular degeneration, proliferative diabetic 
retinopathy or macular edema) based upon having had an ophthalmologic exam within 12 
months prior to Screening. 
REVISED TEXT
Exclusion#15: History of proliferative vascular eye disease (e.g., choroidal or retinal 
disease, such as neovascular age-related macular degeneration, proliferative diabetic 
retinopathy or macular edema) based upon having had an ophthalmologic exam within 12 


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months prior to the end of the Screening period (The screening period is from the screening visit 
until Day -1). 
Section 4.3.2 Meals and Dietary Restrictions
It was stated that subjects would not consume any food and drinks (except water) during 
4 h fasting period after dosing on Day 1 and Day 14. Based on the initial feedback from 
one of study sites, some subjects on peritoneal dialysis are very hungry after they finish 
night portion therapy on peritoneal dialysis cycler. This is most likely due to the 
relatively high insulin dose required to mitigate high dextrose content in the peritoneal 
dialysis fluid needed to achieve adequate ultrafiltration . Thus this section was revised to 
allow subjects to have some light snacks during this 4 h fasting period after dosing.
PREVIOUS TEXT
Subjects will refrain from any food and drink (except water) at least 4 h before dosing 
and 4 h after dosing on Day 1 and Day 14. 
REVISED TEXT
Subjects will refrain from any food and drink (except water) at least 4 h before dosing on 
Day 1 and Day 14.  On Day 1 and Day 14 subjects will be allowed a light snack (e.g., 
crackers and cheese or half a sandwich with a beverage which will not exceed 500 Kcal) 
upon request.
Section 5.3.3. Stopping Criteria; 
The stopping criteria related to the hemoglobin level is updated to meet with country 
specific requirements. For UK only site(s), stopping criteria for absolute hemoglobin 
level now is ≥12.0 g/dL to stop the dosing. 
PREVIOUS TEXT

On Days 3, 7 and 11, subject’s hemoglobin will be assessed prior to dosing using a 
HemoCue device.  Should subjects have an absolute hemoglobin level > 11.0 g/dL, a 
second hemoglobin measurement will be obtained at the same study visit to confirm.  
If confirmed, permanently discontinue GSK1278863 and withdraw subject from the 
study.
REVISED TEXT

On Days 3, 7 and 11, subject’s hemoglobin will be assessed prior to dosing using a 
HemoCue device.  Should subjects have an absolute hemoglobin level > 11.0 g/dL 
(UK site(s) only: ≥ 12.0 g/dL), a second hemoglobin measurement will be obtained 
at the same study visit to confirm.  If confirmed, permanently discontinue 
GSK1278863 and withdraw subject from the study.
Section 6.4.2. Dialysate Sample Collection, on Day 1 and Day 14, the volume of 
dialysate solution to be collected for analysis was specified as 10 mL aliquot. This is 
revised to 1.5 mL.


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PREVIOUS TEXT
On Day 1 and Day 14, “..approximately 10 mL aliquot of dialysate from..” 
REVISED TEXT
On Day 1 and Day 14, “..approximately 1.5 mL aliquot of dialysate from..” 
Section 6.1, Time and Events Table, there was a typo error on the Day of Follow-up visit. 
It was entered as Day 23. This is now corrected as Day 22.
PREVIOUS TEXT
Column “Follow Up (refer to Section 3.1)”, Protocol Activity, Day 23
REVISED TEXT
Column “Follow Up (refer to Section 3.1)”, Protocol Activity, Day 22


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AMENDMENT 5
This amendment will apply to all the study sites and all countries.
This amendment will serve to implement
Summary of Amendment Changes with Rationale
List of Specific Changes
List of Abbreviations
PREVIOUS TEXT
APD
Ambulatory peritoneal dialysis
REVISED TEXT
APD
Automated peritoneal dialysis
Section 4.1 Number of Subjects
PREVIOUS TEXT
Approximately 30 subjects with ESRD will be enrolled (15 subjects in each cohort) 
considering high dropout in the study to ensure completion of 12 evaluable subjects such 
that 6 CAPD subjects and 6 APD subjects complete dosing and critical assessments.
REVISED TEXT
Approximately 30 subjects with ESRD may be enrolled (15 subjects in each cohort) 
considering high dropout in the study to ensure completion of 12 evaluable subjects such 
that 6 CAPD subjects and 6 APD subjects complete dosing and critical assessments.  
However, if during the informal review of the available PK data it is determined that 
there are no clinically-significant differences in PK between the CAPD and APD 
populations, the planned number of subjects may be reduced.
Section 4.2.1 Inclusion Criteria
PREVIOUS TEXT
5.   A subject is eligible to enroll and participate in this study if he/she has ESRD and is 
on peritoneal dialysis for at least 2 months with an average urine output of < 750 
mL/daily with a combined weekly (urine and peritoneal dialysis output) Kt/V urea > 
1.7 measured at any time within last 3 months.


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REVISED TEXT
5.  A subject is eligible to enroll and participate in this study if he/she has ESRD and is 
on peritoneal dialysis for at least 2 months with a combined weekly (urine and 
peritoneal dialysis output) Kt/V urea > 1.7 measured at any time within last 3 months.
Section 4.2.2 Exclusion Criteria
PREVIOUS TEXT
23. The values of ferritin and transferrin within 3 months prior to Screening are:
a. transferrin saturation < 20% 
b. serum ferritin < 100 μg/L
REVISED TEXT
23. The most recent values of ferritin and transferrin within 3 months prior to Screening 
are:
a. transferrin saturation < 20% 
b. serum ferritin < 100 μg/L
Section 4.3.2 Meals and Dietary Restrictions
PREVIOUS TEXT
Consumption of red wine, grapefruit (juice), blood orange (juice), star fruit, onions, kale, 
broccoli, green beans, or apples is prohibited from 7 days prior to the first dose of 
GSK1278863 and throughout the study until Day 14.
REVISED TEXT
Consumption of red wine, grapefruit (juice), blood orange (juice), star fruit, onions, kale, 
broccoli, green beans, or apples is prohibited from 7 days prior to the first dose of 
GSK1278863 until the Follow-Up visit, unless in the opinion of the investigator and GSK 
Medical Monitor this will not interfere with the study procedures and compromise subject 
safety.
Section 5.10 Concomitant Medications
PREVIOUS TEXT
All concomitant medications taken during the study will be recorded in the eCRF.  


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REVISED TEXT
All concomitant medications (including rhEPO) taken in the 4 weeks before and during 
the study will be recorded in the eCRF.  
PREVIOUS TEXT
While no other studies have been performed specifically to evaluate potential interactions 
with drugs that ma
y be co-administered with GSK1278863, in vitro studies showed the potential for 
inhibition of CYP2C8 (IC50: 21 µM) by GSK1278863, while there was no evidence of 
concentration- or metabolism-dependent inhibitory potential towards human CYP1A2, 
2A6, 2B6, 2C9, 2C19, 2D6 or 3A4.  
REVISED TEXT
There are ongoing clinical studies  to evaluate potential interactions with drugs that may 
be co-administered with GSK1278863.  In vitro studies showed the potential for 
inhibition of CYP2C8 (IC50: 21 µM) by GSK1278863, while there was no evidence of 
concentration- or metabolism-dependent inhibitory potential towards human CYP1A2, 
2A6, 2B6, 2C9, 2C19, 2D6 or 3A4
PREVIOUS TEXT
GSK1278863 is a substrate of murine breast cancer resistance protein (Bcrp) 1 in vitro.  
REVISED TEXT
GSK1278863 is a substrate of human breast cancer resistance protein (BCRP) in vitro.  
Section 4.4 Screen and Baseline Failures
PREVIOUS TEXT
Data for screen failures will be collected in source documentation at the site but will not 
be transmitted to GSK.
REVISED TEXT
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any Serious Adverse Events.
Section 9.3.1 Analysis Populations 
PREVIOUS TEXT


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Not applicable. 
REVISED TEXT – New Section in Protocol.
All Screened Population
The “All Screened” population will be defined as all subjects screened.
All Subjects Population
The ‘All Subjects Population’ is defined as all subjects who receive at least one dose of 
study treatment.  This population will be used for the study population and safety 
analyses.
Pharmacokinetic Population
The ‘PK Population' is defined as subjects in the ‘All Subjects’ population for whom a 
pharmacokinetic sample was obtained and analyzed.  This will be the population used for 
all the pharmacokinetic displays.
Section 9.3.1 Analysis Populations (Section 9.3.1 in Previous Amendments)
PREVIOUS TEXT
No formal interim analysis will be performed.
REVISED TEXT
Informal PK reviews will be conducted throughout the study to assist Phase III 
development of the compound.


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AMENDMENT 6
This amendment will apply to all the study sites and all countries.
This amendment will serve to implement
Summary of Amendment Changes with Rationale
List of Specific Changes
Sponsor/Medical monitor information page
PREVIOUS TEXT
Primary & Secondary Medical monitor: fax number: 
 Address:
GlaxoSmithKline, N0410
2301 Renaissance Blvd, Bldg #510, PO Box 61540, King of Prussia, PA 19406
REVISED TEXT
Primary & Secondary Medical monitor: 
 Address: GlaxoSmithKline, 
UP4400, 1250 S. Collegeville Rd. Collegeville, PA 19426
SECTION 1.1.1 
PREVIOUS TEXT
Additional paragraph added at the end of this section
REVISED TEXT
The effective date of the original protocol is 11-APR-2014. In the 2 years that the study 
has been active, only 4 subjects have completed the study. This includes 1 CAPD and 3 
APD subjects. Considering the difficulties with recruitment in general, and the CAPD 
population in particular, this protocol will be amended to enroll ESRD subjects 
undergoing peritoneal dialysis of either modality (i.e., CAPD or APD). In addition, in a 
previous study (PHI115573), the pharmacokinetic properties of daprodustat and the 
predominant metabolites were able to be adequately characterized in an ESRD population 
undergoing hemodialysis with 8 subjects. Finally, preliminary results from this study has 
shown that a subject using CAPD had similar PK to the 3 subjects using APD suggesting 
that, if there are differences in the PK of daprodustat depending upon the peritoneal 
dialysis modality, they are likely to be not considered clinically significant.
SECTION 1.3
PREVIOUS TEXT
As of 28 February 2014, GSK1278863 has been administered as single oral doses ranging 
from 2 to 300 mg to 175 healthy, adult male and female subjects in five completed 
Clinical Pharmacology studies (PHX111427, PHI112843, PHI113634, PHI114703, 
PPD
PPD


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PHI115385) and administered once daily (15 to 100 mg) or 25 mg twice daily for up to 
14 days duration to 20 healthy subjects in completed study PHI112842.
Details of the completed studies, as well as available safety, pharmacokinetic and 
pharmacodynamic (PD) data, may be found in the Investigator’s Brochure (IB) for 
GSK1278863 (GlaxoSmithKline Document Number RM2008/00267/06).
REVISED TEXT
As of 28 August 2015, GSK1278863 has been administered as single oral doses ranging 
from 2 to 500 mg to 235 healthy, adult male and female subjects in nine completed 
Clinical Pharmacology and Biopharmaceutical studies (PHX111427, PHI112842, 
PHI112843, PHI116008, PHI115573, PHI113635, PHI113634, PHI114703, PHI115385) 
and administered once daily (15 to 100 mg) or 25 mg twice daily for up to 14 days 
duration to 20 healthy subjects in completed study PHI112842.
Details of the completed studies, as well as available safety, pharmacokinetic and 
pharmacodynamic (PD) data, may be found in the Investigator’s Brochure (IB) for 
GSK1278863 [GlaxoSmithKline Document Number RM208/00267/07] and associated 
IB Supplements [GlaxoSmithKline Document Number 2015N266524_00,
GlaxoSmithKline Document Number 17-Dec-2015; GlaxoSmithKline Document 
Number 2015N266524_01, 08-Apr-2016].
SECTION 3.1
PREVIOUS TEXT

Cohort 1 will enrol approximately 15 subjects such that at least 6 subjects on
continuous ambulatory peritoneal dialysis (CAPD) will complete all dosing and
critical assessments

Cohort 2 will enrol approximately 15 subjects such that at least 6 subjects on
automated peritoneal dialysis (APD) will complete all dosing and critical
assessments.
REVISED TEXT

Cohort 1 will enrol subjects on continuous ambulatory peritoneal dialysis 
(CAPD) to complete all dosing and critical assessments

Cohort 2 will enrol subjects on automated peritoneal dialysis (APD) to
complete all dosing and critical assessments.  
Once a total of 8 subjects across both cohorts collectively have completed the trial, 
enrolment will be stopped and the study will be concluded. 
A sufficient number of ESRD subjects undergoing peritoneal dialysis will be enrolled in 
this study in order to ensure that at least 8 subjects total complete dosing and all critical 
assessments. However, if during an informal review of available PK data it is determined 
that the PK appears to be adequately characterized, the planned number of subjects may 
be reduced.


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PREVIOUS TEXT
Subjects will be offered to stay in residence at the study site (inpatient) or they are
allowed to remain at home (outpatient) throughout the study. Regardless of whether
subjects remain in residence or not, all subjects are to be at the site every morning for
administration of GSK1278863 and for receiving any scheduled assessments. If a subject
prefers to participate in the study as an outpatient, subjects will be released from the
clinic after dosing or completion of any scheduled assessments.
REVISED TEXT
Subjects will be offered to stay in residence at the study site (inpatient) or they are 
allowed to remain at home (outpatient) throughout the study. For subjects that choose to 
participate in the study as an outpatient, they will be released from the clinic and must 
return to the clinic for scheduled assessments.
PREVIOUS TEXT
At a minimum, study staff must ensure that subjects are in residence at the site on full PK 
Days (Day 1 and Day 14), as well as Days 15, and16 for 48 and 72 h PK sampling.
REVISED TEXT
At a minimum, study staff must ensure that subjects are in residence at the site on full PK 
Days (Day 1 and Day 14), as well as on Days 15, and16 for 48 and 72 h PK sampling.
SECTION 3.3
PREVIOUS TEXT
Please refer to the GlaxoSmithKline Investigator’s Brochure for GSK1278863 for 
additional pre-clinical and clinical details (GlaxoSmithKline Document Number. 
RM2008/00267/06, 04 March 2014).
REVISED TEXT
Please refer to the GlaxoSmithKline Investigator’s Brochure [GlaxoSmithKline 
Document Number. RM2008/00267/07, 14 October 2015] and associated IB 
Supplements for GSK1278863 [GlaxoSmithKline Document Number 2015N266524_00, 
17-Dec-2015; GlaxoSmithKline Document Number 2015N266524_01, 08-Apr-2016] for 
additional pre-clinical and clinical details.
PREVIOUS TEXT
Based on the non-clinical studies, the primary areas of interest for GSK1278863 are 
related to GI tolerability (e.g., stomach erosions with bleeding) and potential for 
thrombosis with ischaemia secondary to erythrocytosis (excessive erythropoiesis).
REVISED TEXT
Based on the non-clinical studies, the primary areas of interest for GSK1278863 are 
related to GI tolerability (e.g., stomach erosions with bleeding) and potential for 
thrombosis and/or tissue ischemia secondary to excessive erythropoiesis.  


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PREVIOUS TEXT
In addition, several events of special interest have been identified based on clinical 
experience with ESAs including increased risk of cancer related morbidity and mortality 
and increased risk of major cardiovascular events (e.g., stroke, myocardial infarction, 
congestive heart failure).  
Lastly based on what is currently known of the possible roles for HIF-regulated pathways 
in mediating hypoxia associated pathophysiology, pulmonary artery hypertension and 
tissue neo-vascularization (e.g., retinal, joint synovium) have also been identified as areas 
of special interest. 
REVISED TEXT
In addition, several events of special interest have been identified based on clinical
experience with ESAs including increased risk of cancer related morbidity and mortality 
and increased risk of major cardiovascular events (e.g., death, stroke, myocardial 
infarction, congestive heart failure).  
Lastly based on what is currently known of the possible roles for HIF-regulated pathways 
in mediating hypoxia associated pathophysiology, pulmonary artery hypertension, 
cardiomyopathy, and tissue neo-vascularization (e.g., retinal, joint synovium) have also 
been identified as areas of special interest. 
SECTION 4.1
PREVIOUS TEXT
Approximately 30 subjects with ESRD may be enrolled (15 subjects in each cohort)
considering high dropout in the study to ensure completion of 12 evaluable subjects such
that 6 CAPD subjects and 6 APD subjects complete dosing and critical assessments.
However, if during the informal review of the available PK data it is determined that
there are no clinically-significant differences in PK between the CAPD and APD
populations, the planned number of subjects may be reduced.
REVISED TEXT
Approximately 24 subjects with ESRD may be enrolled (12 subjects in each cohort) 
considering high dropout in the study to ensure completion of 8 evaluable subjects
complete dosing and critical assessments.  If subjects prematurely discontinue the study, 
additional subjects may be enrolled as replacement subjects at the discretion of the 
Sponsor in consultation with the investigator.
SECTION 4.2
PREVOUS TEXT
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on GSK1278863 or other study treatment that may 
impact subject eligibility is provided in the GSK1278863 IB [GlaxoSmithKline 
Document Number RM2008/00267/06].
REVISED TEXT
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on GSK1278863 that may impact subject eligibility is 


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provided in the GSK1278863 IB [GlaxoSmithKline Document Number 
RM2008/00267/07] and associated IB Supplements for GSK1278863 [GlaxoSmithKline 
Document Number 2015N266524_00, 17-Dec-2015; GlaxoSmithKline Document 
Number 2015N266524_01, 08-Apr-2016].
SECTION 4.2.1
Inclusion criteria #8
PREVIOUS TEXT
Has a hemoglobin value:

For ESA naïve subjects: <10.0 g/dL (UK site(s) only: ≤11.0 g/dL)

For subjects receiving ongoing ESA treatment: ≤11.0 g/dL at Screening (UK
site(s) only: ≤12.0 g/dL at Screening).
REVISED TEXT
Has a hemoglobin value:

For ESA naïve subjects: <10.0 g/dL 

For subjects receiving ongoing ESA treatment: stable Hgb 9.0-11.5 g/dL. 
SECTION 5.3.3 
PREVIOUS TEXT

On Days 3, 7 and 11, subject’s hemoglobin will be assessed prior to dosing 
using a HemoCue device. Should subjects have an absolute hemoglobin level > 
11.0 g/dL (UK site(s) only: ≥ 12.0 g/dL), a second hemoglobin measurement 
will be obtained at the same study visit to confirm. If confirmed, permanently 
discontinue GSK1278863 and withdraw subject from the study.
REVISED TEXT

On Days 3, 7 and 11, subject’s hemoglobin will be assessed prior to dosing using a 
HemoCue device.  Should subjects have an absolute hemoglobin level > 11.0 g/dL, a 
second hemoglobin measurement will be obtained at the same study visit to confirm.  
If confirmed, permanently discontinue GSK1278863 and withdraw subject from the 
study.
SECTION 5.8
PREVIOUS TEXT
No specific antidote for GSK1278863 is known. Any signs or symptoms of possible 
overdosage are to be treated supportively.  In the event of suspected overdose, collect 
blood samples for pharmacokinetics and safety laboratory immediately.
GSK does not recommend specific treatment for an overdose.  The Investigator is to use 
clinical judgment to treat any overdose.


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REVISED TEXT
No specific antidote for GSK1278863 is known. The expected manifestations of 
GSK1278863 overdosage include signs and symptoms associated with an excessive 
and/or rapid increase in Hgb concentration. GSK1278863 is highly protein bound; thus, 
clearance of GSK1278863 by HD or PD is very low and these are not effective methods 
to enhance the elimination of GSK1278863. GSK1278863 metabolites are, in part, 
cleared via hemodialysis. 
In the event of suspected overdose:

collect blood samples for pharmacokinetics and safety laboratory immediately.

it is recommended that the appropriate supportive clinical care be instituted, as 
dictated by the subject’s clinical status. Additionally, subjects should be 
monitored closely for CV events, increased heart rate and hematologic 
abnormalities.
SECTION 5.10
PREVIOUS TEXT
There are ongoing clinical studies to evaluate potential interactions with drugs that may 
be co-administered with GSK1278863.  In vitro studies showed the potential for 
inhibition of CYP2C8 (IC50: 21 µM) by GSK1278863, while there was no evidence of 
concentration- or metabolism-dependent inhibitory potential towards human CYP1A2, 
2A6, 2B6, 2C9, 2C19, 2D6 or 3A4.  
GSK1278863 was also observed to be an inhibitor of organic anion transporting 
polypeptide (OATP) 1B1 and 1B3 in vitro with IC50s of ~6 μM and ~11 μM, 
respectively.  The average Cmax observed after single dose administration of 5 mg 
GSK1278863 to healthy subjects was 0.24 μM, suggesting a low risk of an interaction.
REVISED TEXT
In vitro studies showed the potential for inhibition of CYP2C8 (IC50: 21 µM) by 
GSK1278863, while there was no evidence of concentration- or metabolism-dependent 
inhibitory potential towards human CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6 or 3A4.  In a 
recent drug-drug interaction, there was no apparent evidence of a drug interaction 
between GSK1278863, at doses up to 100 mg, with pioglitazone, a CYP2C8 substrate.
GSK1278863 was also observed to be an inhibitor of organic anion transporting 
polypeptide (OATP) 1B1 and 1B3 in vitro with IC50s of ~6 μM and ~11 μM, 
respectively.  The average Cmax observed after single dose administration of 5 mg 
GSK1278863 to healthy subjects was 0.24 μM, suggesting a low risk of an interaction. In 
a recent drug-drug interaction, there was no apparent evidence of a drug interaction 
between GSK1278863, at doses up to 100 mg, with rosuvastatin, an OATP1B1 substrate.
SECTION 5.10.1.1 
PREVIOUS TEXT
As there are limited data on the potential for pharmacokinetic interactions with 


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GSK1278863, substrates of OATP1B1/1B3 and CYP2C8 should be used with caution 
and subjects should be monitored for any signs of (increased) toxicity (e.g., liver function 
tests and creatinine phosphokinase for ‘statins’).  
A reduction in dose of the OATP1B1/1B3 or CYP2C8 substrate may be considered if 
appropriate.  Consideration should be given to have statin or other OATP1B1/1B3 
substrate dosing held until 12 h after GSK1278863 administration on a case by case 
basis.  
CYP2C8 substrates not described in the prohibited medications section, e.g., including 
rosiglitazone, pioglitazone, and torsemide are permitted for use during the study, as long 
as subjects have been taking a stable dose for more than 3 months.
REVISED TEXT
This section was deleted and amended in Section 5.10
SECTION 6.1 Time and Events Table - footnotes
PREVIOUS TEXT
b Subjects may remain in residence at the site from the afternoon of Day -1 through the 
last assessment on Day 17, at the discretion of the investigator or by request of the 
subject (refer to Section 3.1).
c Each dose will be administered within 30 min after completion of the night APD 
treatment or morning last fill of peritoneal dialysis fluid.
REVISED TEXT
b Subjects may remain in residence at the site from the afternoon of Day -1 through the 
last assessment on Day 17, at the discretion of the investigator or by request of the 
subject (refer to Section 3.1). Outpatients must return to the site for scheduled PK 
assessments.
c Each dose will be administered within 30 min after completion of the night APD 
treatment or morning last fill of peritoneal dialysis fluid. Outpatients can self 
administer their daily dose, following discussion with the investigator.
SECTION 9.2.1
PREVIOUS TEXT
As this study is descriptive in nature and no formal statistical comparisons of PK data 
will be performed, the sample size of 30 subjects (15 in each cohort) will be recruited 
such that at least 12 subjects (6 in each cohort) complete the trial.    Based on PK 
parameter CV% of ~50% in subjects with renal impairment or ESRD (refer to 
GlaxoSmithKline Document Number RM2008/00267/06.GSK1278863 IB) a sample size 
of at least 6 subjects, the lower and upper bounds of the 95% confidence interval for a PK 
parameter geometric mean would be within 50% and 202% of the estimate and for 
sample size of at least 12 subjects, the lower and upper bounds of the 95% confidence 
interval for a PK parameter geometric mean would be within 65% and 153% of the 
estimate.  


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REVISED TEXT
As this study is descriptive in nature and no formal statistical comparisons of PK data 
will be performed, the sample size of 24 subjects (12 in each cohort) will be recruited 
such that at least 8 subjects complete the trial. Based on PK parameter CV% of ~50% in 
subjects with renal impairment or ESRD [refer to GlaxoSmithKline Document Number
RM2008/00267/07, 14-Oct-2015.GSK1278863 IB and associated IB supplements for 
GSK1278863 [GlaxoSmithKline Document Number 2015N266524_00, 17-Dec-2015; 
GlaxoSmithKline Document Number 2015N266524_01, 08-Apr-2016] for a sample size 
of at least 8 statistically evaluable subjects, the half width of the 90% confidence interval 
will be within 56% of the point estimate.
SECTION 9.3.3.2.1
Steady State Assessment
PREVIOUS TEXT
Assessment of plasma GSK1278863 and metabolites steady state will be assessed by 
evaluating the estimated slope for the day parameter and associated 90% CI within each 
cohort.
REVISED TEXT
Assessment of plasma GSK1278863 and metabolites steady state will be assessed by 
evaluating the estimated slope for the day parameter and associated 90% CI for both the 
cohorts combined.
Secondary Comparisons: Assessment of Accumulation
PREVIOUS TEXT
To evaluate the accumulation ratio, statistical analysis of GSK1278863 and metabolites
will be performed separately after a log transformation of the data. 
A mixed effect model will be fitted with day (single and repeat dose), as fixed effects and 
subject as a random effect.  Day 14 will be compared to Day 1 in order to estimate the 
accumulation ratios, Ro= (AUC (0- τ, Day14): AUC (0- τ, Day1).  The ratios will be 
calculated by back-transforming the difference between the LS means. 
Using the pooled estimate of variance, 90% confidence intervals will be calculated for the 
primary comparisons, and back-transformed to the original scale.
REVISED TEXT
To evaluate the accumulation ratio, statistical analysis of GSK1278863 and metabolites
for both the cohorts combined will be performed after a log transformation of the data. 
A mixed effect model will be fitted with day (single and repeat dose), as fixed effects and 
subject as a random effect.  Day 14 will be compared to Day 1 n order to estimate the 
accumulation ratios, Ro= (AUC (0- τ, Day14): AUC (0- τ, Day1).  The ratios will be 
calculated by back-transforming the difference between the LS means. 


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Using the pooled estimate of variance, 90% confidence intervals will be calculated for   
Ro, and back-transformed to the original scale.
Assessment of Time Invariance
PREVIOUS TEXT
To evaluate the time invariance ratio, statistical analysis of (AUC (0-∞) Day 1) and AUC 
(0- τ) (Day14), of GSK1278863 and metabolites for each cohort will be performed 
separately after a log transformation of the data. 
A mixed effect model will be fitted with day as fixed effects and subject as a random 
effect.  Day 14 AUC (0- τ) will be compared to Day 1 AUC (0-∞) by cohort in order to 
estimate the time invariance ratios, RS= AUC (0- τ, Day 14): AUC (0-∞, Day 1). The 
ratios will be calculated by back-transforming the difference between the LS means. 
Using the pooled estimate of variance, 90% confidence intervals will be calculated for the 
primary comparisons, and back-transformed to the original scale.
REVISED TEXT
To evaluate the time invariance ratio, statistical analysis of (AUC (0-∞) Day 1) and AUC 
(0- τ) (Day14), of GSK1278863 and metabolites for both the cohorts combined will be 
performed after a log transformation of the data. 
A mixed effect model will be fitted with day as fixed effects and subject as a random 
effect.  Day 14 AUC (0- τ) will be compared to Day 1 AUC (0-∞) in order to estimate the 
time invariance ratios, RS= AUC (0- τ, Day 14): AUC (0-∞, Day 1). The ratios will be 
calculated by back-transforming the difference between the LS means. 
Using the pooled estimate of variance, 90% confidence intervals will be calculated for 
Rs, and back-transformed to the original scale.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
200942
1
Division: Worldwide Development
Retention Category:GRS019
Information Type:Clinical Pharmacology Reporting and Analysis Plan
Title:
Clinical Pharmacology Reporting and Analysis Plan for a repeat-
dose, open-label, parallel-group study to assess the 
pharmacokinetics of GSK1278863 and metabolites in subjects 
with End Stage Renal Disease undergoing peritoneal dialysis.
Compound Number:
GSK1278863
Effective Date:
14-SEP-2017
Description: 
The purpose of this reporting and analysis plan (RAP) is to describe the planned analyses 
and output to be included in the Clinical Pharmacology Study Report for Protocol
200942.  This study is intended to characterize the pharmacokinetics of GSK1278863 and 
its metabolites in subjects with end stage renal disease (ESRD) undergoing peritoneal 
dialysis. This document will be provided to the study team members to convey the 
content of the Statistical Analysis Complete (SAC) deliverable.
Subject:  GSK1278863, Prolyl hydroxylase inhibitor, Anemia, Chronic kidney disease, 
peritoneal dialysis, erythropoiesis stimulating agents, analysed in, pharmacokinetics
Author’s Name and Functional Area: 
Quantitative Science India
Quantitative Science India
Quantitative Science India
Approved by Email:
The Discovery Biometrics Director (or designee) will give final approval
Director, Statistics & Programming
14-SEP-2017
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD


CONFIDENTIAL
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................4
1.
INTRODUCTION......................................................................................................6
2.
STUDY OBJECTIVE(S) AND ENDPOINT(S) ...........................................................7
2.1.
Study Objective(s) ........................................................................................7
2.1.1.
Primary Objective(s) ......................................................................7
3.
STUDY DESIGN ......................................................................................................8
4.
PLANNED ANALYSES ............................................................................................8
4.1.
Interim Analyses ...........................................................................................8
4.2.
Final Analyses ..............................................................................................8
5.
ANALYSIS POPULATIONS .....................................................................................8
6.
HYPOTHESES AND TREATMENT COMPARISONS ..............................................9
7.
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING .............9
7.1.
Reporting Conventions .................................................................................9
7.2.
Data Management ......................................................................................11
7.3.
Premature Withdrawal and Missing Data ....................................................12
7.4.
Baseline Definition......................................................................................12
7.5.
Derived and Transformed Data...................................................................12
7.5.1.
Demographic and Population parameters....................................12
7.5.1.1.
Study Day...................................................................12
7.5.1.2.
Date of Birth ...............................................................12
7.5.1.3.
Age.............................................................................13
7.5.1.4.
Body Mass Index (BMI) ..............................................13
7.5.1.5.
Exposure....................................................................13
7.5.2.
Safety Parameters.......................................................................13
7.5.2.1.
Adverse Events ..........................................................13
7.5.3.
Change from Baseline .................................................................13
7.5.4.
Pharmacokinetic Parameters.......................................................14
7.5.5.
Multiple Measurements at One Timepoint....................................14
7.6.
Values of Potential Clinical Importance.......................................................14
7.6.1.
Laboratory Values........................................................................14
7.6.2.
Vital Signs....................................................................................16
7.6.3.
ECG.............................................................................................16
8.
STUDY POPULATION...........................................................................................16
8.1.
Subject Disposition and Demographics.......................................................17
8.2.
Protocol Deviations.....................................................................................17
8.3.
Concomitant Medications............................................................................17
9.
SAFETY ANALYSES .............................................................................................18
9.1.
Extent of Exposure .....................................................................................18
9.2.
Adverse Events...........................................................................................19
9.3.
Deaths and Serious Adverse Events...........................................................19


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9.4.
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal from the Study and Other Significant 
Adverse Events...........................................................................................19
9.5.
Clinical Laboratory Evaluations...................................................................19
9.6.
Vital Signs and Body Weight.......................................................................19
9.7.
Electrocardiograms.....................................................................................19
10. PHARMACOKINETIC ANALYSES.........................................................................20
10.1.
Drug Concentration Measures ....................................................................20
10.2.
Deriving and Summarizing Pharmacokinetic Parameters............................20
10.3.
Statistical Analyses.....................................................................................23
11. PHARMACODYNAMIC/BIOMARKER ANALYSES ................................................24
12. PHARMACOGENETIC ANALYSIS ........................................................................24
13. REFERENCES.......................................................................................................25
14. ATTACHMENTS ....................................................................................................26
14.1.
Table of Contents for Data Display Specifications.......................................26
14.1.1.
Study Population..........................................................................27
14.1.2.
Safety Tables...............................................................................28
14.1.3.
Pharmacokinetic Figures and Tables...........................................30
14.1.4.
Pharmacodynamic Figures and Tables........................................35
14.1.5.
ICH Listings .................................................................................37
14.1.6.
Other Listings ..............................................................................39
14.2.
Data Display Specifications (Example Shells).............................................40


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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
ANOVA
Analysis of Variance
APD
Ambulatory Peritoneal Dialysis
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC (0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
%AUCex
Percentage of AUC (0-) obtained by extrapolation
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration 
AUC (0-)
Area under the concentration-time curve over the dosing interval
BMI
Body mass index
BP
Blood pressure
BPM
Beat Per Minute
BQL
Below the quantification limit
BUN
Blood urea nitrogen
CAPD
Continuous Ambulatory Peritoneal Dialysis
CBC
Complete blood count
Cmax
Maximum observed concentration 
IDMC
Independent Data Monitoring Committee
IDSL
Integrated Data Standards Library
IU
International Unit
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
MRT
Mean residence time
MSDS
Material Safety Data Sheet
msec
Milliseconds
NQ
Non-quantifiable concentration measured as below LLQ
PD
Pharmacodynamic
PGx
Pharmacogenetics
PK
Pharmacokinetic
PSRI
Periodic Safety Reports for Investigators
QC
Quality control
QD
Once daily
RAP
Reporting and Analysis Plan
t OR tlast 
Time of last observed quantifiable concentration
t½
Terminal phase half-life
τ
Dosing interval
tlag
Lag time before observation of drug concentrations in sampled matrix
tmax
Time of occurrence of Cmax


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ULN
Upper limit of normal
WBC
White blood cells
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
HARP
SAS
WinNonlin


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Pharmacology Study Report for Protocol 200942:
Revision Chronology: Protocol
2013N179529_00
2014-APR-11
Original
2013N179529_01
2014-JUN-06
Amendment No. 1
2013N179529_02
2014-JUN-24 
Amendment No. 2
2013N179529_03 
2014-JUL-01 
Amendment No. 3
2013N179529_04 
2014-DEC-12
Amendment No. 4
2013N179529_05
2015-SEP-10
Amendment No. 5
2013N179529_06
2016-JUN-20
Amendment No. 6
All decisions regarding final analysis, as defined in this RAP document, have been made 
prior to Database Freeze (unblinding) of the study data. 


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2.
STUDY OBJECTIVE(S) AND ENDPOINT(S)
2.1.
Study Objective(s)
2.1.1.
Primary Objective(s)
Objectives
Endpoints
Primary
Characterize the steady-state PK of
GSK1278863 and metabolites
(GSK2391220 (M2), GSK2506104 (M3),
GSK2487818 (M4), GSK2506102 (M5),
GSK2531398 (M6), GSK2531401 (M13)
in ESRD subjects undergoing peritoneal
dialysis
[AUC(0-τ), AUC (0-∞)] (Day 1 only),
and Cmax of GSK1278863 and
   metabolites on Day 1 and Day 14
Secondary
Evaluate the safety and tolerability of 
GSK1278863 in ESRD subjects 
undergoing peritoneal dialysis
Subject incidence of treatment emergent 
adverse events, including
clinically-significant changes in
physical exams, laboratory safety tests, 
ECG and vital signs
Characterize the peritoneal dialysis 
clearance of GSK1278863 and metabolites 
in ESRD subjects undergoing peritoneal 
dialysis
Peritoneal dialysis clearance, tmax and t½ 
of GSK1278863 and metabolites on Day 
1 and Day 14
Accumulation ratio and time invariance 
ratio (as data permit) of GSK1278863 
and metabolites
Characterize the plasma profile of
erythropoietin and hepcidin after repeat 
dose administration of GSK1278863 in 
ESRD subjects undergoing peritoneal 
dialysis
Erythropoietin and hepcidin plasma
concentrations
Exploratory
Characterize the plasma protein binding of
steady-state GSK1278863 and select
metabolites in ESRD subjects undergoing
peritoneal dialysis
Steady-state GSK1278863 and
metabolite unbound concentration and
free fraction
Characterize the effect of different
peritoneal dialysis solutions on
GSK1278863 and metabolites in ESRD
subjects undergoing peritoneal dialysis
Descriptive summary of GSK1278863
and metabolite PK by different
peritoneal dialysis solutions utilized


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3.
STUDY DESIGN
This is a repeat-dose, open label, 2 cohort study to assess the pharmacokinetics of 
GSK1278863 and metabolites in ESRD subjects undergoing peritoneal dialysis. 
GSK1278863 (5 mg) will be orally administered once daily for 14 days to approximately 
12 ESRD subjects;

Cohort 1 will enrol subjects on continuous ambulatory peritoneal dialysis 
(CAPD) to complete all dosing and critical assessments

Cohort 2 will enrol subjects on automated peritoneal dialysis (APD) to 
complete all dosing and critical assessments.
Further details about the study design can be found in Section 3 of the protocol.
4.
PLANNED ANALYSES
4.1.
Interim Analyses

Informal PK reviews will be conducted throughout the study to assist Phase III 
development of the compound 
4.2.
Final Analyses
The final planned analyses will be performed after all subjects have completed the study 
and after database freeze.  See Section 8 to Section 10 for all final planned analyses for 
this study.
5.
ANALYSIS POPULATIONS
All Screened Population
The “All Screened” population will be defined as all subjects screened.
Enrolled Population
All participants who were enrolled for the trial and for whom a record exists on the study 
database.
All Subjects Population
Any subject enrolled into the study who receives at least one dose of study medication 
will be included in the ‘All Subjects’ Population. This will be the population used for the 
study population and safety analyses. 
Pharmacokinetic Population


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The ‘PK Population’ is defined as subjects in the ‘All Subjects’ population for whom a 
pharmacokinetic sample was obtained and analysed. This will be the population used for 
the Pharmacokinetic displays.
6.
HYPOTHESES AND TREATMENT COMPARISONS
Precision Estimation
This study is designed to estimate pharmacokinetic endpoints of GSK1278863 and 
metabolites in ESRD patients undergoing peritoneal dialysis following repeat 
administration of 5 mg once daily GSK1278863.
There will be two cohorts of subjects in this study: subjects with CAPD and subjects with 
APD.
No formal statistical hypotheses will be tested. An estimation approach will be used to 
evaluate the comparisons of interest, with point estimates and associated 90% confidence
intervals presented to provide a range of plausible values for the comparisons.
Table 1
Treatment and Other Sub-Group Descriptions for Data Displays
Randomisation
Final Data Display 
(i.e. HARP / other)
Treatment 
Cohort Description
Cohort
5 mg GSK1278863
Continuous Ambulatory 
Peritoneal Dialysis
CAPD
Automated Peritoneal Dialysis
APD
7.
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
AND HANDLING
7.1.
Reporting Conventions

All data displays will be presented according to the Integrated Data Standards 
Library (IDSL) reporting standards, where applicable.  In general, data will be 
listed by cohort, subject, and time point and summarized by cohort (i.e. by 
CAPD, APD and combined) and time point

Analyses will be performed using the 9.1.3 version of the SAS System or higher 
(SAS is a registered trademark of the SAS Institute Inc., Cary, NC, USA). 
Programs will be imported into HARP and the final output will be produced by 
running drivers in HARP.

Data collected at unplanned (i.e. unscheduled) time points will not be included in 
the summaries by visit unless otherwise stated. Unscheduled or unplanned 
readings will be presented in the listings and they will be included when 
determining worst-case flagging for post-baseline summaries.


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
In all data displays, planned and actual relative times will be relative to the study 
drug dosing time of the relevant dosing session.

Planned times relative to study drug dosing will be used in all summary tables and 
summary (mean and median) figures.

Actual times relative to study drug will be used in all listings and individual PK 
figures.

Refer to IDSL standards (when applicable) for decimal place conventions.  Raw 
data will generally be presented to the same number of decimal places as it was 
collected.

All data will be reported according to the actual treatment the subject received.  
Any departures from the planned treatment according to the randomization 
schedule will be documented in the report.

All observations that occurred prior to dosing will be considered as part of the 
pre-dose period.  All observations that occur during dosing will be attributed to 
the subject’s treatment.  Observations occurring after 28 days after the last dose of 
study medication will not be recorded in the database.

Deviations from the analyses in the RAP will be identified in the final clinical 
pharmacology study report.


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7.2.
Data Management
Data Type
Source
Format of 
Data
Planned Date of 
Final File1
Responsibility
Safety
SDTM datasets
CDISC
DBF
CPDS
Biomarker
External CRO
CSV file
DBF+X4 days 
CPDS
SDTM PC
PK concentration 
data merged with 
SI PK
CDISC
DBF + X Days
SDTM Conversion 
Service (SCS)
Winnonlin file
created from 
ADPC (PK 
Conc)
Analysis Dataset 
for PK 
Concentrations
CSV file
SDTM PC + X4Days
QSI (Prog)
PK Parameter
Winnonlin-
posted to HARP 
by CPMS3
CSV file
PK Conc Winnonlin 
+ X4 days2
CPMS
SDTM PP
PK parameter 
data
CDISC
PK Parameter 
Winnonlin + X4
days2
SDTM Conversion 
Service (SCS)
1.
This is for study teams to determine upfront if there is a possibility of not meeting the completion of the 
CPSR    within 6 months of LSLV (i.e. novel data that may not be available until several months after 
LSLV).
2.
Provided source data is clean.
3.
PK concentration data is released via SMS2000 by DMPK and the SI PK dataset contains date/times 
and PK sample ID.
4.
Standard timelines are not followed for this study.


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7.3.
Premature Withdrawal and Missing Data
All subjects who withdraw prematurely from the study/study drug will be documented 
and the reason for their withdrawal recorded in the final Clinical Pharmacology Study 
Report (CPSR).  All available data from subjects who withdraw will be listed and all 
available planned data will be included in the summaries according to the populations 
defined in Section 5.
In the event that the study is prematurely discontinued, all available data will be listed 
and a review carried out by the study team to assess which statistical analyses are still 
considered appropriate.
7.4.
Baseline Definition
The following table indicates the baseline day to be used in any change from baseline 
listings / summaries / graphical presentations or as a covariate in a statistical analysis:
Parameter 
Baseline Days Collected
Baseline To Be 
Used in Analysis 
/ Summaries
Screening
Day -1 
Day 1 Predose
Safety:
ECG
X
X
Day -1
Vital Signs
X
X
Day -1 
Lab
X
X
Day -1
EPO, Hepcidin 
X
Day 1 Predose
.
7.5.
Derived and Transformed Data
7.5.1.
Demographic and Population parameters
7.5.1.1.
Study Day
Study day will be calculated as number of days from baseline date, as outlined below:
Scenario
Study Day
reference date is missing
study day = missing
reference date < IP start date
study day = reference date – IP start date
reference date ≥ IP start date
study day = reference date – (IP start date + 1)
7.5.1.2.
Date of Birth
Note that only the year of birth has been captured, so all dates of birth are 30th June 
XXXX, where XXXX is the year of birth.


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7.5.1.3.
Age
Age is calculated based on screening date, using date of birth, truncated to integer value. 
Note that only the year of birth has been collected where the day and month would be
30th June for all patients. Therefore, the derivation of age will be approximate.
The derivation of age will be footnoted on appropriate displays.
7.5.1.4.
Body Mass Index (BMI)
Body Mass Index (BMI) is calculated as follows:
BMI = weight in kg / (height in cm)2
7.5.1.5.
Exposure
Exposure is calculated as follows:
Study Drug Exposure (days) = (Treatment Stop Date – Treatment Start Date) + 1
7.5.2.
Safety Parameters
7.5.2.1.
Adverse Events
Note that the database has been designed such that AE Onset date is missing, unknown or 
complete; a partial/incomplete AE onset date will be considered as missing.
AE
AE Onset Time since First Dose
= AE Onset Date – Treatment Start Date (if treatment 
start date > AE onset date)
= AE Onset Date – Treatment Start Date + 1 (if 
treatment start date <= AE onset date)
= missing otherwise 
AE Duration (in days)
= AE Resolution Date – AE Onset Date + 1
AE is “On Treatment”
if the AE onset date is on or after the treatment start 
date and on or before the treatment stop date
AE is “Post-Treatment”
if the AE onset date is after the treatment stop date
AE is considered drug-related
if the relationship is marked ‘Yes’ on the case report 
form, or the value is missing
7.5.3.
Change from Baseline
The change from baseline will be calculated by subtracting the baseline values from the 
individual post-randomisation values.  If either the baseline or post-randomisation value 
is missing, the change from baseline is set to missing as well.


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7.5.4.
Pharmacokinetic Parameters
For the purposes of calculating summary statistics and for statistical analysis, all PK 
parameters with the exception of tmax will be loge transformed.
Between subject coefficient of variation CVb (%) will be calculated according to the 
following methods:
Untransformed Data : 100 * (SD/Mean) where SD is the standard deviation of the 
untransformed data
Transformed Data 
: SQRT(exp(SD2-1)) * 100where SD is the standard deviation of 
the loge-transformed data.
7.5.5.
Multiple Measurements at One Timepoint
Where multiple measurements are recorded for a particular time point, the mean of the 
measurements will be calculated and used in any derivation of summary statistics.  
However, all available data will be listed.
Where more than the specified number of measurements has been taken, the most 
recently recorded values will be used in the derivation of the appropriate summary 
measure (i.e. mean or maximum).
7.6.
Values of Potential Clinical Importance
The following tables display the ranges to be used for flagging values of potential clinical
importance for various parameters.  These values will be flagged on the listings.
Laboratory Values of Potential Clinical Importance (Renal Failure)
7.6.1.
Laboratory Values
Laboratory Parameter
Units
Clinical Concern Range
Low Flag
High Flag
Albumin 
g/L
< 30 g/L
>55 g/L
Aspartate Aminotransferase
IU/L
3x ULRR
Alanine Aminotransferase
IU/L
3x ULRR
Bilirubin (total and direct/indirect)
mol/L
2x ULRR
Calcium 
mmol/L
> 0.5 mmol/L 
below LLRR
> 0.25 mmol/L above 
ULRR
Glucose, fasting
mmol/L
<3.9
>22
Sodium
mmol/L
<130
>150


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Laboratory Parameter
Units
Clinical Concern Range
Low Flag
High Flag
Total CO2
mmol/L
<20
>32
GGT
IU/L
>=2ULRR
Alkaline phosphatase
IU/L
>=3xULRR
Uric Acid
Mg/dL
>6.0 mg/dL
Total Protein
IU/L
<LLRR
>15 g/L bove ULRR
Potassium (serum)
mmol/L
> 0.5 mmol/L 
below LLRR
> 1.0 mmol/L above 
ULRR
Laboratory Parameter
Units
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hemoglobin
g/dL
< 7.5
>=13.0
Platelet Count 
GI/L
< 80x GI/L
> 500x GI/L
WBC Count 
GI/L
> 1x GI/L below 
LLRR
>5x GI/L above 
ULRR
  Neutrophils
GI/L
< 0.5x LLRR
  Lymphocytes
GI/L
< 0.5x LLRR
Laboratory Parameter
Units
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Ferritin
ng/mL
> 1200
TSAT
%
<15
>40


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7.6.2.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
85
180
Diastolic Blood Pressure
mmHg
45
110
Heart Rate
bpm
40
110
Notes:

At visits where BP and HR are assessed in triplicate, the average of the 3 values will be used to assess 
PCI criteria.

For subjects who undergo in-clinic dialysis, the post-dialysis BP and HR values will be used to assess 
PCI criteria, unless otherwise specified.
7.6.3.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute QTc interval
msec
>480 if with bundle branch 
block
Change from Baseline
QTcB or QTcF
msec
>60 msec
8.
STUDY POPULATION
It was initially expected that 30 subjects (15 in each cohort) would be needed to be 
recruited in order to ensure that at least 12 subjects (6 in each cohort) completed the trial. 
However, during the informal review of the available PK data it was determined that 
there were no clinically-significant differences in PK between the CAPD/APD and CKD 
populations, therefore the planned number of subjects was reduced to enrol 7 subjects and 
5 subjects completed the study in order to minimize unnecessary additional subject 
exposure.
Study population data will be summarised by, or under the direct auspices of, Clinical 
Statistics, GlaxoSmithKline.
The precise format and content of Study Population tables and listings are shown in 
Section 14.1.1 and Section 14.1.5 of the RAP.
The tables will use the “All Subjects” population unless otherwise specified.


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8.1.
Subject Disposition and Demographics
A listing of subject withdrawals will include all subjects who prematurely discontinued 
from the study. This listing will include the discontinuation information for each subject, 
if there are any, including dates of discontinuation and reason for premature 
discontinuation. The number of subjects who completed, withdrew, and reasons for 
withdrawal will be tabulated.
A listing indicating whether a subject was included in each of the analysis populations 
will be prepared. The number of subjects included in each analysis population will be 
tabulated.
Demographic and racial data will be summarized using the “All Subjects” population.
8.2.
Protocol Deviations
As outlined in the protocol deviation plan the protocol deviations will be discussed and 
reviewed by the study team. The frequency of the review may be amended dependent on 
the outcome of the initial reviews. Any protocol deviations identified will be entered into 
InForm eCRF. Prior to each review the DQL will run the protocol deviation check log 
and protocol deviation log report in InForm, discrepancies will be resolved and the report 
issued to the reviewing study team. 
All protocol deviations that are data based will be listed.
8.3.
Concomitant Medications
All medications will be coded using the GSK Drug dictionary. Medications will be 
classified into preferred term and body system, using the GSK-Drug Anatomical 
Therapeutic Clinical (ATC) classification. ATC level 1 (the body system) will be shown. 
Medications will be sorted in descending order of total incidence across treatment groups 
for the ATC level 1 and in descending order of total incidence for the preferred term 
within each ATC level. 
Medications will be defined as follows, where it should be noted that a medication can be 
counted in more than one phase:


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Prior 
-
any medication taken up to, but not including, the start date of study 
medication (pre-treatment phase). Therefore, prior medications have 
stopped prior to the subject taking study medication. 
Concomitant -
if a medication is started or stopped on the same day of taking the first 
or last dose of randomised investigational product then this will be 
considered a concomitant medication (on-treatment phase)
-
any medication started before last day in the study and the drug stop 
date is either missing or on or after treatment start date
-
any medication with start date missing yet the stop date is on or after 
treatment start date
-
if both start and stop dates are missing the drug is specifically 
indicated as continuing in the trial. 
Post study 
-
any drug with start date on or after last day in the study will be 
considered post-study drug. This will not be summarized with 
concomitant drugs but will be included in data listing. 
In situations where the concomitant medication status of the drug cannot be determined, 
available relevant information will be reviewed on a case-by-case basis to determine the 
status whether it should be considered ‘concomitant’ or ‘post-study’ by Clinical; the 
decision of the clinical group will be considered final. However, if such determination 
cannot be made unambiguously, the medication will be considered concomitant.
Concurrent medications will be listed, and summarized by generic term, if more than 20 
concomitant medications were used.
9.
SAFETY ANALYSES
Safety data will be summarised and listed by, or under the direct auspices of Clinical 
Statistics, GlaxoSmithKline.
The precise format and content of Safety tables, ICH and Other listings are shown in 
Section 14.1.2, Section 14.1.5 and Section 14.1.6 of the RAP. 
The tables will use the “All Subjects” population unless otherwise specified.
9.1.
Extent of Exposure
A listing of exposure data will be a by-subject listing including the cohort, treatment 
administered with the dates and times of treatment administration. 


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9.2.
Adverse Events
All adverse events (AEs) will be coded and classified according to system organ class, 
high level term, and preferred term using GSK MedDRA. All AEs will be listed. A listing 
of subject numbers for individual AEs will also be prepared. A summary, overall and by 
treatment, of the number and percent of subjects reporting each event at least once will be 
generated for all AEs and also for drug-related AEs. A listing of the relationship of AE 
body systems, group terms and verbatim text will also be produced.
9.3.
Deaths and Serious Adverse Events
In addition to the listing described above, deaths and serious AEs (SAEs), if they occur, 
will also be listed and summarized separately.
9.4.
Adverse Events Leading to Discontinuation of 
Investigational Product and/or Withdrawal from the Study 
and Other Significant Adverse Events
If any subject withdraws due to an AE, then a listing and a summary by treatment will be 
provided for these subject(s).
9.5.
Clinical Laboratory Evaluations
A listing for hematology and clinical chemistry values of potential clinical importance as 
described in Section 7.6, will be produced where applicable.
For hematology and clinical chemistry data, descriptive summaries for actual values by 
time point will be produced. A summary of urinalysis dipstick data and a listing of 
urinalysis data will be produced.
9.6.
Vital Signs and Body Weight
Listing of vital signs values of potential clinical importance as described in Section 7.6, 
will be produced where applicable. Descriptive summaries for absolute and change from 
baseline values for vital signs by time point will be produced.
9.7.
Electrocardiograms
Descriptive summaries for absolute and change from baseline values of ECG values by 
time point will be produced.
ECG findings will be summarized with the highest (worst) severity across replicated 
assessments at the specified time point used.
ECG abnormalities of clinical significance, if they occur, will be listed for each subject.


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10.
PHARMACOKINETIC ANALYSES
The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be 
performed by, or under the direct auspices of, Clinical Pharmacology Data Sciences 
(CPDS), GlaxoSmithKline. 
The merge of PK concentration data, randomisation and CRF data will be performed by, 
or under the direct auspices of, QSI (Programmer), GlaxoSmithKline.  
Derivation of pharmacokinetic parameters will be performed by, or under the direct 
auspices of, Clinical Pharmacology Modelling and Simulation (CPMS), 
GlaxoSmithKline.
Statistical analysis of pharmacokinetic parameters will be performed by, or under the 
direct auspices of, Clinical Statistics, GlaxoSmithKline.
The precise format and content of PK tables, figures, and listings are shown in Section 
14.1.3 and Section 14.1.6 of the RAP.
10.1.
Drug Concentration Measures
Concentrations of GSK1278863 and its metabolites (GSK2391220 (M2), GSK2506104 
(M3), GSK2487818 (M4), GSK2506102 (M5), GSK2531398 (M6), GSK2531401 
(M13)) in plasma will be listed and summarized by cohort (i.e., CAPD, APD and both 
combined) and nominal time.  Standard summary statistics will be calculated (i.e. mean, 
standard deviation, median, minimum and maximum).  Refer to the PK Guidance 
document, GUI_51487 (3.0), for more information regarding the treatment of plasma 
concentrations below the assay’s lower limit of quantification (NQ).
Individual plasma concentration-time profiles and median/mean profiles by treatment 
cohort will be plotted.  Each of the figures will contain one plot on the untransformed 
scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. log-linear plot). See 
Section 14.1.3 and Section 14.1.5 Pharmacokinetic Source Figures and Tables for details.
GSK1278863 and metabolite protein binding (as a percentage) will be presented in 
tabular form and will be summarized descriptively. Metabolite-to-parent exposure ratios 
(corrected for molecular weight) will also be calculated and summarized descriptively.
Volume of drained dialysate plus concentrations and amounts of GSK1278863 and its 
metabolites (GSK2391220(M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 
(M5), GSK2531398 (M6), GSK2531401 (M13)) in the dialysate will be listed and 
summarized by cohort (i.e., CAPD, APD and both combined).  
10.2.
Deriving and Summarizing Pharmacokinetic Parameters
From the plasma concentration-time data of parent GSK1278863 and metabolites 
(GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), 
GSK2531398 (M6) and GSK2531401 (M13)), the following pharmacokinetic parameters 
will be determined, as data permit:


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Day 1: Maximum observed plasma concentration (Cmax), time to Cmax (tmax), area 
under the plasma concentration-time curve AUC(0-τ) and AUC(0-∞), and apparent 
terminal phase half-life (t½).
Day 14: Cmax, tmax, AUC(0-τ), and apparent terminal phase half-life (t½). AUC(0-∞), 
AUC(0-τ), and Cmax following single (Day 1) and repeat doses (Day 14) will be used 
for determination of accumulation and time-invariance ratios.
Day 12 to 15: Trough concentration (Ctau, or Cτ) samples collected on Days 12 to 15 
will be used to assess attainment of steady state.

Note, to comply with CDISC reporting requirements, the following parameters 
also will be determined:
o
Tlast
o
Where t½ and/or AUC(0-) have been derived the following parameters 
should also be included in the PKPAR file: No_points_lambda_z, 
Lambda_z_lower, Lambda_z_upper, Tlast
o
If partial areas have been calculated, the following parameters should also 
be reported (if not included as above): No_points_lambda_z, 
Lambda_z_lower, Lambda_z_upper
Other Plasma PK Analyses: GSK1278863 and select metabolite (GSK2487818 (M4), 
GSK2506102 (M5)) unbound concentration and free fraction (as a percentage) will be 
presented in tabular form and will be summarized descriptively. Metabolite-to-parent 
exposure ratios (corrected for molecular weight) will also be calculated and summarized 
descriptively.

Percent protein bound will be calculated using the formula:
% Bound = (Concentration in plasma – Concentration in ultrafitrate) * 100 /      
                                                               Concentration in plasma

% Metabolite to parent ratios: (GSK2391220(M2), GSK2506104 (M3), 
GSK2487818 (M4), GSK2506102 (M5), GSK2531398 (M6) and  GSK2531401 
(M13))  (metabolites, M) to GSK1278863 (parent) AUC and Cmax ratios will be 
determined (as a percentage, including a correction for molecular weight, Mr), for 
example:
M : GSK1278863 % = 100* (AUCM/AUCGSK1278863) * (MrGSK1278863/MrM)
Parameters to be used in this calculation are:
Day 1: Cmax, AUC(0-τ), AUC(0-∞)


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Day 14: Cmax, AUC(0-τ)

Molecular weights for compounds are:
Compound
Molecular Weight (g/mol)
GSK1278863
393.442
GSK2391220 (M2)
425.442
GSK2506104 (M3)
425.442
GSK2487818 (M4)
425.442
GSK2506102 (M5)
425.442
GSK2531398 (M6)
425.442
GSK2531401 (M13)
441.442

Percent drug related marterial (%DRM): will be determined for parent as well 
as each metabolite, where the denominator is the sum of the exposures of all 
analytes. Where all these AUCs are corrected for molecular weight (Mr).
Example:
%DRMGSK1278863 = 100* AUCGSK1278863 / 
(AUCGSK1278863+AUCM2+AUCM3+AUCM4+AUCM5+AUCM6+AUCM13). 
Parameters to be used in this calculation are:
Day 1: AUC(0-τ), AUC(0-∞)
Day 14: AUC(0-τ)

Peritoneal dialysis clearance of GSK1278863 and metabolites will be calculated 
from Day 14 dialysate excretion data as total amount of analyte excreted over 
24 h divided by plasma AUC(0-τ).
CLd = Ae (0-) / AUC(0-)
where Ae is the amount of analyte excreted in dialysate over the 24 h dialysate 
collection period
Ae = total dialysate volume * dialysate concentration
All the derived parameters described above will be listed.  For each of these parameters, 
except tmax, the following summary statistics will be calculated for each cohort
(CAPD,APD and combined) as well as different peritoneal dialysis solution (number of 
categories to be determined) : median, maximum, minimum, arithmetic mean, standard 
deviation, coefficient of variation, geometric mean, 95% confidence interval for the 


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23
geometric mean and standard deviation of logarithmically transformed data.  For tmax, 
median, maximum, minimum, arithmetic mean and standard deviation will be calculated.  
The first point, last point and number of points used in the determination of z will be 
included on the listing of the derived parameters.
10.3.
Statistical Analyses
Descriptive statistics (n, arithmetic mean and associated 95% confidence interval, 
standard deviation, minimum, median, maximum) will be calculated for all 
pharmacokinetic endpoints of GSK1278863 and metabolites by Cohort.  In addition 
geometric means, associated 90% CIs, and estimates of between-subject CVs (CVb (%)), 
will be calculated for each Cohort where
Geometric mean=exp (mean on loge scale)
CVb (%)=SQRT(exp(SD**2)-1)x100, where SD is the standard deviation of the loge-
transformed data.
Steady State Assessment
Trough concentration (Cτ) samples collected on the specified days (Days 12, 13, 14, and 
the 24 h post-dose sample on Day 14) will be used to assess attainment of steady state. 
Individual trough concentration data Cτ will be plotted and listed. Cτ will be summarized 
by day and cohort, and the mean and median plots will be provided.
Steady state will be assessed separately for GSK1278863 and metabolites in each cohort.
A linear mixed effects ANOVA model will be used to evaluate steady state for 
GSK1278863 and each metabolite. The dependent variable will be log-transformed 
Predose (trough) concentrations (Cτ) on Days 12 to 15. Independent variables in the 
model include day (as a continuous variable) as a fixed effect and subject as a random 
effect.
Assessment of plasma GSK1278863 and metabolites steady state will be assessed by 
evaluating the estimated slope for the day parameter and associated 90% CI for both the 
cohorts combined..  A steady state attainment is defined as the 90% confidence interval 
of the slope including 0.
Secondary Comparisons:
Assessment of Accumulation
To estimate the extent of accumulation for GSK1278863 and metabolites after repeat 
dosing, the observed accumulation ratio R0 will be determined.


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Where AUC(0-τ )ss is AUC from time zero to t h under steady state and AUC (0 -τ ) is 
AUC from time zero to dosing interval at Day 1.
To evaluate the accumulation ratio, statistical analysis of GSK1278863 and metabolite
PK data for each cohort will be performed separately after a log transformation of the 
data.
A mixed effect model will be fitted with day (single and repeat dose), as fixed effects and 
subject as a random effect. Day 14 will be compared to Day 1 in order to estimate the 
accumulation ratios, Ro= (AUC (0- τ, Day14): AUC (0- τ, Day1). The ratios will be 
calculated by back-transforming the difference between the LS means.
Using the pooled estimate of variance, 90% confidence intervals will be calculated for the 
primary comparisons, and back-transformed to the original scale.
Assessment of Time Invariance
To evaluate the time invariance ratio, statistical analysis of (AUC (0-∞) Day 1) and AUC 
(0- τ) (Day14), of GSK1278863 and metabolites for each cohort will be performed 
separately after a log transformation of the data.
A mixed effect model will be fitted with day as a fixed effect and subject as a random 
effect. Day 14 AUC (0- τ) will be compared to Day 1 AUC (0-∞) in order to estimate the 
time invariance ratios, RS= AUC (0- τ, Day 14): AUC (0-∞, Day 1). The ratios will be 
calculated by back-transforming the difference between the LS means.
Using the pooled estimate of variance, 90% confidence intervals will be calculated for the 
primary comparisons, and back-transformed to the original scale.
11.
PHARMACODYNAMIC/BIOMARKER ANALYSES
Plasma erythropoietin and hepcidin concentrations will be presented in graphical and/or 
tabular form and will be summarized descriptively.  The concentration values will be 
listed by cohort, subject, and time point and will be summarized by cohort and time point.
12.
PHARMACOGENETIC ANALYSIS
Samples will be collected and stored. No prospective analyses will be performed.


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13.
REFERENCES
GlaxoSmithKline Document Number 2013N179529_03 Study ID 200942. A repeat-dose, 
open-label, parallel-group study to assess the pharmacokinetics of GSK1278863 and 
metabolites in subjects with End Stage Renal Disease undergoing peritoneal dialysis. 
(Effective date: 01-JUL-2014)
Schuirmann DJ. 1987. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability,  J Pharmacokinetic and 
Biopharm, 15, 657-680.
Steinijans VW, Diletti, E. Statistical Analysis of Bioavailability Studies: Parametric and 
Nonparametric Confidence Intervals. Eur J Clin Pharmacol, 1983;24:127-136. 


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14.
ATTACHMENTS
14.1.
Table of Contents for Data Display Specifications
For the Clinical Pharmacology Study Report the following section numbering will apply:
Section 8: Study Population
Section 9: Safety
Section 10: Pharmacokinetic
Section 11: Pharmacodynamic / Biomarker
Section 12: Pharmacogenetics Analysis
Listed below are the planned figures, tables and listings to be produced for inclusion in 
the 200942 clinical study report:
IDSL standard displays beginning with “CP_” are specific to Clinical Pharmacology and 
can be found in the IDSL database under “Supporting Documentation -> TST use of 
IDSL Core Choices -> ClinPharm -> All -> Clin Pharm Options for Statistical Displays”.


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14.1.1.
Study Population
Table No.
Population
IDSL No. / 
Example Shell
Title
Additional 
Programming Notes
Responsibility
Deliverable 
Priority
9.1
All Subjects
ES1a
Summary of Subject Disposition
By Cohorts and both 
combined
QSI (Prog)
SAC
9.2
All Subjects
DM1
Summary of Demographic 
Characteristics
1. By Cohorts and both 
combined
2.Add BMI, Weight 
,Height,
QSI (Prog)
SAC
9.3
All Subjects
DM5
Summary of Race and Racial 
Combinations
By Cohorts and both 
combined
QSI (Prog)
SAC
9.4
All Subjects
DM6
Summary of Race and Racial 
Combinations Details
By Cohorts and both 
combined
QSI (Prog)
SAC
9.5
Enrolled
NS1
Summary of Number of Subjects by 
Country and Site ID
By Cohorts and both 
combined
QSI (Prog)
SAC
9.6
Enrolled
DM11
Summary of Age Ranges
By Cohorts and both 
combined
QSI (Prog)
SAC


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14.1.2.
Safety Tables
Tables
Table 
No.
Population
IDSL  No. / 
Example 
Shell
Title
Programming Notes
Responsibility
Deliverable 
Priority
10.1
All Subjects
CP_AE1p
Summary of All Adverse Events
By Cohorts and both 
combined
QSI (Prog)
SAC
10.2
All Subjects
CP_AE1p
Summary of Drug-Related Adverse Events
By Cohorts and both 
combined
QSI (Prog)
SAC
10.3
All Subjects
CP_AE1p
Summary of  Serious Adverse Events
By Cohorts and both 
combined
QSI (Prog)
SAC
10.4
All Subjects
CP_AE1p
Summary of AEs Leading to Permanent Discontinuation of 
Study Drug or Withdrawal from Study
By Cohorts and both 
combined
QSI (Prog)
SAC
10.5
All Subjects
AE15
Summary of Common (>=5%) Non-serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
By Cohorts and both 
combined
QSI (Prog)
SAC
10.6
All Subjects
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences)
By Cohorts and both 
combined
QSI (Prog)
SAC
10.7
All Subjects
LB1
Summary of Haematology Laboratory Values
By Cohorts and both 
combined
QSI (Prog)
SAC
10.8
All Subjects
LB1
Summary of Change from Baseline in Haematology 
Laboratory Values
By Cohorts and both 
combined
QSI (Prog)
SAC
10.9
All Subjects
LB1
Summary of Chemistry Laboratory Values
By Cohorts and both 
combined
QSI (Prog)
SAC


CONFIDENTIAL
200942
29
Table 
No.
Population
IDSL  No. / 
Example 
Shell
Title
Programming Notes
Responsibility
Deliverable 
Priority
10.10
All Subjects
LB1
Summary of Change from Baseline in Chemistry Laboratory 
Values
By Cohorts and both 
combined
QSI (Prog)
SAC
10.11
All Subjects
EG1
Summary of ECG Findings
By Cohorts and both 
combined description
QSI (Prog)
SAC
10.11
All Subjects
EG2
Summary of ECG Values
By Cohorts and both 
combined
QSI (Prog)
SAC
10.12
All Subjects
EG2
Summary of Change from Baseline in ECG Values
By Cohorts and both 
combined
QSI (Prog)
SAC
10.13
All Subjects
VS1
Summary of Vital Signs
By Cohorts and both 
combined
QSI (Prog)
SAC
10.14
All Subjects
VS1
Summary of Change from Baseline for Vital Signs
By Cohorts and both 
combined
QSI (Prog)
SAC


CONFIDENTIAL
200942
30
14.1.3.
Pharmacokinetic Figures and Tables
Figures
Figure 
No.
Population IDSL No. / 
Example 
Shell
Title
Programming Notes
Responsibility
Deliverable 
Priority
11.1
PK
PKCF1p
Individual Plasma GSK1278863 Concentration-Time 
Plots – by Subjects
1. x-axis should display 
Actual relative time 
2. Include line for LLQ 
along with footnote defining 
LLQ value.
3. Include values below
LLQ.
QSI (Prog)
SAC
11.2
PK
PKCF1p
Individual Plasma GSK2391220 (M2) Concentration-
Time Plots – by Subjects
QSI(Prog)
SAC
11.3
PK
PKCF1p
Individual Plasma GSK2506104 (M3) Concentration-
Time Plots – by Subjects
QSI(Prog)
SAC
11.4
PK
PKCF1p
Individual Plasma GSK2487818 (M4) Concentration-
Time Plots – by Subjects
QSI(Prog)
SAC
11.5
PK
PKCF1p
Individual Plasma GSK2506102 (M5) Concentration-
Time Plots – by Subjects
QSI(Prog)
SAC
11.6
PK
PKCF1p
Individual Plasma GSK2531398 (M6) Concentration-
Time Plots – by Subjects
QSI(Prog)
SAC
11.7
PK
PKCF1p
Individual Plasma GSK2531401 (M13) 
Concentration-Time Plots – by Subjects
QSI(Prog)
SAC


CONFIDENTIAL
200942
31
Figure 
No.
Population IDSL No. / 
Example 
Shell
Title
Programming Notes
Responsibility
Deliverable 
Priority
11.8
PK
PKCF4
Mean (SD) Plasma GSK1278863 Concentration-Time 
Plots (Linear and Semi-log) by Cohort
1. X-axis displays planned  
relative time
2.  Include line for LLQ 
along with footnote defining 
LLQ value.
3. Can do both the cohorts 
in one page by adding 
legends
QSI (Prog)
SAC
11.9
PK
PKCF4
Mean (SD) Plasma GSK2391220 (M2) Concentration-
Time Plots (Linear and Semi-log) by Cohort
Can do both the cohorts in 
one page by adding 
legends
QSI(Prog)
SAC
11.10
PK
PKCF4
Mean (SD) Plasma GSK2506104 (M3) Concentration-
Time Plots (Linear and Semi-log) by Cohort
QSI(Prog)
SAC
11.11
PK
PKCF4
Mean (SD) Plasma GSK2487818 (M4) Concentration-
Time Plots (Linear and Semi-log) by Cohort
QSI(Prog)
SAC
11.12
PK
PKCF4
Mean (SD) Plasma GSK2506102 (M5) Concentration-
Time Plots (Linear and Semi-log) by Cohort
QSI(Prog)
SAC
11.13
PK
PKCF4
Mean (SD) Plasma GSK2531398 (M6) Concentration-
Time Plots (Linear and Semi-log) by Cohort
QSI(Prog)
SAC
11.14
PK
PKCF4
Mean (SD) Plasma GSK2531401 (M13) 
Concentration-Time Plots (Linear and Semi-log) by Cohort
QSI(Prog)
SAC


CONFIDENTIAL
200942
32
Figure 
No.
Population IDSL No. / 
Example 
Shell
Title
Programming Notes
Responsibility
Deliverable 
Priority
11.15
PK
PKCF5
Median (range) Plasma GSK1278863 Concentration-Time 
Plots (Linear and Semi-log)  by  Cohort
1. Include bars for range.
2. X-axis displays 
planned relative time.
3. Include line for LLQ 
along with footnote 
defining LLQ value.
3. Can do both the cohorts 
in one page by adding 
legends
QSI (Prog)
SAC
11.16
PK
PKCF5
Median (range) Plasma GSK2391220 (M2) 
Concentration-Time Plots (Linear and Semi-log)  by  
Cohort
Can do both the cohorts in 
one page by adding 
legends
QSI(Prog)
SAC
11.17
PK
PKCF5
Median (range) Plasma GSK2506104 (M3) 
Concentration-Time Plots (Linear and Semi-log)  by  
Cohort
QSI(Prog)
SAC
11.18
PK
PKCF5
Median (range) Plasma GSK2487818 (M4) 
Concentration-Time Plots (Linear and Semi-log)  by  
Cohort
QSI(Prog)
SAC
11.19
PK
PKCF5
Median (range) Plasma GSK2506102 (M5) 
Concentration-Time Plots (Linear and Semi-log)  by  
Cohort
QSI(Prog)
SAC
11.20
PK
PKCF5
Median (range) Plasma GSK2531398 (M6) 
Concentration-Time Plots (Linear and Semi-log)  by  
Cohort
QSI(Prog)
SAC
11.21
PK
PKCF5
Median (range) Plasma GSK2531401 (M13) 
Concentration-Time Plots (Linear and Semi-log)  by  
Cohort
QSI(Prog)
SAC


CONFIDENTIAL
200942
33
Figure 
No.
Population IDSL No. / 
Example 
Shell
Title
Programming Notes
Responsibility
Deliverable 
Priority
11.22
PK
PKCF1p
Individual Plasma GSK1278863 Concentration-Time Plots 
– by Cohort
Can do both the cohorts in 
one page by adding 
legends
QSI(Prog)
SAC
11.23
PK
PKCF6
Individual Plasma GSK2391220 (M2) Concentration-
Time Plots by Cohort (Linear and Semi-Log)
Can do both the cohorts in 
one page by adding 
legends
QSI(Prog)
SAC
11.24
PK
PKCF6
Individual Plasma GSK2506104 (M3) Concentration-
Time Plots by Cohort (Linear and Semi-Log)
QSI(Prog)
SAC
11.25
PK
PKCF6
Individual Plasma GSK2487818 (M4) Concentration-
Time Plots by Cohort (Linear and Semi-Log)
QSI(Prog)
SAC
11.26
PK
PKCF6
Individual Plasma GSK2506102 (M5) Concentration-
Time Plots by Cohort (Linear and Semi-Log)
QSI(Prog)
SAC
11.27
PK
PKCF6
Individual Plasma GSK2531398 (M6) Concentration-
Time Plots by Cohort (Linear and Semi-Log)
QSI(Prog)
SAC
11.28
PK
PKCF6
Individual Plasma GSK2531401 (M13) 
Concentration-Time Plots by Cohort (Linear and Semi-
Log)
QSI(Prog)
SAC
11.29
PK
PKCF6
Individual Plasma Concentration-Time Plots by 
Analyte at Predose (Linear and Semi Log)
QSI (Prog)
SAC
11.30
PK
PKCF6
Mean Plasma Concentration-Time Plots by Analyte 
at Predose (Linear and Semi Log)
QSI (Prog)
SAC
11.31
PK
PKCF6
Median Plasma Concentration-Time Plots by Analyte 
at Predose (Linear and Semi Log)
QSI (Prog)
SAC


CONFIDENTIAL
200942
34
Tables
Table 
No.
Population
IDSL No. / 
Example 
Shell
Title
Programming Notes
Responsibility
Deliverable 
Priority
11.1
PK
PKCT1
Summary of Plasma GSK1278863 and its 
metabolites Concentration-Time Data
By Cohort and combined Refer 
Table 1 for Cohort description
QSI(Prog)
SAC
11.2
PK
PKPT4
Summary of Derived Plasma  Pharmacokinetic 
Parameters  of GSK1278863 and its 
Metabolites
1.By Cohort and combined Refer 
Table 1 for Cohort description
QSI(Prog)
SAC
11.3
PK
Exhibit 1
Summary of Analysis Results for Steady-State 
Pharmacokinetic Profile of Trough 
concentration (C) for each Metabolite 
QSI(Stat)
SAC
11.4
PK
Exhibit 2
Summary of Results of Statistical Analysis of 
Derived  Plasma GSK1278863 Parameters to 
Assess Accumulation for each Metabolite 
QSI(Stat)
SAC
11.5
PK
Exhibit 3
Summary of Results of Statistical Analysis of 
Derived  Plasma GSK1278863 Parameters to 
Assess Time Invariance for each Metabolite 
QSI(Stat)
SAC
11.6
PK
PKCT1
Summary of Percent Protein Bound of Plasma 
GSK1278863 and select metabolites
QSI (Stat)
SAC


CONFIDENTIAL
200942
35
14.1.4.
Pharmacodynamic Figures and Tables
Figures
Figure 
No.
Population
IDSL No. / 
Example Shell
Title
Programming Notes
Responsibility
Deliverable 
Priority
12.1
All 
Subjects 
PKCF1p
Individual Plasma Erythropoietin 
Concentration-Time Plots – by Subjects
1. x-axis should display Actual 
relative time 
2. Include line for LLQ along with 
footnote defining LLQ value.
3. Include values below LLQ.
QSI (Prog)
SAC
12.2
All 
Subjects
PKCF1p
Individual Hepcidin Concentration-Time Plots 
– by Subjects
QSI(Prog)
SAC
12.3
All 
Subjects
PKCF4
Mean (SD) Plasma Erythropoietin 
Concentration-Time Plots (Linear and Semi-
log) by Cohort
1. X-axis displays planned  
relative time
2.  Include line for LLQ along 
with footnote defining LLQ value.
QSI (Prog)
SAC
12.4
All 
Subjects
PKCF4
Mean (SD) Hepcidin Concentration-Time 
Plots (Linear and Semi-log) by Cohort
QSI(Prog)
SAC
12.5
All 
Subjects
PKCF5
Median (range) Plasma Erythropoietin 
Concentration-Time Plots (Linear and Semi-
log)  by  Cohort
1. Include bars for range.
2. X-axis displays planned 
relative time.
3. Include line for LLQ along with 
footnote defining LLQ value.
QSI (Prog)
SAC
12.6
All 
Subjects
PKCF5
Median (range) Hepcidin  Concentration-Time 
Plots (Linear and Semi-log)  by Cohort
QSI(Prog)
SAC


CONFIDENTIAL
200942
36
Figure 
No.
Population
IDSL No. / 
Example Shell
Title
Programming Notes
Responsibility
Deliverable 
Priority
12.7
All 
Subjects
PKCF6
Individual Plasma Erythropoietin 
Concentration-Time Plots by Cohort (Linear 
and Semi-Log)
QSI(Prog)
SAC
12.8
All 
Subjects
PKCF6
Individual Hepcidin Concentration-Time Plots 
by Cohort (Linear and Semi-Log)
QSI(Prog)
SAC
Tables
Table No.
Population
IDSL No. / 
Example Shell
Title
Additional 
Programming 
Notes
Responsibility
Deliverable 
Priority
12.1
All Subjects
PKPT 4
Summary Statistics of Hepcidin and 
Erythropoietin
By Cohort and 
both combined
QSI (Prog)
SAC


CONFIDENTIAL
200942
37
14.1.5.
ICH Listings
Table 
No.
Population
IDSL No. / 
Example 
Shell 
Title
Programming Notes
Responsibility
Deliverable 
Priority
1
All Subjects
DM2
Listing of Demographic Characteristics
1.
By Cohorts 
2. Add BMI, Weight 
,Height, 
QSI(Prog)
SAC
2
All Subjects
DM9
Listing of Race
By Cohorts 
QSI(Prog)
SAC
3
All Subjects
IE3
Listing of  Subjects with Inclusion/Exclusion Criteria 
Deviations
By Cohorts 
QSI(Prog)
SAC
4
All Subjects
DV2
Listing of Protocol Deviations
By Cohorts 
QSI (Prog)
SAC
5
All Subjects
ES2
Listing of Reasons for Withdrawal
By Cohorts 
QSI(Prog)
SAC
6
All Subjects
CP_CM3
Listing of Concomitant Medication by Generic Term
By Cohorts 
QSI(Prog)
SAC
7
All Subjects
EX3
Listing of Exposure data
By Cohorts 
QSI(Prog)
SAC
8
All Subjects
AE7
Listing of Subject Numbers for Individual Adverse 
Events
By Cohorts 
QSI(Prog)
SAC
9
All Subjects
CP_AE8
Listing of All Adverse Events
By Cohorts 
QSI(Prog)
SAC
10
All Subjects
CP_AE8a
Listing of SAE
By Cohorts 
QSI(Prog)
SAC
11
All Subjects
CP_AE8
Listing of AE leading to Withdrawal
By Cohorts 
QSI(Prog)
SAC
12
All Subjects
CP_LB5
Listing of Haematology Abnormalities of Potential 
Clinical Importance
By Cohorts 
QSI(Prog)
SAC
13
All Subjects
CP_LB6
Listing of all Hemeatology Laboratory Data for 
Subjects with PCI Abnormalities
By Cohorts 
QSI(Prog)
SAC


CONFIDENTIAL
200942
38
Table 
No.
Population
IDSL No. / 
Example 
Shell 
Title
Programming Notes
Responsibility
Deliverable 
Priority
14
All Subjects
CP_LB5
Listing of Chemistry Abnormalities of Potential 
Clinical Importance
By Cohorts 
QSI(Prog)
SAC
15
All Subjects
CP_LB6
Listing of all Clinical Chemistry laboratory Data for 
subjects with PCI abnormalities
By Cohorts 
QSI(Prog)
SAC
16
All Subjects
CP_EG5
Listing of Abnormal ECG findings
By Cohorts 
QSI(Prog)
SAC
17
All Subjects
CP_EG3
Listing of All ECG Values for Subjects with Any Value 
of Potential Clinical Importance
By Cohorts 
QSI(Prog)
SAC
18
All Subjects
CP_VS4
Listing of Vital Signs of Potential Clinical Importance
By Cohorts 
QSI(Prog)
SAC
19
All Subjects
CP_VS4
Listing of all Vital Signs for subjects with any value of 
Potential Clinical Importance
By Cohorts 
QSI(Prog)
SAC
Conditional Displays: The following displays will only be produced when a liver event has occurred, as defined in the study protocol, and the Liver Event 
Assessment forms have been completed.
20
All Subjects
LIVER5
Listing of Liver Events in Relation to Time of Treatment
By Cohorts 
QSI(Prog)
SAC
21
All Subjects
LIVER6
Listing of Liver Event Information for RUCAM Score
By Cohorts 
QSI (Prog)
SAC
22
All Subjects
LIVER7
Listing of Liver Biopsy Details
By Cohorts 
QSI (Prog)
SAC
23
All Subjects
LIVER8
Listing of Liver Imaging Details
By Cohorts 
QSI (Prog)
SAC


CONFIDENTIAL
200942
39
14.1.6.
Other Listings
Table 
No.
Population
IDSL No. / 
Example 
Shell
Title
Programming Notes
Responsibility
Delivera
ble 
Priority
1
All Subjects
AE2
Relationship between System Organ Class and 
Verbatim Text
By Cohorts
QSI(Prog)
SAC
2
PK
PKCl1P
Listing of Plasma GSK1278863 and Metabolite
Pharmacokinetic Concentration-Time Data
By Cohorts
QSI(Prog)
SAC
3
PK
PKPL1P
Listing of Derived Plasma Pharmacokinetic Parameters
of GSK1278863 and its Metabolites
By Cohorts
QSI(Prog)
SAC
4
PK
PHI113635/Li
sting 31
Listing of effluent Peritoneal Dialysis Fluid Data
By Cohorts
QSI(Prog)
SAC
5
All Subjects
PHI113635/Li
sting 31
Listing of Hepcidin and Erythropoietin
By Cohorts
QSI(Prog)
SAC
6
PK
Raw SAS Output  for Summary of Analysis Results for 
Steady-State Pharmacokinetic Profile of Trough 
concentration (C)
QSI(Stat)
SAC
7
PK 
Raw SAS Output  for Summary of Results of Statistical 
Analysis of Derived  Plasma GSK1278863 Parameters 
to Assess Accumulation
QSI(Stat)
SAC
8
PK
Raw SAS Output  for Summary of Results of Statistical 
Analysis of Derived  Plasma GSK1278863 Parameters 
to Assess Time Invariance
QSI(Stat)
SAC
9
PK
Raw SAS Output for Summary Analysis Results for 
Comparison of Pharmacokinetic Parameters of 
GSK1278863 and its Metabolites using ANOVA
QSI(Stat)
SAC


CONFIDENTIAL
200942
40
14.2.
Data Display Specifications (Example Shells)
Example 
: Exhibit 1
Page 1 of n
Protocol
: 200942
Population
: PK Population
Table xx.x
                           Summary of Results of Statistical Analysis to Assess Steady state
                Day            Back-Transformed Slope            90% Confidence Interval
                                    -----------------------------------------------------------------------------------------------------------------------------------------------
                                                          1-14        1.05              ( 1.03, 1.08)
                                      


CONFIDENTIAL
200942
41
Example 
: Exhibit 2
Page 1 of n
Protocol
: 200942
Population
: PK Population
                            Table x.x
                           Summary of Results of Statistical Analysis to Estimate Accumulation Ratio
   
        Parameter                          Comparison                   Geom.LsMean                        Ratio                                 90% 
                                                                                             ------------------------------                                     Confidence Interval
                                                                                             n      Test              n    Ref
  --------------------------------------------------------------------------------------------------
AUC(0-t)(pg*hr/mL)      Day 14 vs Day 1   12  0.910    12 0.780   1.166    ( 0.843,  0.978 )


CONFIDENTIAL
200942
42
   Example 
: Exhibit3
Page 1 of n
Protocol
: 200942
Population
: PK Population
                            Table x.x
                           Summary of Results of Statistical Analysis to Estimate Time Invariance
   
Comparison                      
               Geom.LsMean                 Ratio                                          90% 
                                                                                       -------------------------------                                         Confidence Interval
                                                                                       n      Test              n    Ref
  --------------------------------------------------------------------------------------------------
   AUC(0-τ)Day 14 vs AUC(0-∞)Day 1     12  0.910    12 0.780   1.166        ( 0.843,  0.978 )